Vaccination drives superior functional antibody breadth compared to natural infection with SARS-CoV-2

In a recent study posted to the medRxiv* preprint server, researchers assessed the potency and breadth of antibody (Ab) recognition and effector function among healthy and high-risk individuals following natural SARS-CoV-2 infection or messenger ribonucleic acid (mRNA) coronavirus disease 2019 (COVID-19) vaccination.

Background

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) has threatened COVID-19 vaccine efficacy and serological immune responses. Immunity induced by vaccinations and natural infections exhibits several distinctions concerning Ab responses, which may be even more distinct among high-risk populations such as child-bearing females. The breadth and magnitude of cross-reactive Ab effector functions have essential implications for immune protection among diverse persons concerning further viral diversifications.

About the study

In the present study, researchers analyzed Ab Fc-mediated effector functions and the magnitude and characteristics of Ab responses to SARS-CoV-2 VOCs and endemic CoVs among healthy and vulnerable individuals.

Sera were obtained from vaccinated individuals who received double doses of either mRNA-1273 (n=2) or BNT162b2 (n=85) vaccines and had prior SARS-CoV-2 exposure during Wuhan-Hu-1 (ancestral) strain predominance (n=57 individuals), or no prior SARS-CoV-2-exposure [negative for SARS-CoV-2 nucleocapsid (N) protein, n=38]. In addition, serum samples were obtained from 50 vaccinated and 38 convalescent pregnant females (high-risk and immunologically vulnerable persons).

COVID-19 diagnosis was confirmed by reverse transcription-polymerase chain reaction (RT-PCR) analysis among convalescent individuals. The UMAP (uniform manifold approximation and projection) analysis was performed to assess differences and similarities in Ab profiles of seropositive persons, and the team assessed correlations between the ancestral strain and VOCs for Ab isotypes. Further, the team explored potential differences in FcγR tetramer-binding capacity and subclasses among Abs to VOCs since both mediate Ab effector function differences.

Breadth scores and potency curves were obtained for immunoglobulin A (IgA), IgG, and IgM for the VOCs tested across the whole SARS-CoV-2 spike (S) protein or the S protein receptor-binding domain (RBD). For every participant, Ab-dependent cellular cytotoxicity (ADCC), Ab-dependent complement deposition (ADCD), and phagocytosis activities were assessed for whole S or S RBD antigens against VOCs tested.

Further, the team investigated whether Ab Fc effector functions could be elicited by Middle East respiratory syndrome (MERS) CoV, SARS-CoV-1, beta(β)-CoVs HKU1 and OC4, and alpha(α)-CoVs 229E and NL63. For antigen and Fc receptor expression, SARS-CoV-2 antigens were expressed transiently in HEK293 or Expi293 cells, and antigen-specific Abs were characterized using Fc array assays. Antigen-specific Abs specific to human Ig isotypes and subclasses were evaluated, and phagocytosis was assessed based on flow cytometry (FC) analysis and mean fluorescent intensity (MFI) scores.

Results

Similar binding and functional breadth were observed among healthy individuals and immunologically vulnerable pregnant females. The Ab responses correlated strongly with IgG rather than IgA, with S RBD rather than the whole S, and with vaccinated individuals rather than convalescents. However, greater Ab function against OC43 was observed among convalescents, indicative of dichotomous recognition between distant and close human CoVs (hCoVs) associated with prior COVID-19 history.

IgM Ab breadth was greater among convalescents, whereas IgG Ab breadth was greater among vaccinees, and IgA Ab breadth was comparable between the two groups. For IgG, strong inter-VOC correlations were observed. The breadth of IgM Abs was greater among convalescents than in mRNA vaccinees, IgA titers were comparable between the two groups, and IgG Ab breadth was markedly greater among vaccinees, with more prominent differences for S RBD rather than the whole S.

IgG subclass (especially IgG1 and 3) titers were more potent and broader across VOCs among seropositive individuals than in SARS-CoV-2-naïve individuals. The inter-subclass breadth differences between vaccinees and convalescents were greater for S RBD than the full-length S. Ab potency and breadth differences between vaccinees and convalescents were greater for FcγR binding rather than IgG (total IgG or each IgG subclass) titers, and greater for S RBD than full-length S.

Functional Ab responses were equivalent or greater among vaccinees than convalescents for the ancestral strain and SARS-CoV-2 VOCs except for complement deposition against the ancestral strain full-length S. Functional Ab responses to S RBD showed greater sensitivity to reducing serum concentrations than to whole S, with the most pronounced difference in complement deposition and ADCC against the Beta VOC and Gamma VOC RBDs among vaccinated individuals.

Breadth scores obtained for all effector functions showed markedly improved cross-reactive functional Ab response breadth among vaccinees than convalescents toward whole S and S RBD. Strong SARS-CoV-1-targeted effector functions were noted for full-length S and the subunit S1 among vaccinees, whereas cross-reactive functional Ab responses to the targets were lacking among convalescents.

Contrastingly, strong Ab activity was observed for full-length S and subunit S2 of OC43 among convalescents. Greater phagocytosis was observed for HKU1 and OC43 among convalescents and vaccinees, respectively; however, neither group phagocytosed MERS S and αCoVs NL63 and 229E.

Conclusion

Overall, the study showed that vaccination induced superior functional Ab breadth responses than natural SARS-CoV-2 infections. Both vaccinations and natural infections induce Abs with a better-preserved breadth of effector functions than neutralization functions.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.