SARS-CoV-2 S2–targeted vaccination elicits broadly neutralizing antibodies

Abstract

Several variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged during the current coronavirus disease 2019 (COVID-19) pandemic. Although antibody cross-reactivity with the spike glycoproteins (S) of diverse coronaviruses, including endemic common cold coronaviruses (HCoVs), has been documented, it remains unclear whether such antibody responses, typically targeting the conserved S2 subunit, contribute to protection when induced by infection or through vaccination. Using a mouse model, we found that prior HCoV-OC43 S–targeted immunity primes neutralizing antibody responses to otherwise subimmunogenic SARS-CoV-2 S exposure and promotes S2-targeting antibody responses. Moreover, vaccination with SARS-CoV-2 S2 elicited antibodies in mice that neutralized diverse animal and human alphacoronaviruses and betacoronaviruses in vitro and provided a degree of protection against SARS-CoV-2 challenge in vivo. Last, in mice with a history of SARS-CoV-2 Wuhan–based S vaccination, further S2 vaccination induced broader neutralizing antibody response than booster Wuhan S vaccination, suggesting that it may prevent repertoire focusing caused by repeated homologous vaccination. These data establish the protective value of an S2-targeting vaccine and support the notion that S2 vaccination may better prepare the immune system to respond to the changing nature of the S1 subunit in SARS-CoV-2 variants of concern, as well as to future coronavirus zoonoses.

Abstract

Vaccination against the S2 subunit of SARS-CoV-2 induces antibodies in mice that neutralize a broad range of human and animal coronaviruses.

A conserved vaccine target

Because variants of SARS-CoV-2 continue to arise and reduce the protection afforded by vaccination or prior infection, it is becoming increasingly important that vaccines be developed that target more conserved regions of the SARS-CoV-2 spike protein. Here, Ng et al.tested whether antibodies targeting the more conserved S2 subunit of the spike protein could confer protection against infection with distinct coronaviruses. The authors observed that S2-targeted vaccination produced antibodies in mice that could neutralize diverse alphacoronaviruses and betacoronaviruses. These antibodies had increased breadth relative to antibodies elicited by full-length spike protein vaccination, suggesting less repertoire focusing. Thus, S2-targeted vaccination may be a strategy to achieve pan-SARS-CoV-2 immunity.