A Fc-enhanced NTD-binding non-neutralizing antibody delays virus spread and synergizes with a nAb to protect mice from lethal SARS-CoV-2 infection

Beaudoin-Bussières, Guillaume; Chen, Yaozong; Ullah, Irfan; Prévost, Jérémie; Tolbert, W.D.; Symmes, Kelly; Ding, Shilei; Benlarbi, Mehdi; Gong, Shang Yu; Tauzin, Alexandra; Gasser, Romain; Chatterjee, Debashree; Vézina, Dani; Goyette, Guillaume; Richard, Jonathan; Zhou, Fei; Stamatatos, Leonidas; McGuire, Andrew T.; Charest, Hughes; Roger, Michel; Pozharski, Edwin; Kumar, Priti; Mothes, Walther; Uchil, Pradeep D.; Pazgier, M.; Finzi, Andrés

doi:10.1016/j.celrep.2022.110368

Cited by 90 publications

(107 citation statements)

References 115 publications

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“…We observed that intact S309-LS but not S309-GRLR mAb protected K18-hACE2 and hFcγR mice against SARS-CoV-2 variant strains. These results are consistent with prior studies showing a beneficial role of Fc-effector functions in antibody mediated protection in mice and hamsters 25-29 , and may explain why mAbs with markedly different in vitro neutralization potencies against SARS-CoV-2 strains show similar protective activity in animals (https://opendata.ncats.nih.gov/covid19/animal). Furthermore, they also demonstrate that for some mAbs, Fc effector functions can compensate for losses in neutralization potency against SARS-CoV-2 variants and act as a protective mechanism in vivo .…”

Section: Discussionsupporting

confidence: 91%

Resilience of S309 and AZD7442 monoclonal antibody treatments against infection by SARS-CoV-2 Omicron lineage strains

Case

Mackin

Errico

et al. 2022

Preprint

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Omicron variant strains encode large numbers of changes in the spike protein compared to historical SARS-CoV-2 isolates. Although in vitro studies have suggested that several monoclonal antibody therapies lose neutralizing activity against Omicron variants1-4, the effects in vivo remain largely unknown. Here, we report on the protective efficacy against three SARS-CoV-2 Omicron lineage strains (BA.1, BA.1.1, and BA.2) of two monoclonal antibody therapeutics (S309 [Vir Biotechnology] monotherapy and AZD7442 [AstraZeneca] combination), which correspond to ones used to treat or prevent SARS-CoV-2 infections in humans. Despite losses in neutralization potency in cell culture, S309 or AZD7442 treatments reduced BA.1, BA.1.1, and BA.2 lung infection in susceptible mice that express human ACE2 (K18-hACE2). Correlation analyses between in vitro neutralizing activity and reductions in viral burden in K18-hACE2 or human Fc-gamma receptor transgenic mice suggest that S309 and AZD7442 have different mechanisms of protection against Omicron variants, with S309 utilizing Fc effector function interactions and AZD7442 acting principally by direct neutralization. Our data in mice demonstrate the resilience of S309 and AZD7442 mAbs against emerging SARS-CoV-2 variant strains and provide insight into the relationship between loss of antibody neutralization potency and retained protection in vivo.

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Section: Discussionsupporting

confidence: 91%

Resilience of S309 and AZD7442 monoclonal antibody treatments against infection by SARS-CoV-2 Omicron lineage strains

Case

Mackin

Errico

et al. 2022

Preprint

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“…Cross-reactive antibodies could interact with Fc receptors found on the surface of innate immune cells and promote protective effector function activities, including antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity ( Fox et al, 2019 ; Earnest et al, 2019 ; Clark, 1997 ). To this end, a subset of monoclonal antibodies isolated from SARS-CoV patients that were able to cross-react with, but not neutralize, SARS-CoV-2 were able to confer protection or reduce viral spread in mouse models ( Shiakolas et al, 2021 ; Beaudoin-Bussières et al, 2022 ). Indeed, both passive transfer experiments of monoclonal antibodies ( Atyeo et al, 2021 ; Suryadevara et al, 2021 ; Tortorici et al, 2020 ; Winkler et al, 2021 ; Chan et al, 2021 ; Schäfer et al, 2021 ) and evaluation of polyclonal antibodies raised in the context of vaccination or infection ( Alter et al, 2021 ; Francica et al, 2021 ; Adeniji et al, 2021 ) have shown that effector mechanisms contribute to antiviral activity in vivo.…”

Section: Discussionmentioning

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. 2022

eLife

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Preexisting 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.

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“…In our study, we measured the avidity of the IgG against the RBD, which is involved in viral transmission and neutralization. However, while neutralization is an important component of the humoral response, several studies suggest that other functions of Abs may play an important role in humoral responses to SARS-CoV-2, notably antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) which may be mediated by antibodies recognizing other domains than the RBD [ 32 , 33 , 34 ]. Thus, it would be interesting to see whether avidity against other domains of the Spike also increases over time.…”

Section: Discussionmentioning

confidence: 99%

Evolution of Anti-RBD IgG Avidity following SARS-CoV-2 Infection

Tauzin

Gendron‐Lepage

Nayrac

et al. 2022

Viruses

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SARS-CoV-2 infection rapidly elicits anti-Spike antibodies whose quantity in plasma gradually declines upon resolution of symptoms. This decline is part of the evolution of an immune response leading to B cell differentiation into short-lived antibody-secreting cells or resting memory B cells. At the same time, the ongoing class switch and antibody maturation processes occurring in germinal centers lead to the selection of B cell clones secreting antibodies with higher affinity for their cognate antigen, thereby improving their functional activity. To determine whether the decline in SARS-CoV-2 antibodies is paralleled with an increase in avidity of the anti-viral antibodies produced, we developed a simple assay to measure the avidity of anti-receptor binding domain (RBD) IgG elicited by SARS-CoV-2 infection. We longitudinally followed a cohort of 29 convalescent donors with blood samples collected between 6- and 32-weeks post-symptoms onset. We observed that, while the level of antibodies declines over time, the anti-RBD avidity progressively increases and correlates with the B cell class switch. Additionally, we observed that anti-RBD avidity increased similarly after SARS-CoV-2 mRNA vaccination and after SARS-CoV-2 infection. Our results suggest that anti-RBD IgG avidity determination could be a surrogate assay for antibody affinity maturation and, thus, suitable for studying humoral responses elicited by natural infection and/or vaccination.

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A Fc-enhanced NTD-binding non-neutralizing antibody delays virus spread and synergizes with a nAb to protect mice from lethal SARS-CoV-2 infection

Cited by 90 publications

References 115 publications

Resilience of S309 and AZD7442 monoclonal antibody treatments against infection by SARS-CoV-2 Omicron lineage strains

Resilience of S309 and AZD7442 monoclonal antibody treatments against infection by SARS-CoV-2 Omicron lineage strains

Boosting of cross-reactive antibodies to endemic coronaviruses by SARS-CoV-2 infection but not vaccination with stabilized spike

Evolution of Anti-RBD IgG Avidity following SARS-CoV-2 Infection

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