Fab and Fc contribute to maximal protection against SARS-CoV-2 following NVX-CoV2373 subunit vaccine with Matrix-M vaccination

Gorman, Matthew J.; Patel, Nita; Guebre‐Xabier, Mimi; Zhu, Alex; Atyeo, Caroline; Pullen, Krista M.; Loos, Carolin; Goez-Gazi, Yenny; Carrión, Ricardo; Tian, Jing-Hui; Yuan, Dansu; Bowman, Kathryn; Zhou, Bin; Maciejewski, Sonia; McGrath, Marisa E.; Logue, James; Frieman, Matthew B.; Montefiori, David C.; Mann, Colin; Schendel, Sharon L.; Amanat, Fatima; Krammer, Florian; Saphire, Erica Ollmann; Lauffenburger, Douglas A.; Greene, Ann M.; Portnoff, Alyse D.; Massare, Michael J.; Ellingsworth, Larry; Glenn, Gregory M.; Smith, Gale; Alter, Galit

doi:10.1016/j.xcrm.2021.100405

Cited by 107 publications

(81 citation statements)

References 93 publications

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“… 21 , 22 An alternative or additional mechanism by which protection against severe disease may be conferred, despite the reduced neutralizing antibody activity against the omicron variant, is through Fc-mediated effector functions of non-neutralizing antibodies that induce antibody-mediated cellular phagocytosis, complement deposition, and natural killer–cell activation. 19 , 23 In addition, the omicron variant may be less potent in causing serious illness.…”

Section: Discussionmentioning

confidence: 99%

“… 31 These data, together with the very limited neutralizing antibody activity against the omicron variant after two doses of AZD1222 or BNT162b2, further corroborate the evidence that protection against severe Covid-19 due to the omicron variant is probably mediated by much lower neutralizing antibody titers than those required to protect against SARS-CoV-2 infection or mild Covid-19 25 or is provided by cell-mediated immunity or the Fc-effector functions of non-neutralizing antibodies (or a combination of these mechanisms). 19 , 23 …”

Section: Discussionmentioning

confidence: 99%

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Population Immunity and Covid-19 Severity with Omicron Variant in South Africa

et al. 2022

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Background The B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified on November 25, 2021, in Gauteng province, South Africa. Data regarding the seroprevalence of SARS-CoV-2 IgG in Gauteng before the fourth wave of coronavirus disease 2019 (Covid-19), in which the omicron variant was dominant, are needed. Methods We conducted a seroepidemiologic survey from October 22 to December 9, 2021, in Gauteng to determine the seroprevalence of SARS-CoV-2 IgG. Households included in a previous seroepidemiologic survey (conducted from November 2020 to January 2021) were contacted; to account for changes in the survey population, there was a 10% increase in the households contacted, with the use of the same sampling framework. Dried-blood-spot samples were tested for IgG against SARS-CoV-2 spike protein and nucleocapsid protein with the use of quantitative assays. We also evaluated Covid-19 epidemiologic trends in Gauteng, including cases, hospitalizations, recorded deaths, and excess deaths from the start of the pandemic through January 12, 2022. Results Samples were obtained from 7010 participants, of whom 1319 (18.8%) had received a Covid-19 vaccine. The seroprevalence of SARS-CoV-2 IgG ranged from 56.2% (95% confidence interval [CI], 52.6 to 59.7) among children younger than 12 years of age to 79.7% (95% CI, 77.6 to 81.5) among adults older than 50 years of age. Vaccinated participants were more likely to be seropositive for SARS-CoV-2 than unvaccinated participants (93.1% vs. 68.4%). Epidemiologic data showed that the incidence of SARS-CoV-2 infection increased and subsequently declined more rapidly during the fourth wave than it had during the three previous waves. The incidence of infection was decoupled from the incidences of hospitalization, recorded death, and excess death during the fourth wave, as compared with the proportions seen during previous waves. Conclusions Widespread underlying SARS-CoV-2 seropositivity was observed in Gauteng before the omicron-dominant wave of Covid-19. Epidemiologic data showed a decoupling of hospitalizations and deaths from infections while omicron was circulating. (Funded by the Bill and Melinda Gates Foundation.)

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Population Immunity and Covid-19 Severity with Omicron Variant in South Africa

et al. 2022

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“…Along with ADNP, engagement of complement (ADCD) has been associated with survival from COVID-19 (ref. 47 ), and synergy between Fab and Fc effector functions has been shown to be critical for vaccine-elicited protection 48 .…”

Section: Discussionmentioning

confidence: 99%

Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations

et al. 2021

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Prevention of viral escape and increased coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern require therapeutic monoclonal antibodies (mAbs) targeting multiple sites of vulnerability on the coronavirus spike glycoprotein. Here we identify several potent neutralizing antibodies directed against either the N-terminal domain (NTD) or the receptor-binding domain (RBD) of the spike protein. Administered in combinations, these mAbs provided low-dose protection against SARS-CoV-2 infection in the K18-human angiotensin-converting enzyme 2 mouse model, using both neutralization and Fc effector antibody functions. The RBD mAb WRAIR-2125, which targets residue F486 through a unique heavy-chain and light-chain pairing, demonstrated potent neutralizing activity against all major SARS-CoV-2 variants of concern. In combination with NTD and other RBD mAbs, WRAIR-2125 also prevented viral escape. These data demonstrate that NTD/RBD mAb combinations confer potent protection, likely leveraging complementary mechanisms of viral inactivation and clearance.

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“…Thus, reduced neutralizing antibody cannot account for enhanced transmissibility of this new sublineage of omicron. Given our increasing appreciation for a role for nonneutralizing Fc-effector antibody responses in protection against natural severe disease (18,19), in monoclonal therapeutic activity (13)(14)(15)(16), and in vaccine mediated protection (20), here we profiled the Pfizer BNT162b2 functional humoral immune response across VOCs including BA.1 and BA.2. As expected, vaccine induced non-neutralizing antibody responses were lower to omicron variants but were most profoundly diminished against the BA.2 Spike antigen.…”

Section: Discussionmentioning

confidence: 99%

BA.2 evasion of vaccine induced binding and functional non-neutralizing antibodies

Bartsch

Cizmeci

Kang

et al. 2022

Preprint

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The number of mutations in the omicron (B1.1.529) BA.1 variant of concern (VOC) led to an unprecedented evasion of vaccine induced immunity. However, despite the remarkable rise in global infections, severe disease and death did not increase proportionally, linked to persistent recognition of BA.1 by T cells and non-neutralizing opsonophagocytic antibodies. Yet, the emergence of a new sublineage, BA.2, that is more transmissible compared to BA.1, despite relatively preserved neutralizing antibody responses, has raised the possibility that BA.2 may evade other vaccine induced responses that may be key to protection against infection and disease. Here we comprehensively profiled the BNT162b2 vaccine induced response to several VOCs including the omicron BA.1 and BA.2, after the primary vaccine series, 8 months following vaccination, and after a boost. While vaccine induced immune responses were compromised against both Omicron sublineages, vaccine induced antibody isotype titers, FcγR3a- and FcγR3b-receptor binding levels, and non-neutralizing opsonophagocytic functions were significantly attenuated to the omicron BA.2 Spike compared to the BA.1 lineage. Conversely, FcγR2a and FcγR2b binding was elevated to BA.2 potentially contributing to persistent protection against severity of disease. These data point to an attenuation of particular non-neutralizing antibody properties that may be key to protection against transmission, but the maintenance of others that may continue to confer protection against disease.

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Fab and Fc contribute to maximal protection against SARS-CoV-2 following NVX-CoV2373 subunit vaccine with Matrix-M vaccination

Cited by 107 publications

References 93 publications

Population Immunity and Covid-19 Severity with Omicron Variant in South Africa

Population Immunity and Covid-19 Severity with Omicron Variant in South Africa

Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations

BA.2 evasion of vaccine induced binding and functional non-neutralizing antibodies

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