Immunogenicity and protective efficacy of a rhesus adenoviral vaccine targeting conserved COVID-19 replication transcription complex

Author:

Dagotto GabrielORCID,Ventura John D.ORCID,Martinez David R.,Anioke Tochi,Chung Benjamin S.,Siamatu MazubaORCID,Barrett JuliaORCID,Miller Jessica,Schäfer AlexandraORCID,Yu Jingyou,Tostanoski Lisa H.ORCID,Wagh Kshitij,Baric Ralph S.ORCID,Korber BetteORCID,Barouch Dan H.ORCID

Abstract

AbstractThe COVID-19 pandemic marks the third coronavirus pandemic this century (SARS-CoV-1, MERS, SARS-CoV-2), emphasizing the need to identify and evaluate conserved immunogens for a pan-sarbecovirus vaccine. Here we investigate the potential utility of a T-cell vaccine strategy targeting conserved regions of the sarbecovirus proteome. We identified the most conserved regions of the sarbecovirus proteome as portions of the RNA-dependent RNA polymerase (RdRp) and Helicase proteins, both of which are part of the coronavirus replication transcription complex (RTC). Fitness constraints suggest that as SARS-CoV-2 continues to evolve these regions may better preserve cross-reactive potential of T-cell responses than Spike, Nucleocapsid, or Membrane proteins. We sought to determine if vaccine-elicited T-cell responses to the highly conserved regions of the RTC would reduce viral loads following challenge with SARS-CoV-2 in mice using a rhesus adenovirus serotype 52 (RhAd52) vector. The RhAd52.CoV.Consv vaccine generated robust cellular immunity in mice and led to significant reductions in viral loads in the nasal turbinates following challenge with a mouse-adapted SARS-CoV-2. These data suggest the potential utility of T-cell targeting of conserved regions for a pan-sarbecovirus vaccine.

Funder

U.S. Department of Health & Human Services | NIH | National Cancer Institute

Ragon Institute of MGH, MIT and Harvard

U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases

Publisher

Springer Science and Business Media LLC

Subject

Pharmacology (medical),Infectious Diseases,Pharmacology,Immunology

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