Broadly neutralizing antibodies to SARS-related viruses can be readily induced in rhesus macaques

Abstract

To prepare for future coronavirus (CoV) pandemics, it is desirable to generate vaccines capable of eliciting neutralizing antibody responses against multiple CoVs. Because of the phylogenetic similarity to humans, rhesus macaques are an animal model of choice for many virus-challenge and vaccine-evaluation studies, including SARS-CoV-2. Here, we show that immunization of macaques with SARS-CoV-2 spike (S) protein generates potent receptor binding domain cross-neutralizing antibody (nAb) responses to both SARS-CoV-2 and SARS-CoV-1, in contrast to human infection or vaccination where responses are typically SARS-CoV-2-specific. Furthermore, the macaque nAbs are equally effective against SARS-CoV-2 variants of concern. Structural studies show that different immunodominant sites are targeted by the two primate species. Human antibodies generally target epitopes strongly overlapping the ACE2 receptor binding site (RBS), whereas the macaque antibodies recognize a relatively conserved region proximal to the RBS that represents another potential pan-SARS-related virus site rarely targeted by human antibodies. B cell repertoire differences between the two primates appear to significantly influence the vaccine response and suggest care in the use of rhesus macaques in evaluation of vaccines to SARS-related viruses intended for human use.

Targeted isolation of panels of diverse human protective broadly neutralizing antibodies against SARS-like viruses

“…1). None of the convalescent-only or vaccinated-only donors in our cohort had sera that could neutralize SARS-CoV-1, as also noted by us earlier 51 . Of note, many of the existing SARS-CoV-2 cross-reactive or crossneutralizing antibodies were isolated from SARS-CoV-1 convalescent donors 27,28,[52][53][54][55] and only more recently from SARS-CoV-2 infected donors 26,[29][30][31]56 .…”

“…Of note, many of the existing SARS-CoV-2 cross-reactive or cross-neutralizing antibodies were isolated from SARS-CoV-1 convalescent donors 27,28,52–55 and only more recently from SARS-CoV-2 infected donors 26,29–31,56 . These bnAbs appear to target more conserved spike epitopes, and as also illustrated by SARS-CoV-1 cross-neutralizing bnAbs elicited in S-protein vaccinated macaques 51,57,58 . Hence, SARS-CoV-1/2 cross-neutralization appears to be a good indicator of the presence of pan-sarbecovirus activity and possibly greater CoV neutralization breadth 59 .…”

“…Of note, many of the existing SARS-CoV-2 cross-reactive or cross-neutralizing antibodies were isolated from SARS-CoV-1 convalescent donors 27, 32, 53–56 and only more recently from SARS-CoV-2 infected donors 30, 31, 34, 35, 57 . BnAbs have also been isolated from SARS-CoV-2 S-protein vaccinated macaques that show serum cross-neutralizing activity against SARS-CoV-1 52, 58–60 . Hence, SARS-CoV-1/2 cross-neutralization appears to be a good indicator of the presence of pan-sarbecovirus activity and greater CoV neutralization breadth 61 .…”

“…Binding of human nAbs to SARS-CoV-2 RBD. The RBD is shown as a black chain trace, whereas antibodies are represented by solid surfaces in different colors: CC12.1 (pink, PDB 6XC2), CR3022 (yellow, PDB 6W41), S309 (orange, PDB 7R6W), DH1047 (cyan, 7LD1), and K398.22 (blue, PDB submitted) 52 .…”

A broad and potent neutralization epitope in SARS-related coronaviruses

“…Mutated residues in SARS-CoV-2 VOCs are indicated by arrows. Epitopes and the receptor binding site are defined by residues with BSA > 0 Å 2 as calculated by PISA (44) using structures of ADG20 (this study), K398.22 (23), S2X259 (PDB 7RAL) (51), CR3022 (PDB 6W41) (9), S309 (PDB 6WPS) (21), and ACE2 (PDB 6M0J) (48). SARS-CoV-2 variants as well as SARS-CoV-1 can be neutralized by these antibodies, as shown at the bottom of the panel.…”