Abstract
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.
Highlights
Because potent neutralizing antibody epitopes exist in each of the modular structures on CoV spikes [21], we hypothesized that chimeric spikes that encode NTD, RBD, and S2 domains into “bivalent” and “trivalent” vaccine immunogens have the potential to elicit broad protective antibody responses against clades I to III Sarbecoviruses
The Moderna and Pfizer/BioNTech SARS-CoV-2 mRNA-LNP vaccines were safe and efficacious against SARS-CoV-2 infections in large phase 3 efficacy human clinical trials [32,33,34], but there is a growing concern regarding variant of concern (VOC) such as South African B.1.351, which is five- to sixfold more resistant to vaccine-elicited polyclonal neutralizing antibodies [35]
Chimera 4, which contains the RsSHC014 RBD and SARS-CoV-2 NTD and S2, elicited binding and neutralizing antibodies, and mice were fully protected from bat CoVs (Bt-CoVs) RsSHC014 and SARSCoV-2 challenge, whereas SARS-CoV-2 full length did not fully protect against RsSHC014, suggesting that CoV spike vaccines can be designed to maximize their display of protective epitopes and indicates that NTD/RBD/S2 chimeric spikes may enhance protection relative to monovalent spikes
Summary
These results suggest that chimeric spike vaccines elicit broader and higher-magnitude binding responses against pandemic and bat SARS-like viruses as compared with those of monovalent SARS-CoV-2 spike vaccines. Mice from groups 1 and 2 elicited lower binding and neutralizing responses to SARS-CoV-2 as compared with those of group 4, perhaps reflecting a decreased amount of mRNA vaccine incorporated into multiplexed formulations; the monovalent vaccines may drive a more focused B cell response to SARS-CoV-2, whereas chimeric spike antigens lead to more breadth against distant Sarbecoviruses.
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