Hybrid Immunity Shifts the Fc-Effector Quality of SARS-CoV-2 mRNA Vaccine-Induced Immunity

Kathryn A. Bowman; Daniel Stein; Sally Shin; Kathie G. Ferbas; Nicole H. Tobin; Colin Mann; Stephanie Fischinger; Erica Ollmann Saphire; Douglas Lauffenburger; Anne W. Rimoin; Grace Aldrovandi; Galit Alter

doi:10.1128/mbio.01647-22

mBio (Oct 2022)

Hybrid Immunity Shifts the Fc-Effector Quality of SARS-CoV-2 mRNA Vaccine-Induced Immunity

Kathryn A. Bowman,
Daniel Stein,
Sally Shin,
Kathie G. Ferbas,
Nicole H. Tobin,
Colin Mann,
Stephanie Fischinger,
Erica Ollmann Saphire,
Douglas Lauffenburger,
Anne W. Rimoin,
Grace Aldrovandi,
Galit Alter

Affiliations

Kathryn A. Bowman: Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA
Daniel Stein: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
Sally Shin: Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA
Kathie G. Ferbas: Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
Nicole H. Tobin: Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
Colin Mann: Department of Epidemiology, Jonathan and Karin Fielding School of Public Health, University of California Los Angeles, Los Angeles, California, USA
Stephanie Fischinger: Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA
Erica Ollmann Saphire: Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, California, USA
Douglas Lauffenburger: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
Anne W. Rimoin: Department of Epidemiology, Jonathan and Karin Fielding School of Public Health, University of California Los Angeles, Los Angeles, California, USA
Grace Aldrovandi: Department of Pediatrics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
Galit Alter: Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA

DOI: https://doi.org/10.1128/mbio.01647-22
Journal volume & issue: Vol. 13, no. 5

Abstract

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ABSTRACT Despite the robust immunogenicity of SARS-CoV-2 mRNA vaccines, emerging data have revealed enhanced neutralizing antibody and T cell cross-reactivity among individuals that previously experienced COVID-19, pointing to a hybrid immune advantage with infection-associated immune priming. Beyond neutralizing antibodies and T cell immunity, mounting data point to a potential role for additional antibody effector functions, including opsinophagocytic activity, in the resolution of symptomatic COVID-19. Whether hybrid immunity modifies the Fc-effector profile of the mRNA vaccine-induced immune response remains incompletely understood. Thus, here we profiled the SARS-CoV-2 specific humoral immune response in a group of individuals with and without prior COVID-19. As expected, hybrid Spike-specific antibody titers were enhanced following the primary dose of the mRNA vaccine but were similar to those achieved by naive vaccinees after the second mRNA vaccine dose. Conversely, Spike-specific vaccine-induced Fc-receptor binding antibody levels were higher after the primary immunization in individuals with prior COVID-19 and remained higher following the second dose compared to those in naive individuals, suggestive of a selective improvement in the quality, rather than the quantity, of the hybrid humoral immune response. Thus, while the magnitude of antibody titers alone may suggest that any two antigen exposures—either hybrid immunity or two doses of vaccine alone—represent a comparable prime/boost immunologic education, we find that hybrid immunity offers a qualitatively improved antibody response able to better leverage Fc-effector functions against conserved regions of the virus. IMPORTANCE Recent data indicates improved immunity to SARS-CoV-2 in individuals who experience a combination of two mRNA vaccine doses and infection, “hybrid immunity,” compared to individuals who receive vaccination or experience infection alone. While previous infection accelerates the vaccine-induced immune response following the first dose of mRNA vaccination, subsequent doses demonstrate negligible increases in antibody titers or T cell immunity. Here, using systems serology, we observed a unique antibody profile induced by hybrid immunity, marked by the unique induction of robust Fc-recruiting antibodies directed at the conserved region of the viral Spike antigen, the S2-domain, induced at lower levels in individuals who only received mRNA vaccination. Thus, hybrid immunity clearly redirects vaccine-induced immunodominance, resulting in the induction of a robust functional humoral immune response to the most highly conserved region of the SARS-CoV-2 Spike antigen, which may be key to protection against existing and emerging variants of concern. Thus, next-generation vaccines able to mimic hybrid immunity and drive a balanced response to conserved regions of the Spike antigen may confer enhanced protection against disease.

Published in mBio

ISSN: 2161-2129 (Print); 2150-7511 (Online)
Publisher: American Society for Microbiology
Country of publisher: United States
LCC subjects: Science: Microbiology
Website: https://journals.asm.org/journal/mbio

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