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

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.

Heterotypic immunity from prior SARS-CoV-2 infection but not COVID-19 vaccination associates with lower endemic coronavirus incidence

“…Memory T cell responses to these nonstructural antigens have been implicated in the protection against SARS-CoV-2 infections (19,36). Animal models have also implied that cellular responses against nonstructural proteins are important for protection against infection and disease severity (49,59). The nonstructural regions of the different CoVs are generally more conserved, and, thus, cross-reactive responses are more likely preserved (48,60).…”

“…The SARS-CoV-2 infection– and COVID-19 vaccine–generated heterotypic immunity, especially nAbs, may not be able to fully prevent a heterologous CoV infection. After initial infection, however, SARS-CoV-2 heterotypic nonspike protein–specific cellular responses could lower virus load and reduce the onset of symptomatic disease ( 49 ).…”

Heterotypic responses against nsp12/nsp13 from prior SARS-CoV-2 infection associates with lower subsequent endemic coronavirus incidence

“…After initial infection, however, SARS-CoV-2 heterotypic non-spike cellular responses could lower virus levels and reduce the onset of symptomatic disease. 53,54 It remains uncertain if SARS-CoV-2 infection also increases the frequency of abortive eCoV infections as compared to those with COVID-19 vaccination alone.…”

“…27,38 Animal models have also implied that cellular responses against non-structural proteins are important for protection against infection and disease severity. 54,65 Importantly, the non-structural regions of the different CoVs are generally more conserved and thus cross-reactive responses are more likely preserved. 52,66 The heterotypic boost of these cross-reactive T cells likely contributes to the killing of CoV infected cells and the clearance of the infection before the onset of symptomatic disease.…”

Reduced clinical severity during 2022 Shanghai Spring epidemic of SARS-CoV-2 omicron BA.2 variant infection—an integrated account of virus pathogenicity and vaccination effectiveness

“…S7 , Supplementary methods). Although the RdRp-specific T cell response was shown to be cross-protective in a mouse vaccine-and-challenge model [ 11 ], its clinical impact is yet to be determined.…”