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

Gabriel Dagotto; John D Ventura; David R Martinez; Tochi Anioke; Benjamin S Chung; Mazuba Siamatu; Julia Barrett; Jessica Miller; Alexandra Schäfer; Jingyou Yu; Lisa H Tostanoski; Kshitij Wagh; Ralph S Baric; Bette Korber; Dan H Barouch

doi:10.1038/s41541-022-00553-2

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

NPJ Vaccines. 2022 Oct 27;7(1):125. doi: 10.1038/s41541-022-00553-2.

Authors

Gabriel Dagotto^#^{1

2}, John D Ventura^#^{1

3}, David R Martinez⁴, Tochi Anioke¹, Benjamin S Chung¹, Mazuba Siamatu¹, Julia Barrett¹, Jessica Miller¹, Alexandra Schäfer⁴, Jingyou Yu¹, Lisa H Tostanoski¹, Kshitij Wagh^{3

5}, Ralph S Baric⁴, Bette Korber^{3

5}, Dan H Barouch^{6

7

8}

Affiliations

¹ Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
² Harvard Medical School, Boston, MA, USA.
³ Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA.
⁴ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵ The New Mexico Consortium, Los Alamos National Laboratory, Los Alamos, NM, USA.
⁶ Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. dbarouch@bidmc.harvard.edu.
⁷ Harvard Medical School, Boston, MA, USA. dbarouch@bidmc.harvard.edu.
⁸ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA. dbarouch@bidmc.harvard.edu.

^# Contributed equally.

Abstract

The 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.

Abstract

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