Chimeric spike mRNA vaccines protect against Sarbecovirus challenge in mice

Abstract

A broad defense against SARS-like viruses Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third coronavirus that has emerged as a serious human pathogen in the past 20 years. Treatment strategies that are broadly protective against current and future SARS-like coronaviruses are needed. Martinez et al. took on this challenge by developing vaccines based on chimeras of the viral spike protein. The messenger RNA vaccines encode spike proteins composed of domain modules from epidemic and pandemic coronaviruses, as well as bat coronaviruses with the potential to cross to humans. In aged mice vulnerable to infection, the chimeric vaccines protected against challenge from SARS-CoV, SARS-CoV-2 and tested variants of concern, and zoonotic coronaviruses with pandemic potential. Science, abi4506, this issue p. 991 mRNA vaccines that express chimeric spike protein protect mice against epidemic, zoonotic, and pandemic SARS-like viruses. The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and SARS-CoV-2 in 2019 highlights the need to develop universal vaccination strategies against the broader Sarbecovirus subgenus. Using chimeric spike designs, we demonstrate protection against challenge from SARS-CoV, SARS-CoV-2, SARS-CoV-2 B.1.351, bat CoV (Bt-CoV) RsSHC014, and a heterologous Bt-CoV WIV-1 in vulnerable aged mice. Chimeric spike messenger RNAs (mRNAs) induced high levels of broadly protective neutralizing antibodies against high-risk Sarbecoviruses. By contrast, SARS-CoV-2 mRNA vaccination not only showed a marked reduction in neutralizing titers against heterologous Sarbecoviruses, but SARS-CoV and WIV-1 challenge in mice resulted in breakthrough infections. Chimeric spike mRNA vaccines efficiently neutralized D614G, mink cluster five, and the UK B.1.1.7 and South African B.1.351 variants of concern. Thus, multiplexed-chimeric spikes can prevent SARS-like zoonotic coronavirus infections with pandemic potential.