Fc-mediated pan-sarbecovirus protection after alphavirus vector vaccination

Lily E Adams; Sarah R Leist; Kenneth H Dinnon 3rd; Ande West; Kendra L Gully; Elizabeth J Anderson; Jennifer F Loome; Emily A Madden; John M Powers; Alexandra Schäfer; Sanjay Sarkar; Izabella N Castillo; Jenny S Maron; Ryan P McNamara; Harry L Bertera; Mark R Zweigert; Jaclyn S Higgins; Brea K Hampton; Lakshmanane Premkumar; Galit Alter; Stephanie A Montgomery; Victoria K Baxter; Mark T Heise; Ralph S Baric

doi:10.1016/j.celrep.2023.112326

Fc-mediated pan-sarbecovirus protection after alphavirus vector vaccination

Cell Rep. 2023 Apr 25;42(4):112326. doi: 10.1016/j.celrep.2023.112326. Epub 2023 Mar 30.

Authors

Lily E Adams¹, Sarah R Leist², Kenneth H Dinnon 3rd¹, Ande West³, Kendra L Gully⁴, Elizabeth J Anderson⁵, Jennifer F Loome¹, Emily A Madden¹, John M Powers², Alexandra Schäfer², Sanjay Sarkar⁶, Izabella N Castillo¹, Jenny S Maron⁷, Ryan P McNamara⁷, Harry L Bertera⁷, Mark R Zweigert², Jaclyn S Higgins¹, Brea K Hampton⁶, Lakshmanane Premkumar¹, Galit Alter⁷, Stephanie A Montgomery⁸, Victoria K Baxter⁹, Mark T Heise¹⁰, Ralph S Baric¹¹

Affiliations

¹ Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
² Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Division of Comparative Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵ Division of Comparative Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁷ Ragon Institute of MGH, MIT, and Harvard University, Cambridge, MA, USA.
⁸ Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Dallas Tissue Research, Dallas, TX, USA.
⁹ Division of Comparative Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁰ Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Rapidly Emerging Antiviral Drug Discovery Initiative, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: mark_heisem@med.unc.edu.
¹¹ Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Rapidly Emerging Antiviral Drug Discovery Initiative, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: rbaric@email.unc.edu.

Abstract

Group 2B β-coronaviruses (sarbecoviruses) have caused regional and global epidemics in modern history. Here, we evaluate the mechanisms of cross-sarbecovirus protective immunity, currently less clear yet important for pan-sarbecovirus vaccine development, using a panel of alphavirus-vectored vaccines covering bat to human strains. While vaccination does not prevent virus replication, it protects against lethal heterologous disease outcomes in both severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and clade 2 bat sarbecovirus challenge models. The spike vaccines tested primarily elicit a highly S1-specific homologous neutralizing antibody response with no detectable cross-virus neutralization. Rather, non-neutralizing antibody functions, mechanistically linked to FcgR4 and spike S2, mediate cross-protection in wild-type mice. Protection is lost in FcR knockout mice, further supporting a model for non-neutralizing, protective antibodies. These data highlight the importance of FcR-mediated cross-protective immune responses in universal pan-sarbecovirus vaccine designs.

Keywords: CP: Immunology; FcR effector function; animal model; antibody responses; coronavirus; correlates of protection; cross-protection; pan-coronavirus vaccine; sarbecovirus; systems serology; vaccine development.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alphavirus*
Animals
Antibodies, Neutralizing
Antibodies, Viral
COVID-19* / prevention & control
Chiroptera*
Humans
Mice
SARS-CoV-2
Severe acute respiratory syndrome-related coronavirus*
Vaccination
Viral Vaccines*

Substances

Viral Vaccines
Antibodies, Viral
Antibodies, Neutralizing

Abstract

Publication types

MeSH terms

Substances

Grants and funding