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LANCET
Authors Eva Stadler, Khai Li Chai, Timothy E Schlub, Deborah Cromer, Shanchita R Khan, Mark N Polizzotto, Stephen J Kent, Claire Beecher, Heath White, Tari Turner, Nicole Skoetz, Lise Estcourt, Zoe K McQuilten, Erica M Wood, David S Khoury, Miles P Davenport
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THE BMJ
Authors Katharine Lang
NATURE
Authors Chengzi I. Kaku, Tyler N. Starr, Panpan Zhou, Haley L. Dugan, Paul Khalifé, Ge Song, Elizabeth R. Champney, Daniel W. Mielcarzi, James C. Geoghegan, Dennis R. Burton, Raiees Andrabi, Jesse D. Bloom, Laura M. Walker
Abstract Understanding the longitudinal dynamics of antibody immunity following heterologous SAR-CoV-2 breakthrough infection will inform the development of next-generation vaccines. Here, we track SARS-CoV-2 receptor binding domain (RBD)-specific antibody responses up to six months following Omicron BA.1 breakthrough infection in six mRNA-vaccinated individuals. Cross-reactive serum neutralizing antibody and memory B cell (MBC) responses decline by two- to four-fold through the study period. Breakthrough infection elicits minimal de novo Omicron BA.1-specific B cell responses but drives affinity maturation of pre-existing cross-reactive MBCs toward BA.1, which translates into enhanced breadth of activity across other variants. Public clones dominate the neutralizing antibody response at both early and late time points following breakthough infection, and their escape mutation profiles predict newly emergent Omicron sublineages, suggesting that convergent antibody responses continue to shape SARS-CoV-2 evolution. While the study is limited by our relatively small cohort size, these results suggest that heterologous SARS-CoV-2 variant exposure drives the evolution of B cell memory, supporting the continued development of next-generation variant-based vaccines.
Authors Cassandra Willyard
Authors Delphine Planas, Timothée Bruel, Isabelle Staropoli, Florence Guivel-Benhassine, Françoise Porrot, Piet Maes, Ludivine Grzelak, Matthieu Prot, Said Mougari, Cyril Planchais, Julien Puech, Madelina Saliba, Riwan Sahraoui, Florent Fémy, Nathalie Morel, Jérémy Dufloo, Rafael Sanjuán, Hugo Mouquet, Emmanuel André, Laurent Hocqueloux, Etienne Simon-Loriere, David Veyer, Thierry Prazuck, Hélène Péré, Olivier Schwartz
Abstract Convergent evolution of SARS-CoV-2 Omicron BA.2, BA.4, and BA.5 lineages has led to the emergence of several new subvariants, including BA.2.75.2, BA.4.6. and BQ.1.1. The subvariant BQ.1.1 became predominant in many countries in December 2022. The subvariants carry an additional and often redundant set of mutations in the spike, likely responsible for increased transmissibility and immune evasion. Here, we established a viral amplification procedure to easily isolate Omicron strains. We examined their sensitivity to 6 therapeutic monoclonal antibodies (mAbs) and to 72 sera from Pfizer BNT162b2-vaccinated individuals, with or without BA.1/BA.2 or BA.5 breakthrough infection. Ronapreve (Casirivimab and Imdevimab) and Evusheld (Cilgavimab and Tixagevimab) lose antiviral efficacy against BA.2.75.2 and BQ.1.1, whereas Xevudy (Sotrovimab) remaine weakly active. BQ.1.1 is also resistant to Bebtelovimab. Neutralizing titers in triply vaccinated individuals are low to undetectable against BQ.1.1 and BA.2.75.2, 4 months after boosting. A BA.1/BA.2 breakthrough infection increases these titers, which remains about 18-fold lower against BA.2.75.2 and BQ.1.1, than against BA.1. Reciprocally, a BA.5 breakthrough infection increases more efficiently neutralization against BA.5 and BQ.1.1 than against BA.2.75.2. Thus, the evolution trajectory of novel Omicron subvariants facilitates their spread in immunized populations and raises concerns about the efficacy of most available mAbs.
Authors Kiyoto Tsuchiya, Kenji Maeda, Kouki Matsuda, Yuki Takamatsu, Noriko Kinoshita, Satoshi Kutsuna, Tsunefusa Hayashida, Hiroyuki Gatanaga, Norio Ohmagari, Shinichi Oka, Hiroaki Mitsuya
Abstract Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We evaluated the anti-SARS-CoV-2 antibody levels, anti-spike (S)-immunoglobulin G (IgG) and anti-nucleocapsid (N)-IgG, and the neutralization activity of IgG antibody in COVID‑19‑convalescent plasma against variants of SARS-CoV-2, alpha, beta, gamma, delta, kappa, omicron and R.1 strains. The study included 30 patients with clinically diagnosed COVID-19. The anti-S-IgG and anti-N-IgG levels ranged from 30.0 to 555.1 and from 10.1 to 752.6, respectively. The neutralization activity (50% inhibition concentration: IC50) for the wild-type Wuhan strain ranged from < 6.3 to 81.5 µg/ml. IgG antibodies were > 100 µg/ml in 18 of 30 (60%) subjects infected with the beta variant. The IC50 values for wild-type and beta variants correlated inversely with anti-S-IgG levels (p < 0.05), but no such correlation was noted with anti-N-IgG. IgG antibodies prevented infectivity and cytopathic effects of six different variants of concern in the cell-based assays of wild-type, alpha, gamma, delta, kappa and R.1 strains, but not that of the beta and omicron strains. IgG is considered the main neutralizing activity in the blood, although other factors may be important in other body tissues.
Authors Gokhan Tut, Tara Lancaster, Maria Krutikov, Panagiota Sylla, David Bone, Eliska Spalkova, Christopher Bentley, Umayr Amin, Azar Jadir, Samuel Hulme, Nayandeep Kaur, Elif Tut, Rachel Bruton, Mary Y. Wu, Ruth Harvey, Edward J. Carr, Crick COVID Immunity Pipeline, Rupert Beale, Oliver Stirrup, Madhumita Shrotri, Borscha Azmi, Christopher Fuller, Verity Baynton, Aidan Irwin-Singer, Andrew Hayward, Andrew Copas, Laura Shallcross, Paul Moss
Abstract Third-dose coronavirus disease 2019 vaccines are being deployed widely but their efficacy has not been assessed adequately in vulnerable older people who exhibit suboptimal responses after primary vaccination series. This observational study, which was carried out by the VIVALDI study based in England, looked at spike-specific immune responses in 341 staff and residents in long-term care facilities who received an mRNA vaccine following dual primary series vaccination with BNT162b2 or ChAdOx1. Third-dose vaccination strongly increased antibody responses with preferential relative enhancement in older people and was required to elicit neutralization of Omicron. Cellular immune responses were also enhanced with strong cross-reactive recognition of Omicron. However, antibody titers fell 21–78% within 100 d after vaccine and 27% of participants developed a breakthrough Omicron infection. These findings reveal strong immunogenicity of a third vaccine in one of the most vulnerable population groups and endorse an approach for widespread delivery across this population. Ongoing assessment will be required to determine the stability of immune protection.
Authors Leander Witte, Viren A. Baharani, Fabian Schmidt, Zijun Wang, Alice Cho, Raphael Raspe, Camila Guzman-Cardozo, Frauke Muecksch, Marie Canis, Debby J. Park, Christian Gaebler, Marina Caskey, Michel C. Nussenzweig, Theodora Hatziioannou, Paul D. Bieniasz
Abstract Waves of SARS-CoV-2 infection have resulted from the emergence of viral variants with neutralizing antibody resistance mutations. Simultaneously, repeated antigen exposure has generated affinity matured B cells, producing broadly neutralizing receptor binding domain (RBD)-specific antibodies with activity against emergent variants. To determine how SARS-CoV-2 might escape these antibodies, we subjected chimeric viruses encoding spike proteins from ancestral, BA.1 or BA.2 variants to selection by 40 broadly neutralizing antibodies. We identify numerous examples of epistasis, whereby in vitro selected and naturally occurring substitutions in RBD epitopes that do not confer antibody resistance in the Wuhan-Hu-1 spike, do so in BA.1 or BA.2 spikes. As few as 2 or 3 of these substitutions in the BA.5 spike, confer resistance to nearly all of the 40 broadly neutralizing antibodies, and substantial resistance to plasma from most individuals. Thus, epistasis facilitates the acquisition of resistance to antibodies that remained effective against early omicron variants.
Authors James L. Alexander,a,b, * Benjamin H. Mullish,a,b Nathan P. Danckert,a Zhigang Liu,a Marton L. Olbei,a Aamir Saifuddin,a,c Melissa Torkizadeh,a,d Hajir Ibraheim,a,b Jesús Miguéns Blanco,a Lauren A. Roberts,a Claire M. Bewshea,e Rachel Nice,e,f Simeng Lin,e,f Hemanth Prabhudev,b Caroline Sands,g Verena Horneffer-van der Sluis,g Matthew Lewis,g Shaji Sebastian,h,i Charlie W. Lees,j,k Julian P. Teare,a Ailsa Hart,a,c James R. Goodhand,e,f Nicholas A. Kennedy,e,f Tamas Korcsmaros,a,l,m Julian R. Marchesi,a Tariq Ahmad,e,f,n and Nick Powella,b,n, **
Authors Emanuele Andreano, Ida Paciello, Giulio Pierleoni, Giulia Piccini, Valentina Abbiento, Giada Antonelli, Piero Pileri, Noemi Manganaro, Elisa Pantano, Giuseppe Maccari, Silvia Marchese, Lorena Donnici, Linda Benincasa, Ginevra Giglioli, Margherita Leonardi, Concetta De Santi, Massimiliano Fabbiani, Ilaria Rancan, Mario Tumbarello, Francesca Montagnani, Claudia Sala, Duccio Medini, Raffaele De Francesco, Emanuele Montomoli & Rino Rappuoli
Abstract The continuous evolution of SARS-CoV-2 generated highly mutated variants able to escape natural and vaccine-induced primary immunity. The administration of a third mRNA vaccine dose induces a secondary response with increased protection. Here we investigate the longitudinal evolution of the neutralizing antibody response in four donors after three mRNA doses at single-cell level. We sorted 4100 spike protein specific memory B cells identifying 350 neutralizing antibodies. The third dose increases the antibody neutralization potency and breadth against all SARS-CoV-2 variants as observed with hybrid immunity. However, the B cell repertoire generating this response is different. The increases of neutralizing antibody responses is largely due to the expansion of B cell germlines poorly represented after two doses, and the reduction of germlines predominant after primary immunization. Our data show that different immunization regimens induce specific molecular signatures which should be considered while designing new vaccines and immunization strategies.
Authors Annika Rössler, Antonia Netzl, Ludwig Knabl, Helena Schäfer, Samuel H. Wilks, David Bante, Barbara Falkensammer, Wegene Borena, Dorothee von Laer, Derek J. Smith, Janine Kimpel
Abstract Several studies have shown that SARS-CoV-2 BA.1 omicron is an immune escape variant. Meanwhile, however, omicron BA.2 and BA.5 became dominant in many countries and replaced BA.1. As both have several mutations compared to BA.1, we analyzed whether BA.2 and BA.5 show further immune escape relative to BA.1. Here, we characterized neutralization profiles against the BA.2 and BA.5 omicron sub-variants in plasma samples from individuals with different history of exposures to infection/vaccination and found that unvaccinated individuals after a single exposure to BA.2 had limited cross-neutralizing antibodies to pre-omicron variants and to BA.1. Consequently, our antigenic map including all Variants of Concern and BA.1, BA.2 and BA.5 omicron sub-variants, showed that all omicron sub-variants are distinct to pre-omicron variants, but that the three omicron variants are also antigenically distinct from each other. The antibody landscapes illustrate that cross-neutralizing antibodies against the current antigenic space, as described in our maps, are generated only after three or more exposures to antigenically close variants but also after two exposures to antigenically distant variants. Here, we describe the antigenic space inhabited by the relevant SARS-CoV-2 variants, the understanding of which will have important implications for further vaccine strain adaptations.
Authors Hassen Kared, Asia-Sophia Wolf, Amin Alirezaylavasani, Anthony Ravussin, Guri Solum, Trung The Tran, Fridtjof Lund-Johansen, John Torgils Vaage, Lise Sofie Nissen-Meyer, Unni C. Nygaard, Olav Hungnes, Anna H. Robertson, Lisbeth Meyer Næss, Lill Trogstad, Per Magnus, Ludvig A. Munthe, Siri Mjaaland
Abstract The SARS-CoV-2 Omicron variant has more than 15 mutations in the receptor binding domain of the Spike protein enabling increased transmissibility and viral escape from antibodies in vaccinated individuals. It is unclear how vaccine immunity protects against Omicron infection. Here we show that vaccinated participants at a super-spreader event have robust recall response of humoral and pre-existing cellular immunity induced by the vaccines, and an emergent de novo T cell response to non-Spike antigens. Individuals with Omicron SARS-CoV-2 breakthrough infections have significantly increased activated SARS-CoV-2 wild type Spike-specific cytotoxic T cells, activated follicular helper (TFH) cells, functional T cell responses, boosted humoral responses, and rapid release of Spike and RBD-specific IgG+ B cell plasmablasts and memory B cells into circulation. Omicron breakthrough infection affords significantly increased de novo memory T cell responses to non-Spike viral antigens. Concerted T and B cell responses may provide durable and broad immunity.
Authors Michael S. Diamond, John D. Lambris, Jenny P. Ting, John S. Tsang
SCIENCE
Authors Pavel A. Nikitin1*, Jillian M. DiMuzio1 , John P. Dowling1 , Nirja B. Patel1 , Jamie L. Bingaman-Steele1 , Baron C. Heimbach1 , Noeleya Henriquez1 , Chris Nicolescu1 , Antonio Polley1 , Eden L. Sikorski1 , Raymond J. Howanski1 , Mitchell Nath1 , Halley Shukla1 , Suzanne M. Scheaffer3, James P. Finn1 , Li-Fang Liang1 , Todd Smith1 , Nadia Storm2, Lindsay G. A. McKay2, Rebecca I. Johnson2, Lauren E. Malsick2, Anna N. Honko2, Anthony Griffiths, Michael S. Diamond, Purnanand Sarma, Dennis H. Geising, Michael J. Morin, Matthew K. Robinson
Abstract Monoclonal antibodies are an efficacious therapy against SARS-CoV-2. However, rapid viral mutagenesis, led to escape from most of these therapies, outlining the need for an antibody cocktail with a broad neutralizing potency. Using an unbiased interrogation of the memory B cell repertoire of convalescent COVID-19 patients, we identified human antibodies with broad antiviral activity in vitro and efficacy in vivo against all tested SARS-CoV-2 variants of concern, including Delta, Omicron BA.1 and BA.2. Here, we describe an antibody cocktail IMM-BCP-01, that consists of three patient-derived broadly neutralizing antibodies directed at non-overlapping surfaces on the SARS-CoV-2 spike protein. Two antibodies, IMM20184 and IMM20190, directly blocked Spike binding to the ACE2 receptor. Binding of the third antibody, IMM20253, to its cryptic epitope on the outer surface of RBD, altered the conformation of the Spike Trimer, promoting release of Spike monomers. These antibodies decreased Omicron SARS-CoV-2 infection in the lungs of Syrian golden hamsters in vivo, and potently induced antiviral effector response in vitro, including phagocytosis, ADCC, and complement pathway activation. Our pre-clinical data demonstrated that the three antibody cocktail IMM-BCP-01 could be a promising means for preventing or treating infection of SARS-CoV-2 variants of concern, including Omicron BA.1 and BA.2, in susceptible individuals.
Authors AA.VV.
Abstract SARS-CoV-2 has evolved variants with substitutions in the spike receptor-binding domain (RBD) that impact its affinity for ACE2 receptor and recognition by antibodies. These substitutions could also shape future evolution by modulating the effects of mutations at other sites—a phenomenon called epistasis. To investigate this possibility, we performed deep mutational scans to measure the effects on ACE2 binding of all single amino-acid mutations in the Wuhan-Hu-1, Alpha, Beta, Delta, and Eta variant RBDs. Some substitutions, most prominently N501Y, cause epistatic shifts in the effects of mutations at other sites. These epistatic shifts shape subsequent evolutionary change, for example enabling many of the antibody-escape substitutions in the Omicron RBD. These epistatic shifts occur despite high conservation of the overall RBD structure. Our data shed light on RBD sequence-function relationships and facilitate interpretation of ongoing SARS-CoV-2 evolution.
Authors Sheri Harari, Maayan Tahor, Natalie Rutsinsky, Suzy Meijer, Danielle Miller, Oryan Henig, Ora Halutz, Katia Levytskyi, Ronen Ben-Ami, Amos Adler, Yael Paran, Adi Stern
Abstract In some immunocompromised patients with chronic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, considerable adaptive evolution occurs. Some substitutions found in chronic infections are lineage-defining mutations in variants of concern (VOCs), which has led to the hypothesis that VOCs emerged from chronic infections. In this study, we searched for drivers of VOC-like emergence by consolidating sequencing results from a set of 27 chronic infections. Most substitutions in this set reflected lineage-defining VOC mutations; however, a subset of mutations associated with successful global transmission was absent from chronic infections. We further tested the ability to associate antibody evasion mutations with patient-specific and virus-specific features and found that viral rebound is strongly correlated with the emergence of antibody evasion. We found evidence for dynamic polymorphic viral populations in most patients, suggesting that a compromised immune system selects for antibody evasion in particular niches in a patient’s body. We suggest that a tradeoff exists between antibody evasion and transmissibility and that extensive monitoring of chronic infections is necessary to further understanding of VOC emergence.
Authors JACQUI WISE
Authors Catherine J. Reynolds†, Corinna Pade†, Joseph M. Gibbons†, Ashley D. Otter†, Kai-Min Lin, Diana Muñoz Sandoval, Franziska P. Pieper, David K. Butler, Siyi Liu, George Joy, Nasim Forooghi, Thomas A. Treibel, Charlotte Manisty, James C. Moon, COVIDsortium Investigators, COVIDsortium Immune Correlates Network, Amanda Semper, Tim Brooks, Áine McKnight, Daniel M. Altmann, Rosemary J. Boyton
Abstract The Omicron, or Pango lineage B.1.1.529, variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) carries multiple spike mutations with high transmissibility and partial neutralizing antibody (nAb) escape. Vaccinated individuals show protection against severe disease, often attributed to primed cellular immunity. We investigated T and B cell immunity against B.1.1.529 in triple BioNTech BNT162b2 messenger RNA–vaccinated health care workers (HCWs) with different SARS-CoV-2 infection histories. B and T cell immunity against previous variants of concern was enhanced in triple-vaccinated individuals, but the magnitude of T and B cell responses against B.1.1.529 spike protein was reduced. Immune imprinting by infection with the earlier B.1.1.7 (Alpha) variant resulted in less durable binding antibody against B.1.1.529. Previously infection-naïve HCWs who became infected during the B.1.1.529 wave showed enhanced immunity against earlier variants but reduced nAb potency and T cell responses against B.1.1.529 itself. Previous Wuhan Hu-1 infection abrogated T cell recognition and any enhanced cross-reactive neutralizing immunity on infection with B.1.1.529. At the end of 2021, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern (VOC) spread rapidly, displacing the prior most prevalent VOC, B.1.617.2 (Delta) (1, 2). B.1.1.529 (Omicron) diverges more from the ancestral Wuhan Hu-1 sequence than other VOCs so far, with 36 coding mutations in the spike protein, associated with high transmission, tendency to infect cells of the upper bronchus, and presentation with flu-like symptoms (3–5). Across several studies, two- or three-dose vaccination is protective against severe disease and hospitalization, albeit with poor protection against transmission (6–8). A rationale for this high rate of breakthrough infections comes from mapping of virus neutralization using either postvaccination immune sera or monoclonal antibodies, showing Omicron to be the most antibody immune-evasive VOC, with titers generally reduced 20- to 40-fold (9–12). The relative attenuation of severe symptoms in vaccinated compared with unvaccinated groups is likely attributable to the partial protection conferred by the residual neutralizing antibody (nAb) repertoire and the activation of primed B cell and T cell memory (13–18). In this study, we applied our ongoing analysis of a cohort of London health care workers (HCWs) (19–24) to address two key issues of B.1.1.529 (Omicron) immunity. First, following the earlier demonstration that people at this stage in the pandemic carry heterogeneous, immune-imprinted repertoires derived from their distinctive histories of infection and vaccination, we explored how these differences manifest in differential cross-recognition of B.1.1.529 (Omicron) relative to other VOCs, at the level of binding and neutralizing Ab, B cell, and T cell immunity (24). Analyzing a London HCW cohort having detailed longitudinal, clinical, transcriptomic, and immunologic characterization, we considered the extent to which prior encounter with spike antigen through infection and vaccination shapes subsequent immunity to B.1.1.529 (Omicron) through immune imprinting. Second, when B.1.1.529 (Omicron) infections and reinfections have been so pervasive (25), it is possible that B.1.1.529 (Omicron) infection may confer a benign, live booster to vaccine immunity. Hence, we investigated the extent to which B.1.1.529 (Omicron) infection boosts cross-reactive B and T cell immunity against other VOCs and itself.
Authors MENNO C. VAN ZELM
Abstract Analysis of memory B cell responses to Spike antigen after Omicron BA.1 breakthrough infections provides clues on whether “original antigenic sin” is in play.
Authors Kevin R. McCarthy
THE LANCET
Authors Frauke Muecksch*, Helen Wise*, Kate Templeton, Becky Batchelor, Maria Squires, Kirsty McCance, Lisa Jarvis, Kristen Malloy, Elizabeth Furrie, Claire Richardson, Jacqueline MacGuire, Ian Godber, Alana Burns, Sally Mavin, Fengwen Zhang, Fabian Schmidt, Paul D Bieniasz, Sara Jenks, Theodora Hatziioannou
THE NEW ENGLAND JOURNAL OF MEDICINE
Authors Yair Goldberg, Ph.D., Micha Mandel, Ph.D., Yinon M. Bar-On, M.Sc., Omri Bodenheimer, M.Sc., Laurence S. Freedman, Ph.D., Nachman Ash, M.D., Sharon Alroy-Preis, M.D., Amit Huppert, Ph.D., Ron Milo
Abstract BACKGROUND Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) provides natural immunity against reinfection. Recent studies have shown waning of the immunity provided by the BNT162b2 vaccine. The time course of natural and hybrid immunity is unknown. METHODS Using the Israeli Ministry of Health database, we extracted data for August and September 2021, when the B.1.617.2 (delta) variant was predominant, on all persons who had been previously infected with SARS-CoV-2 or who had received coronavirus 2019 vaccine. We used Poisson regression with adjustment for confounding factors to compare the rates of infection as a function of time since the last immunity-conferring event. RESULTS The number of cases of SARS-CoV-2 infection per 100,000 person-days at risk (adjusted rate) increased with the time that had elapsed since vaccination with BNT162b2 or since previous infection. Among unvaccinated persons who had recovered from infection, this rate increased from 10.5 among those who had been infected 4 to less than 6 months previously to 30.2 among those who had been infected 1 year or more previously. Among persons who had received a single dose of vaccine after previous infection, the adjusted rate was low (3.7) among those who had been vaccinated less than 2 months previously but increased to 11.6 among those who had been vaccinated at least 6 months previously. Among previously uninfected persons who had received two doses of vaccine, the adjusted rate increased from 21.1 among those who had been vaccinated less than 2 months previously to 88.9 among those who had been vaccinated at least 6 months previously. CONCLUSIONS Among persons who had been previously infected with SARS-CoV-2 (regardless of whether they had received any dose of vaccine or whether they had received one dose before or after infection), protection against reinfection decreased as the time increased since the last immunity-conferring event; however, this protection was higher than that conferred after the same time had elapsed since receipt of a second dose of vaccine among previously uninfected persons. A single dose of vaccine after infection reinforced protection against reinfection.
Authors Fernanda Ludolf, Fernanda F. Ramos, Flávia F. Bagno, João A. Oliveira-da-Silva, Thiago A. R. Reis, Myron Christodoulides, Paula F. Vassallo, Cecilia G. Ravetti, Vandack Nobre, Flavio G. da Fonseca, Eduardo A. F. Coelho
Abstract Serum-based ELISA (enzyme-linked immunosorbent assay) has been widely used to detect anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies. However, to date, no study has investigated patient urine as a biological sample to detect SARS-CoV-2 virus-specific antibodies. An in-house urine-based ELISA was developed using recombinant SARS-CoV-2 nucleocapsid protein. The presence of SARS-CoV-2 antibodies in urine was established, with 94% sensitivity and 100% specificity for the detection of anti–SARS-CoV-2 antibodies with the urine-based ELISA and 88% sensitivity and 100% specificity with a paired serum-based ELISA. The urine-based ELISA that detects anti–SARS-CoV-2 antibodies is a noninvasive method with potential application as a facile COVID-19 immunodiagnostic platform, which can be used to report the extent of exposure at the population level and/or to assess the risk of infection at the individual level.
Authors Marciela M. DeGrace, Elodie Ghedin, Matthew B. Frieman, Florian Krammer, Alba Grifoni, Arghavan Alisoltani, Galit Alter, Rama R. Amara, Ralph S. Baric, Dan H. Barouch, Jesse D. Bloom, Louis-Marie Bloyet, Gaston Bonenfant, Adrianus C. M. Boon, Eli A. Boritz, Debbie L. Bratt, Traci L. Bricker, Liliana Brown, William J. Buchser, Juan Manuel Carreño, Liel Cohen-Lavi, Tamarand L. Darling, Meredith E. Davis-Gardner, Bethany L. Dearlove, Han Di, Meike Dittmann, Nicole A. Doria-Rose, Daniel C. Douek, Christian Drosten, Venkata-Viswanadh Edara, Ali Ellebedy, Thomas P. Fabrizio, Guido Ferrari, William C. Florence, Ron A. M. Fouchier, John Franks, Adolfo García-Sastre, Adam Godzik, Ana Silvia Gonzalez-Reiche, Aubree Gordon, Bart L. Haagmans, Peter J. Halfmann, David D. Ho, Michael R. Holbrook, Yaoxing Huang, Sarah L. James, Lukasz Jaroszewski, Trushar Jeevan, Robert M. Johnson, Terry C. Jones, Astha Joshi, Yoshihiro Kawaoka, Lisa Kercher, Marion P. G. Koopmans, Bette Korber, Eilay Koren, Richard A. Koup, Eric B. LeGresley, Jacob E. Lemieux, Mariel J. Liebeskind, Zhuoming Liu, Brandi Livingston, James P. Logue, Yang Luo, Adrian B. McDermott, Margaret J. McElrath, Victoria A. Meliopoulos, Vineet D. Menachery, David C. Montefiori, Barbara Mühlemann, Vincent J. Munster, Jenny E. Munt, Manoj S. Nair, Antonia Netzl, Anna M. Niewiadomska, Sijy O’Dell, Andrew Pekosz, Stanley Perlman, Marjorie C. Pontelli, Barry Rockx, Morgane Rolland, Paul W. Rothlauf, Sinai Sacharen, Richard H. Scheuermann, Stephen D. Schmidt, Michael Schotsaert, Stacey Schultz-Cherry, Robert A. Seder, Mayya Sedova, Alessandro Sette, Reed S. Shabman, Xiaoying Shen, Pei-Yong Shi, Maulik Shukla, Viviana Simon, Spencer Stumpf, Nancy J. Sullivan, Larissa B. Thackray, James Theiler, Paul G. Thomas, Sanja Trifkovic, Sina Türeli, Samuel A. Turner, Maria A. Vakaki, Harm van Bakel, Laura A. VanBlargan, Leah R. Vincent, Zachary S. Wallace, Li Wang, Maple Wang, Pengfei Wang, Wei Wang, Scott C. Weaver, Richard J. Webby, Carol D. Weiss
Abstract The global emergence of many severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants jeopardizes the protective antiviral immunity induced following infection or vaccination. To address the public health threat caused by the increasing SARS-CoV-2 genomic diversity, the National Institute of Allergy and Infectious Diseases (NIAID) within the National Institutes of Health (NIH) established the SARS-CoV-2 Assessment of Viral Evolution (SAVE) program. This effort was designed to provide a real-time risk assessment of SARS-CoV-2 variants potentially impacting transmission, virulence, and resistance to convalescent and vaccine-induced immunity. The SAVE program serves as a critical data-generating component of the United States Government SARS-CoV-2 Interagency Group to assess implications of SARS-CoV-2 variants on diagnostics, vaccines, and therapeutics and for communicating public health risk. Here we describe the coordinated approach used to identify and curate data about emerging variants, their impact on immunity, and effects on vaccine protection using animal models. We report the development of reagents, methodologies, models, and pivotal findings facilitated by this collaborative approach and identify future challenges. This program serves as a template for the response against rapidly evolving pandemic pathogens by monitoring viral evolution in the human population to identify variants that could erode the effectiveness of countermeasures.
Authors Daniel J Sheward, Changil Kim, Roy A Ehling, Alec Pankow, Xaquin Castro Dopico, Robert Dyrdak, Darren P Martin, Sai T Reddy, Joakim Dillner, Gunilla B Karlsson Hedestam, Jan Albert, Ben Murrell
Authors Adriana Tomic, Donal T. Skelly, Ane Ogbe, Daniel O’Connor, Matthew Pace, Emily Adland, Frances Alexander, Mohammad Ali, Kirk Allott, M. Azim Ansari, Sandra Belij-Rammerstorfer, Sagida Bibi, Luke Blackwell, Anthony Brown, Helen Brown, Breeze Cavell, Elizabeth A. Clutterbuck, Thushan de Silva, David Eyre, Sheila Lumley, Amy Flaxman, James Grist, Carl-Philipp Hackstein, Rachel Halkerston, Adam C. Harding, Jennifer Hill, Tim James, Cecilia Jay, Síle A. Johnson, Barbara Kronsteiner, Yolanda Lie, Aline Linder, Stephanie Longet, Spyridoula Marinou, Philippa C. Matthews, Jack Mellors, Christos Petropoulos, Patpong Rongkard, Cynthia Sedik, Laura Silva-Reyes, Holly Smith, Lisa Stockdale, Stephen Taylor, Stephen Thomas, Timothy Tipoe, Lance Turtle, Vinicius Adriano Vieira, Terri Wrin, OPTIC Clinical Group, PITCH Study Group, C-MORE Group, Andrew J. Pollard, Teresa Lambe, Chris P. Conlon, Katie Jeffery, Simon Travis, Philip Goulder, John Frater, Alex J. Mentzer, Lizzie Stafford, Miles W. Carroll, William S. James, Paul Klenerman, Eleanor Barnes, Christina Dold, Susanna J. Dunachie
Abstract The trajectories of acquired immunity to severe acute respiratory syndrome coronavirus 2 infection are not fully understood. We present a detailed longitudinal cohort study of UK healthcare workers prior to vaccination, presenting April-June 2020 with asymptomatic or symptomatic infection. Here we show a highly variable range of responses, some of which (T cell interferon-gamma ELISpot, N-specific antibody) wane over time, while others (spike-specific antibody, B cell memory ELISpot) are stable. We use integrative analysis and a machine-learning approach (SIMON - Sequential Iterative Modeling OverNight) to explore this heterogeneity. We identify a subgroup of participants with higher antibody responses and interferon-gamma ELISpot T cell responses, and a robust trajectory for longer term immunity associates with higher levels of neutralising antibodies against the infecting (Victoria) strain and also against variants B.1.1.7 (alpha) and B.1.351 (beta). These variable trajectories following early priming may define subsequent protection from severe disease from novel variants.
Authors V. Hall, S. Foulkes, F. Insalata, P. Kirwan, A. Saei, A. Atti, E. Wellington, J. Khawam, K. Munro, M. Cole, C. Tranquillini, A. Taylor‐Kerr, N. Hettiarachchi, D. Calbraith, N. Sajedi, I. Milligan, Y. Themistocleous, D. Corrigan, L. Cromey, L. Price, S. Stewart, E. de Lacy, C. Norman, E. Linley, A.D. Otter, A. Semper, J. Hewson, S. D’Arcangelo, M. Chand, C.S. Brown, T. Brooks, J. Islam, A. Charlett, S. Hopkins
Abstract BACKGROUND The duration and effectiveness of immunity from infection with and vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are relevant to pandemic policy interventions, including the timing of vaccine boosters. METHODS We investigated the duration and effectiveness of immunity in a prospective cohort of asymptomatic health care workers in the United Kingdom who underwent routine polymerase-chain-reaction (PCR) testing. Vaccine effectiveness (≤10 months after the first dose of vaccine) and infection-acquired immunity were assessed by comparing the time to PCR-confirmed infection in vaccinated persons with that in unvaccinated persons, stratified according to previous infection status. We used a Cox regression model with adjustment for previous SARS-CoV-2 infection status, vaccine type and dosing interval, demographic characteristics, and workplace exposure to SARS-CoV-2. RESULTS Of 35,768 participants, 27% (9488) had a previous SARS-CoV-2 infection. Vaccine coverage was high: 97% of the participants had received two doses (78% had received BNT162b2 vaccine [Pfizer–BioNTech] with a long interval between doses, 9% BNT162b2 vaccine with a short interval between doses, and 8% ChAdOx1 nCoV-19 vaccine [AstraZeneca]). Between December 7, 2020, and September 21, 2021, a total of 2747 primary infections and 210 reinfections were observed. Among previously uninfected participants who received long-interval BNT162b2 vaccine, adjusted vaccine effectiveness decreased from 85% (95% confidence interval [CI], 72 to 92) 14 to 73 days after the second dose to 51% (95% CI, 22 to 69) at a median of 201 days (interquartile range, 197 to 205) after the second dose; this effectiveness did not differ significantly between the long-interval and short-interval BNT162b2 vaccine recipients. At 14 to 73 days after the second dose, adjusted vaccine effectiveness among ChAdOx1 nCoV-19 vaccine recipients was 58% (95% CI, 23 to 77) — considerably lower than that among BNT162b2 vaccine recipients. Infection-acquired immunity waned after 1 year in unvaccinated participants but remained consistently higher than 90% in those who were subsequently vaccinated, even in persons infected more than 18 months previously. CONCLUSIONS Two doses of BNT162b2 vaccine were associated with high short-term protection against SARS-CoV-2 infection; this protection waned considerably after 6 months. Infection-acquired immunity boosted with vaccination remained high more than 1 year after infection. (Funded by the U.K. Health Security Agency and others; ISRCTN Registry number, ISRCTN11041050. opens in new tab.)
Authors Yang Yang, Minghui Yang, Yun Peng, Yanhua Liang, Jinli Wei, Li Xing, Liping Guo, Xiaohe Li, Jie Li, Jun Wang, Mianhuan Li, Zhixiang Xu, Mingxia Zhang, Fuxiang Wang, Yi Shi, Jing Yuan, Yingxia Liu
Abstract Elucidating the dynamics of the neutralizing antibody (nAb) response in coronavirus disease 2019 (COVID-19) convalescents is crucial in controlling the pandemic and informing vaccination strategies. Here we measured nAb titres across 411 sequential plasma samples collected during 1–480 d after illness onset or laboratory confirmation (d.a.o.) from 214 COVID-19 convalescents, covering the clinical spectrum of disease and without additional exposure history after recovery or vaccination against SARS-CoV-2, using authentic SARS-CoV-2 microneutralization (MN) assays. Forty-eight samples were also tested for neutralizing activities against the circulating variants using pseudotyped neutralization assay. Results showed that anti-RBD IgG and MN titres peaked at ~120 d.a.o. and subsequently declined, with significantly reduced nAb responses found in 91.67% of COVID-19 convalescents (≥50% decrease in current MN titres compared with the paired peak MN titres). Despite this decline, majority of the COVID-19 convalescents maintained detectable anti-RBD IgG and MN titres at 400–480 d.a.o., with undetectable neutralizing activity found in 14.41% (16/111) of the mild and 50% (5/10) of the asymptomatic infections at 330–480 d.a.o. Persistent antibody-dependent immunity could provide protection against circulating variants after one year, despite significantly decreased neutralizing activities against Beta, Delta and Mu variants. In conclusion, these data show that despite a marked decline in neutralizing activity over time, nAb responses persist for up to 480 d in most convalescents of symptomatic COVID-19, whereas a high rate of undetectable nAb responses was found in convalescents from asymptomatic infections.
JAMA
Authors Jennifer L. Alejo, Jonathan Mitchell, Amy Chang, Teresa P. Y. Chiang, Allan B. Massie, Dorry L. Segev, Martin A. Makary
Authors CORINE H. GEURTSVANKESSEL, DARYL GEERS, KATHARINA S. SCHMITZ, ANNA Z. MYKYTYN, MART M LAMERS, SUSANNE BOGERS, SANDRA SCHERBEIJN, LENNERT GOMMERS, ROOS S.G. SABLEROLLES, NELLA N. NIEUWKOOP, LAURINE C. RIJSBERGEN, LAURA L.A. VAN DIJK, JANET DE WILDEKIMBERLEY ALBLAS, TIM I. BREUGEMBART, J.A. RIJNDERS, HERBERT DE JAGER, DANIELA WEISKOPF, P. HUGO M. VAN DER KUY, ALESSANDRO SETTE, MARION P.G. KOOPMANS, ALBA GRIFONI, BART L. HAAGMANS, RORY D. DE VRIES
Abstract The severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2) Omicron variant (B.1.1.529) is spreading rapidly, even in vaccinated individuals, raising concerns about immune escape. Here, we studied neutralizing antibodies and T-cell responses targeting SARS-CoV-2 D614G (wildtype, WT), and the B.1.351 (Beta), B.1.617.2 (Delta), and B.1.1.529 (Omicron) variants of concern (VOC) in a cohort of 60 health care workers after immunization with ChAdOx-1 S, Ad26.COV2.S, mRNA-1273 or BNT162b2. High binding antibody levels against WT SARS-CoV-2 spike (S) were detected 28 days after vaccination with both mRNA vaccines (mRNA-1273 or BNT162b2), which significantly decreased after 6 months. In contrast, antibody levels were lower after Ad26.COV2.S vaccination but did not wane. Neutralization assays with infectious virus showed consistent cross-neutralization of the Beta and Delta variants, but neutralization of Omicron was significantly lower or absent (up to a 34-fold decrease compared to WT). Notably, BNT162b2 booster vaccination after either two mRNA-1273 immunizations or Ad26.COV.2 priming partially restored neutralization of the Omicron variant, but responses were still up to-17-fold decreased compared to WT. SARS-CoV-2-specific T-cells were detected up to 6 months after all vaccination regimens, with more consistent detection of specific CD4+ than CD8+ T-cells. No significant differences were detected between WT- and variant-specific CD4+ or CD8+ T-cell responses, including Omicron, indicating minimal escape at the T-cell level. This study shows that vaccinated individuals retain T-cell immunity to the SARS-CoV-2 Omicron variant, potentially balancing the lack of neutralizing antibodies in preventing or limiting severe COVID-19. Booster vaccinations are needed to further restore Omicron cross-neutralization by antibodies.
Authors Mandeep Dhaliwal, Roy Small, Douglas Webb, Lucie Cluver, Mona Ibrahim, Ludo Bok, Collin Nascimento, Cheng Wang, Aidan Garagic, Lars Jensen
ELSEVIER
Authors P. Ferrara, D. Ponticelli, F. Agüero, G. Caci, A. Vitale, M. Borrelli, B. Schiavone, I.C. Antonazzo, L.G. Mantovani, V. Tomaselli, R. Polosa
Abstract Objectives The aim of this study was to investigate the possible impact of smoking on the humoral response to the BNT162b2 mRNA COVID-19 vaccine (also known as the BioNTech-Pfizer COVID-19 vaccine). Study design A longitudinal sero-epidemiological study was conducted in sample of Italian healthcare workers (HCWs). Methods HCWs who were administered two doses of the BNT162b2 mRNA vaccine, 21 days apart, between December 2020 and January 2021, were invited to undergo multiple serology tests to identify SARS-CoV-2 S-RBD-specific immunoglobulin G (IgG) antibodies. Participants also responded to questions about their smoking status (i.e. current smokers vs non-smokers) in a survey. Results Sixty days after the completion of the vaccination cycle, serological analyses showed a difference in vaccine-induced IgG titre between current smokers and non-smokers, with median antibody titres of 211.80 AU/mL (interquartile range [IQR] 149.80–465.50) and 487.50 AU/mL (IQR 308.45–791.65) [P-value = 0.002], respectively. This significant difference in vaccine-induced IgG titres between current smokers and non-smokers remained after adjusting for age, sex, and previous infection with SARS-CoV-2. Conclusions This study observed that vaccine-induced antibody titres decrease faster among current smokers than non-smokers. Further research to investigate the impact of smoking on the immunological response to COVID-19 and non-COVID-19 vaccines is required.
Authors Rhia Kundu, Janakan Sam Narean, Lulu Wang, Joseph Fenn, Timesh Pillay, Nieves Derqui Fernandez, Emily Conibear, Aleksandra Koycheva, Megan Davies, Mica Tolosa-Wright, Seran Hakki, Robert Varro, Eimear McDermott, Sarah Hammett, Jessica Cutajar, Ryan S. Thwaites, Eleanor Parker, Carolina Rosadas, Myra McClure, Richard Tedder, Graham P. Taylor, Jake Dunning, Ajit Lalvani
Abstract Cross-reactive immune responses to SARS-CoV-2 have been observed in pre-pandemic cohorts and proposed to contribute to host protection. Here we assess 52 COVID-19 household contacts to capture immune responses at the earliest timepoints after SARS-CoV-2 exposure. Using a dual cytokine FLISpot assay on peripheral blood mononuclear cells, we enumerate the frequency of T cells specific for spike, nucleocapsid, membrane, envelope and ORF1 SARS-CoV-2 epitopes that cross-react with human endemic coronaviruses. We observe higher frequencies of cross-reactive (p = 0.0139), and nucleocapsid-specific (p = 0.0355) IL-2-secreting memory T cells in contacts who remained PCR-negative despite exposure (n = 26), when compared with those who convert to PCR-positive (n = 26); no significant difference in the frequency of responses to spike is observed, hinting at a limited protective function of spike-cross-reactive T cells. Our results are thus consistent with pre-existing non-spike cross-reactive memory T cells protecting SARS-CoV-2-naïve contacts from infection, thereby supporting the inclusion of non-spike antigens in second-generation vaccines.
JOURNAL OF CLINICAL MEDICINE RESEARCH
Authors Marilena Greco, Federico Cucci, Pierfrancesco Portulano, Roberta Assunta Lazzari, Cosimo Caldararo, Fernando Sicuro, Carmelo Catanese, Giambattista Lobreglio
ABSTRACT Background: Vaccine-induced immunity is at present the main strategy to stop the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent evidences suggested a protective effect of influenza vaccination against coronavirus disease 2019 (COVID-19) severity, while impact on the immune response to BNT162b2 messenger RNA (mRNA) vaccine is under investigation. Methods: We aimed to evaluate this aspect in a cohort of 297 healthcare workers (108 males, 189 females) after seasonal influenza vaccination compared to no-flu-vaccination. VAX+ (165 individuals; 63 males and 102 females) had tetravalent influenza vaccine, and VAX- (132 individuals; 45 males and 87 females) had no flu vaccination. Anti-spike-receptor binding domain (RBD) level was tested 15 - 70 days after BNT162b2 second inoculum. Results: Increased antibody response was observed in total VAX+ compared to VAX- (2,047.4 vs. 1,494.2 binding antibody unit (BAU)/mL, P = 0.0039), independently from gender and body mass index (BMI). Younger total individuals (< 35 years) showed significant increase of the level of binding antibodies (2,184.8 vs. 1,590.9 BAU/mL, P = 0.0038) compared to ? 35 years; young/old difference was lost restricting to VAX+ subgroup. Flu vaccinations appear associated to better antibody response in older individuals (P = 0.027, ? 35 years VAX+ vs. VAX-). A decreasing trend during time was observed for both VAX+ and VAX-, except for < 35 years VAX- individuals. Early response was higher in VAX+ compared to VAX-; however a more rapid waning was observed in VAX+ subjects. Conclusions: Our data showed better antibody response to SARS-CoV-2 vaccine in subjects already vaccinated against seasonal influenza; this may represent one of the mechanisms underlying the cross-protective effects of influenza vaccination against heterologous infections reported in recent epidemiological studies.
Authors Jay K. Kolls, Robert F. Garry
Authors Jennifer S. Chen, Ryan D. Chow, Eric Song, Tianyang Mao, Benjamin Israelow, Kathy Kamath, Joel Bozekowski, Winston A. Haynes, Renata B. Filler, Bridget L. Menasche, Jin Wei, Mia Madel Alfajaro, Wenzhi Song, Lei Peng, Lauren Carter, Jason S. Weinstein, Uthaman Gowthaman, Sidi Chen, Joe Craft, John C. Shon, Akiko Iwasaki, Craig B. Wilen, Stephanie C. Eisenbarth
Abstract T follicular helper (TFH) cells are the conventional drivers of protective, germinal center (GC)–based antiviral antibody responses. However, loss of TFH cells and GCs has been observed in patients with severe COVID-19. As T cell–B cell interactions and immunoglobulin class switching still occur in these patients, noncanonical pathways of antibody production may be operative during SARS-CoV-2 infection. We found that both TFH-dependent and -independent antibodies were induced against SARS-CoV-2 infection, SARS-CoV-2 vaccination, and influenza A virus infection. Although TFH-independent antibodies to SARS-CoV-2 had evidence of reduced somatic hypermutation, they were still high affinity, durable, and reactive against diverse spike-derived epitopes and were capable of neutralizing both homologous SARS-CoV-2 and the B.1.351 (beta) variant of concern. We found by epitope mapping and B cell receptor sequencing that TFH cells focused the B cell response, and therefore, in the absence of TFH cells, a more diverse clonal repertoire was maintained. These data support an alternative pathway for the induction of B cell responses during viral infection that enables effective, neutralizing antibody production to complement traditional GC-derived antibodies that might compensate for GCs damaged by viral inflammation.
Authors Lok-Yin Roy Wong, Stanley Perlman
Human coronaviruses cause a wide spectrum of disease, ranging from mild common colds to acute respiratory distress syndrome and death. Three highly pathogenic human coronaviruses — severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus and SARS-CoV-2 — have illustrated the epidemic and pandemic potential of human coronaviruses, and a better understanding of their disease-causing mechanisms is urgently needed for the rational design of therapeutics. Analyses of patients have revealed marked dysregulation of the immune system in severe cases of human coronavirus infection, and there is ample evidence that aberrant immune responses to human coronaviruses are typified by impaired induction of interferons, exuberant inflammatory responses and delayed adaptive immune responses. In addition, various viral proteins have been shown to impair interferon induction and signalling and to induce inflammasome activation. This suggests that severe disease associated with human coronaviruses is mediated by both dysregulated host immune responses and active viral interference. Here we discuss our current understanding of the mechanisms involved in each of these scenarios.
Authors Deborah Cromer, Megan Steain, Arnold Reynaldi, Timothy E Schlub, Adam K Wheatley, Jennifer A Juno, Stephen J Kent, James A Triccas, David S Khoury, Miles P Davenport
Authors Brahm Coler, Kristina Adams Waldorf
Authors Jennifer A. Juno, Adam K. Wheatley
Authors Barak Mizrahi, Roni Lotan, Nir Kalkstein, Asaf Peretz, Galit Perez, Amir Ben-Tov, Gabriel Chodick, Sivan Gazit, Tal Patalon
Abstract The short-term effectiveness of a two-dose regimen of the BioNTech/Pfizer mRNA BNT162b2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine was widely demonstrated. However, long term effectiveness is still unknown. Leveraging the centralized computerized database of Maccabi Healthcare Services (MHS), we assessed the correlation between time-from-vaccine and incidence of breakthrough infection between June 1 and July 27, the date of analysis. After controlling for potential confounders as age and comorbidities, we found a significant 1.51 fold (95% CI, 1.38–1.66) increased risk for infection for early vaccinees compared to those vaccinated later that was similar across all ages groups. The increased risk reached 2.26- fold (95% CI, 1.80–3.01) when comparing those who were vaccinated in January to those vaccinated in April. This preliminary finding of vaccine waning as a factor of time from vaccince should prompt further investigations into long-term protection against different strains.
Authors Jia Wei, Philippa C. Matthews, Nicole Stoesser, Thomas Maddox, Luke Lorenzi, Ruth Studley, John I. Bell, John N. Newton, Jeremy Farrar, Ian Diamond, Emma Rourke, Alison Howarth, Brian D. Marsden, Sarah Hoosdally, E. Yvonne Jones, David I. Stuart, Derrick W. Crook, Tim E. A. Peto, Koen B. Pouwels, A. Sarah Walker, David W. Eyre
Abstract Understanding the trajectory, duration, and determinants of antibody responses after SARS-CoV-2 infection can inform subsequent protection and risk of reinfection, however large-scale representative studies are limited. Here we estimated antibody response after SARS-CoV-2 infection in the general population using representative data from 7,256 United Kingdom COVID-19 infection survey participants who had positive swab SARS-CoV-2 PCR tests from 26-April-2020 to 14-June-2021. A latent class model classified 24% of participants as ‘non-responders’ not developing anti-spike antibodies, who were older, had higher SARS-CoV-2 cycle threshold values during infection (i.e. lower viral burden), and less frequently reported any symptoms. Among those who seroconverted, using Bayesian linear mixed models, the estimated anti-spike IgG peak level was 7.3-fold higher than the level previously associated with 50% protection against reinfection, with higher peak levels in older participants and those of non-white ethnicity. The estimated anti-spike IgG half-life was 184 days, being longer in females and those of white ethnicity. We estimated antibody levels associated with protection against reinfection likely last 1.5-2 years on average, with levels associated with protection from severe infection present for several years. These estimates could inform planning for vaccination booster strategies.
Authors Gregory Milne, Thomas Hames, Chris Scotton, Nick Gent, Alexander Johnsen, Roy M Anderson, Tom Ward
Authors Jeffrey P Townsend, Hayley B Hassler, Zheng Wang, Sayaka Miura, Jaiveer Singh, Sudhir Kumar, Nancy H Ruddle, Alison P Galvani, Alex Dornburg
Authors Stephen J. Thomas, Edson D. Moreira, Jr, Nicholas Kitchin, Judith Absalon, Alejandra Gurtman, Stephen Lockhart, D.M., John L. Perez, Gonzalo Pérez Marc, Fernando P. Polack, Cristiano Zerbini, Ruth Bailey, Kena A. Swanson, Xia Xu, Satrajit Roychoudhury, Kenneth Koury, Salim Bouguermouh, Warren V. Kalina, David Cooper, Robert W. Frenck, Jr., Laura L. Hammitt, Özlem Türeci, Haylene Nell, Axel Schaefer, Serhat Ünal, Qi Yang, Paul Liberator, Dina B. Tresnan, D.V.M., Susan Mather, Philip R. Dormitzer, Uğur Şahin, William C. Gruber, Kathrin U. Jansen
Abstract BACKGROUND BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine encoding a prefusion-stabilized, membrane-anchored severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) full-length spike protein. BNT162b2 is highly efficacious against coronavirus disease 2019 (Covid-19) and is currently approved, conditionally approved, or authorized for emergency use worldwide. At the time of initial authorization, data beyond 2 months after vaccination were unavailable. METHODS In an ongoing, placebo-controlled, observer-blinded, multinational, pivotal efficacy trial, we randomly assigned 44,165 participants 16 years of age or older and 2264 participants 12 to 15 years of age to receive two 30-μg doses, at 21 days apart, of BNT162b2 or placebo. The trial end points were vaccine efficacy against laboratory-confirmed Covid-19 and safety, which were both evaluated through 6 months after vaccination. RESULTS BNT162b2 continued to be safe and have an acceptable adverse-event profile. Few participants had adverse events leading to withdrawal from the trial. Vaccine efficacy against Covid-19 was 91.3% (95% confidence interval [CI], 89.0 to 93.2) through 6 months of follow-up among the participants without evidence of previous SARS-CoV-2 infection who could be evaluated. There was a gradual decline in vaccine efficacy. Vaccine efficacy of 86 to 100% was seen across countries and in populations with diverse ages, sexes, race or ethnic groups, and risk factors for Covid-19 among participants without evidence of previous infection with SARS-CoV-2. Vaccine efficacy against severe disease was 96.7% (95% CI, 80.3 to 99.9). In South Africa, where the SARS-CoV-2 variant of concern B.1.351 (or beta) was predominant, a vaccine efficacy of 100% (95% CI, 53.5 to 100) was observed. CONCLUSIONS Through 6 months of follow-up and despite a gradual decline in vaccine efficacy, BNT162b2 had a favorable safety profile and was highly efficacious in preventing Covid-19. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728. opens in new tab.)
Authors Juliet M. Bartleson, Dina Radenkovic, Anthony J. Covarrubias, David Furman, Daniel A. Winer, Eric Verdin
Abstract The coronavirus disease 2019 (COVID-19) pandemic is a global health threat with particular risk for severe disease and death in older adults and in adults with age-related metabolic and cardiovascular disease. Recent advances in the science of aging have highlighted how aging pathways control not only lifespan but also healthspan - the healthy years of life. Here, we discuss the aging immune system and its ability to respond to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We specifically focus on the intersect of severe COVID-19 and immunosenescence to highlight pathways that may be determinant for the risk of complications and death following infection with SARS-CoV-2. New or adapted therapeutics that target aging-associated pathways may be important tools to reduce the burden of death and long-term disability caused by this pandemic. Proposed interventions aimed at immunosenescence could enhance immune function not only in older adults but in susceptible younger individuals as well, ultimately improving complications of severe COVID-19 for all ages.
Authors Ilaria Dorigatti, Enrico Lavezzo, Laura Manuto, Constanze Ciavarella, Monia Pacenti, Caterina Boldrin, Margherita Cattai, Francesca Saluzzo, Elisa Franchin, Claudia Del Vecchio, Federico Caldart, Gioele Castelli, Michele Nicoletti, Eleonora Nieddu, Elisa Salvadoretti, Beatrice Labella, Ludovico Fava, Simone Guglielmo, Mariateresa Fascina, Marco Grazioli, Gualtiero Alvisi, Maria Cristina Vanuzzo, Tiziano Zupo, Reginetta Calandrin, Vittoria Lisi, Lucia Rossi, Ignazio Castagliuolo, Stefano Merigliano, H. Juliette T. Unwin, Mario Plebani, Andrea Padoan, Alessandra R. Brazzale, Stefano Toppo, Neil M. Ferguson, Christl A. Donnelly & Andrea Crisanti
Abstract In February and March 2020, two mass swab testing campaigns were conducted in Vo’, Italy. In May 2020, we tested 86% of the Vo’ population with three immuno-assays detecting antibodies against the spike and nucleocapsid antigens, a neutralisation assay and Polymerase Chain Reaction (PCR). Subjects testing positive to PCR in February/March or a serological assay in May were tested again in November. Here we report on the results of the analysis of the May and November surveys. We estimate a seroprevalence of 3.5% (95% Credible Interval (CrI): 2.8–4.3%) in May. In November, 98.8% (95% Confidence Interval (CI): 93.7–100.0%) of sera which tested positive in May still reacted against at least one antigen; 18.6% (95% CI: 11.0–28.5%) showed an increase of antibody or neutralisation reactivity from May. Analysis of the serostatus of the members of 1,118 households indicates a 26.0% (95% CrI: 17.2–36.9%) Susceptible-Infectious Transmission Probability. Contact tracing had limited impact on epidemic suppression.
Authors Delphine Planas, David Veyer, Artem Baidaliuk, Isabelle Staropoli, Florence Guivel-Benhassine, Maaran Michael Rajah, Cyril Planchais, Françoise Porrot, Nicolas Robillard, Julien Puech, Matthieu Prot, Floriane Gallais, Pierre Gantner, Aurélie Velay, Julien Le Guen, Najibi Kassis-Chikhani, Dhiaeddine Edriss, Laurent Belec, Aymeric Seve, Laura Courtellemont, Hélène Péré, Laurent Hocqueloux, Samira Fafi-Kremer, Thierry Prazuck, Hugo Mouquet, Timothée Bruel, Etienne Simon-Lorière, Felix A. Rey, Olivier Schwartz
Abstract The SARS-CoV-2 B.1.617 lineage was identified in October 2020 in India1–5. It has since then become dominant in some indian regions and UK and further spread to many countries6. The lineage includes three main subtypes (B1.617.1, B.1.617.2 and B.1.617.3), harbouring diverse Spike mutations in the N-terminal domain (NTD) and the receptor binding domain (RBD) which may increase their immune evasion potential. B.1.617.2, also termed variant Delta, is believed to spread faster than other variants. Here, we isolated an infectious Delta strain from a traveller returning from India. We examined its sensitivity to monoclonal antibodies (mAbs) and to antibodies present in sera from COVID-19 convalescent individuals or vaccine recipients, in comparison to other viral strains. Variant Delta was resistant to neutralization by some anti-NTD and anti-RBD mAbs including Bamlanivimab, which were impaired in binding to the Spike. Sera from convalescent patients collected up to 12 months post symptoms were 4 fold less potent against variant Delta, relative to variant Alpha (B.1.1.7). Sera from individuals having received one dose of Pfizer or AstraZeneca vaccines barely inhibited variant Delta. Administration of two doses generated a neutralizing response in 95% of individuals, with titers 3 to 5 fold lower against Delta than Alpha. Thus, variant Delta spread is associated with an escape to antibodies targeting non-RBD and RBD Spike epitopes.
Authors Andreas Radbruch, Hyun-Dong Chang
MEDRXIV
Authors Matteo Stravalaci, Isabel Pagani, Elvezia Maria Paraboschi, Mattia Pedotti, Andrea Doni, Francesco Scavello, Sarah N. Mapelli, Marina Sironi, Luca Varani, Milos Matkovic, Andrea Cavalli, Daniela Cesana, Pierangela Gallina, Nicoletta Pedemonte, Valeria Capurro, Nicola Clementi, Nicasio Mancini, Pietro Invernizzi, Rino Rappuoli, Stefano Duga, Barbara Bottazzi, Mariagrazia Uguccioni, Rosanna Asselta, Elisa Vicenzi, Alberto Mantovani, Cecilia Garlanda
BIORXIV
Authors Delphine Planas, David Veyer, Artem Baidaliuk, Isabelle Staropoli, Florence Guivel-Benhassine, Maaran Michael Rajah, Cyril Planchais, Françoise Porrot, Nicolas Robillard, Julien Puech, Matthieu Prot, Floriane Gallais, Pierre Gantner, Aurélie Velay, Julien Le Guen, Najibi Kassis-Chikhani, Dhiaeddine Edriss, Laurent Belec, Aymeric Seve, Hélène Péré, Laura Courtellemont, Laurent Hocqueloux, Samira Fafi-Kremer, Thierry Prazuck, Hugo Mouquet, Timothée Bruel, Etienne Simon-Lorière, Felix A. Rey, Olivier Schwartz
Abstract The SARS-CoV-2 B.1.617 lineage emerged in October 2020 in India1–6. It has since then become dominant in some indian regions and further spread to many countries. The lineage includes three main subtypes (B1.617.1, B.1617.2 and B.1.617.3), which harbour diverse Spike mutations in the N-terminal domain (NTD) and the receptor binding domain (RBD) which may increase their immune evasion potential. B.1.617.2 is believed to spread faster than the other versions. Here, we isolated infectious B.1.617.2 from a traveller returning from India. We examined its sensitivity to monoclonal antibodies (mAbs) and to antibodies present in sera from COVID-19 convalescent individuals or vaccine recipients, in comparison to other viral lineages. B.1.617.2 was resistant to neutralization by some anti-NTD and anti-RBD mAbs, including Bamlanivimab, which were impaired in binding to the B.1.617.2 Spike. Sera from convalescent patients collected up to 12 months post symptoms and from Pfizer Comirnaty vaccine recipients were 3 to 6 fold less potent against B.1.617.2, relative to B.1.1.7. Sera from individuals having received one dose of AstraZeneca Vaxzevria barely inhibited B.1.617.2. Thus, B.1.617.2 spread is associated with an escape to antibodies targeting non-RBD and RBD Spike epitopes.
Authors Hye Kyung Lee, Ludwig Knabl, Ludwig Knabl Sr, Manuel Wieser, Anna Mur, August Zabernigg, Jana Schumacher, Norbert Kaiser, Priscilla A. Furth, Lothar Hennighausen
Abstract Fast-spreading variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) energize the COVID-19 pandemic. B.1.1.7 (VOC-202012/01) has become the predominant variant in many countries and a new lineage (VOC-202102/02) harboring the E484K escape mutation in the B.1.1.7 background emerged in February 20211. This variant is of concern due to reduced neutralizing activity by vaccine-elicited antibodies2,3. However, it is not known whether this single amino acid change leads to an altered immune response. Here, we investigate differences in the immune transcriptome in hospitalized patients infected with either B.1.1.7 (n=28) or B.1.1.7+E484K (n=12). RNA-seq conducted on PBMCs isolated within five days after the onset of COVID symptoms demonstrated elevated activation of specific immune pathways, including JAK-STAT signaling, in B.1.1.7+E484K patients as compared to B.1.1.7. Longitudinal transcriptome studies demonstrated a delayed dampening of interferon-activated pathways in B.1.1.7+E484K patients. Prior vaccination with BNT162b vaccine (n=8 one dose; n=1 two doses) reduced the transcriptome inflammatory response to B.1.1.7+E484K infection relative to unvaccinated patients. Lastly, the immune transcriptome of patients infected with additional variants (B.1.258, B.1.1.163 and B.1.7.7) displayed a reduced activation compared to patients infected with B.1.1.7. Acquisition of the E484K substitution in the B.1.1.7 background elicits an altered immune response, which could impact disease progression.
Authors Jussipekka Salo, Milla Hägg, Mika Kortelainen, Tuija Leino, Tanja Saxell, Markku Siikanen, Lauri Sääksvuori
Abstract This paper studies the direct and indirect effectiveness of Covid-19 vaccines among vaccinated healthcare workers and their unvaccinated adult household members in a mass vaccine program in Finland. Methods We used national databases that record all polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infections and mRNA-based (BNT162b2 by Pfizer-BioNTech or mRNA-1273 by Moderna) vaccine doses administered in Finland since the beginning of the epidemic. These data were merged with administrative full population datasets that include information on each person’s occupation and unique identifiers for spouses living in the same household. To estimate the direct and indirect effectiveness of mRNA-based vaccines in a household setting, we compared the cumulative incidence of PCR-confirmed SARS-CoV-2 infections between vaccinated and unvaccinated healthcare workers as well as between their unvaccinated spouses. Findings Our estimates imply indirect effectiveness of 8.7% (95% CI: -28.9 to 35.4) two weeks and 42.9% (95% CI: 22.3 to 58.1) 10 weeks after the first dose. The effectiveness estimates for unvaccinated household members are substantial, but smaller than the direct effect and occur more gradually among unvaccinated household members than among vaccinated individuals. Interpretation Our results suggest that mRNA-based vaccines do not only prevent SARS-CoV-2 infections among vaccinated individuals but lead to a substantial reduction in infections among unvaccinated household members. The results are consistent with the notion that mRNA-based vaccines affect susceptibility in vaccinated individuals and prevent transmission from vaccinated to unvaccinated individuals.
ANNALS OF INTERNAL MEDICINE
Authors Caoilfhionn M. Connolly, Brian J. Boyarsky, Jake A. Ruddy, William A. Werbel, Lisa Christopher-Stine, Jacqueline M. Garonzik-Wang, Dorry L. Segev, Julie J. Paik
CDC (CENTER FOR DISEASE CONTROL AND PREVENTION)
Authors Mark B. SalzmanComments to Author , Cheng-Wei Huang, Christopher M. O’Brien, Rhina D. Castillo
Abstract We report 3 patients in California, USA, who experienced multisystem inflammatory syndrome (MIS) after immunization and severe acute respiratory syndrome coronavirus 2 infection. During the same period, 3 adults who were not vaccinated had MIS develop at a time when ≈7% of the adult patient population had received >1 vaccine.
Authors Maxwell I. Zimmerman, Justin R. Porter, Michael D. Ward, Sukrit Singh, Neha Vithani, Artur Meller, Upasana L. Mallimadugula, Catherine E. Kuhn, Jonathan H. Borowsky, Rafal P. Wiewiora, Matthew F. D. Hurley, Aoife M. Harbison, Carl A. Fogarty, Joseph E. Coffland, Elisa Fadda, Vincent A. Voelz, John D. Chodera, Gregory R. Bowman
Abstract SARS-CoV-2 has intricate mechanisms for initiating infection, immune evasion/suppression and replication that depend on the structure and dynamics of its constituent proteins. Many protein structures have been solved, but far less is known about their relevant conformational changes. To address this challenge, over a million citizen scientists banded together through the Folding@home distributed computing project to create the first exascale computer and simulate 0.1 seconds of the viral proteome. Our adaptive sampling simulations predict dramatic opening of the apo spike complex, far beyond that seen experimentally, explaining and predicting the existence of ‘cryptic’ epitopes. Different spike variants modulate the probabilities of open versus closed structures, balancing receptor binding and immune evasion. We also discover dramatic conformational changes across the proteome, which reveal over 50 ‘cryptic’ pockets that expand targeting options for the design of antivirals. All data and models are freely available online, providing a quantitative structural atlas.
Authors Keying Guo, Shofarul Wustoni, Anil Koklu, Escarlet Díaz-Galicia, Maximilian Moser, Adel Hama, Ahmed A. Alqahtani, Adeel Nazir Ahmad, Fatimah Saeed Alhamlan, Muhammad Shuaib, Arnab Pain, Iain McCulloch, Stefan T. Arold, Raik Grünberg, Sahika Inal
Abstract The coronavirus disease 2019 (COVID-19) pandemic has highlighted the need for rapid and sensitive protein detection and quantification in simple and robust formats for widespread point-of-care applications. Here, we report on nanobody-functionalized organic electrochemical transistors with a modular architecture for the rapid quantification of single-molecule-to-nanomolar levels of specific antigens in complex bodily fluids. The sensors combine a solution-processable conjugated polymer in the transistor channel and high-density and orientation-controlled bioconjugation of nanobody–SpyCatcher fusion proteins on disposable gate electrodes. The devices provide results after 10 min of exposure to 5 μl of unprocessed samples, maintain high specificity and single-molecule sensitivity in human saliva and serum, and can be reprogrammed to detect any protein antigen if a corresponding specific nanobody is available. We used the sensors to detect green fluorescent protein, and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV) spike proteins, and for the COVID-19 screening of unprocessed clinical nasopharyngeal swab and saliva samples with a wide range of viral loads.
CELL REPORTS MEDICINE
Authors Andrew Kam Ho Wong, Isaac Woodhouse, Frank Schneider, Deanna A. Kulpa, Guido Silvestri, Cheryl L. Maier
CELL
Authors Yafei Liu, Wai Tuck Soh, Jun-ichi Kishikawa, Mika Hirose, Emi E. Nakayama, Songling Li, Miwa Sasai, Tatsuya Suzuki, Asa Tada, Akemi Arakawa, Sumiko Matsuoka, Kanako Akamatsu, Makoto Matsuda, Chikako Ono, Shiho Torii, Kazuki Kishida, Hui Jin, Wataru Nakai, Noriko Arase, Atsushi Nakagawa, Maki Matsumoto, Yukoh Nakazaki, Yasuhiro Shindo, Masako Kohyama, Keisuke Tomii, Koichiro Ohmura, Shiro Ohshima, Toru Okamoto, Masahiro Yamamoto, Hironori Nakagami, Yoshiharu Matsuura, Atsushi Nakagawa, Takayuki Kato, Masato Okada, Daron M. Standley, Tatsuo Shioda, Hisashi Arase
SPRINGER LINK
Authors Sara E. Vazquez, Paul Bastard, Kathleen Kelly, Adrian Gervais, Philip J. Norris, Larry J. Dumont, Jean-Laurent Casanova, Mark S. Anderson, Joseph L. DeRisi
Authors Daniel M.Altmann, Catherine J.Reynolds, Rosemary J.Boyton
Authors Gareth Iacobucci
Authors Shea A. Lowery, Alan Sariol, Stanley Perlman
Abstract COVID-19 can result in severe disease characterized by significant immunopathology that is spurred by an exuberant, yet dysregulated, innate immune response with a poor adaptive response. A limited and delayed interferon I (IFN-I) and IFN-III response results in exacerbated proinflammatory cytokine production and in extensive cellular infiltrates in the respiratory tract, resulting in lung pathology. The development of effective therapeutics for patients with severe COVID-19 depends on our understanding the pathological elements of this unbalanced innate immune response. Here, we review the mechanisms by which SARS-CoV-2 both activates and antagonizes the IFN and inflammatory response following infection, how a dysregulated cytokine and cellular response contributes to immune-mediated pathology in COVID-19, and therapeutic strategies that target elements of the innate response.
Authors David S. Khoury, Deborah Cromer, Arnold Reynaldi, Timothy E. Schlub, Adam K. Wheatley, Jennifer A. Juno, Kanta Subbarao, Stephen J. Kent, James A. Triccas, Miles P. Davenport
Abstract Predictive models of immune protection from COVID-19 are urgently needed to identify correlates of protection to assist in the future deployment of vaccines. To address this, we analyzed the relationship between in vitro neutralization levels and the observed protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using data from seven current vaccines and from convalescent cohorts. We estimated the neutralization level for 50% protection against detectable SARS-CoV-2 infection to be 20.2% of the mean convalescent level (95% confidence interval (CI) = 14.4–28.4%). The estimated neutralization level required for 50% protection from severe infection was significantly lower (3% of the mean convalescent level; 95% CI = 0.7–13%, P = 0.0004). Modeling of the decay of the neutralization titer over the first 250 d after immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained. Neutralization titers against some SARS-CoV-2 variants of concern are reduced compared with the vaccine strain, and our model predicts the relationship between neutralization and efficacy against viral variants. Here, we show that neutralization level is highly predictive of immune protection, and provide an evidence-based model of SARS-CoV-2 immune protection that will assist in developing vaccine strategies to control the future trajectory of the pandemic.
Authors Eva Krause, Andreas Puyskens, Daniel Bourquain , Annika Brinkman, Barbara Biere, Lars Schaade, Janine Michel, Andreas Nitsche
Abstract Point of care detection of SARS-CoV-2 is one pillar in a containment strategy and important to break infection chains. Here we report the sensitive, specific and robust detection of SARS-CoV-2 and respective variants of concern by the ID NOW COVID-19 device.
Authors ELISABETH MAHASE
EMA
Authors EMA PRESS OFFICE
Authors Johannes F. Scheid, Christopher O. Barnes, Basak Eraslan, Andrew Hudak, Jennifer R. Keeffe, Lisa A. Cosimi, Eric M. Brown, Frauke Muecksch, Yiska Weisblum, Shuting Zhang, Toni Delorey, Ann E. Woolley, Fadi Ghantous, Sung-Moo Park, Devan Phillips, Betsabeh Tusi, Kathryn E. Huey-Tubman, Alexander A. Cohen, Priyanthi N.P. Gnanapragasam, Kara Rzasa, Theodora Hatziioanno, Michael A. Durney, Xiebin Gu, Takuya Tada, Nathaniel R. Landau, Anthony P. West, Jr., Orit Rozenblatt-Rosen, Michael S. Seaman, Lindsey R. Baden, Daniel B. Graham, Jacques Deguine, Paul D. Bieniasz, Aviv Regev, Deborah Hung, Pamela J. Bjorkman, Ramnik J. Xavier
Authors Annachiara Rosa , Valerie E. Pye, Carl Graham, Luke Muir, Jeffrey Seow, Kevin W. Ng, Nicola J. Cook, Chloe Rees-Spear, Eleanor Parker, Mariana Silva dos Santos, Carolina Rosadas, Alberto Susana, Hefin Rhys, Andrea Nans, Laura Masino, Chloe Roustan, Evangelos Christodoulou, Rachel Ulferts, Antoni G. Wrobel, Charlotte-Eve Short, Michael Fertleman, Rogier W. Sanders, Judith Heaney, Moira Spyer, Svend Kjær, Andy Riddell, Michael H. Malim, Rupert Beale, James I. MacRae, Graham P. Taylor, Eleni Nastouli, Marit J. van Gils, Peter B. Rosenthal, Massimo Pizzato, Myra O. McClure, Richard S. Tedder, George Kassiotis, Laura E. McCoy, Katie J. Doores, Peter Cherepanov
Abstract The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of haem metabolism, with nanomolar affinity. Using cryo-electron microscopy and X-ray crystallography, we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Our results indicate that SARS-CoV-2 spike NTD harbors a dominant epitope, access to which can be controlled by an allosteric mechanism that is regulated through the recruitment of a metabolite.
Authors Mark M. Painter, Divij Mathew, Rishi R. Goel, Sokratis A. Apostolidis, Ajinkya Pattekar, Oliva Kuthuru, Amy E. Baxter, Ramin S. Herati, Derek A. Oldridge, Sigrid Gouma, Philip Hicks, Sarah Dysinger, Kendall A. Lundgreen, Leticia Kuri-Cervantes, Sharon Adamski, Amanda Hicks, Scott Korte, Josephine R. Giles, Madison E. Weirick, Christopher M. McAllister, Jeanette Dougherty, Sherea Long, Kurt D’Andrea, Jacob T. Hamilton, Michael R. Betts, Paul Bates, Scott E. Hensley, Alba Grifoni, Daniela Weiskopf, Alessandro Sette, Allison R. Greenplate, E. John Wherry
ABSTRACT The SARS-CoV-2 mRNA vaccines have shown remarkable clinical efficacy, but questions remain about the nature and kinetics of T cell priming. We performed longitudinal antigen-specific T cell analyses in healthy individuals following mRNA vaccination. Vaccination induced rapid near-maximal antigen-specific CD4+ T cell responses in all subjects after the first vaccine dose. CD8+ T cell responses developed gradually after the first and second dose and were variable. Vaccine-induced T cells had central memory characteristics and included both Tfh and Th1 subsets, similar to natural infection. Th1 and Tfh responses following the first dose predicted post-boost CD8+ T cell and neutralizing antibody levels, respectively. Integrated analysis of 26 antigen-specific T cell and humoral responses revealed coordinated features of the immune response to vaccination. Lastly, whereas booster vaccination improved CD4+ and CD8+ T cell responses in SARS-CoV-2 naïve subjects, the second vaccine dose had little effect on T cell responses in SARS-CoV-2 recovered individuals. Thus, longitudinal analysis revealed robust T cell responses to mRNA vaccination and highlighted early induction of antigen-specific CD4+ T cells.
UNIVERSITY OF OXFORD
Authors UNIVERSITY OF OXFORD
Authors Victoria Jane Hall, Sarah Foulkes, Andre Charlett, Ana Atti, Edward J Monk, Ruth Simmons , Edgar Wellington, Michelle J Cole, Ayoub Saei, Blanche Oguti, Katie Munro, Sarah Wallace, Peter D Kirwan, Madhumita Shrotri, Amoolya Vusirikala, Sakib Rokadiya, Meaghan Kall, Maria Zambon, Mary Ramsay, Tim Brooks, Colin S Brown, Meera A Chand, Susan Hopkins
Authors Rutger Koning, Paul Bastard, Jean‐Laurent Casanova, Matthijs C. Brouwer, Diederik van de Beek
Authors Matthew K. Siggins, Ryan S. Thwaites, Peter J.M. Openshaw
Authors Christine M. Wardell, Megan K. Levings
Authors Changfu Yao, Stephanie A. Bora, Tanyalak Parimon, Tanzira Zaman, Oren A. Friedman, Joseph A. Palatinus, Nirmala S. Surapaneni, Yuri P. Matusov, Giuliana Cerro Chiang, Alexander G. Kassar, Nayan Patel, Chelsi E.R. Green, Adam W. Aziz, Harshpreet Suri, Jo Suda, Andres A. Lopez, Gislaine A. Martins, Barry R. Stripp, Sina A. Gharib, Helen S. Goodridge, Peter Chen
Authors Sandile Cele, Inbal Gazy, Laurelle Jackson, Shi-Hsia Hwa, Houriiyah Tegally, Gila Lustig, Jennifer Giandhari, Sureshnee Pillay, Eduan Wilkinson, Yeshnee Naidoo, Farina Karim, Yashica Ganga, Khadija Khan, Mallory Bernstein, Alejandro B. Balazs, Bernadett I. Gosnell, Willem Hanekom, Mahomed-Yunus S. Moosa, , Richard J. Lessells, Tulio de Oliveira, Alex Sigal
Abstract SARS-CoV-2 variants of concern (VOC) have arisen independently at multiple locations [1, 2] and may reduce the efficacy of current vaccines targeting the spike glycoprotein [3]. Here, using a live virus neutralization assay (LVNA), we compared neutralization of a non-VOC variant versus the 501Y.V2 variant using plasma collected from adults hospitalized with COVID-19 from two South African infection waves, with the second wave dominated by 501Y.V2 infections. Sequencing demonstrated that infections in first wave plasma donors were with viruses harbouring none of the 501Y.V2-defining mutations, except for one with the E484K mutation in the receptor binding domain. 501Y.V2 virus was effectively neutralized by plasma from second wave infections and first wave virus was effectively neutralized by first wave plasma. In cross-neutralization, 501Y.V2 virus was poorly neutralized by first wave plasma, with a 15.1-fold drop relative to 501Y.V2 neutralization by second wave plasma across participants. In contrast, second wave plasma cross-neutralization of first wave virus was more effective, showing only a 2.3-fold decline relative to first wave plasma neutralization of first wave virus. While we only tested one plasma elicited by E484K alone, this potently neutralized both variants. The observed effective neutralization of first wave virus by 501Y.V2 infection elicited plasma provides preliminary evidence that vaccines based on VOC sequences could retain activity against other circulating SARS-CoV-2 lineages.
Authors Jun Wu, Boyun Liang, Cunrong Chen, Hua Wang, Yaohui Fang, Shu Shen, Xiaoli Yang, Baoju Wang, Liangkai Chen, Qi Chen, Yang Wu, Jia Liu, Xuecheng Yang, Wei Li, Bin Zhu, Wenqing Zhou, Huan Wang, Sumeng Li, Sihong Lu, Di Liu, Huadong Li, Adalbert Krawczyk, Mengji Lu, Dongliang Yang, Fei Deng, Ulf Dittmer, Mirko Trilling, Xin Zheng
Abstract Long-term antibody responses and neutralizing activities in response to SARS-CoV-2 infection are not yet clear. Here we quantify immunoglobulin M (IgM) and G (IgG) antibodies recognizing the SARS-CoV-2 receptor-binding domain (RBD) of the spike (S) or the nucleocapsid (N) protein, and neutralizing antibodies during a period of 6 months from COVID-19 disease onset in 349 symptomatic COVID-19 patients who were among the first be infected world-wide. The positivity rate and magnitude of IgM-S and IgG-N responses increase rapidly. High levels of IgM-S/N and IgG-S/N at 2-3 weeks after disease onset are associated with virus control and IgG-S titers correlate closely with the capacity to neutralize SARS-CoV-2. Although specific IgM-S/N become undetectable 12 weeks after disease onset in most patients, IgG-S/N titers have an intermediate contraction phase, but stabilize at relatively high levels over the 6 month observation period. At late time points, the positivity rates for binding and neutralizing SARS-CoV-2-specific antibodies are still >70%. These data indicate sustained humoral immunity in recovered patients who had symptomatic COVID-19, suggesting prolonged immunity.
Authors He S. Yang, Victoria Costa, Sabrina E. Racine-Brzostek, Karen P. Acker, Jim Yee, Zhengming Chen, Mohsen Karbaschi, Robert Zuk, Sophie Rand, Ashley Sukhu, P. J. Klasse, Melissa M. Cushing, Amy Chadburn, Zhen Zhao
Abstract Importance Accumulating evidence suggests that children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are more likely to manifest mild symptoms and are at a lower risk of developing severe respiratory disease compared with adults. It remains unknown how the immune response in children differs from that of adolescents and adults. Objective To investigate the association of age with the quantity and quality of SARS-CoV-2 antibody responses. Design, Setting, and Participants This cross-sectional study used 31 426 SARS-CoV-2 antibody test results from pediatric and adult patients. Data were collected from a New York City hospital from April 9 to August 31, 2020. The semiquantitative immunoglobin (Ig) G levels were compared between 85 pediatric and 3648 adult patients. Further analysis of SARS-CoV-2 antibody profiles was performed on sera from 126 patients aged 1 to 24 years. Main Outcomes and Measures SARS-CoV-2 antibody positivity rates and IgG levels were evaluated in patients from a wide range of age groups (1-102 years). SARS-CoV-2 IgG level, total antibody (TAb) level, surrogate neutralizing antibody (SNAb) activity, and antibody binding avidity were compared between children (aged 1-10 years), adolescents (aged 11-18 years), and young adults (aged 19-24 years). Results Among 31 426 antibody test results (19 797 [63.0%] female patients), with 1194 pediatric patients (mean [SD] age, 11.0 [5.3] years) and 30 232 adult patients (mean [SD] age, 49.2 [17.1] years), the seroprevalence in the pediatric (197 [16.5%; 95% CI, 14.4%-18.7%]) and adult (5630 [18.6%; 95% CI, 18.2%-19.1%]) patient populations was similar. The SARS-CoV-2 IgG level showed a negative correlation with age in the pediatric population (r = −0.45, P < .001) and a moderate but positive correlation with age in adults (r = 0.24, P < .001). Patients aged 19 to 30 years exhibited the lowest IgG levels (eg, aged 25-30 years vs 1-10 years: 99 [44-180] relative fluorescence units [RFU] vs 443 [188-851] RFU). In the subset cohort aged 1 to 24 years, IgG, TAb, SNAb and avidity were negatively correlated with age (eg, IgG: r = −0.51; P < .001). Children exhibited higher median (IQR) IgG levels, TAb levels, and SNAb activity compared with adolescents (eg, IgG levels: 473 [233-656] RFU vs 191 [82-349] RFU; P < .001) and young adults (eg, IgG levels: 473 [233-656] RFU vs 85 [38-150] RFU; P < .001). Adolescents also exhibited higher median (IQR) TAb levels, IgG levels, and SNAb activity than young adults (eg, TAb levels: 961 [290-2074] RFU vs 370 [125-697]; P = .006). In addition, children had higher antibody binding avidity compared with young adults, but the difference was not significant. Conclusions and Relevance The results of this study suggest that SARS-CoV-2 viral specific antibody response profiles are distinct in different age groups. Age-targeted strategies for disease screening and management as well as vaccine development may be warranted.
Authors Christian Dameff, Edward M. Castillo, Alexandrea O. Cronin, Christopher J. Coyne
Authors Zhenyu He, Lili Ren, Juntao Yang, Li Guo, Luzhao Feng, Chao Ma, Xia Wang, Zhiwei Leng, Xunliang Tong, Wang Zhou, Geng Wang, Ting Zhang, Yan Guo, Chao Wu, Qing Wang, Manqing Liu, Conghui Wang, Mengmeng Jia, Xuejiao Hu, Ying Wang, Xingxing Zhang, Rong Hu, Jingchuan Zhong, Jin Yang, Juan Dai, Lan Chen, Xiaoqi Zhou, Jianwei Wang, Weizhong Yang, Chen Wang
Authors ANDREW FOX-LEWIS, SHIVANI FOX-LEWIS, JENNA BEAUMONT, DRAGANA DRINKOVIC, JAY HARROWER, KEVIN HOWE, CATHERINE JACKSON, FAHIMEH RAHNAMA, BLAIR SHILTON, HELEN QIAO, KEVIN K. SMITH, SUSAN C. MORPETH, SUSAN TAYLOR, MATTHEW BLAKISTON, SALLY ROBERTS, GARY MCAULIFFE
Authors Venkata Viswanadh Edara, William H. Hudson, Xuping Xie, Rafi Ahmed, Mehul S. Suthar
MED
Authors Halima A. Shuwa, Tovah N. Shaw, Sean B. Knight, Kelly Wemyss, Flora A. McClure, Laurence Pearmain, Ian Prise, Christopher Jagger, David.J. Morgan, Saba Khan, Oliver Brand, Elizabeth R. Mann, Andrew Ustianowski, Nawar Diar Bakerly, Paul Dark, Christopher E. Brightling, Seema Brij, CIRCO, Timothy Felton, Angela Simpson, John R. Grainger, Tracy Hussell, Joanne E. Konkel, Madhvi Menon
Authors Christie Aschwanden
Authors M.J. Joyner, R.E. Carter, J.W. Senefeld, S.A. Klassen, J.R. Mills, P.W. Johnson, E.S. Theel, C.C. Wiggins, K.A. Bruno, A.M. Klompas, E.R. Lesser, K.L. Kunze, M.A. Sexton, J.C. Diaz Soto, S.E. Baker, J.R.A. Shepherd, N. van Helmond, N.C. Verdun, P. Marks, C.M. van Buskirk, J.L. Winters, J.R. Stubbs, R.F. Rea, D.O. Hodge, V. Herasevich, E.R. Whelan, A.J. Clayburn, K.F. Larson, J.G. Ripoll, K.J. Andersen, M.R. Buras, M.N.P. Vogt, J.J. Dennis, R.J. Regimbal, P.R. Bauer, J.E. Blair, N.S. Paneth, D.L. Fairweather, R.S. Wright, A. Casadevall
Abstract BACKGROUND Convalescent plasma has been widely used to treat coronavirus disease 2019 (Covid-19) under the presumption that such plasma contains potentially therapeutic antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that can be passively transferred to the plasma recipient. Whether convalescent plasma with high antibody levels rather than low antibody levels is associated with a lower risk of death is unknown. METHODS In a retrospective study based on a U.S. national registry, we determined the anti–SARS-CoV-2 IgG antibody levels in convalescent plasma used to treat hospitalized adults with Covid-19. The primary outcome was death within 30 days after plasma transfusion. Patients who were enrolled through July 4, 2020, and for whom data on anti–SARS-CoV-2 antibody levels in plasma transfusions and on 30-day mortality were available were included in the analysis. RESULTS Of the 3082 patients included in this analysis, death within 30 days after plasma transfusion occurred in 115 of 515 patients (22.3%) in the high-titer group, 549 of 2006 patients (27.4%) in the medium-titer group, and 166 of 561 patients (29.6%) in the low-titer group. The association of anti–SARS-CoV-2 antibody levels with the risk of death from Covid-19 was moderated by mechanical ventilation status. A lower risk of death within 30 days in the high-titer group than in the low-titer group was observed among patients who had not received mechanical ventilation before transfusion (relative risk, 0.66; 95% confidence interval [CI], 0.48 to 0.91), and no effect on the risk of death was observed among patients who had received mechanical ventilation (relative risk, 1.02; 95% CI, 0.78 to 1.32). CONCLUSIONS Among patients hospitalized with Covid-19 who were not receiving mechanical ventilation, transfusion of plasma with higher anti–SARS-CoV-2 IgG antibody levels was associated with a lower risk of death than transfusion of plasma with lower antibody levels. (Funded by the Department of Health and Human Services and others; ClinicalTrials.gov number, NCT04338360. opens in new tab.)
GOV.UK
Authors Public Health England
Authors Thiago Carvalho, Florian Krammer, Akiko Iwasaki
Abstract Since the initial reports of a cluster of pneumonia cases of unidentified origin in Wuhan, China, in December 2019, the novel coronavirus that causes this disease — severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) — has spread throughout the world, igniting the twenty-first century’s deadliest pandemic. Over the past 12 months, a dizzying array of information has emerged from numerous laboratories, covering everything from the putative origin of SARS-CoV-2 to the development of numerous candidate vaccines. Many immunologists quickly pivoted from their existing research to focus on coronavirus disease 2019 (COVID-19) and, owing to this unprecedented convergence of efforts on one viral infection, a remarkable body of work has been produced and disseminated, through both preprint servers and peer-reviewed journals. Here, we take readers through the timeline of key discoveries during the first year of the pandemic, which showcases the extraordinary leaps in our understanding of the immune response to SARS-CoV-2 and highlights gaps in our knowledge as well as areas for future investigations.
Authors Tatjana Bilich, Annika Nelde, Jonas S. Heitmann, Yacine Maringer, Malte Roerden, Jens Bauer, Jonas Rieth, Marcel Wacker, Andreas Peter, Sebastian Hörber, David Rachfalski, Melanie Märklin, Stefan Stevanović, Hans-Georg Rammensee, Helmut R. Salih, Juliane S. Walz
Abstract Long-term immunological memory to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for the development of population-level immunity, which is the aim of vaccination approaches. Reports on rapidly decreasing antibody titers have led to questions regarding the efficacy of humoral immunity alone. The relevance of T cell memory after coronavirus disease 2019 (COVID-19) remains unclear. Here, we investigated SARS-CoV-2 antibody and T cell responses in matched samples of COVID-19 convalescent individuals up to six months post-infection. Longitudinal analysis revealed decreasing and stable spike- and nucleocapsid-specific antibody responses, respectively. In contrast, functional T cell responses remained robust, and even increased, in both frequency and intensity. Single peptide mapping of T cell diversity over time identified open reading frame-independent, dominant T cell epitopes mediating long-term SARS-CoV-2 T cell responses. Identification of these epitopes may be fundamental for COVID-19 vaccine design.
Authors Gabriele Cerutti, icheng Guo, Tong qing Zhou, Jason Gorman, Myungjin Lee, Micah Rapp, Eswar R.Reddem, Jian Yu, Fabiana Bahna, Jude Bimela, Yaoxing Huang, Phinikoula S.Katsamba, Lihong Liu, Manoj S.Nair, Reda Rawi, Adam S.Olia, Peng fei Wang, Baoshan Zhang, Lawrence Shapiro
Authors Daniel M. Altmann, Rosemary J. Boyton, Rupert Beale
Authors Lubbertus C.F. Mulder, Ariel J. Raskin, Kayla T. Russo, Ashley-Beathrese T. Salimbangon, Miti Saksena, Amber S. Shin, Gagandeep Singh, Levy A. Sominsky, Daniel Stadlbauer, Ania Wajnberg, Viviana Simon, Florian Krammer, Komal Srivastava, Hala Alshammary, Angela A. Amoako, Mahmoud H. Awawda, Katherine F. Beach, Maria C. Bermúdez-González, Dominika A. Bielak, Juan M. Carreño, Rachel L. Chernet, Lily Q. Eaker, Emily D. Ferreri, Daniel L. Floda, Charles R. Gleason, Joshua Z. Hamburger, Kaijun Jiang, Giulio Kleiner, Denise Jurczyszak, Julia C. Matthews, Wanni A. Mendez, Ismail Nabeel,
Authors Yang Liu, Jianying Liu, Hongjie Xia, Xianwen Zhang, Camila R. Fontes‐Garfias, Kena A. Swanson, Hui Cai, Ritu Sarkar, Wei Chen, Mark Cutler, David Cooper, Alexander Muik, Ph.D. Ugur Sahin, Kathrin U. Jansen, Xuping Xie, Philip R. Dormitzer, Pei‐Yong Shi
Authors Jianmin Zuo, Alexander C. Dowell, Hayden Pearce, Kriti Verma, Heather M. Long, Jusnara Begum, Felicity Aiano, Zahin Amin-Chowdhury, Bassam Hallis, Lorrain Stapley, Ray Borrow, Ezra Linley, Shazaad Ahmad, Ben Parker, Alex Horsley, Gayatri Amirthalingam, Kevin Brown, Mary E. Ramsay, Shamez Ladhani, Paul Moss
Abstract The immune response to SARS-CoV-2 is critical in controlling disease, but there is concern that waning immunity may predispose to reinfection. We analyzed the magnitude and phenotype of the SARS-CoV-2-specific T cell response in 100 donors at 6 months following infection. T cell responses were present by ELISPOT and/or intracellular cytokine staining analysis in all donors and characterized by predominant CD4+ T cell responses with strong interleukin (IL)-2 cytokine expression. Median T cell responses were 50% higher in donors who had experienced a symptomatic infection, indicating that the severity of primary infection establishes a ‘set point’ for cellular immunity. T cell responses to spike and nucleoprotein/membrane proteins were correlated with peak antibody levels. Furthermore, higher levels of nucleoprotein-specific T cells were associated with preservation of nucleoprotein-specific antibody level although no such correlation was observed in relation to spike-specific responses. In conclusion, our data are reassuring that functional SARS-CoV-2-specific T cell responses are retained at 6 months following infection.
Authors Xiaoying Shen, Haili Tang, Charlene McDanal, Kshitij Wagh, William Fischer, James Theiler, Hyejin Yoon, Dapeng Li, Barton F. Haynes, Kevin O. Sanders, Sandrasegaram Gnanakaran, Nick Hengartner, Rolando Pajon, Gale Smith, Gregory M. Glenn, Bette Korber, David C. Montefiori
Authors Chloe Rees-Spear, Luke Muir, Sarah A. Griffith, Judith Heaney, Yoann Aldon, Jonne L. Snitselaar, Peter Thomas, Carl Graham, Jeffrey Seow, Nayung Lee, Annachiara Rosa, Chloe Roustan, Catherine F. Houlihan, Rogier W. Sanders, Ravindra K. Gupta, Peter Cherepanov, Hans J. Stauss, Eleni Nastouli, on behalf of the SAFER Investigators, Katie J. Doores, Marit J. van Gils, Laura E. McCoy
Authors Lina Ma, Sanjaya K. Sahu, Marlene Cano, Vasanthan Kuppuswamy, Jamal Bajwa, Ja’Nia McPhatter, Alexander Pine, Matthew Meizlish, George Goshua, C-Hong Chang, Hanming Zhang, Christina Price, Parveen Bahel, Henry Rinder, Tingting Lei, Aaron Day, Daniel Reynolds, Xiaobo Wu, Rebecca Schriefer, Adriana M. Rauseo, Charles W. Goss, Jane A. O’Halloran, Rachel M. Presti, Alfred H. Kim, Andrew E. Gelman, Charles Dela Cruz, Alfred I. Lee, Phillip Mudd, Hyung J. Chun, John P. Atkinson, Hrishikesh S. Kulkarni
ABSTRACT Complement activation has been implicated in the pathogenesis of severe SARS-CoV-2 infection. However, it remains to be determined whether increased complement activation is a broad indicator of critical illness (and thus, no different in COVID-19). It is also unclear which pathways are contributing to complement activation in COVID-19, and, if complement activation is associated with certain features of severe SARS-CoV-2 infection, such as endothelial injury and hypercoagulability. To address these questions, we investigated complement activation in the plasma from patients with COVID-19 prospectively enrolled at two tertiary care centers. We compared our patients to two non-COVID cohorts: (a) patients hospitalized with influenza, and (b) patients admitted to the intensive care unit (ICU) with acute respiratory failure requiring invasive mechanical ventilation (IMV). We demonstrate that circulating markers of complement activation (i.e., sC5b-9) are elevated in patients with COVID-19 compared to those with influenza and to patients with non-COVID-19 respiratory failure. Further, the results facilitate distinguishing those who are at higher risk of worse outcomes such as requiring ICU admission, or IMV. Moreover, the results indicate enhanced activation of the alternative complement pathway is most prevalent in patients with severe COVID-19 and is associated with markers of endothelial injury (i.e., Ang2) as well as hypercoagulability (i.e., thrombomodulin and von Willebrand factor). Our findings identify complement activation to be a distinctive feature of COVID-19, and provide specific targets that may be utilized for risk prognostication, drug discovery and personalized clinical trials. SUMMMARY Complement has been implicated in COVID-19. However, whether this is distinctive of COVID-19 remains unanswered. Ma et al report increased complement activation in COVID-19 compared to influenza and non-COVID respiratory failure, and demonstrate alternative pathway activation as a key marker of multiorgan failure and death.
Authors Joachim L. Schultze, Anna C. Aschenbrenner
Abstract The introduction of SARS-CoV-2 into the human population represents a tremendous medical and economical crisis. Innate immunity - as the first line of defense of our immune system - plays a central role in combating this novel virus. Here, we provide a conceptual framework for the interaction of the human innate immune system with SARS-CoV-2 to link the clinical observations with experimental findings that have been made during the first year of the pandemic. We review evidence that variability in innate immune system components among humans is a main contributor to the heterogeneous disease courses observed for COVID-19, the disease spectrum induced by SARS-CoV-2. A better understanding of the pathophysiological mechanisms observed for cells and soluble mediators involved in innate immunity is a prerequisite for the development of diagnostic markers and therapeutic strategies targeting COVID-19. However, this will also require additional studies addressing causality of events, which is so far lacking behind.
Authors Mrunal Sakharkar, C. Garrett Rappazzo, Wendy F. Wieland-Alter , Ching-Lin Hsieh, Daniel Wrapp, Emma S. Esterman, Chengzi I. Kaku, Anna Z. Wec, James C. Geoghegan, Jason S. McLellan, Ruth I. Connor, Peter F. Wright, Laura M. Walker
Abstract A comprehensive understanding of the kinetics and evolution of the human B cell response to SARS-CoV-2 infection will facilitate the development of next-generation vaccines and therapies. Here, we longitudinally profiled this response in mild and severe COVID-19 patients over a period of five months. Serum neutralizing antibody (nAb) responses waned rapidly but spike (S)-specific IgG+ memory B cells (MBCs) remained stable or increased over time. Analysis of 1,213 monoclonal antibodies (mAbs) isolated from S-specific MBCs revealed a primarily de novo response that displayed increased somatic hypermutation, binding affinity, and neutralization potency over time, providing evidence for prolonged antibody affinity maturation. B cell immunodominance hierarchies were similar across donor repertoires and remained relatively stable as the immune response progressed. Cross-reactive B cell populations, likely re-called from prior endemic beta-coronavirus exposures, comprised a small but stable fraction of the repertoires and did not contribute to the neutralizing response. The neutralizing antibody response was dominated by public clonotypes that displayed significantly reduced activity against SARS-CoV-2 variants emerging in Brazil and South Africa that harbor mutations at positions 501, 484 and 417 in the S protein. Overall, the results provide insight into the dynamics, durability, and functional properties of the human B cell response to SARS-CoV-2 infection and have implications for the design of immunogens that preferentially stimulate protective B cell responses.
Authors Robert Markewitz, Antje Torge, Klaus-Peter Wandinger, Daniela Pauli, Andre Franke, Luis Bujanda, José Maria Marimón, Jesus M. Banales, María A. Gutierrez-Stampa, Beatriz Nafría, Ralf Junker
Abstract Laboratory testing for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) consists of two pillars: the detection of viral RNA via rt-PCR as the diagnostic gold standard in acute cases, and the detection of antibodies against SARS-CoV-2. However, concerning the latter, questions remain about their diagnostic and prognostic value and it is not clear whether all patients develop detectable antibodies. We examined sera from 347 Spanish COVID-19 patients, collected during the peak of the epidemic outbreak in Spain, for the presence of IgA and IgG antibodies against SARS-CoV-2 and evaluated possible associations with age, sex and disease severity (as measured by duration of hospitalization, kind of respiratory support, treatment in ICU and death). The presence and to some degree the levels of anti-SARS-CoV-2 antibodies depended mainly on the amount of time between onset of symptoms and the collection of serum. A subgroup of patients did not develop antibodies at the time of sample collection. Compared to the patients that did, no differences were found. The presence and level of antibodies was not associated with age, sex, duration of hospitalization, treatment in the ICU or death. The case-fatality rate increased exponentially with older age. Neither the presence, nor the levels of anti-SARS-CoV-2 antibodies served as prognostic markers in our cohort. This is discussed as a possible consequence of the timing of the sample collection. Age is the most important risk factor for an adverse outcome in our cohort. Some patients appear not to develop antibodies within a reasonable time frame. It is unclear, however, why that is, as these patients differ in no respect examined by us from those who developed antibodies.
Authors Matteo Gentili, Nir Hacohen
Authors Heidi Ledford
Authors Alessandro Sette, Shane Crotty
Authors Xiao-Lin Jiang, Guo-Lin Wang, Xiang-Na Zhao, Fei-Hu Yan, Lin Yao, Zeng-Qiang Kou, Sheng-Xiang Ji, Xiao-Li Zhang, Cun-Bao Li, Li-Jun Duan, Yan Li, Yu-Wen Zhang, Qing Duan, Tie-Cheng Wang, En-Tao Li, Xiao Wei, Qing-Yang Wang, Xue-Feng Wang, Wei-Yang Sun, Yu-Wei Gao, Dian-Min Kang, Ji-Yan Zhang, Mai-Juan Ma
Abstract The dynamics, duration, and nature of immunity produced during SARS-CoV-2 infection are still unclear. Here, we longitudinally measured virus-neutralising antibody, specific antibodies against the spike (S) protein, receptor-binding domain (RBD), and the nucleoprotein (N) of SARS-CoV-2, as well as T cell responses, in 25 SARS-CoV-2-infected patients up to 121 days post-symptom onset (PSO). All patients seroconvert for IgG against N, S, or RBD, as well as IgM against RBD, and produce neutralising antibodies (NAb) by 14 days PSO, with the peak levels attained by 15–30 days PSO. Anti-SARS-CoV-2 IgG and NAb remain detectable and relatively stable 3–4 months PSO, whereas IgM antibody rapidly decay. Approximately 65% of patients have detectable SARS-CoV-2-specific CD4+ or CD8+ T cell responses 3–4 months PSO. Our results thus provide critical evidence that IgG, NAb, and T cell responses persist in the majority of patients for at least 3–4 months after infection.
Authors Elizabeth M. Anderson, Eileen C. Goodwin, Anurag Verma, Claudia P. Arevalo, Marcus J. Bolton, Madison E. Weirick, Sigrid Gouma, Christopher M. McAllister, Shannon R. Christensen, JoEllen Weaver, Philip Hicks, Tomaz B. Manzoni, Oluwatosin Oniyide, Holly Ramage, Divij Mathew, Amy E. Baxter, Derek A. Oldridge, Allison R. Greenplate, Jennifer E. Wu, Cécile Alanio, Kurt D’Andrea, Oliva Kuthuru, Jeanette Dougherty, Ajinkya Pattekar, Justin Kim, Nicholas Han, Sokratis A. Apostolidis, Alex C. Huang, Laura A. Vella, Leticia Kuri-Cervantes, M. Betina Pampena, The UPenn COVID Processing Unit, Michael R. Betts, E. John Wherry, Nuala J. Meyer, Sara Cherry, Paul Bates, Daniel J. Rader, Scott E. Hensley
Authors Stéphane Marot, Isabelle Malet, Valentin Leducq, Karen Zafilaza, Delphine Sterlin, Delphine Planas, Adélie Gothland, Aude Jary, Karim Dorgham, Timothée Bruel, the Sorbonne Université SARS-CoV-2 Neutralizing Antibodies Study Group, Sonia Burrel, David Boutolleau, Olivier Schwartz, Guy Gorochov, Vincent Calvez, Anne-Geneviève Marcelin
Abstract There are only few data concerning persistence of neutralizing antibodies (NAbs) among SARS-CoV-2-infected healthcare workers (HCW). These individuals are particularly exposed to SARS-CoV-2 infection and at potential risk of reinfection. We followed 26 HCW with mild COVID-19 three weeks (D21), two months (M2) and three months (M3) after the onset of symptoms. All the HCW had anti-receptor binding domain (RBD) IgA at D21, decreasing to 38.5% at M3 (p < 0.0001). Concomitantly a significant decrease in NAb titers was observed between D21 and M2 (p = 0.03) and between D21 and M3 (p < 0.0001). Here, we report that SARS-CoV-2 can elicit a NAb response correlated with anti-RBD antibody levels. However, this neutralizing activity declines, and may even be lost, in association with a decrease in systemic IgA antibody levels, from two months after disease onset. This short-lasting humoral protection supports strong recommendations to maintain infection prevention and control measures in HCW, and suggests that periodic boosts of SARS-CoV-2 vaccination may be required.
Authors Jennifer M. Dan, Jose Mateus, Yu Kato, Kathryn M. Hastie, Esther Dawen Yu, Caterina E. Faliti, Alba Grifoni, Sydney I. Ramirez, Sonya Haupt, April Frazier, Catherine Nakao, Vamseedhar Rayaprolu, Stephen A. Rawlings, Bjoern Peters, Florian Krammer, Viviana Simon, Erica Ollmann Saphire, Davey M. Smith, Daniela Weiskopf, Alessandro Sette, Shane Crotty
Abstract INTRODUCTION Immunological memory is the basis for durable protective immunity after infections or vaccinations. Duration of immunological memory after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 is unclear. Immunological memory can consist of memory B cells, antibodies, memory CD4+ T cells, and/or memory CD8+ T cells. Knowledge of the kinetics and interrelationships among those four types of memory in humans is limited. Understanding immune memory to SARS-CoV-2 has implications for understanding protective immunity against COVID-19 and assessing the likely future course of the COVID-19 pandemic. RATIONALE Assessing virus-specific immune memory over at least a 6-month period is likely necessary to ascertain the durability of immune memory to SARS-CoV-2. Given the evidence that antibodies, CD4+ T cells, and CD8+ T cells can all participate in protective immunity to SARS-CoV-2, we measured antigen-specific antibodies, memory B cells, CD4+ T cells, and CD8+ T cells in the blood from subjects who recovered from COVID-19, up to 8 months after infection. RESULTS The study involved 254 samples from 188 COVID-19 cases, including 43 samples at 6 to 8 months after infection. Fifty-one subjects in the study provided longitudinal blood samples, allowing for both cross-sectional and longitudinal analyses of SARS-CoV-2–specific immune memory. Antibodies against SARS-CoV-2 spike and receptor binding domain (RBD) declined moderately over 8 months, comparable to several other reports. Memory B cells against SARS-CoV-2 spike actually increased between 1 month and 8 months after infection. Memory CD8+ T cells and memory CD4+ T cells declined with an initial half-life of 3 to 5 months. This is the largest antigen-specific study to date of the four major types of immune memory for any viral infection. Among the antibody responses, spike immunoglobulin G (IgG), RBD IgG, and neutralizing antibody titers exhibited similar kinetics. Spike IgA was still present in the large majority of subjects at 6 to 8 months after infection. Among the memory B cell responses, IgG was the dominant isotype, with a minor population of IgA memory B cells. IgM memory B cells appeared to be short-lived. CD8+ T cell and CD4+ T cell memory was measured for all SARS-CoV-2 proteins. Although ~70% of individuals possessed detectable CD8+ T cell memory at 1 month after infection, that proportion declined to ~50% by 6 to 8 months after infection. For CD4+ T cell memory, 93% of subjects had detectable SARS-CoV-2 memory at 1 month after infection, and the proportion of subjects positive for CD4+ T cells (92%) remained high at 6 to 8 months after infection. SARS-CoV-2 spike-specific memory CD4+ T cells with the specialized capacity to help B cells [T follicular helper (TFH) cells] were also maintained. The different types of immune memory each had distinct kinetics, resulting in complex interrelationships between the abundance of T cell, B cell, and antibody immune memory over time. Additionally, substantially heterogeneity in memory to SARS-CoV-2 was observed. CONCLUSION Substantial immune memory is generated after COVID-19, involving all four major types of immune memory. About 95% of subjects retained immune memory at ~6 months after infection. Circulating antibody titers were not predictive of T cell memory. Thus, simple serological tests for SARS-CoV-2 antibodies do not reflect the richness and durability of immune memory to SARS-CoV-2. This work expands our understanding of immune memory in humans. These results have implications for protective immunity against SARS-CoV-2 and recurrent COVID-19.
Authors Emma S. Winkler, Pavlo Gilchuk, Jinsheng Yu, Adam L. Bailey, Rita E. Chen, Zhenlu Chong, Seth J. Zost, Hyesun Jang, Ying Huang, James D. Allen, James Brett Case, Rachel E. Sutton, Robert H. Carnahan, Tamarand L. Darling, Adrianus C.M. Boon, Matthias Mack, Richard D. Head, Ted M. Ross, James E. Crowe, Jr., Michael S. Diamond
CELL PRESS
Authors Edwards Pradenas, Benjamin Trinite, Vıctor Urrea, Silvia Marfil, Carlos A ́ vila-Nieto, Marıa Luisa Rodrı ́guez de la Concepcio , Ferran Tarre ́ s-Freixas, Silvia Pe ́rez-Yanes, Carla Rovirosa, Erola Ainsua-Enrich, Jordi Rodon, Ju ́ lia Vergara-Alert, Joaquim Segale, Victor Guallar, Alfonso Valencia, Nuria Izquierdo-Useros, Roger Paredes, Lourdes Mateu, Anna Chamorro, Marta Massanella, Jorge Carrillo, Bonaventura Clotet, Julia` Blanco
Authors Jennifer L. Hope, Linda M. Bradley
SCIENCE DIRECT
Authors Alison Tarke, John Sidney, Conner K. Kidd, Jennifer M. Dan, Sydney I. Ramirez, Esther Dawen Yu, Jose Mateus, Ricardo da Silva Antunes, Erin Moore, Paul Rubiro, Nils Methot, Elizabeth Phillips, Simon Mallal, April Frazier, Stephen A. Rawlings, Jason A. Greenbaum, Bjoern Peters, Davey M. Smith, Shane Crotty, Daniela Weiskopf, Alba Grifoni, Alessandro Sette
Authors Simone Pecetta, Mariagrazia Pizza, Claudia Sala, Emanuele Andreano, Piero Pileri, Marco Troisi, Elisa Pantano, Noemi Manganaro, Rino Rappuoli
Authors Takehiro Takahashi, Akiko Iwasaki
Authors Anthony Kusnadi, Ciro Ramírez-Suástegui, Vicente Fajardo, Serena J Chee, Benjamin J Meckiff, Hayley Simon, Emanuela Pelosi, Grégory Seumois, Ferhat Ay, Pandurangan Vijayanand, Christian H Ottensmeier
Abstract The molecular properties of CD8+ T cells that respond to SARS-CoV-2 infection are not fully known. Here, we report on the single-cell transcriptomes of >80,000 virus-reactive CD8+ T cells, obtained using a modified Antigen-Reactive T cell Enrichment (ARTE) assay, from 39 COVID-19 patients and 10 healthy subjects. COVID-19 patients segregated into two groups based on whether the dominant CD8+ T cell response to SARS-CoV-2 was ‘exhausted’ or not. SARS-CoV-2-reactive cells in the exhausted subset were increased in frequency and displayed lesser cytotoxicity and inflammatory features in COVID-19 patients with mild compared to severe illness. In contrast, SARS-CoV-2-reactive cells in the dominant non-exhausted subset from patients with severe disease showed enrichment of transcripts linked to co-stimulation, pro-survival NF-κB signaling, and anti-apoptotic pathways, suggesting the generation of robust CD8+ T cell memory responses in patients with severe COVID-19 illness. CD8+ T cells reactive to influenza and respiratory syncytial virus from healthy subjects displayed polyfunctional features and enhanced glycolysis. Cells with such features were largely absent in SARS-CoV-2-reactive cells from both COVID-19 patients and healthy controls non-exposed to SARS-CoV-2. Overall, our single-cell analysis revealed substantial diversity in the nature of CD8+ T cells responding to SARS-CoV-2.
Authors Jason T.Ladner, Sierra N.Henson, Annalee S.Boyle, Anna L.Engel brektson, Zane W.Fink, Fatima Rahee, Jonathan D’ambrozio, Kurt E.Schaecher, Mars Stone, Wenjuan Dong, Sanjeet Dadwal, Jianhua Yu, Michael A.Caligiuri, Piotr Cieplak, Magnar Bjørås, Mona H.Fenstad, Svein A.Nordbø, Denis E.Kainov, John A.Altin
Authors Christian Gaebler, Zijun Wang, Julio C. C. Lorenzi, Frauke Muecksch, Shlomo Finkin, Minami Tokuyama, Alice Cho, Mila Jankovic, Dennis Schaefer-Babajew, Thiago Y. Oliveira, Melissa Cipolla, Charlotte Viant, Christopher O. Barnes, Yaron Bram, Gaëlle Breton, Thomas Hägglöf, Pilar Mendoza, Arlene Hurley, Martina Turroja, Kristie Gordon, Katrina G. Millard, Victor Ramos, Fabian Schmidt, Yiska Weisblum, Divya Jha, Michael Tankelevich, Gustavo Martinez-Delgado, Jim Yee, Roshni Patel, Juan Dizon, Cecille Unson-O’Brien, Irina Shimeliovich, Davide F. Robbiani, Zhen Zhao, Anna Gazumyan, Robert E. Schwartz, Theodora Hatziioannou, Pamela J. Bjorkman, Saurabh Mehandru, Paul D. Bieniasz, Marina Caskey, Michel C. Nussenzweig
Abstract Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected 78 million individuals and is responsible for over 1.7 million deaths to date. Infection is associated with development of variable levels of antibodies with neutralizing activity that can protect against infection in animal models1,2. Antibody levels decrease with time, but the nature and quality of the memory B cells that would be called upon to produce antibodies upon re-infection has not been examined. Here we report on the humoral memory response in a cohort of 87 individuals assessed at 1.3 and 6.2 months after infection. We find that IgM, and IgG anti-SARS-CoV-2 spike protein receptor binding domain (RBD) antibody titres decrease significantly with IgA being less affected. Concurrently, neutralizing activity in plasma decreases by fivefold in pseudotype virus assays. In contrast, the number of RBD-specific memory B cells is unchanged. Memory B cells display clonal turnover after 6.2 months, and the antibodies they express have greater somatic hypermutation, increased potency and resistance to RBD mutations, indicative of continued evolution of the humoral response. Analysis of intestinal biopsies obtained from asymptomatic individuals 4 months after the onset of coronavirus disease-2019 (COVID-19), using immunofluorescence, or polymerase chain reaction, revealed persistence of SARS-CoV-2 nucleic acids and immunoreactivity in the small bowel of 7 out of 14 volunteers. We conclude that the memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence.
SCIENCE IMMUNOLOGY
Authors Nivedya Swarnalekha, David Schreiner, Ludivine C. Litzler, Saadia Iftikhar, Daniel Kirchmeier, Marco Künzli, Young Min Son, Jie Sun, Etori Aguiar Moreira, Carolyn G. King
Abstract Influenza is a deadly and costly infectious disease, even during flu seasons when an effective vaccine has been developed. To improve vaccines against respiratory viruses, a better understanding of the immune response at the site of infection is crucial. After influenza infection, clonally expanded T cells take up permanent residence in the lung, poised to rapidly respond to subsequent infection. Here, we characterized the dynamics and transcriptional regulation of lung-resident CD4+ T cells during influenza infection and identified a long-lived, Bcl6-dependent population that we have termed T resident helper (TRH) cells. TRH cells arise in the lung independently of lymph node T follicular helper cells but are dependent on B cells, with which they tightly colocalize in inducible bronchus-associated lymphoid tissue (iBALT). Deletion of Bcl6 in CD4+ T cells before heterotypic challenge infection resulted in redistribution of CD4+ T cells outside of iBALT areas and impaired local antibody production. These results highlight iBALT as a homeostatic niche for TRH cells and advocate for vaccination strategies that induce TRH cells in the lung.
Authors Eric H. Y. Lau, Owen T. Y. Tsang, David S. C. Hui, Mike Y. W. Kwan, Wai-hung Chan, Susan S. Chiu, Ronald L. W. Ko, Kin H. Chan, Samuel M. S. Cheng, Ranawaka A. P. M. Perera, Benjamin J. Cowling, Leo L. M. Poon, Malik Peiris
Abstract The SARS-CoV-2 pandemic poses the greatest global public health challenge in a century. Neutralizing antibody is a correlate of protection and data on kinetics of virus neutralizing antibody responses are needed. We tested 293 sera from an observational cohort of 195 reverse transcription polymerase chain reaction (RT-PCR) confirmed SARS-CoV-2 infections collected from 0 to 209 days after onset of symptoms. Of 115 sera collected ≥61 days after onset of illness tested using plaque reduction neutralization (PRNT) assays, 99.1% remained seropositive for both 90% (PRNT90) and 50% (PRNT50) neutralization endpoints. We estimate that it takes at least 372, 416 and 133 days for PRNT50 titres to drop to the detection limit of a titre of 1:10 for severe, mild and asymptomatic patients, respectively. At day 90 after onset of symptoms (or initial RT-PCR detection in asymptomatic infections), it took 69, 87 and 31 days for PRNT50 antibody titres to decrease by half (T1/2) in severe, mild and asymptomatic infections, respectively. Patients with severe disease had higher peak PRNT90 and PRNT50 antibody titres than patients with mild or asymptomatic infections. Age did not appear to compromise antibody responses, even after accounting for severity. We conclude that SARS-CoV-2 infection elicits robust neutralizing antibody titres in most individuals.
Authors Catherine J. Reynolds, Leo Swadling, Joseph M. Gibbons, Corinna Pade, Melanie P. Jensen, Mariana O. Diniz, Nathalie M. Schmidt, David K. Butler, Oliver E. Amin, Sasha N. L. Bailey, Sam M. Murray, Franziska P. Pieper, Stephen Taylor, Jessica Jones, Meleri Jones, Wing-Yiu Jason Lee, Joshua Rosenheim, Aneesh Chandran, George Joy, Cecilia Di Genova, Nigel Temperton, Jonathan Lambourne, Teresa Cutino-Moguel, Mervyn Andiapen, Marianna Fontana, Angelique Smit, Amanda Semper, Ben O’Brien, Benjamin Chain, Tim Brooks, Charlotte Manisty, Thomas Treibel, James C. Moon, Mahdad Noursadeghi, Daniel M. Altmann, Mala K. Maini, Áine McKnight, Rosemary J. Boyton
Abstract Understanding the nature of immunity following mild/asymptomatic infection with SARS-CoV-2 is crucial to controlling the pandemic. We analyzed T cell and neutralizing antibody responses in 136 healthcare workers (HCW) 16-18 weeks after United Kingdom lockdown, 76 of whom had mild/asymptomatic SARS-CoV-2 infection captured by serial sampling. Neutralizing antibodies (nAb) were present in 89% of previously infected HCW. T cell responses tended to be lower following asymptomatic infection than in those reporting case-definition symptoms of COVID-19, while nAb titers were maintained irrespective of symptoms. T cell and antibody responses were sometimes discordant. Eleven percent lacked nAb and had undetectable T cell responses to spike protein but had T cells reactive with other SARS-CoV-2 antigens. Our findings suggest that the majority of individuals with mild or asymptomatic SARS-CoV-2 infection carry nAb complemented by multispecific T cell responses at 16-18 weeks after mild or asymptomatic SARS-CoV-2 infection.
Authors Gemma E. Hartley, Emily S.J. Edwards, Pei M. Aui, Nirupama Varese, Stephanie Stojanovic, James McMahon, Anton Y. Peleg, Irene Boo, Heidi E. Drummer, P. Mark Hogarth, Robyn E. O’Hehir, Menno C. van Zelm
Abstract Lasting immunity following SARS-CoV-2 infection is questioned because serum antibodies decline in convalescence. However, functional immunity is mediated by long-lived memory T and B (Bmem) cells. Therefore, we generated fluorescently-labeled tetramers of the spike receptor binding domain (RBD) and nucleocapsid protein (NCP) to determine the longevity and immunophenotype of SARS-CoV-2-specific Bmem cells in COVID-19 patients. A total of 36 blood samples were obtained from 25 COVID-19 patients between 4 and 242 days post-symptom onset including 11 paired samples. While serum IgG to RBD and NCP was identified in all patients, antibody levels began declining at 20 days post-symptom onset. RBD- and NCP-specific Bmem cells predominantly expressed IgM+ or IgG1+ and continued to rise until 150 days. RBD-specific IgG+ Bmem were predominantly CD27+, and numbers significantly correlated with circulating follicular helper T cell numbers. Thus, the SARS-CoV-2 antibody response contracts in convalescence with persistence of RBD- and NCP-specific Bmem cells. Flow cytometric detection of SARS-CoV-2-specific Bmem cells enables detection of long-term immune memory following infection or vaccination for COVID-19.
Authors Andrea G. Edlow, Jonathan Z. Li, Ai-ris Y. Collier, Caroline Atyeo, Kaitlyn E. James, Adeline A. Boatin, Kathryn J. Gray, Evan A. Bordt, Lydia L. Shook, Lael M. Yonker, Alessio Fasano, Khady Diouf, Natalie Croul, Samantha Devane, Laura J. Yockey, Rosiane Lima, Jessica Shui, Juan D. Matute, Paul H. Lerou, Babatunde O. Akinwunmi, Aaron Schmidt, Jared Feldman, Blake M. Hauser, Timothy M. Caradonna, Denis De la Flor, Paolo D’Avino, James Regan, Heather Corry, Kendyll Coxen, Jesse Fajnzylber, David Pepin, Michael S. Seaman, Dan H. Barouch, Bruce D. Walker, Xu G. Yu, Anjali J. Kaimal, Drucilla J. Roberts, Galit Alter
Abstract Importance Biological data are lacking with respect to risk of vertical transmission and mechanisms of fetoplacental protection in maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Objective To quantify SARS-CoV-2 viral load in maternal and neonatal biofluids, transplacental passage of anti–SARS-CoV-2 antibody, and incidence of fetoplacental infection. Design, Setting, and Participants This cohort study was conducted among pregnant women presenting for care at 3 tertiary care centers in Boston, Massachusetts. Women with reverse transcription–polymerase chain reaction (RT-PCR) results positive for SARS-CoV-2 were recruited from April 2 to June 13, 2020, and follow-up occurred through July 10, 2020. Contemporaneous participants without SARS-CoV-2 infection were enrolled as a convenience sample from pregnant women with RT-PCR results negative for SARS-CoV-2. Exposures SARS-CoV-2 infection in pregnancy, defined by nasopharyngeal swab RT-PCR. Main Outcomes and Measures The main outcomes were SARS-CoV-2 viral load in maternal plasma or respiratory fluids and umbilical cord plasma, quantification of anti–SARS-CoV-2 antibodies in maternal and cord plasma, and presence of SARS-CoV-2 RNA in the placenta. Results Among 127 pregnant women enrolled, 64 with RT-PCR results positive for SARS-CoV-2 (mean [SD] age, 31.6 [5.6] years) and 63 with RT-PCR results negative for SARS-CoV-2 (mean [SD] age, 33.9 [5.4] years) provided samples for analysis. Of women with SARS-CoV-2 infection, 23 (36%) were asymptomatic, 22 (34%) had mild disease, 7 (11%) had moderate disease, 10 (16%) had severe disease, and 2 (3%) had critical disease. In viral load analyses among 107 women, there was no detectable viremia in maternal or cord blood and no evidence of vertical transmission. Among 77 neonates tested in whom SARS-CoV-2 antibodies were quantified in cord blood, 1 had detectable immunoglobuilin M to nucleocapsid. Among 88 placentas tested, SARS-CoV-2 RNA was not detected in any. In antibody analyses among 37 women with SARS-CoV-2 infection, anti–receptor binding domain immunoglobin G was detected in 24 women (65%) and anti-nucleocapsid was detected in 26 women (70%). Mother-to-neonate transfer of anti–SARS-CoV-2 antibodies was significantly lower than transfer of anti-influenza hemagglutinin A antibodies (mean [SD] cord-to-maternal ratio: anti–receptor binding domain immunoglobin G, 0.72 [0.57]; anti-nucleocapsid, 0.74 [0.44]; anti-influenza, 1.44 [0.80]; P < .001). Nonoverlapping placental expression of SARS-CoV-2 receptors angiotensin-converting enzyme 2 and transmembrane serine protease 2 was noted. Conclusions and Relevance In this cohort study, there was no evidence of placental infection or definitive vertical transmission of SARS-CoV-2. Transplacental transfer of anti-SARS-CoV-2 antibodies was inefficient. Lack of viremia and reduced coexpression and colocalization of placental angiotensin-converting enzyme 2 and transmembrane serine protease 2 may serve as protective mechanisms against vertical transmission.
Authors Jason Rosado, Stéphane Pelleau, Charlotte Cockram, Sarah Hélène Merkling, Narimane Nekkab, Caroline Demeret, Annalisa Meola, Solen Kerneis, Benjamin Terrier, Samira Fafi-Kremer, Jerome de Seze, Timothée Bruel, François Dejardin, Stéphane Petres, Rhea Longley, Arnaud Fontanet, Marija Backovic, Ivo Mueller, Michael T White
Authors Els Duysburgh Laure Mortgat Cyril Barbezange Katelijne Dierick Natalie Fischer Leo Heyndrickx Veronik Hutse Isabelle Thomas Steven Van Gucht Bea Vuylsteke Kevin Arien Isabelle Desombere
NIH (NATIONAL INSTITUTE OF HEALTH)
Authors Sharon Reynolds
Authors Marco Vincenzo Lenti, Nicola Aronico, Ivan Pellegrino, Emanuela Boveri, Paolo Giuffrida, Federica Borrelli de Andreis, Patrizia Morbini, Laura Vanelli, Alessandra Pasini, Cristina Ubezio, Federica Melazzini, Alessandro Rascaroli, Valentina Antoci, Stefania Merli, Francesco Di Terlizzi, Umberto Sabatini, Ginevra Cambiè, Annamaria Tenore, Cristina Picone, Alessandro Vanoli, Luca Arcaini, Fausto Baldanti, Marco Paulli, Gino Roberto Corazza, Antonio Di Sabatino
Abstract Impaired immune responses have been hypothesised to be a possible trigger of unfavourable outcomes in coronavirus disease 2019 (COVID-19). We aimed to characterise IgM memory B cells in patients with COVID-19 admitted to an internal medicine ward in Northern Italy. Overall, 66 COVID-19 patients (mean age 74 ± 16.6 years; 29 females) were enrolled. Three patients (4.5%; 1 female) had been splenectomised and were excluded from further analyses. Fifty-five patients (87.3%) had IgM memory B cell depletion, and 18 (28.6%) died during hospitalisation (cumulative incidence rate 9.26/100 person-week; 5.8–14.7 95% CI). All patients who died had IgM memory B cell depletion. A superimposed infection was found in 6 patients (9.5%), all of them having IgM memory B cell depletion (cumulative incidence rate 3.08/100 person-week; 1.3–6.8 95% CI). At bivariable analyses, older age, sex, number of comorbidities, and peripheral blood lymphocyte count < 1500/µl were not correlated with IgM memory B cell depletion. A discrete-to-marked reduction of the B-cell compartment was also noticed in autoptic spleen specimens of two COVID-19 patients. We conclude that IgM memory B cells are commonly depleted in COVID-19 patients and this correlates with increased mortality and superimposed infections.
EUROSURVEILLANCE
Authors Jennifer Mehew, Rachel Johnson, David Roberts, Heli Harvala
ABSTRACT We analysed factors associated with neutralising antibody levels in 330 convalescent plasma donors. Women and younger donors were more likely not to have measurable neutralising antibodies, while higher antibody levels were observed in men, in older donors and in those who had been hospitalised. These data will be of value in the timely recruitment of convalescent plasma donors most likely to have high levels of neutralising antibodies for ongoing studies investigating its effectiveness.
Authors Jorge Carrillo, Nuria Izquierdo-Useros, Carlos Avila-Nieto, Edwards Pradenas, Bonaventura Clotet, Julia Blanco
Abstract The magnitude and the quality of humoral responses against SARS-CoV-2 have been associated with clinical outcome. Although the elicitation of humoral responses against different viral proteins is rapid and occurs in most infected individuals, its magnitude is highly variable among them and positively correlates with COVID-19 disease severity. This rapid response is characterized by the almost concomitant appearance of virus-specific IgG, IgA and IgM antibodies that contain neutralizing antibodies directed against different epitopes of the Spike glycoprotein. Of particularly interest, the antibodies against domain of the Spike that interacts with the cellular receptor ACE2, known as the receptor binding domain (RBD), are present in most infected individuals and are block viral entry and infectivity. Such neutralizing antibodies protect different animal species when administered before virus exposure; therefore, its elicitation is the main target of current vaccine approaches and their clinical use as recombinant monoclonal antibodies (mAbs) is being explored. Yet, little information exists on the duration of humoral responses during natural infection. This is a key issue that will impact the management of the pandemic and determine the utility of seroconversion studies and the level of herd immunity. Certainly, several cases of reinfection have been reported, suggesting that immunity could be transient, as reported for other coronaviruses. In summary, although the kinetics of the generation of antibodies against SASR-CoV-2 and their protective activity have been clearly defined, their role in COVID-19 pathogenesis and the length of these responses are still open questions.
Authors Kevin W. Ng, Georgina H. Cornish, Annachiara Rosa, Ruth Harvey, Saira Hussain, Rachel Ulferts, Christopher Earl, Antoni G. Wrobel,Donald J. Benton, Chloe Roustan, William Bolland, Rachael Thompson, Ana Agua-Doce, Philip Hobson, Judith Heaney, Hannah Rickman, Stavroula Paraskevopoulou, Catherine F. Houlihan, Kirsty Thomson, Emilie Sanchez, Gee Yen Shin, Moira J. Spyer,Dhira Joshi, Nicola O’Reilly, Philip A. Walker,Svend Kjaer, Andrew Riddell, Catherine Moore, Bethany R. Jebson, Meredyth Wilkinson, Lucy R. Marshall, Elizabeth C. Rosser, Anna Radziszewska, Hannah Peckham, Coziana Ciurtin, Lucy R. Wedderburn, Rupert Beale, Charles Swanton, Sonia Gandhi, Brigitta Stockinger, John McCauley, Steve J. Gamblin, Laura E. McCoy, Peter Cherepanov, Eleni Nastouli, George Kassiotis
Abstract Zoonotic introduction of novel coronaviruses may encounter preexisting immunity in humans. Using diverse assays for antibodies recognizing SARS-CoV-2 proteins, we detect preexisting humoral immunity. SARS-CoV-2 spike glycoprotein (S)-reactive antibodies were detectable by a flow cytometry-based method in SARS-CoV-2-uninfected individuals and were particularly prevalent in children and adolescents. They were predominantly of the IgG class and targeted the S2 subunit. By contrast, SARS-CoV-2 infection induced higher titers of SARS-CoV-2 S-reactive IgG antibodies, targeting both the S1 and S2 subunits, and concomitant IgM and IgA antibodies, lasting throughout the observation period. Notably, SARS-CoV-2-uninfected donor sera exhibited specific neutralizing activity against SARS-CoV-2 and SARS-CoV-2 S pseudotypes. Distinguishing preexisting and de novo immunity will be critical for our understanding of susceptibility to and the natural course of SARS-CoV-2 infection.
VIROLOGY BLOG
Authors Gertrud U. Rey
Authors Stuart P. Weisberg, Thomas J. Connors, Yun Zhu, Matthew R. Baldwin, Wen-Hsuan Lin, Sandeep Wontakal, Peter A. Szabo, Steven B. Wells, Pranay Dogra, Joshua Gray, Emma Idzikowski, Debora Stelitano, Francesca T. Bovier, Julia Davis-Porada, Rei Matsumoto, Maya Meimei Li Poon, Michael Chait, Cyrille Mathieu, Branka Horvat, Didier Decimo, Krystalyn E. Hudson, Flavia Dei Zotti, Zachary C. Bitan, Francesca La Carpia, Stephen A. Ferrara, Emily Mace, Joshua Milner, Anne Moscona, Eldad Hod, Matteo Porotto, Donna L. Farber
Abstract Clinical manifestations of COVID-19 caused by the new coronavirus SARS-CoV-2 are associated with age1,2. Adults develop respiratory symptoms, which can progress to acute respiratory distress syndrome (ARDS) in the most severe form, while children are largely spared from respiratory illness but can develop a life-threatening multisystem inflammatory syndrome (MIS-C)3,4,5. Here, we show distinct antibody responses in children and adults after SARS-CoV-2 infection. Adult COVID-19 cohorts had anti-spike (S) IgG, IgM and IgA antibodies, as well as anti-nucleocapsid (N) IgG antibody, while children with and without MIS-C had reduced breadth of anti-SARS-CoV-2-specific antibodies, predominantly generating IgG antibodies specific for the S protein but not the N protein. Moreover, children with and without MIS-C had reduced neutralizing activity as compared to both adult COVID-19 cohorts, indicating a reduced protective serological response. These results suggest a distinct infection course and immune response in children independent of whether they develop MIS-C, with implications for developing age-targeted strategies for testing and protecting the population.
Authors Yuezhou Chen, Adam Zuiani, Stephanie Fischinger, Douglas A. Lauffenburger, Galit Alter, Duane R. Wesemann
Authors Jacqui Wise
Authors Oon Tek Ng, Kalisvar Marimuthu, Vanessa Koh, Junxiong Pang, Kyaw Zaw Linn, Jie Sun, Liang De Wang, Wan Ni Chia, Charles Tiu, Monica Chan, Li Min Ling, Shawn Vasoo, Mohammad Yazid Abdad, Po Ying Chia, Tau Hong Lee, Ray Junhao Lin, Sapna P Sadarangani, Mark I-Cheng Chen, Zubaidah Said, Lalitha Kurupatham, Rachael Pung, Lin-Fa Wang, Alex R Cook, Yee-Sin Leo, Vernon JM Lee
Authors Peter Chen, Ajay Nirula, Barry Heller, Robert L. Gottlieb, Joseph Boscia, Jason Morris, Gregory Huhn, Jose Cardona, Bharat Mocherla, Valentina Stosor, Imad Shawa, Andrew C. Adams, Jacob Van Naarden, Kenneth L. Custer, Lei Shen, Michael Durante, Gerard Oakley, Andrew E. Schade, Janelle Sabo, Dipak R. Patel, Paul Klekotka, Daniel M. Skovronsky
Abstract BACKGROUND Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (Covid-19), which is most frequently mild yet can be severe and life-threatening. Virus-neutralizing monoclonal antibodies are predicted to reduce viral load, ameliorate symptoms, and prevent hospitalization. METHODS In this ongoing phase 2 trial involving outpatients with recently diagnosed mild or moderate Covid-19, we randomly assigned 452 patients to receive a single intravenous infusion of neutralizing antibody LY-CoV555 in one of three doses (700 mg, 2800 mg, or 7000 mg) or placebo and evaluated the quantitative virologic end points and clinical outcomes. The primary outcome was the change from baseline in the viral load at day 11. The results of a preplanned interim analysis as of September 5, 2020, are reported here. RESULTS At the time of the interim analysis, the observed mean decrease from baseline in the log viral load for the entire population was −3.81, for an elimination of more than 99.97% of viral RNA. For patients who received the 2800-mg dose of LY-CoV555, the difference from placebo in the decrease from baseline was −0.53 (95% confidence interval [CI], −0.98 to −0.08; P=0.02), for a viral load that was lower by a factor of 3.4. Smaller differences from placebo in the change from baseline were observed among the patients who received the 700-mg dose (−0.20; 95% CI, −0.66 to 0.25; P=0.38) or the 7000-mg dose (0.09; 95% CI, −0.37 to 0.55; P=0.70). On days 2 to 6, the patients who received LY-CoV555 had a slightly lower severity of symptoms than those who received placebo. The percentage of patients who had a Covid-19–related hospitalization or visit to an emergency department was 1.6% in the LY-CoV555 group and 6.3% in the placebo group. CONCLUSIONS In this interim analysis of a phase 2 trial, one of three doses of neutralizing antibody LY-CoV555 appeared to accelerate the natural decline in viral load over time, whereas the other doses had not by day 11. (Funded by Eli Lilly; BLAZE-1 ClinicalTrials.gov number, NCT04427501. opens in new tab.)
Authors Ania Wajnberg, Fatima Amanat, Adolfo Firpo, Deena R. Altman, Mark J. Bailey, Mayce Mansour, Meagan McMahon, Philip Meade, Damodara Rao Mendu, Kimberly Muellers, Daniel Stadlbauer, Kimberly Stone, Shirin Strohmeier, Viviana Simon, Judith Aberg, David L. Reich, Florian Krammer, Carlos Cordon-Cardo
Abstract SARS-CoV-2 has caused a global pandemic with millions infected and numerous fatalities. Questions regarding the robustness, functionality, and longevity of the antibody response to the virus remain unanswered. Here we report that the vast majority of infected individuals with mild-to-moderate COVID-19 experience robust IgG antibody responses against the viral spike protein, based on a dataset of 30,082 individuals screened at Mount Sinai Health System in New York City. We also show that titers are relatively stable for at least a period approximating 5 months and that anti-spike binding titers significantly correlate with neutralization of authentic SARS-CoV-2. Our data suggests that more than 90% of seroconverters make detectible neutralizing antibody responses. These titers remain relatively stable for several months after infection.
Authors Jeffrey Seow, Carl Graham, Blair Merrick, Sam Acors, Suzanne Pickering, Kathryn J. A. Steel, Oliver Hemmings, Aoife O’Byrne, Neophytos Kouphou, Rui Pedro Galao, Gilberto Betancor, Harry D. Wilson, Adrian W. Signell, Helena Winstone, Claire Kerridge, Isabella Huettner, Jose M. Jimenez-Guardeño, Maria Jose Lista, Nigel Temperton, Luke B. Snell, Karen Bisnauthsing, Amelia Moore, Adrian Green, Lauren Martinez, Brielle Stokes, Johanna Honey, Alba Izquierdo-Barras, Gill Arbane, Amita Patel, Mark Kia Ik Tan, Lorcan O’Connell, Geraldine O’Hara, Eithne MacMahon, Sam Douthwaite, Gaia Nebbia, Rahul Batra, Rocio Martinez-Nunez, Manu Shankar-Hari, Jonathan D. Edgeworth, Stuart J. D. Neil, Michael H. Malim, Katie J. Doores
Abstract Antibody responses to SARS-CoV-2 can be detected in most infected individuals 10–15 d after the onset of COVID-19 symptoms. However, due to the recent emergence of SARS-CoV-2 in the human population, it is not known how long antibody responses will be maintained or whether they will provide protection from reinfection. Using sequential serum samples collected up to 94 d post onset of symptoms (POS) from 65 individuals with real-time quantitative PCR-confirmed SARS-CoV-2 infection, we show seroconversion (immunoglobulin (Ig)M, IgA, IgG) in >95% of cases and neutralizing antibody responses when sampled beyond 8 d POS. We show that the kinetics of the neutralizing antibody response is typical of an acute viral infection, with declining neutralizing antibody titres observed after an initial peak, and that the magnitude of this peak is dependent on disease severity. Although some individuals with high peak infective dose (ID50 > 10,000) maintained neutralizing antibody titres >1,000 at >60 d POS, some with lower peak ID50 had neutralizing antibody titres approaching baseline within the follow-up period. A similar decline in neutralizing antibody titres was observed in a cohort of 31 seropositive healthcare workers. The present study has important implications when considering widespread serological testing and antibody protection against reinfection with SARS-CoV-2, and may suggest that vaccine boosters are required to provide long-lasting protection.
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Authors Carlo Cervia, Jakob Nilsson, Yves Zurbuchen, Alan Valaperti, Jens Schreiner, Aline Wolfensberger, Miro E. Raeber, Sarah Adamo, Sebastian Weigang, Marc Emmenegger, Sara Hasler, Philipp P. Bosshard, Elena De Cecco, Esther Bächli, Alain Rudiger, Melina Stüssi-Helbling, Lars C. Huber, Annelies S. Zinkernagel, Dominik J. Schaer, Adriano Aguzzi, Georg Kochs, Ulrike Held, Elsbeth Probst-Müller, Silvana K. Rampini, Onur Boyman
ASH PUBLICATIONS
Authors Mohammed Osman, Rehan M. Faridi, Wendy Sligl, Meer-Taher Shabani-Rad, Poonam Dharmani-Khan, Arabesque Parker, Amit Kalra, Minal Borkar Tripathi, Jan Storek, Jan Willem Cohen Tervaert, Faisal M. Khan
Abstract The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–driven coronavirus disease 2019 (COVID-19) has caused unprecedented human death and has seriously threatened the global economy. Early data suggest a surge in proinflammatory cytokines in patients with severe COVID-19, which has been associated with poor outcomes. We recently postulated that the inflammatory response in patients with severe COVID-19 disease is not inhibited by natural killer (NK) cells, resulting in a “cytokine storm.” Here, we assessed the NK-cell functional activity and the associated cytokines and soluble mediators in hospitalized COVID-19 patients. Significantly impaired NK-cell counts and cytolytic activity were observed in COVID-19 patients when compared with healthy controls. Also, cytokines like interleukin 12 (IL12), IL15, and IL21 that are important for NK-cell activity were not detected systematically. Serum concentrations of soluble CD25 (sCD25)/soluble IL2 receptor α (sIL2-Rα) were significantly elevated and were inversely correlated with the percentage of NK cells. Impaired NK-cell cytolytic activity together with other laboratory trends including elevated sCD25 were consistent with a hyperinflammatory state in keeping with macrophage-activation syndrome. Our findings suggest that impaired counts and cytolytic activity of NK cells are important characteristics of severe COVID-19 and can potentially facilitate strategies for immunomodulatory therapies.
Authors Reiichiro Obata, Tetsuro Maeda, Dahlia Rizk, Toshik iKuno
Authors Akiko Iwasaki
Authors Satria P. Sajuthi, Peter DeFord, Yingchun Li, Nathan D. Jackson, Michael T. Montgomery, Jamie L. Everman, Cydney L. Rios, Elmar Pruesse, James D. Nolin, Elizabeth G. Plender, Michael E. Wechsler, Angel C. Y. Mak, Celeste Eng, Sandra Salazar, Vivian Medina, Eric M. Wohlford, Scott Huntsman, Deborah A. Nickerson, Soren Germer, Michael C. Zody, Gonçalo Abecasis, Hyun Min Kang, Kenneth M. Rice, Rajesh Kumar, Sam Oh, Jose Rodriguez-Santana, Esteban G. Burchard, Max A. Seibold
Abstract Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, an emerging virus that utilizes host proteins ACE2 and TMPRSS2 as entry factors. Understanding the factors affecting the pattern and levels of expression of these genes is important for deeper understanding of SARS-CoV-2 tropism and pathogenesis. Here we explore the role of genetics and co-expression networks in regulating these genes in the airway, through the analysis of nasal airway transcriptome data from 695 children. We identify expression quantitative trait loci for both ACE2 and TMPRSS2, that vary in frequency across world populations. We find TMPRSS2 is part of a mucus secretory network, highly upregulated by type 2 (T2) inflammation through the action of interleukin-13, and that the interferon response to respiratory viruses highly upregulates ACE2 expression. IL-13 and virus infection mediated effects on ACE2 expression were also observed at the protein level in the airway epithelium. Finally, we define airway responses to common coronavirus infections in children, finding that these infections generate host responses similar to other viral species, including upregulation of IL6 and ACE2. Our results reveal possible mechanisms influencing SARS-CoV-2 infectivity and COVID-19 clinical outcomes.
Authors Lucia Gabriele, Alessandra Fragale, Giulia Romagnoli, Stefania Parlato, Caterina Lapenta, Stefano Maria Santini, Keiko Ozato, Imerio Capone
Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic, induces severe pneumonia mainly in elderly males. Epidemiological data clearly indicate sex-based differences in disease outcomes, with men accounting for about 70% of deaths, despite similar susceptibility to infection. It is well known that females are endowed with higher capacity to produce antibodies, which correlates with viral clearance and disease resolution in the context of SARS-Cov-2 infection. Many X-linked immune genes escape X inactivation showing biallelic expression in female immune cells, particularly in plasmacytoid dendritic cells (pDCs). PDCs are more active in females and endowed with high capability to induce IFN-α-mediated B cell activation and differentiation into antibody-producing plasma cells throughout epigenetic mechanisms linked to trained immunity. Thus, we hypothesize that following SARS-CoV-2 infection, epigenetic modifications of X-linked genes involved in pDC-mediated type I IFN (IFN-I) signaling occurs more effectively in females, for inducing neutralizing antibody response as an immune correlate driving sex-biased disease outcome.
AJOG (AMERICAN JOURNAL OBSTRETICS GYNECOLOGY)
Authors Arvind Palanisamy, Tusar Giri
Authors Baweleta Isho, Kento T. Abe, Michelle Zuo, Alainna J. Jamal, Bhavisha Rathod, Jenny H. Wang, Zhijie Li, Gary Chao, Olga L. Rojas, Yeo Myong Bang, Annie Pu, Natasha Christie-Holmes, Christian Gervais, Derek Ceccarelli, Payman Samavarchi-Tehrani, Furkan Guvenc, Patrick Budylowski, Angel Li, Aimee Paterson, Yue Feng Yun, Lina M. Marin, Lauren Caldwell, Jeffrey L. Wrana, Karen Colwill, Frank Sicheri, Samira Mubareka, Scott D. Gray-Owen, Steven J. Drews, Walter L. Siqueira, Miriam Barrios- Rodiles, Mario Ostrowski, James M. Rini, Yves Durocher, Allison J. McGeer, Jennifer L. Gommerman, Anne-Claude Gingras
Abstract While the antibody response to SARS-CoV-2 has been extensively studied in blood, relatively little is known about the antibody response in saliva and its relationship to systemic antibody levels. Here, we profiled by enzyme-linked immunosorbent assays (ELISAs) IgG, IgA and IgM responses to the SARS-CoV-2 spike protein (full length trimer) and its receptor-binding domain (RBD) in serum and saliva of acute and convalescent patients with laboratory-diagnosed COVID-19 ranging from 3–115 days post-symptom onset (PSO), compared to negative controls. Anti-SARS-CoV-2 antibody responses were readily detected in serum and saliva, with peak IgG levels attained by 16–30 days PSO. Longitudinal analysis revealed that anti-SARS-CoV-2 IgA and IgM antibodies rapidly decayed, while IgG antibodies remained relatively stable up to 105 days PSO in both biofluids. Lastly, IgG, IgM and to a lesser extent IgA responses to spike and RBD in the serum positively correlated with matched saliva samples. This study confirms that serum and saliva IgG antibodies to SARS-CoV-2 are maintained in the majority of COVID-19 patients for at least 3 months PSO. IgG responses in saliva may serve as a surrogate measure of systemic immunity to SARS-CoV-2 based on their correlation with serum IgG responses.
Authors Matthew C. Woodruff, Richard P. Ramonell, Doan C. Nguyen, Kevin S. Cashman, Ankur Singh Saini, Natalie S. Haddad, Ariel M. Ley, Shuya Kyu, J. Christina Howell, Tugba Ozturk, Saeyun Lee, Naveenchandra Suryadevara, James Brett Case, Regina Bugrovsky, Weirong Chen, Jacob Estrada, Andrea Morrison-Porter, Andrew Derrico, Fabliha A. Anam, Monika Sharma, Henry M. Wu, Sang N. Le, Scott A. Jenks, Christopher M. Tipton, Bashar Staitieh, John L. Daiss, Eliver Ghosn, Michael S. Diamond, Robert H. Carnahan, James E. Crowe Jr., William T. Hu, F. Eun-Hyung Lee, Ignacio Sanz
Abstract A wide spectrum of clinical manifestations has become a hallmark of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19 pandemic, although the immunological underpinnings of diverse disease outcomes remain to be defined. We performed detailed characterization of B cell responses through high-dimensional flow cytometry to reveal substantial heterogeneity in both effector and immature populations. More notably, critically ill patients displayed hallmarks of extrafollicular B cell activation and shared B cell repertoire features previously described in autoimmune settings. Extrafollicular activation correlated strongly with large antibody-secreting cell expansion and early production of high concentrations of SARS-CoV-2-specific neutralizing antibodies. Yet, these patients had severe disease with elevated inflammatory biomarkers, multiorgan failure and death. Overall, these findings strongly suggest a pathogenic role for immune activation in subsets of patients with COVID-19. Our study provides further evidence that targeted immunomodulatory therapy may be beneficial in specific patient subpopulations and can be informed by careful immune profiling.
BLOOD (AMERICAN SOCIETY OF HEMATOLOGY)
Authors Josée Perreault, Tony Tremblay, Marie-Josée Fournier, Mathieu Drouin, Guillaume Beaudoin-Bussières, Jérémie Prévost, Antoine Lewin, Philippe Bégin, Andrés Finzi, Renée Bazin
OXFORD ACADEMY
Authors Omar Hasan Ali, David Bomze, Lorenz Risch, Silvio D Brugger, Matthias Paprotny, Myriam Weber, Sarah Thiel, Lukas Kern, Werner C Albrich, Philipp Kohler, Christian R Kahlert, Pietro Vernazza, Philipp K Buehler, Reto A Schuepbach, Alejandro Gomez-Mejia, Alexandra M Popa, Andreas Bergthaler, Josef M Penninger, Lukas Flatz
Abstract Background Severe coronavirus disease 2019 (COVID-19) frequently entails complications that bear similarities to autoimmune diseases. To date, there is little data on possible IgA-mediated autoimmune responses. Here, we aim to determine whether COVID-19 is associated with a vigorous total IgA response and if IgA antibodies are associated with complications of severe illness. Since thrombotic events are frequent in severe COVID-19 and resemble hypercoagulation of antiphospholipid syndrome (APS), our approach focused on antiphospholipid antibodies (aPL). Methods In this retrospective cohort study clinical data and aPL from 64 patients with COVID-19 were compared from three independent tertiary hospitals (one in Liechtenstein, two in Switzerland). Samples were collected from April 9 th to May 1 st, 2020. Results Clinical records of 64 patients with COVID-19 were reviewed and divided into a cohort with mild illness (mCOVID) (41%), a discovery cohort with severe illness (sdCOVID) (22%) and a confirmation cohort with severe illness (scCOVID) (38%). Total IgA, IgG and aPL were measured with clinical diagnostic kits. Severe illness was significantly associated with increased total IgA (sdCOVID, P=0.01; scCOVID, p-value<0.001), but not total IgG. Among aPL, both cohorts with severe illness significantly correlated with elevated anti-Cardiolipin IgA (sdCOVID and scCOVID, p-value<0.001), anti-Cardiolipin IgM (sdCOVID, P=0.003; scCOVID, P<0.001), and anti-Beta2 Glycoprotein-1 IgA (sdCOVID and scCOVID, P<0.001). Systemic lupus erythematosus was excluded from all patients as a potential confounder. Conclusions Higher total IgA and IgA-aPL were consistently associated with severe illness. These novel data strongly suggest that a vigorous antiviral IgA-response, possibly triggered in the bronchial mucosa, induces systemic autoimmunity.
Authors Annika Nelde, Tatjana Bilich, Jonas S. Heitmann, Yacine Maringer, Helmut R. Salih, Malte Roerden, Maren Lübke, Jens Bauer, Jonas Rieth, Marcel Wacker, Andreas Peter, Sebastian Hörber, Bjoern Traenkle, Philipp D. Kaiser, Ulrich Rothbauer, Matthias Becker, Daniel Junker, Gérard Krause, Monika Strengert, Nicole Schneiderhan-Marra, Markus F. Templin, Thomas O. Joos, Daniel J. Kowalewski, Vlatka Stos-Zweifel, Michael Fehr, Armin Rabsteyn, Valbona Mirakaj, Julia Karbach, Elke Jäger, Michael Graf, Lena-Christin Gruber, David Rachfalski, Beate Preuß, Ilona Hagelstein, Melanie Märklin, Tamam Bakchoul, Cécile Gouttefangeas, Oliver Kohlbacher, Reinhild Klein, Stefan Stevanović, Hans-Georg Rammensee, Juliane S. Walz
Abstract T cell immunity is central for the control of viral infections. To characterize T cell immunity, but also for the development of vaccines, identification of exact viral T cell epitopes is fundamental. Here we identify and characterize multiple dominant and subdominant SARS-CoV-2 HLA class I and HLA-DR peptides as potential T cell epitopes in COVID-19 convalescent and unexposed individuals. SARS-CoV-2-specific peptides enabled detection of post-infectious T cell immunity, even in seronegative convalescent individuals. Cross-reactive SARS-CoV-2 peptides revealed pre-existing T cell responses in 81% of unexposed individuals and validated similarity with common cold coronaviruses, providing a functional basis for heterologous immunity in SARS-CoV-2 infection. Diversity of SARS-CoV-2 T cell responses was associated with mild symptoms of COVID-19, providing evidence that immunity requires recognition of multiple epitopes. Together, the proposed SARS-CoV-2 T cell epitopes enable identification of heterologous and post-infectious T cell immunity and facilitate development of diagnostic, preventive and therapeutic measures for COVID-19.
Authors Shuchi Anand, Maria Montez-Rath, Jialin Han, Julie Bozeman, Russell Kerschmann, Paul Beyer, Julie Parsonnet, Glenn M Chertow
Authors M. Alejandra Tortorici, Martina Beltramello, Florian A. Lempp, Dora Pinto, Ha V. Dang, Laura E. Rosen, Matthew McCallum, John Bowen, Andrea Minola, Stefano Jaconi, Fabrizia Zatta, Anna De Marco, Barbara Guarino, Siro Bianchi3, Elvin J. Lauron, Heather Tucker, Jiayi Zhou, Alessia Peter, Colin Havenar- Daughton, Jason A. Wojcechowskyj, James Brett Case, Rita E. Chen, Hannah Kaiser, Martin Montiel-Ruiz, Marcel Meury, Nadine Czudnochowski, Roberto Spreafico, Josh Dillen, Cindy Ng, Nicole Sprugasci, Katja Culap, Fabio Benigni, Rana Abdelnabi, Shi-Yan Caroline Foo, Michael A. Schmid, Elisabetta Cameroni, Agostino Riva, Arianna Gabrieli, Massimo Galli, Matteo S. Pizzuto, Johan Neyts, Michael S. Diamond, Herbert W. Virgin, Gyorgy Snell, Davide Corti, Katja Fink, David Veesler
Abstract Efficient therapeutic options are needed to control the spread of SARS-CoV-2 that has caused more than 922,000 fatalities as of September 13th, 2020. We report the isolation and characterization of two ultrapotent SARS-CoV-2 human neutralizing antibodies (S2E12 and S2M11) that protect hamsters against SARS-CoV-2 challenge. Cryo-electron microscopy structures show that S2E12 and S2M11 competitively block ACE2 attachment and that S2M11 also locks the spike in a closed conformation by recognition of a quaternary epitope spanning two adjacent receptor-binding domains. Cocktails including S2M11, S2E12 or the previously identified S309 antibody broadly neutralize a panel of circulating SARS-CoV-2 isolates and activate effector functions. Our results pave the way to implement antibody cocktails for prophylaxis or therapy, circumventing or limiting the emergence of viral escape mutants.
Authors Meredith Wadman
Authors Catherine F Houlihan, Rupert Beale
Authors Pedro C Hallal, Fernando P Hartwig, Bernardo L Horta, Mariângela F Silveira, Claudio J Struchiner, Luís P Vidaletti, Nelson A Neumann, Lucia C Pellanda, Odir A Dellagostin, Marcelo N Burattini, Gabriel D Victora, Ana M B Menezes, Fernando C Barros, Aluísio J D Barros, Cesar G Victora
Authors The National SARS-CoV-2 Serology Assay Evaluation Group
Authors Edwin Bölke, Christiane Matuschek, Johannes C. Fischer
Authors Vivek Gupta, Rahul C Bhoyar, Abhinav Jain, Saurabh Srivastava, Rashmi Upadhayay, Mohamed Imran, Bani Jolly, Mohit Kumar Divakar, Disha Sharma, Paras Sehgal, Gyan Ranjan, Rakesh Gupta, Vinod Scaria, Sridhar Sivasubbu
INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES
Authors M. Vassallo, S. Manni, P. Pini, E. Blanchouin, M. Ticchioni, B. Seitz-Polski, A. Puchois, A. Sindt, L. Lotte, P. Fauque, J. Durant
Abstract Objectives: A novel beta coronavirus has been identified as responsible for the 2019 coronavirus infection (Covid-19). Clinical presentations range from asymptomatic cases to acute respiratory distress syndrome with fatal outcome. Such a broad spectrum of disease expression calls for an investigation of immune response characteristics. Methods: We identified subjects admitted for Covid-19 in whom a large panel of immunological markers were measured, including B- and T- and NKlymphocyte phenotypes, T-lymphocyte subpopulation cells and plasma cytokines. Patients were divided according to symptom severity during hospitalisation, in those with uncomplicated and complicated infection. Differences between groups were analyzed. Results: Seventeen patients were included (mean age: 83 years; 9 women; mean delay of symptoms onset: 4 days). Six had uncomplicated infection, while 11 developed complicated forms during the hospitalization. CD10+ B lymphocyte levels were inversely correlated with clinical severity (5.8% vs 2.0%, p = 0.04) and CD10+ levels above 3% were independently associated with uncomplicated forms [Odds Ratio 0.04 (CI 0.002-0.795, p = 0.034)]. Journal Pre-proof 4 TNF-alpha, IL-1, Il-6 and Il-8 measurements upon admission differed between patients who died and those who survived (p < 0.01 for all comparisons). Conclusions: In a population of elderly patients recently infected with Covid19, CD10+ B cell levels were inversely correlated with clinical severity. Cytokine values upon admission were highly predictive of fatal outcome during hospitalisation. These findings could explain differences in the clinical presentation and allow rapid identification of patients at risk for complications
Authors Angkana T. Huang, Bernardo Garcia-Carreras, Matt D. T. Hitchings, Bingyi Yang, Leah C. Katzelnick, Susan M. Rattigan, Brooke A. Borgert, Carlos A. Moreno, Benjamin D. Solomon, Luke Trimmer-Smith, Veronique Etienne, Isabel Rodriguez-Barraquer, Justin Lessler, Henrik Salje, Donald S. Burke, Amy Wesolowski, Derek A. T. Cummings
Abstract Many public health responses and modeled scenarios for COVID-19 outbreaks caused by SARS-CoV-2 assume that infection results in an immune response that protects individuals from future infections or illness for some amount of time. The presence or absence of protective immunity due to infection or vaccination (when available) will affect future transmission and illness severity. Here, we review the scientific literature on antibody immunity to coronaviruses, including SARS-CoV-2 as well as the related SARS-CoV, MERS-CoV and endemic human coronaviruses (HCoVs). We reviewed 2,452 abstracts and identified 491 manuscripts relevant to 5 areas of focus: 1) antibody kinetics, 2) correlates of protection, 3) immunopathogenesis, 4) antigenic diversity and cross-reactivity, and 5) population seroprevalence. While further studies of SARS-CoV-2 are necessary to determine immune responses, evidence from other coronaviruses can provide clues and guide future research.
Authors Manish M. Patel, Natalie J. Thornburg, William B. Stubblefield, H. Keipp Talbot, Melissa M. Coughlin, Leora R. Feldstein, Wesley H. Self
TAYLOR & FRANCIS ONLINE
Authors Na Du , Yanfang Jiang , Qing Zhang , Lihe Che , Xiaohua Li , Lixin Lou , Wanguo Bao, Shucheng Hua
ABSTRACT Eight members of a big family with laboratory-confirmed COVID-19 pneumonia were admitted to First Hospital of Jilin University, Changchun, China, from 28 January to 5 February 2020. The clinical records, laboratory results, and chest computed tomography (CT) scans were retrospectively reviewed. Throat swab samples were positive for severe acute respiratory syndrome coronavirus 2, confirmed by the Center for Disease Control and Prevention of Changchun. All eight patients had fever of different degrees; and 6, 3, and 2 had cough; diarrhea; and sore throat. With disease progression, the percentage of lymphocytes in older patients increased, CT images worsened, and the ratio of lymphocytes increased when images revealed inflammation absorption. Although the CT images showed ground-glass opacities in the youngest patient, his lymphocyte count did not decrease with mild clinical symptoms, and the images showed that inflammation was quickly absorbed. Only the oldest patient developed critical illness. The C reaction protein (CRP) levels of Patient 5 increased significantly, and the rate of decline was the slowest, while his condition was the most severe. The clinical manifestations of COVID-19 in this family cluster varied with contact, age, and underlying disease. Lymphocyte count and quality of chest CT images appeared inversely associated with disease severity. CRP changes may be an indicator of disease severity and prognosis.
CELL DISCOVERY
Authors Min Huang, Qing-Bin Lu, Han Zhao, Yulan Zhang, Zhiwei Sui, Liqun Fang, Di Liu, Xiulian Sun, Ke Peng, Wei Liu, Wuxiang Guan
CDC (CENTERS FOR DISEASE CONTROL AND PREVENTION)
Authors Pawinee Doung-ngern, Repeepong Suphanchaimat, Apinya Panjangampatthana, Chawisar Janekrongtham, Duangrat Ruampoom, Nawaporn Daochaeng, Napatchakorn Eungkanit, Nichakul Pisitpayat, Nuengruethai Srisong, Oiythip Yasopa, Patchanee Plernprom, Pitiphon Promduangsi, Panita Kumphon, Paphanij Suangtho, Peeriya Watakulsin, Sarinya Chaiya, Somkid Kripattanapong, Thanawadee Chantian, Emily Bloss, Chawetsan Namwat, Direk Limmathurotsakul
Abstract We evaluated effectiveness of personal protective measures against severe acute respiratory disease coronavirus 2 (SARS-CoV-2) infection. Our case-control study included 211 cases of coronavirus disease (COVID-19) and 839 controls in Thailand. Cases were defined as asymptomatic contacts of COVID-19 patients who later tested positive for SARS-CoV-2; controls were asymptomatic contacts who never tested positive. Wearing masks all the time during contact was independently associated with lower risk for SARS-CoV-2 infection compared with not wearing masks; wearing a mask sometimes during contact did not lower infection risk. We found the type of mask worn was not independently associated with infection and that contacts who always wore masks were more likely to practice social distancing. Maintaining >1 m distance from a person with COVID-19, having close contact for <15 minutes, and frequent handwashing were independently associated with lower risk for infection. Our findings support consistent wearing of masks, handwashing, and social distancing to protect against COVID-19.
Authors Yiqi Ruben Luo, Indrani Chakraborty, Cassandra Yun, Alan H B Wu, Kara L Lynch
Abstract The kinetics of IgG avidity maturation during SARS-CoV-2 infection was studied. The IgG avidity assay used a novel label-free immunoassay technology. It was found that there was a strong correlation between IgG avidity and days since symptom onset, and peak readings were significantly higher in severe than mild disease cases.
Authors Arthur W. D. Edridge, Joanna Kaczorowska, Alexis C. R. Hoste, Margreet Bakker, Michelle Klein, Katherine Loens, Maarten F. Jebbink, Amy Matser, Cormac M. Kinsella, Paloma Rueda, Margareta Ieven, Herman Goossens, Maria Prins, Patricia Sastre, Martin Deijs, Lia van der Hoek
Abstract A key unsolved question in the current coronavirus disease 2019 (COVID-19) pandemic is the duration of acquired immunity. Insights from infections with the four seasonal human coronaviruses might reveal common characteristics applicable to all human coronaviruses. We monitored healthy individuals for more than 35 years and determined that reinfection with the same seasonal coronavirus occurred frequently at 12 months after infection.
Authors David S. Stephens, M. Juliana McElrath
Authors I. Van De Walle, K. Silence, K. Budding, Liesbeth Van de Ven, Kim Dijkxhoorn, Elisabeth de Zeeuw, Cafer Yildiz, Sofie Gabriels, Jean-Michel Percier, Johanna Wildemann, J. Meeldijk, P. J. Simons, L. Boon, L. Cox, R. Holgate, R. Urbanus, H. Otten, J. Leusen, C. Blanchetot, H. de Haard, C. Hack, P. Boross
Authors Alberto Mantovani., Mihai G. Netea
Authors Wen Shi Lee, Adam K. Wheatley, Stephen J. Kent & Brandon J. DeKosky
ABSTRACT Antibody-based drugs and vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being expedited through preclinical and clinical development. Data from the study of SARS-CoV and other respiratory viruses suggest that anti-SARS-CoV-2 antibodies could exacerbate COVID-19 through antibody-dependent enhancement (ADE). Previous respiratory syncytial virus and dengue virus vaccine studies revealed human clinical safety risks related to ADE, resulting in failed vaccine trials. Here, we describe key ADE mechanisms and discuss mitigation strategies for SARS-CoV-2 vaccines and therapies in development. We also outline recently published data to evaluate the risks and opportunities for antibody-based protection against SARS-CoV-2.
Authors Leo Swadling, Mala K. Maini
Authors Lawrence B. Afrin, Leonard B. Weinstock, Gerhard J. Molderings
Abstract Objectives: One-fifth of Covid-19 patients suffer a severely symptomatic, hyperinflammatory course, but specific causes remain unclear. Mast cells (MCs) are activated by SARS-CoV-2. Though only recently recognized, MC activation syndrome (MCAS), usually due to acquired MC clonality, is a chronic multisystem disorder with inflammatory and allergic themes and estimated prevalence of 17%. We describe a novel conjecture explaining how MCAS might cause propensity for severe acute Covid-19 infection and chronic post-Covid-19 illnesses. Methods: Observations of Covid-19 illness in patients with/without MCAS, set against our extensive clinical experience with MCAS. Journal Pre-proof 4 Results: The prevalence of MCAS is concordant with the prevalence of severe cases within the Covid-19-infected population. Much of Covid-19’s hyperinflammation is concordant with manners of inflammation which MC activation can drive. Drugs with activity against MCs or their mediators have been preliminarily observed helpful in Covid-19 patients. None of our treated MCAS patients who have endured Covid-19 infection have suffered severe courses of the infection, let alone mortality. Conclusions: Hyperinflammatory cytokine storms in many severely symptomatic Covid-19 patients may be rooted in aberrant response to SARS-CoV-2 by the dysfunctional MCs of MCAS rather than normal response by normal MCs. If provable, our conjecture has significant therapeutic and prognostic implications.
JEM (JOURNAL OF EXPERIMENTAL MEDICINE)
Authors Youenn Jouan, Antoine Guillon, Loïc Gonzalez, Yonatan Perez, Chloé Boisseau, Stephan Ehrmann, Marion Ferreira, Thomas Daix, Robin Jeannet, Bruno François, Pierre-François Dequin, Mustapha Si-Tahar, Thomas Baranek, Christophe Paget
Authors Wei Li, Alexandra Schäfer Swarali S. Kulkarni Xianglei Liu David R. Martinez Chuan Chen Zehua Sun Sarah R. Leist Aleksandra Drelich Liyong Zhang Marcin L. Ura Alison Berezuk Sagar Chittori Karoline Leopold Dhiraj Mannar Shanti S. Srivastava Xing Zhu Eric C. Peterson Chien-Te Tseng John W. Mellors Darryl Falzarano Sriram Subramaniam Ralph S. Baric Dimiter S. Dimitrov
Authors Yanchun Peng, Alexander J. Mentzer, Guihai Liu, Xuan Yao, Zixi Yin, Danning Dong, Wanwisa Dejnirattisai, Timothy Rostron, Piyada Supasa, Chang Liu, César López-Camacho, Jose Slon-Campos, Yuguang Zhao, David I. Stuart, Guido C. Paesen, Jonathan M. Grimes, Alfred A. Antson, Oliver W. Bayfield, Dorothy E. D. P. Hawkins, De-Sheng Ker, Beibei Wang, Lance Turtle, Krishanthi Subramaniam, Paul Thomson, Ping Zhang, Christina Dold, Jeremy Ratcliff, Peter Simmonds, Thushan de Silva, Paul Sopp, Dannielle Wellington, Ushani Rajapaksa, Yi-Ling Chen, Mariolina Salio, Giorgio Napolitani, Wayne Paes, Persephone Borrow, Benedikt M. Kessler, Jeremy W. Fry, Nikolai F. Schwabe, Malcolm G. Semple, J. Kenneth Baillie, Shona C. Moore, Peter J. M. Openshaw, M. Azim Ansari, Susanna Dunachie, Eleanor Barnes, John Frater, Georgina Kerr, Philip Goulder, Teresa Lockett, Robert Levin, Yonghong Zhang, Ronghua Jing, Ling-Pei Ho, Oxford Immunology Network Covid-19 Response T cell Consortium, ISARIC4C Investigators, Richard J. Cornall, Christopher P. Conlon, Paul Klenerman, Gavin R. Screaton, Juthathip Mongkolsapaya, Andrew McMichael, Julian C. Knight, Graham Ogg, Tao Dong
ABSTRACT The development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and therapeutics will depend on understanding viral immunity. We studied T cell memory in 42 patients following recovery from COVID-19 (28 with mild disease and 14 with severe disease) and 16 unexposed donors, using interferon-γ-based assays with peptides spanning SARS-CoV-2 except ORF1. The breadth and magnitude of T cell responses were significantly higher in severe as compared with mild cases. Total and spike-specific T cell responses correlated with spike-specific antibody responses. We identified 41 peptides containing CD4+ and/or CD8+ epitopes, including six immunodominant regions. Six optimized CD8+ epitopes were defined, with peptide–MHC pentamer-positive cells displaying the central and effector memory phenotype. In mild cases, higher proportions of SARS-CoV-2-specific CD8+ T cells were observed. The identification of T cell responses associated with milder disease will support an understanding of protective immunity and highlights the potential of including non-spike proteins within future COVID-19 vaccine design.
Authors Li Yang, Jianjun Gou, Jianbo Gao, Lan Huang, Zhiqiang Zhu, Shaofei Ji, Hongchun Liu, Lihua Xing, Mengying Yao, Yi Zhang
Authors William T. Hu, J. Christina Howell, Tugba Ozturk, Karima Benameur, Leda C. Bassit, Richard Ramonell, Kevin S. Cashman, Shama Pirmohammed, John D. Roback, Vincent C. Marconi, Irene Yang, Valerie V. Mac, Daniel Smith, Ignacio Sanz, Whitney Wharton, F. Eun-Hyung Lee, Raymond F. Schinazi
Abstract Among patients with coronavirus disease (COVID-19), IgM levels increased early after symptom onset for those with mild and severe disease, but IgG levels increased early only in those with severe disease. A similar pattern was observed in a separate serosurveillance cohort. Mild COVID-19 should be investigated separately from severe COVID-19.
Authors Bart L. Haagmans, Danny Noack, Nisreen M.A. OkbWentao Li, Chunyan Wang, Theo Bestebroer, Rory de Vries, Sander Herfst, Dennis de Meulder, Peter van Run, Mart M. Lamers, Bart Rijnders, Casper Rokx, Frank van Kuppeveld, Frank Grosveld, Dubravka Drabek, Corine Geurtsvan Kessel, Marion Koopmans, Berend Jan Bosch, Thijs Kuiken, Barry Rockx
ABSTRACT Effective clinical intervention strategies for COVID-19 are urgently needed. Although several clinical trials have evaluated the use of convalescent plasma containing virus-neutralizing antibodies, the effectiveness has not been proven. We show that hamsters treated with a high dose of human convalescent plasma or a monoclonal antibody were protected against weight loss showing reduced pneumonia and pulmonary virus replication compared to control animals. However, a ten-fold lower dose of convalescent plasma showed no protective effect. Thus, variable and relatively low levels of virus neutralizing antibodies in convalescent plasma may limit their use for effective antiviral therapy, favouring concentrated, purified (monoclonal) antibodies. Competing Interest Statement A patent application has been filed for antibody 47D11 targeting SARS-CoV-2 (United Kingdom patent application no. 2003632.3; patent applicants: Utrecht University, Erasmus Medical Center and Harbour BioMed). Others declare no competing interests.
Authors Monir Ejemel, Qi Li, Shurong Hou, Zachary A. Schiller, Julia A. Tree, Aaron Wallace, Alla Amcheslavsky, Nese Kurt Yilmaz, Karen R. Buttigieg, Michael J. Elmore, Kerry Godwin, Naomi Coombes, Jacqueline R. Toomey, Ryan Schneider, Anudeep S. Ramchetty, Brianna J. Close, Da-Yuan Chen, Hasahn L. Conway, Mohsan Saeed, Chandrashekar Ganesa, Miles W. Carroll, Lisa A. Cavacini, Mark S. Klempner, Celia A. Schiffer, Yang Wang
ABSTRACT COVID-19 caused by SARS-CoV-2 has become a global pandemic requiring the development of interventions for the prevention or treatment to curtail mortality and morbidity. No vaccine to boost mucosal immunity, or as a therapeutic, has yet been developed to SARS-CoV-2. In this study, we discover and characterize a cross-reactive human IgA monoclonal antibody, MAb362. MAb362 binds to both SARS-CoV and SARS-CoV-2 spike proteins and competitively blocks ACE2 receptor binding, by overlapping the ACE2 structural binding epitope. Furthermore, MAb362 IgA neutralizes both pseudotyped SARS-CoV and SARS-CoV-2 in 293 cells expressing ACE2. When converted to secretory IgA, MAb326 also neutralizes authentic SARS-CoV-2 virus while the IgG isotype shows no neutralization. Our results suggest that SARS-CoV-2 specific IgA antibodies, such as MAb362, may provide effective immunity against SARS-CoV-2 by inducing mucosal immunity within the respiratory system, a potentially critical feature of an effective vaccine.
Authors JasonNeidleman, XiaoyuLuo, JulieFrouard, GuoruiXie, GurjotGill, Ellen S.Stein, MatthewMcGregor, TongcuiMa, Ashley F.George, AstridKosters, Warner C.Greene, JoshuaVasquez, EliverGhosn, SulggiLee, Nadia R.Roan
Authors STANLEY PERLMAN
Authors Julian Braun, Lucie Loyal, Marco Frentsch, Daniel Wendisch, Philipp Georg, Florian Kurth, Stefan Hippenstiel, Manuela Dingeldey, Beate Kruse, Florent Fauchere, Emre Baysal, Maike Mangold, Larissa Henze, Roland Lauster, Marcus A. Mall, Kirsten Beyer, Jobst Röhmel, Sebastian Voigt, Jürgen Schmitz, Stefan Miltenyi, Ilja Demuth, Marcel A. Müller, Andreas Hocke, Martin Witzenrath, Norbert Suttorp, Florian Kern, Ulf Reimer, Holger Wenschuh, Christian Drosten, Victor M. Corman, Claudia Giesecke-Thiel, Leif Erik Sander, Andreas Thiel
Authors Hejun Liu, Nicholas C. Wu, Meng Yuan, ..., Rogier W. Sanders, Andrew B. Ward, Ian A. Wilson
ABSTRACT Most antibodies isolated from COVID-19 patients are specific to SARS-CoV-2. COVA1-16 is a relatively rare antibody that also cross-neutralizes SARS-CoV. Here we determined a crystal structure of COVA1-16 Fab with the SARS-CoV-2 RBD, and a negative-stain EM reconstruction with the spike glycoprotein trimer, to elucidate the structural basis of its cross-reactivity. COVA1-16 binds a highly conserved epitope on the SARS-CoV-2 RBD, mainly through a long CDR H3, and competes with ACE2 binding due to steric hindrance rather than epitope overlap. COVA1-16 binds to a flexible up conformation of the RBD on the spike and relies on antibody avidity for neutralization. These findings, along with structural and functional rationale for the epitope conservation, provide a blueprint for development of more universal SARS-like coronavirus vaccines and therapies. Competing Interest Statement Amsterdam UMC previously filed a patent application on the SARS-CoV-2 antibody COVA1-16 described here.
ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the rapidly unfolding coronavirus disease 2019 (COVID-19) pandemic1,2. Clinical manifestations of COVID-19 vary, ranging from asymptomatic infection to respiratory failure. The mechanisms determining such variable outcomes remain unresolved. Here, we investigated SARS-CoV-2 spike glycoprotein (S)-reactive CD4+ T cells in peripheral blood of patients with COVID-19 and SARS-CoV-2-unexposed healthy donors (HD). We detected SARS-CoV-2 S-reactive CD4+ T cells in 83% of patients with COVID-19 but also in 35% of HD. S-reactive CD4+ T cells in HD reacted primarily to C-terminal S epitopes, which show a higher homology to spike glycoproteins of human endemic coronaviruses, compared to N-terminal epitopes. S-reactive T cell lines generated from SARS-CoV-2-naive HD responded similarly to C-terminal S of human endemic coronaviruses 229E and OC43 and SARS-CoV-2, demonstrating the presence of S-cross-reactive T cells, probably generated during past encounters with endemic coronaviruses. The role of pre-existing SARS-CoV-2 cross-reactive T cells for clinical outcomes remains to be determined in larger cohorts. However, the presence of S-cross-reactive T cells in a sizable fraction of the general population may affect the dynamics of the current pandemic, and has important implications for the design and analysis of upcoming COVID-19 vaccine trials.
NIH
Authors Francis Collins
Authors Carolina Lucas, Patrick Wong, Jon Klein, Tiago B. R. Castro, Julio Silva, Maria Sundaram, Mallory K. Ellingson, Tianyang Mao, Ji Eun Oh, Benjamin Israelow, Takehiro Takahashi, Maria Tokuyama, Peiwen Lu, Arvind Venkataraman, Annsea Park, Subhasis Mohanty, Haowei Wang, Anne L. Wyllie, Chantal B. F. Vogels, Rebecca Earnest, Sarah Lapidus, Isabel M. Ott, Adam J. Moore, M. Catherine Muenker, John B. Fournier, Melissa Campbell, Camila D. Odio, Arnau Casanovas-Massana, Yale IMPACT Team, Roy Herbst, Albert C. Shaw, Ruslan Medzhitov, Wade L. Schulz, Nathan D. Grubaugh, Charles Dela Cruz, Shelli Farhadian, Albert I. Ko, Saad B. Omer, Akiko Iwasaki
ABSTRACT Recent studies have provided insights into the pathogenesis of coronavirus disease 2019 (COVID-19)1–4. Yet, longitudinal immunological correlates of disease outcome remain unclear. Here, we serially analysed immune responses in 113 COVID-19 patients with moderate (non-ICU) and severe (ICU) disease. Immune profiling revealed an overall increase in innate cell lineages with a concomitant reduction in T cell number. We identify an association between early, elevated cytokines and worse disease outcomes. Following an early increase in cytokines, COVID-19 patients with moderate disease displayed a progressive reduction in type-1 (antiviral) and type-3 (antifungal) responses. In contrast, patients with severe disease maintained these elevated responses throughout the course of disease. Moreover, severe disease was accompanied by an increase in multiple type 2 (anti-helminths) effectors including, IL-5, IL-13, IgE and eosinophils. Unsupervised clustering analysis identified 4 immune signatures, representing (A) growth factors, (B) type-2/3 cytokines, (C) mixed type-1/2/3 cytokines, and (D) chemokines that correlated with three distinct disease trajectories of patients. The immune profile of patients who recovered with moderate disease was enriched in tissue reparative growth factor signature (A), while the profile for those with worsened disease trajectory had elevated levels of all four signatures. Thus, we identified development of a maladapted immune response profile associated with severe COVID-19 outcome and early immune signatures that correlate with divergent disease trajectories.
Authors Li Yang, Shasha Liu, Jinyan Liu, Zhixin Zhang, Xiaochun Wan, Bo Huang, Youhai Chen, Yi Zhang
ABSTRACT The recent novel coronavirus disease (COVID-19) outbreak, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is seeing a rapid increase in infected patients worldwide. The host immune response to SARS-CoV-2 appears to play a critical role in disease pathogenesis and clinical manifestations. SARS-CoV-2 not only activates antiviral immune responses, but can also cause uncontrolled inflammatory responses characterized by marked pro-inflammatory cytokine release in patients with severe COVID-19, leading to lymphopenia, lymphocyte dysfunction, and granulocyte and monocyte abnormalities. These SARS-CoV-2-induced immune abnormalities may lead to infections by microorganisms, septic shock, and severe multiple organ dysfunction. Therefore, mechanisms underlying immune abnormalities in patients with COVID-19 must be elucidated to guide clinical management of the disease. Moreover, rational management of the immune responses to SARS-CoV-2, which includes enhancing anti-viral immunity while inhibiting systemic inflammation, may be key to successful treatment. In this review, we discuss the immunopathology of COVID-19, its potential mechanisms, and clinical implications to aid the development of new therapeutic strategies against COVID-19.
Authors Scott J C Pallett, Michael Rayment, Aatish Patel, Sophia A M Fitzgerald-Smith, Sarah J Denny, Esmita Charani, Annabelle L Mai, Kimberly C Gilmour, James Hatcher, Christopher Scott, Paul Randell, Nabeela Mughal, Rachael Jones, Luke S P Moore, Gary W Davies
Authors Bruce J. Tromberg, Tara A. Schwetz,, Eliseo J. Pérez‐Stable, Richard J. Hodes, Richard P. Woychik, Rick A. Bright, Rachael L. Fleurence, Francis S. Collins
Authors Phuong Nguyen-Contant, A. Karim Embong, Preshetha Kanagaiah, Francisco A. Chaves, Hongmei Yang, Angela R. Branche, David J. Topham, Mark Y. Sangstera
ABSTRACT The high susceptibility of humans to SARS-CoV-2 infection, the cause of COVID-19, reflects the novelty of the virus and limited preexisting B cell immunity. IgG against the SARS-CoV-2 spike (S) protein, which carries the novel receptor binding domain (RBD), is absent or at low levels in unexposed individuals. To better understand the B cell response to SARS-CoV-2 infection, we asked whether virus-reactive memory B cells (MBCs) were present in unexposed subjects and whether MBC generation accompanied virus-specific IgG production in infected subjects. We analyzed sera and PBMCs from non-SARS-CoV-2-exposed healthy donors and COVID-19 convalescent subjects. Serum IgG levels specific for SARS-CoV-2 proteins (S, including the RBD and S2 subunit, and nucleocapsid [N]) and non-SARS-CoV-2 proteins were related to measurements of circulating IgG MBCs. Anti-RBD IgG was absent in unexposed subjects. Most unexposed subjects had anti-S2 IgG and a minority had anti-N IgG, but IgG MBCs with these specificities were not detected, perhaps reflecting low frequencies. Convalescent subjects had high levels of IgG against the RBD, S2, and N, together with large populations of RBD- and S2-reactive IgG MBCs. Notably, IgG titers against the S protein of the human coronavirus OC43 in convalescent subjects were higher than in unexposed subjects and correlated strongly with anti-S2 titers. Our findings indicate cross-reactive B cell responses against the S2 subunit that might enhance broad coronavirus protection. Importantly, our demonstration of MBC induction by SARS-CoV-2 infection suggests that a durable form of B cell immunity is maintained even if circulating antibody levels wane. IMPORTANCE Recent rapid worldwide spread of SARS-CoV-2 has established a pandemic of potentially serious disease in the highly susceptible human population. Key questions are whether humans have preexisting immune memory that provides some protection against SARS-CoV-2 and whether SARS-CoV-2 infection generates lasting immune protection against reinfection. Our analysis focused on pre- and post-infection IgG and IgG memory B cells (MBCs) reactive to SARS-CoV-2 proteins. Most importantly, we demonstrate that infection generates both IgG and IgG MBCs against the novel receptor binding domain and the conserved S2 subunit of the SARS-CoV-2 spike protein. Thus, even if antibody levels wane, long-lived MBCs remain to mediate rapid antibody production. Our study also suggests that SARS-CoV-2 infection strengthens preexisting broad coronavirus protection through S2-reactive antibody and MBC formation.
Authors Phuong Nguyen-Contant, A. Karim Embong, Preshetha Kanagaiah, Francisco A. Chaves, Hongmei Yang, Angela R. Branche, David J. Topham, Y. Sangster
ABSTRACT The high susceptibility of humans to SARS-CoV-2 infection, the cause of COVID-19, reflects the novelty of the virus and limited preexisting B cell immunity. IgG against the SARS-CoV-2 spike (S) protein, which carries the novel receptor binding domain (RBD), is absent or at low levels in unexposed individuals. To better understand the B cell response to SARS-CoV-2 infection, we asked whether virus-reactive memory B cells (MBCs) were present in unexposed subjects and whether MBC generation accompanied virus-specific IgG production in infected subjects. We analyzed sera and PBMCs from non-SARS-CoV-2-exposed healthy donors and COVID-19 convalescent subjects. Serum IgG levels specific for SARS-CoV-2 proteins (S, including the RBD and S2 subunit, and nucleocapsid [N]) and non-SARS-CoV-2 proteins were related to measurements of circulating IgG MBCs. Anti-RBD IgG was absent in unexposed subjects. Most unexposed subjects had anti-S2 IgG and a minority had anti-N IgG, but IgG MBCs with these specificities were not detected, perhaps reflecting low frequencies. Convalescent subjects had high levels of IgG against the RBD, S2, and N, together with large populations of RBD- and S2-reactive IgG MBCs. Notably, IgG titers against the S protein of the human coronavirus OC43 in convalescent subjects were higher than in unexposed subjects and correlated strongly with anti-S2 titers. Our findings indicate cross-reactive B cell responses against the S2 subunit that might enhance broad coronavirus protection. Importantly, our demonstration of MBC induction by SARS-CoV-2 infection suggests that a durable form of B cell immunity is maintained even if circulating antibody levels wane.
Authors Matthias Thoms, Robert Buschauer, Michael Ameismeier, Lennart Koepke, Timo Denk, Maximilian Hirschenberger, Hanna Kratzat, Manuel Hayn, Timur Mackens-Kiani, Jingdong Cheng, Jan H. Straub, Christina M. Stürzel, Thomas Fröhlich, Otto Berninghausen, Thomas Becker, Frank Kirchhoff, Konstantin M. J. Sparrer, Roland Beckmann
ABSTRACT SARS-CoV-2 is the causative agent of the current COVID-19 pandemic. A major virulence factor of SARS-CoVs is the nonstructural protein 1 (Nsp1) which suppresses host gene expression by ribosome association. Here, we show that Nsp1 from SARS-CoV-2 binds to the 40S ribosomal subunit, resulting in shutdown of mRNA translation both in vitro and in cells. Structural analysis by cryo-electron microscopy (cryo-EM) of in vitro reconstituted Nsp1-40S and various native Nsp1-40S and -80S complexes revealed that the Nsp1 C terminus binds to and obstructs the mRNA entry tunnel. Thereby, Nsp1 effectively blocks RIG-I-dependent innate immune responses that would otherwise facilitate clearance of the infection. Thus, the structural characterization of the inhibitory mechanism of Nsp1 may aid structure-based drug design against SARS-CoV-2.
Authors Kaja Abbas, Simon R Procter, Kevin van Zandvoort, Andrew Clark, Sebastian Funk, Tewodaj Mengistu, Dan Hogan, Emily Dansereau, Mark Jit, Stefan Flasche,
Authors Zhiqiang Zheng, Vanessa Marthe Monteil , Sebastian Maurer-Stroh , Chow Wenn Yew , Carol Leong , Nur Khairiah Mohd-Ismail, Suganya Cheyyatraivendran Arularasu, Vincent Tak Kwong Chow, Raymond Tzer Pin Lin, Ali Mirazimi , Wanjin Hong, Yee-Joo Tan
ABSTRACT Background A novel coronavirus, SARS-CoV-2, which emerged at the end of 2019 and causes COVID-19, has resulted in worldwide human infections. While genetically distinct, SARS-CoV-1, the aetiological agent responsible for an outbreak of severe acute respiratory syndrome (SARS) in 2002–2003, utilises the same host cell receptor as SARS-CoV-2 for entry: angiotensin-converting enzyme 2 (ACE2). Parts of the SARS-CoV-1 spike glycoprotein (S protein), which interacts with ACE2, appear conserved in SARS-CoV-2. Aim The cross-reactivity with SARS-CoV-2 of monoclonal antibodies (mAbs) previously generated against the S protein of SARS-CoV-1 was assessed. Methods The SARS-CoV-2 S protein sequence was aligned to those of SARS-CoV-1, Middle East respiratory syndrome (MERS) and common-cold coronaviruses. Abilities of mAbs generated against SARS-CoV-1 S protein to bind SARS-CoV-2 or its S protein were tested with SARS-CoV-2 infected cells as well as cells expressing either the full length protein or a fragment of its S2 subunit. Quantitative ELISA was also performed to compare binding of mAbs to recombinant S protein. Results An immunogenic domain in the S2 subunit of SARS-CoV-1 S protein is highly conserved in SARS-CoV-2 but not in MERS and human common-cold coronaviruses. Four murine mAbs raised against this immunogenic fragment could recognise SARS-CoV-2 S protein expressed in mammalian cell lines. In particular, mAb 1A9 was demonstrated to detect S protein in SARS-CoV-2-infected cells and is suitable for use in a sandwich ELISA format. Conclusion The cross-reactive mAbs may serve as useful tools for SARS-CoV-2 research and for the development of diagnostic assays for COVID-19.
Authors Nina Le Bert, Anthony T. Tan, Kamini Kunasegaran, Christine Y. L. Tham, Morteza Hafezi, Adeline Chia, Melissa Hui Yen Chng, Meiyin Lin, Nicole Tan, Martin Linster, Wan Ni Chia, Mark I-Cheng Chen, Lin-Fa Wang, Eng Eong Ooi, Shirin Kalimuddin, Paul Anantharajal Tambyah, Jenny Guek-Hong Low, Yee-Joo Tan, Antonio Bertoletti
ABSTRACT Memory T cells induced by previous pathogens can shape the susceptibility to, and clinical severity of, subsequent infections1. Little is known about the presence of pre-existing memory T cells in humans with the potential to recognize SARS-CoV-2. Here, we first studied T cell responses to structural (nucleocapsid protein, NP) and non-structural (NSP-7 and NSP13 of ORF1) regions of SARS-CoV-2 in COVID-19 convalescents (n=36). In all of them we demonstrated the presence of CD4 and CD8 T cells recognizing multiple regions of the NP protein. We then showed that SARS-recovered patients (n=23) still possess long-lasting memory T cells reactive to SARS-NP 17 years after the 2003 outbreak, which displayed robust cross-reactivity to SARS-CoV-2 NP. Surprisingly, we also frequently detected SARS-CoV-2 specific T cells in individuals with no history of SARS, COVID-19 or contact with SARS/COVID-19 patients (n=37). SARS-CoV-2 T cells in uninfected donors exhibited a different pattern of immunodominance, frequently targeting the ORF-1-coded proteins NSP7 and 13 as well as the NP structural protein. Epitope characterization of NSP7-specific T cells showed recognition of protein fragments with low homology to “common cold” human coronaviruses but conserved amongst animal betacoranaviruses. Thus, infection with betacoronaviruses induces multispecific and long-lasting T cell immunity to the structural protein NP. Understanding how pre-existing NP- and ORF-1-specific T cells present in the general population impact susceptibility and pathogenesis of SARS-CoV-2 infection is of paramount importance for the management of the current COVID-19 pandemic.
Authors Alison Callahan, Ethan Steinberg, Jason A. Fries, Saurabh Gombar, Birju Patel, Conor K. Corbin, Nigam H. Shah
ABSTRACT There is substantial interest in using presenting symptoms to prioritize testing for COVID-19 and establish symptom-based surveillance. However, little is currently known about the specificity of COVID-19 symptoms. To assess the feasibility of symptom-based screening for COVID-19, we used data from tests for common respiratory viruses and SARS-CoV-2 in our health system to measure the ability to correctly classify virus test results based on presenting symptoms. Based on these results, symptom-based screening may not be an effective strategy to identify individuals who should be tested for SARS-CoV-2 infection or to obtain a leading indicator of new COVID-19 cases.
WILEY ONLINE LIBRARY
Authors Brendan Clark, Kay Poulton
ABSTRACT Susceptibility to viral infection, development of immunity, response to treatment and patient clinical outcomes are all under the control of heritable factors in the host. In the context of the current SARS‐Cov‐2 pandemic, this review considers existing immunogenetic knowledge of virus‐immune system interactions. A major focus is to highlight areas in which work is required in order to improve understanding of antiviral immune responses and to move towards improved patient management.
Authors Veerle Matheeussen , Victor M Corman , Oliver Donoso Mantke , Elaine McCulloch , Christine Lammens , Herman Goossens , Daniela Niemeyer , Paul S Wallace , Paul Klapper , Hubert GM Niesters , Christian Drosten , Margareta Ieven
ABSTRACT Laboratory preparedness with quality-assured diagnostic assays is essential for controlling the current coronavirus disease (COVID-19) outbreak. We conducted an external quality assessment study with inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) samples to support clinical laboratories with a proficiency testing option for molecular assays. To analyse SARS-CoV-2 testing performance, we used an online questionnaire developed for the European Union project RECOVER to assess molecular testing capacities in clinical diagnostic laboratories.
Authors Wan Ni Chia , Chee Wah Tan , Randy Foo , Adrian Eng Zheng Kang , Yilong Peng , Velraj Sivalingam , Charles Tiu , Xin Mei Ong , Feng Zhu , Barnaby E. Young , Mark I.-C. Chen , Yee-Joo Tan , David C. Lye , Danielle E. Anderson, Lin-Fa Wang
ABSTRACT In response to the coronavirus disease 2019 (COVID-19) outbreak, caused by SARS-CoV-2, multiple diagnostic tests are required for acute disease diagnosis, contact tracing, monitoring asymptomatic infection rates and assessing herd immunity. While PCR remains the frontline test of choice in the acute diagnostic setting, serological tests are urgently needed. Unlike PCR tests which are highly specific, cross-reactivity is a major challenge for COVID-19 antibody tests considering there are six other coronaviruses known to infect humans. SARS-CoV is genetically related to SARS-CoV-2 sharing approximately 80% sequence identity and both belong to the species SARS related coronavirus in the genus Betacoronavirus of family Coronaviridae. We developed and compared the performance of four different serological tests to comprehensively assess the cross-reactivity between COVID-19 and SARS patient sera. There is significant cross-reactivity when N protein of either virus is used. The S1 or RBD regions from the spike (S) protein offers better specificity. Amongst the different platforms, capture ELISA performed best. We found that SARS survivors all have significant levels of antibodies remaining in their blood 17 years after infection. Anti-N antibodies waned more than anti-RBD antibodies, and the latter is known to play a more important role in providing protective immunity.
Authors Corine H. GeurtsvanKessel, Nisreen M. A. Okba, Zsofia Igloi, Susanne Bogers, Carmen W. E. Embregts, Brigitta M. Laksono, Lonneke Leijten, Casper Rokx, Bart Rijnders, Janette Rahamat-Langendoen, Johannes P. C. van den Akker, Jeroen J. A. van Kampen, Annemiek A. van der Eijk, Rob S. van Binnendijk, Bart Haagmans, Marion Koopmans
ABSTRACT The world is entering a new era of the COVID-19 pandemic in which there is an increasing call for reliable antibody testing. To support decision making on the deployment of serology for either population screening or diagnostics, we present a detailed comparison of serological COVID-19 assays. We show that among the selected assays there is a wide diversity in assay performance in different scenarios and when correlated to virus neutralizing antibodies. The Wantai ELISA detecting total immunoglobulins against the receptor binding domain of SARS CoV-2, has the best overall characteristics to detect functional antibodies in different stages and severity of disease, including the potential to set a cut-off indicating the presence of protective antibodies. The large variety of available serological assays requires proper assay validation before deciding on deployment of assays for specific applications.
CDC
Authors Catherine A. Hogan, Natasha Garamani, Malaya K. Sahoo, ChunHong Huang, James Zehnder, Benjamin A. Pinsky
ABSTRACT To investigate the possibility of earlier cases of severe acute respiratory syndrome coronavirus 2 infection than previously recognized, we retrospectively tested pooled samples from 1,700 persons with respiratory signs/symptoms seen at Stanford Health Care, Palo Alto, California, USA, during the last 2 months of 2019. We found no evidence of earlier infection.
Authors Li Liu , Kelvin Kai-Wang To , Kwok-Hung Chan , Yik-Chun Wong , Runhong Zhou , Ka-Yi Kwan , Carol Ho-Yan Fong , Lin-Lei Chen , Charlotte Yee-Ki Choi , Lu Lu , Owen Tak-Yin Tsang , Wai-Shing Leung , Wing-Kin To , Ivan Fan-Ngai Hung , Kwok-Yung Yuen, Zhiwei Chen
ABSTRACT Coronavirus disease 2019 (COVID-19) has a wide spectrum of disease severity from mild upper respiratory symptoms to respiratory failure. The role of neutralizing antibody (NAb) response in disease progression remains elusive. This study determined the seroprevalence of 733 non-COVID-19 individuals from April 2018 to February 2020 in the Hong Kong Special Administrative Region and compared the neutralizing antibody (NAb) responses of eight COVID-19 patients admitted to the intensive care unit (ICU) with those of 42 patients not admitted to the ICU. We found that NAb against SARS-CoV-2 was not detectable in any of the anonymous serum specimens from the 733 non-COVID-19 individuals. The peak serum geometric mean NAb titer was significantly higher among the eight ICU patients than the 42 non-ICU patients (7280 [95% confidence interval (CI) 1468-36099]) vs 671 [95% CI, 368-1223]). Furthermore, NAb titer increased significantly at earlier infection stages among ICU patients than among non-ICU patients. The median number of days to reach the peak Nab titers after symptoms onset was shorter among the ICU patients (17.6) than that of the non-ICU patients (20.1). Multivariate analysis showed that oxygen requirement and fever during admission were the only clinical factors independently associated with higher NAb titers. Our data suggested that SARS-CoV-2 was unlikely to have silently spread before the COVID-19 emergence in Hong Kong. ICU patients had an accelerated and augmented NAb response compared to non-ICU patients, which was associated with disease severity. Further studies are required to understand the relationship between high NAb response and disease severity.
Authors Deborah Soong, Rachel Leeman, Asha Pillai
ABSTRACT Engineered camelid antibody multimers can potently block SARS-CoV-2 viral entry.
Authors Claudio Napoli, Isabella Tritto, Gelsomina Mansueto, Enrico Coscioni, Giuseppe Ambrosio
Authors National Center for Immunization and Respiratory Diseases (NCIRD), Division of Viral Diseases
Authors Mark W. Hall, Ila Joshi, Luis Leal ,Eng Eong Ooi
ABSTRACT We are learning that the host response to SARS-CoV-2 infection is complex and highly dynamic. Effective initial host defense in the lung is associated with mild symptoms and disease resolution. Viral evasion of the immune response can lead to refractory alveolar damage, ineffective lung repair mechanisms, and systemic inflammation with associated organ dysfunction. The immune response in these patients is highly variable and can include moderate to severe systemic inflammation and/or marked systemic immune suppression. There is unlikely to be a “one size fits all” approach to immunomodulation in patients with COVID-19. We believe that a personalized, immunophenotype-driven approach to immunomodulation that may include anti-cytokine therapy in carefully selected patients and immunostimulatory therapies in others is the shortest path to success in the study and treatment of patients with critical illness due to COVID-19.
Authors Arnaud G. L’Huillier, Giulia Torriani, Fiona Pigny, Laurent Kaiser, Isabella Eckerle
ABSTRACT Children do not seem to drive transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We isolated culture-competent virus in vitro from 12 (52%) of 23 SARS-CoV-2–infected children; the youngest was 7 days old. Our findings show that symptomatic neonates, children, and teenagers shed infectious SARS-CoV-2, suggesting that transmission from them is plausible.
ARS TOSCANA
Authors C. Silvestri, C. Stasi
Authors Dobri Kiprov, Michael J.Conboy, Irina M.Conboy
Authors Daniel B. Larremore, Bryan Wilder, Evan Lester, Soraya Shehata, James M. Burke, James A. Hay, Milind Tambe, Michael J. Mina, Roy Parker
ABSTRACT The COVID-19 pandemic has created a public health crisis. Because SARS-CoV-2 can spread from individuals with pre-symptomatic, symptomatic, and asymptomatic infections, the re-opening of societies and the control of virus spread will be facilitated by robust surveillance, for which virus testing will often be central. After infection, individuals undergo a period of incubation during which viral titers are usually too low to detect, followed by an exponential growth of virus, leading to a peak viral load and infectiousness, and ending with declining viral levels and clearance. Given the pattern of viral load kinetics, we model surveillance effectiveness considering test sensitivities, frequency, and sample-to-answer reporting time. These results demonstrate that effective surveillance, including time to first detection and outbreak control, depends largely on frequency of testing and the speed of reporting, and is only marginally improved by high test sensitivity. We therefore conclude that surveillance should prioritize accessibility, frequency, and sample-to-answer time; analytical limits of detection should be secondary.
COCHRANE LIBRARY
Authors Jonathan J Deeks, Jacqueline Dinnes,Yemisi Takwoingi, Clare Davenport, René Spijker, Sian Taylor-Phillips, Ada Adriano, Sophie Beese, Janine Dretzke, Lavinia Ferrante di Ruffano, Isobel M Harris, Malcolm J Price, Sabine Dittrich, Devy Emperador, Lotty Hooft, Mariska MG Leeflang, Ann Van den Bruel
ABSTRACT Background The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) virus and resulting COVID‐19 pandemic present important diagnostic challenges. Several diagnostic strategies are available to identify current infection, rule out infection, identify people in need of care escalation, or to test for past infection and immune response. Serology tests to detect the presence of antibodies to SARS‐CoV‐2 aim to identify previous SARS‐CoV‐2 infection, and may help to confirm the presence of current infection. Objectives To assess the diagnostic accuracy of antibody tests to determine if a person presenting in the community or in primary or secondary care has SARS‐CoV‐2 infection, or has previously had SARS‐CoV‐2 infection, and the accuracy of antibody tests for use in seroprevalence surveys. Search methods We undertook electronic searches in the Cochrane COVID‐19 Study Register and the COVID‐19 Living Evidence Database from the University of Bern, which is updated daily with published articles from PubMed and Embase and with preprints from medRxiv and bioRxiv. In addition, we checked repositories of COVID‐19 publications. We did not apply any language restrictions. We conducted searches for this review iteration up to 27 April 2020. Selection criteria We included test accuracy studies of any design that evaluated antibody tests (including enzyme‐linked immunosorbent assays, chemiluminescence immunoassays, and lateral flow assays) in people suspected of current or previous SARS‐CoV‐2 infection, or where tests were used to screen for infection. We also included studies of people either known to have, or not to have SARS‐CoV‐2 infection. We included all reference standards to define the presence or absence of SARS‐CoV‐2 (including reverse transcription polymerase chain reaction tests (RT‐PCR) and clinical diagnostic criteria). Data collection and analysis We assessed possible bias and applicability of the studies using the QUADAS‐2 tool. We extracted 2x2 contingency table data and present sensitivity and specificity for each antibody (or combination of antibodies) using paired forest plots. We pooled data using random‐effects logistic regression where appropriate, stratifying by time since post‐symptom onset. We tabulated available data by test manufacturer. We have presented uncertainty in estimates of sensitivity and specificity using 95% confidence intervals (CIs). Main results We included 57 publications reporting on a total of 54 study cohorts with 15,976 samples, of which 8526 were from cases of SARS‐CoV‐2 infection. Studies were conducted in Asia (n = 38), Europe (n = 15), and the USA and China (n = 1). We identified data from 25 commercial tests and numerous in‐house assays, a small fraction of the 279 antibody assays listed by the Foundation for Innovative Diagnostics. More than half (n = 28) of the studies included were only available as preprints. We had concerns about risk of bias and applicability. Common issues were use of multi‐group designs (n = 29), inclusion of only COVID‐19 cases (n = 19), lack of blinding of the index test (n = 49) and reference standard (n = 29), differential verification (n = 22), and the lack of clarity about participant numbers, characteristics and study exclusions (n = 47). Most studies (n = 44) only included people hospitalised due to suspected or confirmed COVID‐19 infection. There were no studies exclusively in asymptomatic participants. Two‐thirds of the studies (n = 33) defined COVID‐19 cases based on RT‐PCR results alone, ignoring the potential for false‐negative RT‐PCR results. We observed evidence of selective publication of study findings through omission of the identity of tests (n = 5). We observed substantial heterogeneity in sensitivities of IgA, IgM and IgG antibodies, or combinations thereof, for results aggregated across different time periods post‐symptom onset (range 0% to 100% for all target antibodies). We thus based the main results of the review on the 38 studies that stratified results by time since symptom onset. The numbers of individuals contributing data within each study each week are small and are usually not based on tracking the same groups of patients over time. Pooled results for IgG, IgM, IgA, total antibodies and IgG/IgM all showed low sensitivity during the first week since onset of symptoms (all less than 30.1%), rising in the second week and reaching their highest values in the third week. The combination of IgG/IgM had a sensitivity of 30.1% (95% CI 21.4 to 40.7) for 1 to 7 days, 72.2% (95% CI 63.5 to 79.5) for 8 to 14 days, 91.4% (95% CI 87.0 to 94.4) for 15 to 21 days. Estimates of accuracy beyond three weeks are based on smaller sample sizes and fewer studies. For 21 to 35 days, pooled sensitivities for IgG/IgM were 96.0% (95% CI 90.6 to 98.3). There are insufficient studies to estimate sensitivity of tests beyond 35 days post‐symptom onset. Summary specificities (provided in 35 studies) exceeded 98% for all target antibodies with confidence intervals no more than 2 percentage points wide. False‐positive results were more common where COVID‐19 had been suspected and ruled out, but numbers were small and the difference was within the range expected by chance. Assuming a prevalence of 50%, a value considered possible in healthcare workers who have suffered respiratory symptoms, we would anticipate that 43 (28 to 65) would be missed and 7 (3 to 14) would be falsely positive in 1000 people undergoing IgG/IgM testing at days 15 to 21 post‐symptom onset. At a prevalence of 20%, a likely value in surveys in high‐risk settings, 17 (11 to 26) would be missed per 1000 people tested and 10 (5 to 22) would be falsely positive. At a lower prevalence of 5%, a likely value in national surveys, 4 (3 to 7) would be missed per 1000 tested, and 12 (6 to 27) would be falsely positive. Analyses showed small differences in sensitivity between assay type, but methodological concerns and sparse data prevent comparisons between test brands. Authors' conclusions The sensitivity of antibody tests is too low in the first week since symptom onset to have a primary role for the diagnosis of COVID‐19, but they may still have a role complementing other testing in individuals presenting later, when RT‐PCR tests are negative, or are not done. Antibody tests are likely to have a useful role for detecting previous SARS‐CoV‐2 infection if used 15 or more days after the onset of symptoms. However, the duration of antibody rises is currently unknown, and we found very little data beyond 35 days post‐symptom onset. We are therefore uncertain about the utility of these tests for seroprevalence surveys for public health management purposes. Concerns about high risk of bias and applicability make it likely that the accuracy of tests when used in clinical care will be lower than reported in the included studies. Sensitivity has mainly been evaluated in hospitalised patients, so it is unclear whether the tests are able to detect lower antibody levels likely seen with milder and asymptomatic COVID‐19 disease. The design, execution and reporting of studies of the accuracy of COVID‐19 tests requires considerable improvement. Studies must report data on sensitivity disaggregated by time since onset of symptoms. COVID‐19‐positive cases who are RT‐PCR‐negative should be included as well as those confirmed RT‐PCR, in accordance with the World Health Organization (WHO) and China National Health Commission of the People's Republic of China (CDC) case definitions. We were only able to obtain data from a small proportion of available tests, and action is needed to ensure that all results of test evaluations are available in the public domain to prevent selective reporting. This is a fast‐moving field and we plan ongoing updates of this living systematic review.
Authors Chris Baraniuk
Authors Francesco Nicoli, Maria Teresa Solis-Soto, Deepak Paudel, Peggy Marconi, Riccardo Gavioli, Victor Appay, Antonella Caputo
Authors Christopher O. Barnes, Anthony P. West, Jr., Kathryn E. Huey-Tubman, ..., Davide F. Robbiani, Michel C. Nussenzweig, Pamela J. Bjorkman
AGING
Authors Guilhem Bousquet, Géraldine Falgarone, David Deutsch, Sophie Derolez, Marilucy Lopez-Sublet, François-Xavier Goudot, Khadaoudj Amari, Yurdagul Uzunhan, Olivier Bouchaud, Frédéric Pamoukdjian
ABSTRACT Background: To assess factors associated with one-month mortality among older inpatients with Covid-19. Results: The mean age was 78 ± 7.8 years, 55.5% were men, CT scan lung damage was observed in 76% of the patients (mild 23%, moderate 38%, extensive 22%, and severe 7%). The mortality rate was 26%. Dependency/Activities of Daily Living (ADL) score ≤ 5/6, D-Dimers, LDH, and no anticoagulation by reference for curative were independently associated with one-month mortality. A score derived from the multivariate model showed good calibration and very good discrimination (Harrell’s C index [95%CI] = 0.83 [0.79-0.87]). Conclusion: ADL-dependency, high serum levels of D-Dimers and LDH and the absence of anticoagulation were independently associated with one-month mortality among older inpatients with Covid-19. Methods: 108 consecutive older inpatients aged 65 and over with Covid-19 confirmed by RT-PCR and/or typical CT chest scan were prospectively included in a French single-centre cohort study from March to April 2020. A systematic geriatric assessment was performed. Covariates were lymphocyte count, serum levels of albumin, C-Reactive Protein, D-Dimers and Lactate Dehydrogenase (LDH), anticoagulation level, and exposure to the hydroxychloroquine and azithromycin combined therapy. Cox uni- and multivariate proportional-hazard regressions were performed to identify predictors of one-month mortality.
Authors Maximilian Muenchhoff, Helga Mairhofer, Hans Nitschko, Natascha Grzimek-Koschewa, Dieter Hoffmann, Annemarie Berger, Holger Rabenau, Marek Widera, Nikolaus Ackermann, Regina Konrad, Sabine Zange, Alexander Graf, Stefan Krebs, Helmut Blum, Andreas Sing, Bernhard Liebl, Roman Wölfel, Sandra Ciesek, Christian Drosten, Ulrike Protzer, Stephan Boehm, Oliver T Keppler
ABSTRACT Containment strategies and clinical management of coronavirus disease (COVID-19) patients during the current pandemic depend on reliable diagnostic PCR assays for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we compare 11 different RT-PCR test systems used in seven diagnostic laboratories in Germany in March 2020. While most assays performed well, we identified detection problems in a commonly used assay that may have resulted in false-negative test results during the first weeks of the pandemic.
Authors Davide F. Robbiani, Christian Gaebler, Michel C. Nussenzweig
ABSTRACT During the COVID-19 pandemic, SARS-CoV-2 infected millions of people and claimed hundreds of thousands of lives. Virus entry into cells depends on the receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S). Although there is no vaccine, it is likely that antibodies will be essential for protection. However, little is known about the human antibody response to SARS-CoV-21–5. Here we report on 149 COVID-19 convalescent individuals. Plasmas collected an average of 39 days after the onset of symptoms had variable half-maximal pseudovirus neutralizing titres: less than 1:50 in 33% and below 1:1,000 in 79%, while only 1% showed titres above 1:5,000. Antibody sequencing revealed expanded clones of RBD-specific memory B cells expressing closely related antibodies in different individuals. Despite low plasma titres, antibodies to three distinct epitopes on RBD neutralized at half-maximal inhibitory concentrations (IC50 values) as low as single digit nanograms per millitre. Thus, most convalescent plasmas obtained from individuals who recover from COVID-19 do not contain high levels of neutralizing activity. Nevertheless, rare but recurring RBD-specific antibodies with potent antiviral activity were found in all individuals tested, suggesting that a vaccine designed to elicit such antibodies could be broadly effective.
Authors Nicolas Vabret, Graham J. Britton, Conor Gruber, Samarth Hegde, Joel Kim, Maria Kuksin, Rachel Levantovsky, Louise Malle, Alvaro Moreira, Matthew D. Park, Luisanna Pia, Emma Risson, Miriam Saffern, Be ́rengere Salome, Myvizhi Esai Selvan, Matthew P. Spindler, Jessica Tan, Verena van der Heide, Jill K. Gregory, Konstantina Alexandropoulos, Nina Bhardwaj, Brian D. Brown, Benjamin Greenbaum, Zeynep H., Dirk Homann, Amir Horowitz, Alice O. Kamphorst, Maria A. Curotto de Lafaille, Saurabh Mehandru, Miriam Merad, Robert M. Samstein
ABSTRACT The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide, igniting an unprecedented effort from the scientific community to understand the biological underpinning of COVID19 pathophysiology. In this Review, we summarize the current state of knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection and the immunological pathways that likely contribute to disease severity and death. We also discuss the rationale and clinical outcome of current therapeutic strategies as well as prospective clinical trials to prevent or treat SARS-CoV-2 infection.
Authors Philip J. M. Brouwer, Tom G. Caniels, Karlijn van der Straten, Jonne L. Snitselaar, Yoann Aldon, Sandhya Bangaru, Jonathan L. Torres, Nisreen M. A. Okba, Mathieu Claireaux, Gius Kerster, Arthur E. H. Bentlage, Marlies M. van Haaren, Denise Guerra, Judith A. Burger, Edith E. Schermer, Kirsten D. Verheul, Niels van der Velde, Alex van der Kooi, Jelle van Schooten, Mariëlle J. van Breemen, Tom P. L. Bijl,Kwinten Sliepen, Aafke Aartse, Ronald Derking, Ilja Bontjer, Neeltje A. Kootstra, W. Joost Wiersinga, Gestur Vidarsson, Bart L. Haagmans, Andrew B. Ward,Godelieve J. de Bree, Rogier W. Sanders, J. van Gils
ABSTRACT The rapid spread of SARS-CoV-2 has a significant impact on global health, travel and economy. Therefore, preventative and therapeutic measures are urgently needed. Here, we isolated monoclonal antibodies from three convalescent COVID-19 patients using a SARS-CoV-2 stabilized prefusion spike protein. These antibodies had low levels of somatic hypermutation and showed a strong enrichment in VH1-69, VH3-30-3 and VH1-24 gene usage. A subset of the antibodies were able to potently inhibit authentic SARS-CoV-2 infection as low as 0.007 μg/mL. Competition and electron microscopy studies illustrate that the SARS-CoV-2 spike protein contains multiple distinct antigenic sites, including several receptor-binding domain (RBD) epitopes as well as non-RBD epitopes. In addition to providing guidance for vaccine design, the antibodies described here are promising candidates for COVID-19 treatment and prevention.
Authors Anna Z. Wec, Daniel Wrapp, Andrew S. Herbert, Daniel P. Maurer, Denise Haslwanter, Mrunal Sakharkar, Rohit K. Jangra, M. Eugenia Dieterle, Asparouh Lilov, Deli Huang, Longping V. Tse, Nicole V. Johnson, Ching-Lin Hsieh, Nianshuang Wang, Juergen H. Nett, Elizabeth Champney, Irina Burnina, Michael Brown, Shu Lin, Melanie Sinclair, Carl Johnson, Sarat Pudi, Robert Bortz III, Ariel S. Wirchnianski, Ethan Laudermilch, Catalina Florez, J. Maximilian Fels, Cecilia M. O’Brien, Barney S. Graham,David Nemazee, Dennis R. Burton, Ralph S. Baric, James E. Voss, Kartik Chandran, John M. Dye, Jason S. McLellan, Laura M. Walker
ABSTRACT Broadly protective vaccines against known and pre-emergent human coronaviruses (HCoVs) are urgently needed. To gain a deeper understanding of cross-neutralizing antibody responses, we mined the memory B cell repertoire of a convalescent SARS donor and identified 200 SARS-CoV-2 binding antibodies that target multiple conserved sites on the spike (S) protein. A large proportion of the non-neutralizing antibodies display high levels of somatic hypermutation and cross-react with circulating HCoVs, suggesting recall of pre-existing memory B cells (MBCs) elicited by prior HCoV infections. Several antibodies potently cross-neutralize SARS-CoV, SARS-CoV-2, and the bat SARS-like virus WIV1 by blocking receptor attachment and inducing S1 shedding. These antibodies represent promising candidates for therapeutic intervention and reveal a target for the rational design of pan-sarbecovirus vaccines.
Authors Alina Baum, Benjamin O. Fulton, Elzbieta Wloga, Richard Copin, Kristen E. Pascal, Vincenzo Russo, Stephanie Giordano, Kathryn Lanza, Nicole Negron, Min Ni, Yi Wei, Gurinder S. Atwal, Andrew J. Murphy, Neil Stahl, George D. Yancopoulos, Christos A. Kyratsous
ABSTRACT Antibodies targeting the spike protein of SARS-CoV-2 present a promising approach to combat the COVID19 pandemic; however, concerns remain that mutations can yield antibody resistance. We investigate the development of resistance against four antibodies to the spike protein that potently neutralize SARS-CoV-2, individually as well as when combined into cocktails. These antibodies remain effective against spike variants that have arisen in the human population. However, novel spike mutants rapidly appeared following in vitro passaging in the presence of individual antibodies, resulting in loss of neutralization; such escape also occurred with combinations of antibodies binding diverse but overlapping regions of the spike protein. Importantly, escape mutants were not generated following treatment with a non-competing antibody cocktail.
Authors RICHARD VIZE
Authors Silvia Stringhini, Ania Wisniak, Giovanni Piumatti, Andrew S Azman, Stephen A Lauer, Hélène Baysson, David De Ridder, Dusan Petrovic, Stephanie Schrempft, Kailing Marcus, Sabine Yerly, Isabelle Arm Vernez, Prof Olivia Keiser, Prof Samia Hurst, Prof Klara M Posfay-Barbe, Prof Didier Trono, Prof Didier Pittet, Laurent Gétaz, Prof François Chappuis, Prof Isabella Eckerle, Prof Nicolas Vuilleumier, Benjamin Meyer, Prof Antoine Flahault, Prof Laurent Kaiser, Prof Idris Guessous,
Authors James R. Gill, Maura E. DeJoseph
Authors Chiara Agrati, Alessandra Sacchi, Veronica Bordoni, Eleonora Cimini, Stefania Notari, Germana Grassi, Rita Casetti, Eleonora Tartaglia, Eleonora Lalle, Alessandra D’Abramo, Concetta Castilletti, Luisa Marchioni, Yufang Shi, Andrea Mariano, Jin-Wen Song, Ji-Yuan Zhang, Fu-Sheng Wang, Chao Zhang, Gian Maria Fimia, Maria R. Capobianchi, Mauro Piacentini, Andrea Antinori, Emanuele Nicastri, Markus Maeurer, Alimuddin Zumla, Giuseppe Ippolito
ABSTRACT SARS-CoV-2 is associated with a 3.4% mortality rate in patients with severe disease. The pathogenesis of severe cases remains unknown. We performed an in-depth prospective analysis of immune and inflammation markers in two patients with severe COVID-19 disease from presentation to convalescence. Peripheral blood from 18 SARS-CoV-2-infected patients, 9 with severe and 9 with mild COVID-19 disease, was obtained at admission and analyzed for T-cell activation profile, myeloid-derived suppressor cells (MDSCs) and cytokine profiles. MDSC functionality was tested in vitro. In four severe and in four mild patients, a longitudinal analysis was performed daily from the day of admission to the early convalescent phase. Early after admission severe patients showed neutrophilia, lymphopenia, increase in effector T cells, a persisting higher expression of CD95 on T cells, higher serum concentration of IL-6 and TGF-β, and a cytotoxic profile of NK and T cells compared with mild patients, suggesting a highly engaged immune response. Massive expansion of MDSCs was observed, up to 90% of total circulating mononuclear cells in patients with severe disease, and up to 25% in the patients with mild disease; the frequency decreasing with recovery. MDSCs suppressed T-cell functions, dampening excessive immune response. MDSCs decline at convalescent phase was associated to a reduction in TGF-β and to an increase of inflammatory cytokines in plasma samples. Substantial expansion of suppressor cells is seen in patients with severe COVID-19. Further studies are required to define their roles in reducing the excessive activation/inflammation, protection, influencing disease progression, potential to serve as biomarkers of disease severity, and new targets for immune and host-directed therapeutic approaches.
Authors Aaron J. Wilk, Arjun Rustagi, Nancy Q. Zhao, Jonasel Roque, Giovanny J. Martínez-Colón, Julia L. McKechnie, Geoffrey T. Ivison, Thanmayi Ranganath, Rosemary Vergara, Taylor Hollis, Laura J. Simpson, Philip Grant, Aruna Subramanian, Angela J. Rogers, Catherine A. Blish
ABSTRACT There is an urgent need to better understand the pathophysiology of Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, which has infected more than three million people worldwide1. Approximately 20% of patients with COVID-19 develop severe disease and 5% of patients require intensive care2. Severe disease has been associated with changes in peripheral immune activity, including increased levels of pro-inflammatory cytokines3,4 that may be produced by a subset of inflammatory monocytes5,6, lymphopenia7,8 and T cell exhaustion9,10. To elucidate pathways in peripheral immune cells that might lead to immunopathology or protective immunity in severe COVID-19, we applied single-cell RNA sequencing (scRNA-seq) to profile peripheral blood mononuclear cells (PBMCs) from seven patients hospitalized for COVID-19, four of whom had acute respiratory distress syndrome, and six healthy controls. We identify reconfiguration of peripheral immune cell phenotype in COVID-19, including a heterogeneous interferon-stimulated gene signature, HLA class II downregulation and a developing neutrophil population that appears closely related to plasmablasts appearing in patients with acute respiratory failure requiring mechanical ventilation. Importantly, we found that peripheral monocytes and lymphocytes do not express substantial amounts of pro-inflammatory cytokines. Collectively, we provide a cell atlas of the peripheral immune response to severe COVID-19.
Authors Milton C. Weinstein, Kenneth A. Freedberg, Emily P. Hyle, A. David Paltiel
Authors Steven Woloshin, Neeraj Patel, Aaron S. Kesselheim
CENTRE FOR DISEASE AND CONTROL PREVENTION
Authors Mi Seon Han, Moon-Woo Seong, Namhee Kim, Sue Shin, Sung Im Cho, Hyunwoong Park, Taek Soo Kim, Sung Sup Park, Eun Hwa Choi
Authors Lorena Porte, Paulette Legarraga, Valeska Vollrath, Ximena Aguilera, José M.Munita, Rafael Araos,Gabriel Pizarro, Pablo Vial ,Mirentxu Iruretagoyena, Sabine Dittrichfg, Thomas Weitzelad
ABSTRACT Objectives In the context of the Covid-19 pandemic, the development and validation of rapid and easy-to-perform diagnostic methods are of high priority. We evaluated a novel rapid antigen detection test (RDT) for SARS-CoV-2 in respiratory samples. Methods The fluorescence immunochromatographic SARS-CoV-2 antigen test (Bioeasy Biotechnology Co., Shenzhen, China) was evaluated using universal transport medium with nasopharyngeal (NP) and oropharyngeal (OP) swabs from suspected Covid-19 cases. Diagnostic accuracy was determined in comparison to SARS-CoV-2 real time (RT)-PCR. Results A total of 127 samples were included; 82 were RT-PCR positive. Median patients’ age was 38 years, 53.5% were male, and 93.7% were from the first week after symptom onset. Overall sensitivity and specificity were 93.9% (CI95% 86.5–97.4) and 100% (CI95% 92.1–100), respectively, with a diagnostic accuracy of 96.1% and Kappa coefficient of 0.9. Sensitivity was significantly higher in samples with high viral loads. Conclusions The evaluated RDT showed a high sensitivity and specificity in samples mainly obtained during the first week of symptoms and with high viral loads, despite the use of a non-validated sample material. The assay has the potential to become an important tool for early diagnosis of SARS-CoV-2, particularly in situations with limited access to molecular methods.
Authors Chek Meng Poh, Guillaume Carissimo, Bei Wang, Siti Naqiah Amrun, Cheryl Yi-Pin Lee, Rhonda Sin-Ling Chee, Siew-Wai Fong, Nicholas Kim-Wah Yeo, Wen-Hsin Lee, Anthony Torres-Ruesta, Yee-Sin Leo, Mark I-Cheng Chen, Seow-Yen Tan, Louis Yi Ann Chai, Shirin Kalimuddin, Shirley Seah Gek Kheng, Siew-Yee Thien, Barnaby Edward Young, David C. Lye, Brendon John Hanson, Cheng-I Wang, Laurent Renia & Lisa F. P. Ng
ABSTRACT Given the ongoing SARS-CoV-2 pandemic, identification of immunogenic targets against the coronavirus spike glycoprotein will provide crucial advances towards the development of sensitive diagnostic tools and potential vaccine candidate targets. In this study, using pools of overlapping linear B-cell peptides, we report two IgG immunodominant regions on SARS-CoV-2 spike glycoprotein that are recognised by sera from COVID-19 convalescent patients. Notably, one is specific to SARS-CoV-2, which is located in close proximity to the receptor binding domain. The other region, which is localised at the fusion peptide, could potentially function as a pan-SARS target. Functionally, antibody depletion assays demonstrate that antibodies targeting these immunodominant regions significantly alter virus neutralisation capacities. Taken together, identification and validation of these neutralising B-cell epitopes will provide insights towards the design of diagnostics and vaccine candidates against this high priority coronavirus.
Authors Liang Shen, Chunhua Wang, Jianzhong Zhao, Xiaoyong Tang, Ying Shen, Mingqing Lu, Zhe Ding, Canping Huang, Ji Zhang, Shichao Li, Jiaming Lan, Gary Wong, Yufang Zhu
ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly worldwide since it was confirmed as the causative agent of COVID-19. Molecular diagnosis of the disease is typically performed via nucleic acid-based detection of the virus from swabs, sputum or bronchoalveolar lavage fluid (BALF). However, the positive rate from the commonly used specimens (swabs or sputum) was less than 75%. Immunological assays for SARS-CoV-2 are needed to accurately diagnose COVID-19. Sera were collected from patients or healthy people in a local hospital in Xiangyang, Hubei Province, China. The SARS-CoV-2 specific IgM antibodies were then detected using a SARS-CoV-2 IgM colloidal gold immunochromatographic assay (GICA). Results were analysed in combination with sera collection date and clinical information. The GICA was found to be positive with the detected 82.2% (37/45) of RT-qPCR confirmed COVID-19 cases, as well as 32.0% (8/25) of clinically confirmed, RT-qPCR negative patients (4–14 days after symptom onset). Investigation of IgM-negative, RT-qPCR-positive COVID-19 patients showed that half of them developed severe disease. The GICA was found to be a useful test to complement existing PCR-based assays for confirmation of COVID-19, and a delayed specific IgM antibody response was observed among COVID-19 patients with severe progression.
Authors Valentina Giardini, Andrea Carrer, Marco Casati, Ernesto Contro, Patrizia Vergani, Carlo Gambacorti‐Passerini
The Lancet
Authors Nuno Sampaio Osório, Margarida Correia-Neves
FRONTIERS IN IMMUNOLOGY
Authors Luciano Mutti, Francesca Pentimalli, Giovanni Baglio, Patrizia Maiorano, Rita Emilena Saladino, Pierpaolo Correale, Antonio Giordano
Authors Bin Ju, Qi Zhang, Jiwan Ge, Ruoke Wang, Jing Sun, Xiangyang Ge, Jiazhen Yu, Sisi Shan, Bing Zhou, Shuo Song, Xian Tang, Jinfang Yu, Jun Lan, Jing Yuan, Haiyan Wang, Juanjuan Zhao, Shuye Zhang, Youchun Wang, Xuanling Shi, Lei Liu, Jincun Zhao, Xinquan Wang, Zheng Zhang & Linqi Zhang
ABSTRACT The emerging coronavirus SARS-CoV-2 pandemic presents a global health emergency in urgent need of interventions1–3. SARS-CoV-2 entry into the target cells depends on binding between the receptor-binding domain (RBD) of the viral Spike protein and the ACE2 cell receptor2,4–6. Here, we report the isolation and characterization of 206 RBD-specific monoclonal antibodies derived from single B cells of eight SARS-CoV-2 infected individuals. We identified antibodies with potent anti-SARS-CoV-2 neutralization activity that correlates with their competitive capacity with ACE2 for RBD binding. Surprisingly, neither the anti-SARS-CoV-2 antibodies nor the infected plasma cross-reacted with SARS-CoV or MERS-CoV RBDs, although substantial plasma cross-reactivity to their trimeric Spike proteins was found. Crystal structure analysis of RBD-bound antibody revealed steric hindrance that inhibits viral engagement with ACE2 and thereby blocks viral entry. These findings suggest that anti-RBD antibodies are viral species-specific inhibitors. The antibodies identified here may be candidates for the development of SARS-CoV-2 clinical interventions.
Authors Rui Shi, Chao Shan, Xiaomin Duan, Zhihai Chen, Peipei Liu, Jinwen Song, Tao Song, Xiaoshan Bi, Chao Han, Lianao Wu, Ge Gao, Xue Hu, Yanan Zhang, Zhou Tong, Weijin Huang, William Jun Liu, Guizhen Wu, Bo Zhang, Lan Wang, Jianxun Qi, Hui Feng, Fu-sheng Wang, Qihui Wang, George Fu Gao, Zhiming Yuan & Jinghua Yan
ABSTRACT An outbreak of the coronavirus disease 2019 (COVID-19)1–3, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)4 spread globally. Countermeasures are needed to treat and prevent further dissemination of the virus. In this study, we report the isolation of 2 specific human monoclonal antibodies (MAbs) from a convalescent COVID-19 patient. CA1 and CB6 demonstrated potent SARS-CoV-2-specific neutralization activity in vitro against SARS-CoV-2. In addition, CB6 inhibited SARS-CoV-2 infection in rhesus monkeys at both prophylactic and treatment settings. Further structural studies revealed that CB6 recognizes an epitope that overlaps with angiotensin converting enzyme 2 (ACE2)-binding sites in SARS-CoV-2 receptor binding domain (RBD), thereby interfering with the virus/receptor interactions by both steric hindrance and direct interface-residue competition. Our results suggest CB6 deserves further clinical translation.
Authors Davide F. Robbiani, Christian Gaebler, Frauke Muecksch, Julio C. C. Lorenzi, Zijun Wang, Alice Cho, Marianna Agudelo, Christopher O. Barnes, Anna Gazumyan, Shlomo Finkin, Thomas Hagglof, Thiago Y. Oliveira, Charlotte Viant, Arlene Hurley, Hans-Heinrich Hoffmann, Katrina G. Millard, Rhonda G. Kost, Melissa Cipolla, Kristie Gordon, Filippo Bianchini, Spencer T. Chen, Victor Ramos, Roshni Patel, Juan Dizon, Irina Shimeliovich, Pilar Mendoza, Harald Hartweger, Lilian Nogueira, Maggi Pack, Jill Horowitz, Fabian Schmidt, Yiska Weisblum, Eleftherios Michailidis, Alison W. Ashbrook, Eric Waltari, John E. Pak, Kathryn E. Huey-Tubman, Nicholas Koranda, Pauline R. Hoffman, Anthony P. West Jr., Charles M. Rice, Theodora Hatziioannou, Pamela J. Bjorkman, Paul D. Bieniasz, Marina Caskey, Michel C. Nussenzweig
ABSTRACT During the COVID-19 pandemic, SARS-CoV-2 infected millions of people and claimed hundreds of thousands of lives. Virus entry into cells depends on the receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S). Although there is no vaccine, it is likely that antibodies will be essential for protection. However, little is known about the human antibody response to SARS-CoV-21–5. Here we report on 149 COVID-19 convalescent individuals. Plasmas collected an average of 39 days after the onset of symptoms had variable half-maximal neutralizing titers ranging from undetectable in 33% to below 1:1000 in 79%, while only 1% showed titers >1:5000. Antibody cloning revealed expanded clones of RBD-specific memory B cells expressing closely related antibodies in different individuals. Despite low plasma titers, antibodies to three distinct epitopes on RBD neutralized at half-maximal inhibitory concentrations (IC50s) as low as single digit ng/mL. Thus, most convalescent plasmas obtained from individuals who recover from COVID-19 do not contain high levels of neutralizing activity. Nevertheless, rare but recurring RBD-specific antibodies with potent antiviral activity were found in all individuals tested, suggesting that a vaccine designed to elicit such antibodies could be broadly effective.
Authors Bruno Tilocca, Alessio Soggiu, Maurizio Sanguinetti, Gabriele Babini, Flavio De Maio, Domenico Britti, Alfonso Zecconi, Luigi Bonizzi, Andrea Urbani, Paola Roncada
ABSTRACT Envelope protein of coronaviruses is a structural protein existing in both monomeric and homo-pentameric form. It has been related to a multitude of roles including virus infection, replication, dissemination and immune response stimulation. In the present study, we employed an immunoinformatic approach to investigate the major immunogenic domains of the SARS-CoV-2 envelope protein and map them among the homologue proteins of coronaviruses with tropism for animal species that are closely inter-related with the human beings population all over the world. Also, when not available, we predicted the envelope protein structural folding and mapped SARS-CoV-2 epitopes. Envelope sequences alignment provides evidence of high sequence homology for some of the investigated virus specimens; while the structural mapping of epitopes resulted in the interesting maintenance of the structural folding and epitope sequence localization also in the envelope proteins scoring a lower alignment score. In line with the One-Health approach, our evidences provide a molecular structural rationale for a potential role of taxonomically related coronaviruses in conferring protection from SARS-CoV-2 infection and identifying potential candidates for the development of diagnostic tools and prophylactic-oriented strategies.
Authors Alba Grifoni, Daniela Weiskopf, Sydney I. Ramirez, Jose Mateus, Jennifer M. Dan, Carolyn Rydyznski Moderbacher, Stephen A. Rawlings, Aaron Sutherland, Lakshmanane Premkumar, Ramesh S. Jadi, Daniel Marrama, Aravinda M. de Silva, April Frazier, Aaron Carlin, Jason A. Greenbaum, Bjoern Peters, Florian Krammer, Davey M. Smith, Shane Crotty, Alessandro Sette
Authors Jixin Zhong, Jungen Tang, Cong Ye, Lingli Dong
Authors Dora Pinto, Young-Jun Park, Martina Beltramello, Alexandra C. Walls, M. Alejandra Tortorici, Siro Bianchi, Stefano Jaconi, Katja Culap, Fabrizia Zatta, Anna De Marco, Alessia Peter, Barbara Guarino, Roberto Spreafico, Elisabetta Cameroni, James Brett Case, Rita E. Chen, Colin Havenar-Daughton, Gyorgy Snell, Amalio Telenti, Herbert W. Virgin, Antonio Lanzavecchia, Michael S. Diamond, Katja Fink, David Veesler, Davide Corti
ABSTRACT SARS-CoV-2 is a newly emerged coronavirus responsible for the current COVID-19 pandemic that has resulted in more than 3.7 million infections and 260,000 deaths as of 6 May 20201,2. Vaccine and therapeutic discovery efforts are paramount to curb the pandemic spread of this zoonotic virus. The SARS-CoV-2 spike (S) glycoprotein promotes entry into host cells and is the main target of neutralizing antibodies. Here we describe multiple monoclonal antibodies targeting SARS-CoV-2 S identified from memory B cells of an individual who was infected with SARS-CoV in 2003. One antibody, named S309, potently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2 by engaging the S receptor-binding domain. Using cryo-electron microscopy and binding assays, we show that S309 recognizes a glycan-containing epitope that is conserved within the sarbecovirus subgenus, without competing with receptor attachment. Antibody cocktails including S309 along with other antibodies identified here further enhanced SARS-CoV-2 neutralization and may limit the emergence of neutralization-escape mutants. These results pave the way for using S309- and S309-containing antibody cocktails for prophylaxis in individuals at high risk of exposure or as a post-exposure therapy to limit or treat severe disease.
Authors Jialin Teng, Jin Dai, Yutong Su, Zhuochao Zhou, Huihui Chi, Liyan Wan, Jianfen Meng, Zhihong Wang, Fan Wang, Yuning Ma, Qiongyi Hu, Xiaobing Cheng, Honglei Liu, Junna Ye, Hui Shi, Yue Sun, Chengde Yang, Xuefeng Wang
Authors Gregory A. Storch
Authors Nigel Curtis, Annie Sparrow, Tedros A Ghebreyesus, Mihai G Netea
Cellular & Molecular Immunology
Authors Chunyan Yi, Xiaoyu Sun, Jing Ye, Longfei Ding, Meiqin Liu, Zhuo Yang, Xiao Lu, Yaguang Zhang, Liyang Ma, Wangpeng Gu, Aidong Qu, Jianqing Xu, Zhengli Shi, Zhiyang Ling, Bing Sun
ABSTRACT Coronavirus disease 2019 (COVID-19), caused by the novel human coronavirus SARS-CoV-2, is currently a major threat to public health worldwide. The viral spike protein binds the host receptor angiotensin-converting enzyme 2 (ACE2) via the receptor-binding domain (RBD), and thus is believed to be a major target to block viral entry. Both SARS-CoV-2 and SARS-CoV share this mechanism. Here we functionally analyzed the key amino acid residues located within receptor binding motif of RBD that may interact with human ACE2 and available neutralizing antibodies. The in vivo experiments showed that immunization with either the SARS-CoV RBD or SARS-CoV-2 RBD was able to induce strong clade-specific neutralizing antibodies in mice; however, the cross-neutralizing activity was much weaker, indicating that there are distinct antigenic features in the RBDs of the two viruses. This finding was confirmed with the available neutralizing monoclonal antibodies against SARS-CoV or SARS-CoV-2. It is worth noting that a newly developed SARS-CoV-2 human antibody, HA001, was able to neutralize SARS-CoV-2, but failed to recognize SARS-CoV. Moreover, the potential epitope residues of HA001 were identified as A475 and F486 in the SARS-CoV-2 RBD, representing new binding sites for neutralizing antibodies. Overall, our study has revealed the presence of different key epitopes between SARS-CoV and SARS-CoV-2, which indicates the necessity to develop new prophylactic vaccine and antibody drugs for specific control of the COVID-19 pandemic although the available agents obtained from the SARS-CoV study are unneglectable.
Authors Rachel E Jordan, Peymane Adab
ABSTRACT The rapid spread of the corona virus pandemic is an existential problem for many people in numerous countries. So far, there is no effective vaccine protection or proven therapy available against the SARS-CoV-2 virus. In this review, we describe the role of passive immunization in times of the corona virus. Passive immunization could be a bridging technology to improve the immune defense of critically ill patients until better approaches with effective medications are available.
BMW
Authors Johannes C. Fischer, Kurt Zänker, Martijn van Griensven, Marion Schneider, Detlef Kindgen-Milles, Wolfram Trudo Knoefel, Artur Lichtenberg, Balint Tamaskovics, Freddy Joel Djiepmo-Njanang, Wilfried Budach, Stefanie Corradini, Ute Ganswindt, Dieter Häussinger, Torsten Feldt, Hubert Schelzig, Hans Bojar, Matthias Peiper, Edwin Bölke, Jan Haussmann, Christiane Matuschek
Authors Prannoy Paul
Authors Giorgia Guglielmi
Authors Dennis McGonagle, James S O’Donnell, Kassem Sharif, Paul Emery, Charles Bridgewood
Authors Roos E Barth, Marieke J A De Regt
Authors Nandini Sethuraman, Sundararaj Stanleyraj Jeremiah; Akihide Ryo
Authors Rita Carsetti, Concetta Quintarelli, Isabella Quinti, Eva Piano Mortari, Alimuddin Zumla, Giuseppe Ippolito, Franco Locatelli
Authors Michael C. Wehrhahna, Jennifer Robsonb, Suzanne Brownc, Evan Bursleb, Shane Byrneb, David Newd, Smathi Chongd, James P. Newcombea,Terri Siverstena, Narelle Hadlowd
ABSTRACT Objectives To evaluate the reliability of self-collection for SARS-CoV-2 and other respiratory viruses because swab collections for SARS-CoV-2 put health workers at risk of infection and require use of personal protective equipment (PPE). Methods In a prospective study, patients from two states in Australia attending dedicated COVID-19 collection clinics were offered the option to first self-collect (SC) nasal and throat swabs (SCNT) prior to health worker collect (HC) using throat and nasal swabs (Site 1) or throat and nasopharyngeal swabs (Site 2). Samples were analysed for SARS-CoV-2 as well as common respiratory viruses. Concordance of results between methods was assessed using Cohen's kappa (κ) and Cycle threshold (Ct) values were recorded for all positive results as a surrogate measure for viral load. Results Of 236 patients sampled by HC and SC, 25 had SARS-CoV-2 (24 by HC and 25 by SC) and 63 had other respiratory viruses (56 by HC and 58 by SC). SC was highly concordant with HC (κ = 0.890) for all viruses including SARS-CoV-2 and more concordant than HC to positive results by any method (κ = 0.959 vs 0.933). Mean SARS-CoV-2 E-gene and N-gene, rhinovirus and parainfluenza Ct values did not differ between HC and SCNT. Conclusions Self-collection of nasal and throat swabs offers a reliable alternative to health worker collection for the diagnosis of SARS-CoV-2 and other respiratory viruses and provides patients with easier access to testing, reduces exposure of the community and health workers to those being tested and reduces requirement for PPE.
NATURE COMMUNICATIONS<
Authors Chunyan Wang, Wentao Li, Dubravka Drabek, Nisreen M. A. Okba, Rien van Haperen, Albert D. M. E. Osterhaus, Frank J. M. van Kuppeveld, Bart L. Haagmans, Frank Grosveld & Berend-Jan Bosch
ABSTRACT The emergence of the novel human coronavirus SARS-CoV-2 in Wuhan, China has caused a worldwide epidemic of respiratory disease (COVID-19). Vaccines and targeted therapeutics for treatment of this disease are currently lacking. Here we report a human monoclonal antibody that neutralizes SARS-CoV-2 (and SARS-CoV) in cell culture. This cross-neutralizing antibody targets a communal epitope on these viruses and may offer potential for prevention and treatment of COVID-19.
Authors Zhang Yongchen, Han Shen, Xinning Wang, Xudong Shi, Yang Li, Jiawei Yan, Yuxin Chen, Bing Gu
ABSTRACT Effective strategy to mitigate the ongoing pandemic of 2019 novel coronavirus (COVID-19) require a comprehensive understanding of humoral responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the emerging virus causing COVID-19. The dynamic profile of viral replication and shedding along with viral antigen specific antibody responses among COVID-19 patients started to be reported but there is no consensus on their patterns. Here, we conducted a serial investigation on 21 individuals infected with SARS-CoV-2 in two medical centres from Jiangsu Province, including 11 non-severe COVID-19 patients, and 5 severe COVID-19 patients and 5 asymptomatic carriers based on nucleic acid test and clinical symptoms. The longitudinal swab samples and sera were collected from these people for viral RNA testing and antibody responses, respectively. Our data revealed different pattern of seroconversion among these groups. All 11 non-severe COVID-19 patients and 5 severe COVID-19 patients were seroconverted during hospitalization or follow-up period, suggesting that serological testing is a complementary assay to nucleic acid test for those symptomatic COVID-19 patients. Of note, immediate antibody responses were identified among severe cases, compared to non-severe cases. On the other hand, only one were seroconverted for asymptomatic carriers. The SARS-CoV-2 specific antibody responses were well-maintained during the observation period. Such information is of immediate relevance and would assist COVID-19 clinical diagnosis, prognosis and vaccine design.
BMJ
Authors Elisabeth Mahase
NATURE MEDICINE
Authors Quan-Xin Long, Bai-Zhong Liu, Hai-Jun Deng, Gui-Cheng Wu, Kun Deng, Yao-Kai Chen, Pu Liao, Jing-Fu Qiu, Yong Lin, Xue-Fei Cai, De-Qiang Wang, Yuan Hu, Ji-Hua Ren, Ni Tang, Yin-Yin Xu, Li-Hua Yu, Zhan Mo, Fang Gong, Xiao-Li Zhang, Wen-Guang Tian, Li Hu, Xian-Xiang Zhang, Jiang-Lin Xiang, Hong-Xin Du, Hua-Wen Liu, Chun-Hui Lang, Xiao-He Luo, Shao-Bo Wu, Xiao-Ping Cui, Zheng Zhou, Man-Man Zhu, Jing Wang, Cheng-Jun Xue, Xiao-Feng Li, Li Wang, Zhi-Jie Li, Kun Wang, Chang-Chun Niu, Qing-Jun Yang, Xiao-Jun Tang, Yong Zhang, Xia-Mao Liu, Jin-Jing Li, De-Chun Zhang, Fan Zhang, Ping Liu, Jun Yuan, Qin Li, Jie-Li Hu, Juan Chen & Ai-Long Huang
ABSTRACT We report acute antibody responses to SARS-CoV-2 in 285 patients with COVID-19. Within 19 days after symptom onset, 100% of patients tested positive for antiviral immunoglobulin-G (IgG). Seroconversion for IgG and IgM occurred simultaneously or sequentially. Both IgG and IgM titers plateaued within 6 days after seroconversion. Serological testing may be helpful for the diagnosis of suspected patients with negative RT–PCR results and for the identification of asymptomatic infections.
Authors Antonio M. Risitano, Dimitrios C. Mastellos , Markus Huber-Lang, Despina Yancopoulou Cecilia Garlanda Fabio Ciceri and John D. Lambris
Authors Farzad Taghizadeh-Hesarya, Hassan Akbaria
ABSTRACT On March 11, 2020, the World Health Organization declared the coronavirus outbreak a pandemic. Since December 2019, the world has experienced an outbreak of coronavirus disease 2019 (COVID-19). Epidemiology, risk factors, and clinical characteristics of patients with COVID-19 have been reported but the factors affecting the immune system against COVID-19 have not been well described. In this article, we provide a novel hypothesis to describe how an increase in cellular adenosine triphosphate (c-ATP) can potentially improve the efficiency of innate and adaptive immune systems to either prevent and fight off COVID-19.
WILEY
Authors Cristina De RosE Riccardo Inchingolo Andrea Smargiassi Giuseppe Zampino Piero Valentini Danilo Buonsenso
Authors Amy K Winter, Sonia T Hegde
Authors Christine Dahlke, Jasmin Heidepriem, Robin Kobbe, Rene Santer, Till Koch, Anahita Fathi, My L. Ly, Stefan Schmiedel, Peter H. Seeberger,, Marylyn M. Addo, Felix F. Loeffler
ABSTRACT SARS-CoV-2 is the causative agent of COVID-19 and is a severe threat to global health. Patients infected with SARS-CoV-2 show a wide range of symptoms and disease severity, while limited data is available on its immunogenicity. Here, the kinetics of the development of SARS-CoV-2-specific antibody responses in relation to clinical features and dynamics of specific B-cell populations are reported. Immunophenotyping of B cells was performed by flow cytometry with longitudinally collected PBMCs. In parallel, serum samples were analyzed for the presence of SARS-CoV-2-specific IgA, IgG, and IgM antibodies using whole proteome peptide microarrays. Soon after disease onset in a mild case, we observed an increased frequency of plasmablasts concomitantly with a strong SARS-CoV-2-specific IgA response. In contrast, a case with more severe progression showed a delayed, but eventually very strong and broad SARS-CoV-2-specific IgA response. This case study shows that determining SARS-CoV-2-specific antibody epitopes can be valuable to monitor the specificity and magnitude of the early B-cell response, which could guide the development of vaccine candidates. Follow-up studies are required to evaluate whether the kinetics and strength of the SARS-CoV-2-specific IgA response could be potential prognostic markers of viral control.
Authors Wayne C. Koff, Michelle A. Williams
Authors JENNIFER ABBASI
Science
Authors Janelle S. Ayres
Authors Xiaohua Chen, Binghong Zhao, Yueming Qu, Yurou Chen, Jie Xiong, Yong Feng, Dong Men, Qianchuan Huang, Ying Liu, Bo Yang, Jinya Ding, Feng Li
Background Although the detection of SARS-CoV-2 viral load in respiratory specimens has been widely used to diagnose coronavirus disease-19 (COVID-19), it is undeniable that serum SARS-CoV-2 nucleic acid (RNAaemia) could be detected in a fraction of COVID-19 patients. However, it is not clear whether testing for RNAaemia is correlated with the occurrence of cytokine storms or with the specific class of patients.
NATURE BIOTECHNOLOGY
ABSTRACT An outbreak of betacoronavirus severe acute respiratory syndrome (SARS)-CoV-2 began in Wuhan, China in December 2019. COVID-19, the disease associated with SARS-CoV-2 infection, rapidly spread to produce a global pandemic. We report development of a rapid (<40 min), easy-to-implement and accurate CRISPR–Cas12-based lateral flow assay for detection of SARS-CoV-2 from respiratory swab RNA extracts. We validated our method using contrived reference samples and clinical samples from patients in the United States, including 36 patients with COVID-19 infection and 42 patients with other viral respiratory infections. Our CRISPR-based DETECTR assay provides a visual and faster alternative to the US Centers for Disease Control and Prevention SARS-CoV-2 real-time RT–PCR assay, with 95% positive predictive agreement and 100% negative predictive agreement.
Authors Fatima Amanat, Daniel Stadlbauer, Shirin Strohmeier, Thi Nguyen, Veronika Chromikova, Meagan McMahon, Kaijun Jiang, Guha Asthagiri-Arunkumar, Denise Jurczyszak, Jose Polanco, Maria Bermudez-Gonzalez, Giulio Kleiner, Teresa Aydillo, Lisa Miorin, Daniel Fierer, Luz Amarilis Lugo, Erna Milunka Kojic, Jonathan Stoever, Sean T.H. Liu, Charlotte Cunningham-Rundles, Philip L. Felgner, Daniel Caplivski, Adolfo Garcia-Sastre, Allen Cheng, Katherine Kedzierska, Olli Vapalahti, View ORCID ProfileJussi Hepojoki, Viviana Simon, Florian Krammer, Thomas Moran
ABSTRACT SARS-Cov-2 (severe acute respiratory disease coronavirus 2), which causes Coronavirus Disease 2019 (COVID19) was first detected in China in late 2019 and has since then caused a global pandemic. While molecular assays to directly detect the viral genetic material are available for the diagnosis of acute infection, we currently lack serological assays suitable to specifically detect SARS-CoV-2 antibodies. Here we describe serological enzyme-linked immunosorbent assays (ELISA) that we developed using recombinant antigens derived from the spike protein of SARS-CoV-2. Using negative control samples representing pre-COVID 19 background immunity in the general adult population as well as samples from COVID19 patients, we demonstrate that these assays are sensitive and specific, allowing for screening and identification of COVID19 seroconverters using human plasma/serum as early as two days post COVID19 symptoms onset. Importantly, these assays do not require handling of infectious virus, can be adjusted to detect different antibody types and are amendable to scaling. Such serological assays are of critical importance to determine seroprevalence in a given population, define previous exposure and identify highly reactive human donors for the generation of convalescent serum as therapeutic. Sensitive and specific identification of coronavirus SARS-Cov-2 antibody titers may, in the future, also support screening of health care workers to identify those who are already immune and can be deployed to care for infected patients minimizing the risk of viral spread to colleagues and other patients.
CYTOMETRY
Authors Andrea Cossarizza, Lara Gibellini, Sara De Biasi, Domenico Lo Tartaro, Marco Mattioli, Annamaria Paolini, Lucia Fidanza, Caterina Bellinazzi, Rebecca Borella, Ivana Castaniere, Marianna Meschiari, Marco Sita, Gianrocco Manco, Enrico Clini, Roberta Gelmini, Massimo Girardis, Giovanni Guaraldi, Cristina Mussini
Authors Peking Union Medical College Hospital, Beijing, China
Nature Review
Authors Natalie Vaninov
Authors Anna Petherick
Trends in Immunolog
Authors Shibo Jiang, Christopher Hillyer, Lanying Du
ABSTRACT Coronavirus (CoV) disease 2019 (COVID-19) caused by severe acute respiratory syndrome (SARS)-CoV-2 (also known as 2019-nCoV) is threatening global public health, social stability, and economic development. To meet this challenge, this article discusses advances in the research and development of neutralizing antibodies (nAbs) for the prevention and treatment of infection by SARS-CoV-2 and other human CoVs. Keywords human coronaviruses / SARS-CoV-2 / SARS-CoV / MERS-CoV /neutralizing antibodies
Authors Dennis McGonagle, Kassem Sharifa, Anthony O'Regand, Charlie Bridgewooda
ABSTRACT Severe COVID-19 associated pneumonia patients may exhibit features of systemic hyper-inflammation designated under the umbrella term of macrophage activation syndrome (MAS) or cytokine storm, also known as secondary haemophagocytic lymphohistocytosis (sHLH). This is distinct from HLH associated with immunodeficiency states termed primary HLH -with radically different therapy strategies in both situations. COVID-19 infection with MAS typically occurs in subjects with adult respiratory distress syndrome (ARDS) and historically, non-survival in ARDS was linked to sustained IL-6 and IL-1 elevation. We provide a model for the classification of MAS to stratify the MAS-like presentation in COVID-19 pneumonia and explore the complexities of discerning ARDS from MAS. We discuss the potential impact of timing of anti-cytokine therapy on viral clearance and the impact of such therapy on intra-pulmonary macrophage activation and emergent pulmonary vascular disease.
NCBI
Authors Zhao J, Yuan Q, Wang H, Liu W, Liao X, Su Y, Wang X, Yuan J, Li T, Li J, Qian S, Hong C, Wang F, Liu Y, Wang Z, He Q, Li Z, He B, Zhang T, Fu Y, Ge S, Liu L, Zhang J, Xia N, Zhang Z
Elsevier
Authors Qingqing Lin, Li Zhu, Zuowei Ni, Haitao Meng, Liangshun You
Nature Research
Authors Nidhi Subbaraman
Oxford University Press
Authors Li Guo, Lili Ren, Siyuan Yang, Meng Xiao, De Chang, Fan Yang, Charles S Dela Cruz, Yingying Wang, Chao Wu, Yan Xiao, Lulu Zhang, Lianlian Han, Shengyuan Dang, Yan Xu, Qiwen Yang, Shengyong Xu, Huadong Zhu, Yingchun, Qi Jin, Lokesh Sharma, Linghang Wang, Jianwei Wang
Background Emergence of coronavirus disease 2019 (COVID-19) is a major healthcare threat. Current method of detection involves qPCR-based technique, which identifies the viral nucleic acids when present in sufficient quantity. False negative results can be achieved and failure to quarantine the infected patient would be a major setback in containing the viral transmission. We here aim to describe the time kinetics of various antibodies produced against the 2019 novel coronavirus (SARS-CoV-2) and evaluate the potential of antibody testing to diagnose COVID-19. Methods The host humoral response against SARS-CoV-2 including IgA, IgM and IgG response were examined by using an ELISA based assay on the recombinant viral nucleocapsid protein. Total 208 plasma samples were collected from 82 confirmed and 58 probable cases (qPCR negative but had typical manifestation). The diagnostic value of IgM was evaluated in this cohort. Results The median duration of IgM and IgA antibody detection were 5 days (IQR 3-6), while IgG was detected on 14 days (IQR 10-18) after symptom onset, with a positive rate of 85.4%, 92.7% and 77.9% respectively. In confirmed and probable cases, the positive rates of IgM antibodies were 75.6% and 93.1%, respectively. The detection efficiency by IgM ELISA is higher than that of qPCR method after 5.5 days of symptom onset. The positive detection rate is significantly increased (98.6%) when combined IgM ELISA assay with PCR for each patient compare with a single qPCR test (51.9%). Conclusions Humoral response to SARS-CoV-2 can aid to the diagnosis of COVID-19, including subclinical cases.
novel coronavirus, COVID-19, antibody, ELISA, diagnosis
Authors Li Ran, Xuyu Chen, Ying Wang, Wenwen Wu, Ling Zhang, Xiaodong Tan
Corona Virus Disease 2019 (COVID-19) originated in Wuhan, China has caused many healthcare workers (HCWs) infected. Seventy-two HCWs manifested with acute respiratory illness were retrospectively enrolled to analyze the risk factors. The high-risk department, longer duty hours, and suboptimal hand hygiene after contacting with patients were linked to COVID-19.
risk factors, COVID-19, healthcare workers
NatureMedicine
Authors Irani Thevarajan, Thi H. O. Nguyen, Marios Koutsakos, Julian Druce, Leon Caly, Carolien E. van de Sandt, Xiaoxiao Jia, Suellen Nicholson, Mike Catton4, Benjamin Cowie, Steven Y. C. Tong, Sharon R. Lewin, Katherine Kedzierska
Authors Ruiyun Li, Sen Pei, Bin Chen, Yimeng Song, Tao Zhang, Wan Yang, Jeffrey Shaman
ABSTRACT Estimation of the prevalence and contagiousness of undocumented novel coronavirus (SARS-CoV2) infections is critical for understanding the overall prevalence and pandemic potential of this disease. Here we use observations of reported infection within China, in conjunction with mobility data, a networked dynamic metapopulation model and Bayesian inference, to infer critical epidemiological characteristics associated with SARS-CoV2, including the fraction of undocumented infections and their contagiousness. We estimate 86% of all infections were undocumented (95% CI: [82%–90%]) prior to 23 January 2020 travel restrictions. Per person, the transmission rate of undocumented infections was 55% of documented infections ([46%–62%]), yet, due to their greater numbers, undocumented infections were the infection source for 79% of documented cases. These findings explain the rapid geographic spread of SARS-CoV2 and indicate containment of this virus will be particularly challenging.
Authors Yonggang Zhou, Binqing Fu, Xiaohu Zheng, Dongsheng Wang, Changcheng Zhao, Yingjie qi, Rui Sun, Zhigang Tian, Xiaoling Xu, Haiming Wei
JCI The Journal of Clinical Investigation
Authors Arturo Casadevall, Liise-anne Pirofski
As of early 2020, humanity is confronting a pandemic in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 causes coronavirus disease, abbreviated as COVID-19. At the time of this writing, SARS-CoV-2 is spreading in multiple countries, threatening a pandemic that will affect billions of people. This virus appears to be a new human pathogen. Currently there are no vaccines, monoclonal antibodies (mAbs), or drugs available for SARS-CoV-2, although many are in rapid development and some may be available in a short time. This Viewpoint argues that human convalescent serum is an option for prevention and treatment of COVID-19 disease that could be rapidly available when there are sufficient numbers of people who have recovered and can donate immunoglobulin-containing serum. Passive antibody therapy Passive antibody therapy involves the administration of antibodies against a given agent to a susceptible individual for the purpose of preventing or treating an infectious disease due to that agent. In contrast, active vaccination requires the induction of an immune response that takes time to develop and varies depending on the vaccine recipient. Thus, passive antibody administration is the only means of providing immediate immunity to susceptible persons. Passive antibody therapy has a storied history going back to the 1890s and was the only means of treating certain infectious diseases prior to the development of antimicrobial therapy in [...]
Authors Huanqin Han, Qingfeng Luo, Fan Mo, Lieming Long, Weiqiang Zheng
Wiley Online Library
Authors Zhengtu Li, Yongxiang Yi, Xiaomei Luo, Nian Xiong, Yang Liu, Shaoqiang Li,Ruilin Sun, Yanqun Wang, Bicheng Hu, Wei Chen, Yongchen Zhang, Jing Wang, Baofu Huang, Ye Lin, Jiasheng Yang, Wensheng Cai, Xuefeng Wang, Jing Cheng, Zhiqiang Chen, Kangjun Sun, Weimin Pan, Zhifei Zhan, Liyan Chen, Feng Ye
The outbreak of the novel coronavirus disease (COVID-19) quickly spread all over China and to more than 20 other countries. Although the virus (SARS-Cov-2) nucleic acid RT- PCR test has become the standard method for diagnosis of SARS-CoV-2 infection, these real-time PCR test kits have many limitations. In addition, high false negative rates were reported. There is an urgent need for an accurate and rapid test method to quickly identify large number of infected patients and asymptomatic carriers to prevent virus transmission and assure timely treatment of patients. We have developed a rapid and simple point-of-care lateral flow immunoassay which can detect IgM and IgG antibodies simultaneously against SARS-CoV-2 virus in human blood within 15 minutes which can detect patients at different infection stages. With this test kit, we carried out clinical studies to validate its clinical efficacy uses. The clinical detection sensitivity and specificity of this test were measured using blood samples collected from 397 PCR confirmed COVID-19 patients and 128 negative patients at 8 different clinical sites. The overall testing sensitivity was 88.66% and specificity was 90.63%. In addition, we evaluated clinical diagnosis results obtained from different types of venous and fingerstick blood samples. The results indicated great detection consistency among samples from fingerstick blood, serum and plasma of venous blood. The IgM-IgG combined assay has better utility and sensitivity compared with a single IgM or IgG test. It can be used for the rapid screening of SARS-CoV-2 carriers, symptomatic or asymptomatic, in hospitals, clinics, and test laboratories.
COVID-19, SARS-CoV-2 Virus Infection, Lateral flow immunoassay, rapid IgM-IgG Combined test, fingerstick blood, Point-of-Care Testing
MDPI
Authors Junxiong Pang et all.
ABSTRACT Rapid diagnostics, vaccines and therapeutics are important interventions for the management of the 2019 novel coronavirus (2019-nCoV) outbreak. It is timely to systematically review the potential of these interventions, including those for Middle East respiratory syndrome-Coronavirus (MERS-CoV) and severe acute respiratory syndrome (SARS)-CoV, to guide policymakers globally on their prioritization of resources for research and development. A systematic search was carried out in three major electronic databases (PubMed, Embase and Cochrane Library) to identify published studies in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Supplementary strategies through Google Search and personal communications were used. A total of 27 studies fulfilled the criteria for review. Several laboratory protocols for confirmation of suspected 2019-nCoV cases using real-time reverse transcription polymerase chain reaction (RT-PCR) have been published. A commercial RT-PCR kit developed by the Beijing Genomic Institute is currently widely used in China and likely in Asia. However, serological assays as well as point-of-care testing kits have not been developed but are likely in the near future. Several vaccine candidates are in the pipeline. The likely earliest Phase 1 vaccine trial is a synthetic DNA-based candidate. A number of novel compounds as well as therapeutics licensed for other conditions appear to have in vitro efficacy against the 2019-nCoV. Some are being tested in clinical trials against MERS-CoV and SARS-CoV, while others have been listed for clinical trials against 2019-nCoV. However, there are
The New England Journal of Medicine
Authors Camilla Rothe, Mirjam Schunk, Peter Sothmann, Gisela Bretzel, Guenter Froeschl, Claudia Wallrauch, Thorbjörn Zimmer, Verena Thiel, Christian Janke, Wolfgang Guggemos, Michael Seilmaier, Christian Drosten, Patrick Vollmar, Katrin Zwirglmaier, Sabine Zange, Roman Wölfel, Michael Hoelscher
Authors Daniel K W Chu, Yang Pan, Samuel M S Cheng, Kenrie P Y Hui, Pavithra Krishnan, Yingzhi Liu, Daisy Y M Ng, Carrie K C Wan, Peng Yang, Quanyi Wang, Malik Peiris
BACKGROUND: A novel coronavirus of zoonotic ori- gin (2019-nCoV) has recently been identified in patients with acute respiratory disease. This virus is genetically similar to SARS coronavirus and bat SARS-like coronaviruses. The outbreak was initially detected in Wuhan, a major city of China, but has subsequently been detected in other provinces of China. Travel-associated cases have also been reported in a few other countries. Outbreaks in health care workers indicate human-to-human transmission. Molecular tests for rapid detection of this virus are ur- gently needed for early identification of infected patients. METHODS: We developed two 1-step quantitative real- time reverse-transcription PCR assays to detect two dif- ferent regions (ORF1b and N) of the viral genome. The primer and probe sets were designed to react with this novel coronavirus and its closely related viruses, such as SARS coronavirus. These assays were evaluated using a panel of positive and negative controls. In addition, re- spiratory specimens from two 2019-nCoV-infected patients were tested. RESULTS: Using RNA extracted from cells infected by SARS coronavirus as a positive control, these assays were shown to have a dynamic range of at least seven orders of magnitude (2x104-2000 TCID50/re- action). Using DNA plasmids as positive standards, the detection limits of these assays were found to be below 10 copies per reaction. All negative control sam- ples were negative in the assays. Samples from two 2019-nCoV-infected patients were positive in the tests. CONCLUSIONS: The established assays can achieve a rapid detection of 2019n-CoV in human samples, thereby allowing early identification of patients.
Authors Victor M Corman, Olfert Landt, Marco Kaiser, Richard Molenkamp, Adam Meijer, Daniel KW Chu, Tobias Bleicker, Sebastian Brünink, Julia Schneider, Marie Luisa Schmidt, Daphne GJC Mulders, Bart L Haagmans, Bas van der Veer, Sharon van den Brink, Lisa Wijsman, Gabriel Goderski, Jean-Louis Romette, Joanna Ellis, Maria Zambon, Malik Peiris, Herman Goossens, Chantal Reusken, Marion PG Koopmans, Christian Drosten
The ongoing outbreak of the recently emerged novel coronavirus (2019-nCoV) poses a chal- lenge for public health laboratories as virus isolates are unavailable while there is growing evidence that the outbreak is more widespread than initially thought, and international spread through travellers does already occur. Aim: We aimed to develop and deploy robust diagnostic methodology for use in public health laboratory settings without having virus material avail- able. Methods: Here we present a validated diagnostic workflow for 2019-nCoV, its design relying on close genetic relatedness of 2019-nCoV with SARS coronavi- rus, making use of synthetic nucleic acid technology. Results: The workflow reliably detects 2019-nCoV, and further discriminates 2019-nCoV from SARS-CoV. Through coordination between academic and public laboratories, we confirmed assay exclusivity based on 297 original clinical specimens containing a full spectrum of human respiratory viruses. Control mate- rial is made available through European Virus Archive – Global (EVAg), a European Union infrastructure pro- ject. Conclusion: The present study demonstrates the enormous response capacity achieved through coordi- nation of academic and public laboratories in national and European research networks.
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