Chimeric spike mRNA vaccines protect against Sarbecovirus challenge in mice
David R. Martinez, Alexandra Schäfer, Sarah R. Leist, Gabriela De la Cruz, Ande West, Elena N. Atochina‐Vasserman, Lisa C. Lindesmith, Norbert Pardi, Robert Parks, Maggie Barr, Dapeng Li, Boyd L. Yount, Kevin O. Saunders, Drew Weissman, Barton F. Haynes, Stephanie A. Montgomery, Ralph S. Baric
Abstract
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.