In vitro and in vivo functions of SARS-CoV-2 infection-enhancing and neutralizing antibodies

Li, Dapeng; Edwards, Robert J.; Manne, Kartik; Martinez, David R.; Schäfer, Alexandra; Alam, S. Munir; Wiehe, Kevin; Lu, Xiaozhi; Parks, Robert; Sutherland, Laura L.; Oguin, Thomas H.; McDanal, Charlene; Perez, Lautaro G.; Mansouri, Katayoun; Gobeil, S.; Janowska, Katarzyna; Stalls, Victoria; Kopp, Megan; Cai, Fangping; Lee, Esther; Foulger, Andrew; Hernandéz, Giovanna; Sanzone, Aja; Tilahun, Kedamawit; Jiang, Chuancang; Tse, Longping V.; Bock, Kevin W.; Minai, Mahnaz; Nagata, Bianca M.; Cronin, Kenneth; Gee-Lai, Victoria; Deyton, Margaret; Barr, Maggie; Holle, Tarra Von; Macintyre, Andrew N.; Stover, Erica; Feldman, Jared; Hauser, Blake M.; Caradonna, Timothy M.; Scobey, Trevor; Rountree, Wes; Wang, Yunfei; Moody, M. Anthony; Cain, Derek W.; DeMarco, C. Todd; Denny, Thomas N.; Woods, Christopher W.; Petzold, Elizabeth; Schmidt, Aaron; Teng, I-Ting; Zhou, Tongqing; Kwong, Peter D.; Mascola, John R.; Graham, Barney S.; Moore, Ian N.; Seder, Robert A.; Andersen, Hanné; Lewis, Mark G.; Montefiori, David C.; Sempowski, Gregory D.; Baric, Ralph S.; Acharya, Priyamvada; Haynes, Barton F.; Saunders, Kevin O.

doi:10.1016/j.cell.2021.06.021

Cited by 276 publications

(354 citation statements)

References 104 publications

(93 reference statements)

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“…It is widely accepted that neutralizing serum antibodies provide a strong protective role from SARS-CoV-2 in both nonhuman primates animal models and in humans(D. Li et al, 2021; McMahan et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Large-scale study of antibody titer decay following BNT162b2 mRNA vaccine or SARS-CoV-2 infection

Israel

Shenhar

Green

et al. 2021

Preprint

112

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BackgroundImmune protection following either vaccination or infection with SARS-CoV-2 decreases over time.ObjectiveTo determine the kinetics of SARS-CoV-2 IgG antibodies following administration of two doses of BNT162b2 vaccine, or SARS-CoV-2 infection in unvaccinated individuals.MethodsAntibody titers were measured between January 31, 2021, and July 31, 2021 in two mutually exclusive groups: i) vaccinated individuals who received two doses of BNT162b2 vaccine and had no history of previous infection with COVID-19 and ii) SARS-CoV-2 convalescents who had not received the vaccine.ResultsA total of 2,653 individuals fully vaccinated by two doses of vaccine during the study period and 4,361 convalescent patients were included. Higher SARS-CoV-2 IgG antibody titers were observed in vaccinated individuals (median 1581 AU/mL IQR [533.8-5644.6]) after the second vaccination, than in convalescent individuals (median 355.3 AU/mL IQR [141.2-998.7]; p<0.001). In vaccinated subjects, antibody titers decreased by up to 40% each subsequent month while in convalescents they decreased by less than 5% per month. Six months after BNT162b2 vaccination 16.1% subjects had antibody levels below the seropositivity threshold of <50 AU/mL, while only 10.8% of convalescent patients were below <50 AU/mL threshold after 9 months from SARS-CoV-2 infection.ConclusionsThis study demonstrates individuals who received the Pfizer-BioNTech mRNA vaccine have different kinetics of antibody levels compared to patients who had been infected with the SARS-CoV-2 virus, with higher initial levels but a much faster exponential decrease in the first group.FundingThis research was internally funded by Leumit Health Services (LHS) and was supported in part by the Intramural Research Program, National Institutes of Health, National Cancer Institute, Center for Cancer Research.The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.Impact statementLarge scale study display the kinetics of SARS-CoV-2 IgG antibodies present in individuals vaccinated with two doses of mRNA vaccine vs. unvaccinated patients who had recovered from the disease: initial levels of antibody are much higher in vaccinated patients, but decrease faster.

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Section: Discussionmentioning

confidence: 99%

Large-scale study of antibody titer decay following BNT162b2 mRNA vaccine or SARS-CoV-2 infection

Israel

Shenhar

Green

et al. 2021

Preprint

112

View full text Add to dashboard Cite

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“…S21B and C). In line with binding orientation, many of the δ antibodies were shown to present infection enhancing activities in vitro (54,90). Perhaps correlated with being a "hot" immunogenic site that is amenable to potent neutralization, highly frequent mutations, including a number of deletions within the NTD supersite were identified in most VOCs under ongoing selective pressure, leading to significant reduction and in some cases even complete loss of neutralization activity for these NTD supersite NAbs (94).…”

Section: Low Levels Of Nabs Elicited By Either Natural Infection or Vaccination During In Vivomentioning

confidence: 93%

“…We performed cluster analysis on 26 structures of the NTD-NAb complexes (including 2 structures solved in this manuscript) (fig. S21A) (54,(85)(86)(87)(88)(89)(90)(91)(92)(93). A dominant site α, defined as the "supersite" in more recent studies (85)(86)(87)(88), comprising of three flexible loops (N1, N3 and N5), is the largest glycan-free surface of NTD facing away from the viral membrane (facing up).…”

Section: Low Levels Of Nabs Elicited By Either Natural Infection or Vaccination During In Vivomentioning

confidence: 99%

A third dose of inactivated vaccine augments the potency, breadth, and duration of anamnestic responses against SARS-CoV-2

Wang

Cao

Zhou

et al. 2021

Preprint

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Emergence of variants of concern (VOC) with altered antigenic structures and waning humoral immunity to SARS-CoV-2 are harbingers of a long pandemic. Administration of a third dose of an inactivated virus vaccine can boost the immune response. Here, we have dissected the immunogenic profiles of antibodies from 3-dose vaccinees, 2-dose vaccinees and convalescents. Better neutralization breadth to VOCs, expeditious recall and long-lasting humoral response bolster 3-dose vaccinees in warding off COVID-19. Analysis of 171 complex structures of SARS-CoV-2 neutralizing antibodies identified structure-activity correlates, revealing ultrapotent, VOCs-refractory and broad-spectrum antigenic patches. Construction of immunogenic and mutational heat maps revealed a direct relationship between "hot" immunogenic sites and areas with high mutation frequencies. Ongoing antibody somatic mutation, memory B cell clonal turnover and antibody composition changes in B cell repertoire driven by prolonged and repeated antigen stimulation confer development of monoclonal antibodies with enhanced neutralizing potency and breadth. Our findings rationalize the use of 3-dose immunization regimens for inactivated vaccines.

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“…Antibody-dependent enhancement (ADE), a phenomenon by which cross-reactive antibodies induced by a prior exposure to a related pathogen promote infection of cell types bearing antibody Fc receptors and potentially elevate morbidity and mortality (reviewed in 12,13 ), suggests further potential advantages of a humoral blank slate. Though observed in vitro 14,15 , there has not been abundant evidence for the biological relevance of classical ADE in the context of SARS-CoV-2 in vivo 15,16 . Nonetheless, the role of non-neutralizing antibodies resulting from cross-strain challenges in promoting ADE in cases of dengue fever 17 has motivated concern about COVID-19 enhancement [18][19][20] .…”

Section: Introductionmentioning

confidence: 99%

Boosting of Cross-Reactive Antibodies to Endemic Coronaviruses by SARS-CoV-2 Infection but not Vaccination with Stabilized Spike

Crowley

Natarajan

Hederman

et al. 2021

Preprint

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Pre-existing antibodies to endemic coronaviruses (CoV) that cross-react with SARS-CoV-2 have the potential to influence the antibody response to COVID-19 vaccination and infection for better or worse. In this observational study of mucosal and systemic humoral immunity in acutely infected, convalescent, and vaccinated subjects, we tested for cross reactivity against endemic CoV spike (S) protein at subdomain resolution. Elevated responses, particularly to the β-CoV OC43, were observed in all natural infection cohorts tested and were correlated with the response to SARS-CoV-2. The kinetics of this response and isotypes involved suggest that infection boosts preexisting antibody lineages raised against prior endemic CoV exposure that cross react. While further research is needed to discern whether this recalled response is desirable or detrimental, the boosted antibodies principally targeted the better conserved S2 subdomain of the viral spike and were not associated with neutralization activity. In contrast, vaccination with a stabilized spike mRNA vaccine did not robustly boost cross-reactive antibodies, suggesting differing antigenicity and immunogenicity. In sum, this study provides evidence that antibodies targeting endemic CoV are robustly boosted in response to SARS-CoV-2 infection but not to vaccination with stabilized S, and that depending on conformation or other factors, the S2 subdomain of the spike protein triggers a rapidly recalled, IgG-dominated response that lacks neutralization activity.Graphical AbstractGraphical AbstractAntibody responses to SARS-CoV-2 and endemic CoV spike proteins were measured in diverse cohorts. While antibodies to SARS-CoV-2 were induced across all isotypes, only IgA and IgG responses to endemic CoV were robustly boosted, and only among naturally-infected but not vaccinated individuals. These recalled, cross-reactive responses to endemic CoV primarily recognized the better conserved S2 domain and were non-neutralizing. While other antiviral activities of broadly cross-reactive S2-specifc antibodies are not known, the differing antigenicity of natural infection and vaccination with stabilized pre-fusion spike has potential implications for the breadth and level of protection afforded by each.

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In vitro and in vivo functions of SARS-CoV-2 infection-enhancing and neutralizing antibodies

Cited by 276 publications

References 104 publications

Large-scale study of antibody titer decay following BNT162b2 mRNA vaccine or SARS-CoV-2 infection

Large-scale study of antibody titer decay following BNT162b2 mRNA vaccine or SARS-CoV-2 infection

A third dose of inactivated vaccine augments the potency, breadth, and duration of anamnestic responses against SARS-CoV-2

Boosting of Cross-Reactive Antibodies to Endemic Coronaviruses by SARS-CoV-2 Infection but not Vaccination with Stabilized Spike

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