Analysis of a SARS-CoV-2-Infected Individual Reveals Development of Potent Neutralizing Antibodies with Limited Somatic Mutation

Seydoux, Emilie; Homad, Leah J.; MacCamy, Anna J.; Parks, K. Rachael; Hurlburt, Nicholas K.; Jennewein, Madeleine F.; Akins, Nicholas R.; Stuart, Andrew B.; Wan, Yu; Feng, Junli; Whaley, Rachael E.; Singh, Suruchi; Boeckh, Michael; Cohen, Kristen W.; McElrath, M. Juliana; Englund, Janet A.; Chu, Helen Y.; Pancera, Marie; McGuire, Andrew T.; Stamatatos, Leonidas

doi:10.1016/j.immuni.2020.06.001

Cited by 379 publications

(463 citation statements)

References 45 publications

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“…5) and the rapid development of potent virus neutralizing antibody responses in macaques after a single dose suggested a minimal requirement for somatic hypermutation (SHM) of the response. This is consistent with recent data showing that neutralizing monoclonal antibodies isolated from SARS CoV-2 convalescent individuals display low levels of SHM 12,27,28 . The polyclonality, antibody germline VDJ usage, and level of SHM that characterizes vaccine-induced SARS CoV-2 spike-induced antibody responses will be a matter of interest, both in the macaque model and in human vaccine trials.…”

Section: Resultssupporting

confidence: 93%

SARS-CoV-2 protein subunit vaccination elicits potent neutralizing antibody responses

Mandolesi

Sheward

Hanke

et al. 2020

Preprint

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The outbreak and spread of SARS-CoV-2 (Severe Acute Respiratory Syndrome coronavirus 2), the cause of coronavirus disease 2019 (COVID-19), is a current global health emergency and a prophylactic vaccine is needed urgently. The spike glycoprotein of SARS-CoV-2 mediates entry into host cells, and thus is a target for neutralizing antibodies and vaccine design. Here we show that adjuvanted protein immunization with SARS-CoV-2 spike trimers, stabilized in prefusion conformation, results in potent antibody responses in mice and rhesus macaques with neutralizing antibody titers orders of magnitude greater than those typically measured in serum from SARS-CoV-2 seropositive humans. Neutralizing antibody responses were observed after a single dose, with exceptionally high titers achieved after boosting. Furthermore, neutralizing antibody titers elicited by a dose-sparing regimen in mice were similar to those obtained from a high dose regimen. Taken together, these data strongly support the development of adjuvanted SARS-CoV-2 prefusion-stabilized spike protein subunit vaccines.

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Section: Resultssupporting

confidence: 93%

SARS-CoV-2 protein subunit vaccination elicits potent neutralizing antibody responses

Mandolesi

Sheward

Hanke

et al. 2020

Preprint

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“…Interestingly, although no sequence variance was observed on M protein from all sequenced COVID-19 cases, two consecutive mutations (K203RR204G) were found in the highly conserved serine-rich linker Eleven and seventeen epitope regions epitopes were found to elicit neutralization antibodies that inhibit the cell entry of D614 and G614 pseudo-virus, respectively. The antibodies induced by four epitopes (S406-420, S439-454, S455-469, and S475-499) but not S366-381 or S495-509 in RBD region exhibited neutralization effect on both D614 and G614 pseudo-virus, which is consistent with the interaction interface between SARS-CoV-2 receptor-binding motif (RBM) and ACE2 (Seydoux et al, 2020;Shang et al, 2020), indicating that these epitopes are suitable for designing universal vaccines. Previous report showed that a cryptic epitope in the trimeric interface of S protein induced neutralization antibodies for SARS-CoV but not SARS-CoV2.…”

Section: Discussionsupporting

confidence: 61%

The immunodominant and neutralization linear epitopes for SARS-CoV-2

Lü

Xie

Zhao

et al. 2020

Preprint

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The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) becomes a tremendous threat to global health. Although vaccines against the virus are under development, the antigen epitopes on the virus and their immunogenicity are poorly understood. Here, we simulated the three-dimensional structures of SARS-CoV-2 proteins with high performance computer, predicted the B cell epitopes on spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins of SARS-CoV-2 using structure-based approaches, and then validated the epitope immunogenicity by immunizing mice. Almost all 33 predicted epitopes effectively induced antibody production, six of which were immunodominant epitopes in patients identified via the binding of epitopes with the sera from domestic and imported COVID-19 patients, and 23 were conserved within SARS-CoV-2, SARS-CoV and bat coronavirus RaTG13. We also found that the immunodominant epitopes of domestic SARS-CoV-2 were different from that of the imported, which may be caused by the mutations on S (G614D) and N proteins. Importantly, we validated that eight epitopes on S protein elicited neutralizing antibodies that blocked the cell entry of both D614 and G614 pseudo-virus of SARS-CoV-2, three and nine epitopes induced D614 or G614 neutralizing antibodies, respectively. Our present study shed light on the immunodominance, neutralization, and conserved epitopes on SARS-CoV-2 which are potently used for the diagnosis, virus classification and the vaccine design tackling inefficiency, virus mutation and different species of coronaviruses.

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“…Second, plasma from the majority of COVID-19 convalescent patients does not contain high levels of neutralizing activity (41). Third, plasma antibodies in infected individuals that do develop neutralizing antibodies are minimally mutated (42). These data suggest that CD8 T cells may contribute to the control of SARS-CoV-2, and while a protracted germinal center response may not be critical for the generation of neutralizing antibodies it could improve antibody durability by enhancing plasma cell numbers.…”

Section: Humoral Responses To Sars-cov-2 Are Dominated By Igg Antibodiesmentioning

confidence: 97%

SARS-CoV-2 infection induces germinal center responses with robust stimulation of CD4 T follicular helper cells in rhesus macaques

Elizaldi

Lakshmanappa

Roh

et al. 2020

Preprint

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ABSTRACTCD4 T follicular helper (Tfh) cells are important for the generation of long-lasting and specific humoral protection against viral infections. The degree to which SARS-CoV-2 infection generates Tfh cells and stimulates the germinal center response is an important question as we investigate vaccine options for the current pandemic. Here we report that, following infection with SARS-CoV-2, adult rhesus macaques exhibited transient accumulation of activated, proliferating Tfh cells in their peripheral blood on a transitory basis. The CD4 helper cell responses were skewed predominantly toward a Th1 response in blood, lung, and lymph nodes, reflective of the interferon-rich cytokine environment following infection. We also observed the generation of germinal center Tfh cells specific for the SARS-CoV-2 spike (S) and nucleocapsid (N) proteins, and a corresponding early appearance of antiviral serum IgG antibodies but delayed or absent IgA antibodies. Our data suggest that a vaccine promoting Th1-type Tfh responses that target the S protein may lead to protective immunity.

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Analysis of a SARS-CoV-2-Infected Individual Reveals Development of Potent Neutralizing Antibodies with Limited Somatic Mutation

Cited by 379 publications

References 45 publications

SARS-CoV-2 protein subunit vaccination elicits potent neutralizing antibody responses

SARS-CoV-2 protein subunit vaccination elicits potent neutralizing antibody responses

The immunodominant and neutralization linear epitopes for SARS-CoV-2

SARS-CoV-2 infection induces germinal center responses with robust stimulation of CD4 T follicular helper cells in rhesus macaques

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