A broadly cross-reactive antibody neutralizes and protects against sarbecovirus challenge in mice

Abstract

Severe acute respiratory syndrome coronaviruses 1 (SARS-CoV) and 2 (SARS-CoV-2), including SARS-CoV-2 variants of concern, can cause deadly infections. The mortality associated with sarbecovirus infection underscores the importance of developing broadly effective countermeasures against them, which could be key in the prevention and mitigation of current and future zoonotic events. Here, we demonstrate the neutralization of SARS-CoV; bat coronaviruses WIV-1 and RsSHC014; and SARS-CoV-2 variants D614G, B.1.1.7, B.1.351, P.1, B.1.429, B.1.526, B.1.617.1, and B.1.617.2 by a receptor binding domain (RBD)–specific human antibody, DH1047. Prophylactic and therapeutic treatment with DH1047 was protective against SARS-CoV, WIV-1, RsSHC014, and SARS-CoV-2 B.1.351 infection in mice. Binding and structural analysis showed high affinity binding of DH1047 to an epitope that is highly conserved among sarbecoviruses. Thus, DH1047 is a broadly protective antibody that can prevent infection and mitigate outbreaks caused by SARS-related strains and SARS-CoV-2 variants. Our results also suggest that the conserved RBD epitope bound by DH1047 is a rational target for a universal sarbecovirus vaccine.

Structural basis of SARS-CoV-2 Omicron immune evasion and receptor engagement

“…The RBD is the main target of plasma neutralizing activity in convalescent and vaccinated individuals and comprises several antigenic sites recognized by neutralizing Abs with a range of neutralization potencies and breadth (12,13,21,(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36) (Fig. 3A).…”

Omicron BA.2 specifically evades broad sarbecovirus neutralizing antibodies

“…For pandemic preparedness, pan-sarbecovirus therapeutics and vaccines that are effective against future SARS-CoV-2 variants and other sarbecoviruses are urgently needed 11–14 . Several broad sarbecovirus neutralizing antibodies have been reported 20,23–34 ; however, since the number of antibodies studied has been limited, we still lack a comprehensive understanding of the RBD epitopes that could induce broad sarbecovirus neutralizing antibodies.…”

Breadth of SARS-CoV-2 Neutralization and Protection Induced by a Nanoparticle Vaccine

“…RBD-scNP and soluble RBD monomer immunization elicited similar titers of antibodies binding to SARS-CoV-2 and other CoV spike antigens ( Supplementary Figure 1A ), which also similarly blocked ACE2-binding on SARS-CoV-2 spike and bat CoV RsSHC014 spike ( Supplementary Figure 1B-C ). RBD-scNPs and soluble RBD induced similar levels of antibodies targeting the sarbecovirus cross-neutralizing DH0147-epitope (Hastie et al, 2021; Li et al, 2021a; Li et al, 2021b; Martinez et al, 2021a) on SARS-CoV-2 spike as well as on RsSHC014 spike ( Supplementary Figure 1B-C ). In pseudovirus neutralization assays, the RBD-scNP group exhibited higher titers of neutralizing antibodies than the soluble RBD group against the WA-1, Alpha, Epsilon, Iota, and Delta viruses, with comparable neutralizing titers against Beta, Gamma, and Kappa variants ( Supplementary Figure 1D ).…”

“…For the SARS-CoV-2 B.1.351 and SARS-CoV-1 study, mice were immunized on week 0 and 4, and challenged on week 6. All mice were anesthetized and infected intranasally with 1 × 10 4 PFU/ml of SARS-CoV MA15, 1 × 10 4 PFU/ml of SARS-CoV-2 WA1- MA10 or B.1.351-MA10, 1 × 10 4 PFU/ml RsSHC014, which have been described previously (Leist et al, 2020; Martinez et al ., 2021a; Martinez et al ., 2021b; Menachery et al, 2015; Roberts et al, 2007). Mice were weighted daily and monitored for signs of clinical disease, and selected groups were subjected to daily whole-body plethysmography.…”