RT Journal Article
SR Electronic
T1 Engineered receptor binding domain immunogens elicit pan-sarbecovirus neutralizing antibodies outside the receptor binding motif
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.12.07.415216
DO 10.1101/2020.12.07.415216
A1 Blake M. Hauser
A1 Maya Sangesland
A1 Evan C. Lam
A1 Kerri J. St. Denis
A1 Jared Feldman
A1 Ashraf S. Yousif
A1 Timothy M. Caradonna
A1 Ty Kannegieter
A1 Alejandro B. Balazs
A1 Daniel Lingwood
A1 Aaron G. Schmidt
YR 2021
UL http://biorxiv.org/content/early/2021/06/29/2020.12.07.415216.abstract
AB Effective countermeasures are needed against emerging coronaviruses of pandemic potential, similar to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Designing immunogens that elicit broadly neutralizing antibodies to conserved viral epitopes on the major surface glycoprotein, spike, such as the receptor binding domain (RBD) is one potential approach. Here, we report the generation of homotrimeric RBD immunogens from different sarbecoviruses using a stabilized, immune-silent trimerization tag. In mice, we find that a cocktail of these homotrimeric sarbecovirus RBDs elicits antibodies to conserved viral epitopes outside of the ACE2 receptor binding motif (RBM). Importantly, these responses neutralize all sarbecovirus components even in context of prior SARS-CoV-2 imprinting. We further show that a substantial fraction of the neutralizing antibodies elicited after vaccination in humans also engages non-RBM epitopes on the RBD. Collectively, our results suggest a strategy for eliciting broadly neutralizing responses leading to a pan-sarbecovirus vaccine.Author summary Immunity to SARS-CoV-2 in the human population will be widespread due to natural infection and vaccination. However, another novel coronavirus will likely emerge in the future and may cause a subsequent pandemic. Humoral responses induced by SARS-CoV-2 infection and vaccination provide limited protection against even closely related coronaviruses. We show immunization with a cocktail of trimeric coronavirus receptor binding domains induces a neutralizing antibody response that is broadened to related coronaviruses with pandemic potential. Importantly, this broadening occurs in context of an initial imprinted SARS-CoV-2 spike immunization showing that preexisting immunity can be expanded to recognize other related coronaviruses. Our immunogens focused the serum antibody response to conserved epitopes on the receptor binding domain outside of the ACE2 receptor binding motif; this contrasts with current SARS-CoV-2 therapeutic antibodies, which predominantly target the receptor binding motif.Competing Interest StatementThe authors have declared no competing interest.