SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape

Abstract

An ideal anti-SARS-CoV-2 antibody would resist viral escape [1][2][3] , have activity against diverse SARS-related coronaviruses (sarbecoviruses) [4][5][6][7] , and be highly protective through viral neutralization [8][9][10][11] and effector functions 12,13 . Understanding how these properties relate to each other and vary across epitopes would aid development of antibody therapeutics and guide vaccine design. Here, we comprehensively characterize escape, breadth, and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD). Despite a tradeoff between in vitro neutralization potency and breadth of sarbecovirus binding, we identify neutralizing antibodies with exceptional sarbecovirus breadth and a corresponding resistance to SARS-CoV-2 escape. One of these antibodies, S2H97, binds with high affinity across all sarbecovirus clades to a previously undescribed cryptic epitope and prophylactically protects hamsters from viral challenge. Antibodies targeting the ACE2 receptor binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency. Nevertheless, we characterize one potent RBM antibody (S2E12 8 ) with breadth across sarbecoviruses related to SARS-CoV-2 and a high barrier to viral escape. These data highlight principles underlying variation in escape, breadth, and potency among antibodies targeting the RBD, and identify epitopes and features to prioritize for therapeutic development against the current and potential future pandemics.The most potently neutralizing antibodies to SARS-CoV-2-including those in clinical use 14 and dominant in polyclonal sera 15,16 -target the spike receptor-binding domain (RBD). Mutations in the RBD that reduce binding by antibodies have emerged among SARS-CoV-2 variants [17][18][19][20][21] , highlighting the need for antibodies and vaccines that are robust to viral escape. We have previously described an antibody, S309 4 , that exhibits potent effector functions and neutralizes all current SARS-CoV-2 variants 22,23 and the divergent sarbecovirus SARS-CoV-1. S309 forms the basis for an antibody therapy (VIR-7831, recently renamed sotrovimab) that has received Emergency Use Authorization from the FDA for treatment of COVID-19 24 . Longer term, antibodies with broad activity across SARS-related coronaviruses (sarbecoviruses) would be useful to combat potential future spillovers 6 . These efforts would be aided by a systematic understanding of the relationships among antibody epitope,

Molecular basis of immune evasion by the delta and kappa SARS-CoV-2 variants

“…We demonstrate here that S309, the parent mAb of sotrovimab which has received an emergency use authorization from the FDA, is unaffected by antigenic drift observed in variants of concern and interest due to recognition of a conserved RBD epitope (12,15,56). The recent discovery of multiple additional conserved antigenic sites recognized by RBD-specific mAbs with (near) pan-sarbecovirus neutralizing activity (16,17,21,(73)(74)(75) and the anticipated continued emergence of SARS-CoV-2 variants motivate the clinical development and deployment of some of these mAbs for prophylaxis with at-risk patients and for treatments of unvaccinated individuals or breakthrough infections. Moreover, next-generation vaccine candidates have recently been described to elicit broad sarbecovirus immunity (41,76,77), holding the promise to be resilient to the emergence of SARS-CoV-2 variants and of new zoonotic sarbecoviruses.…”

“…The S2 subunit contains the fusion machinery and undergoes large-scale conformational changes to drive fusion of the virus and host membranes (14), enabling genome delivery and initiation of infection. Abs that bind to specific sites on the RBD (15)(16)(17)(18)(19)(20)(21)(22), the NTD (23)(24)(25)(26), or the fusion machinery stem helix (27)(28)(29)(30)(31) interfere with receptor attachment or membrane fusion. Serum neutralizing Ab titers are a correlate of protection against SARS-CoV-2 in non-human primates (32)(33)(34)(35).…”

“…S3). The RBD is the main target of serum neutralizing activity in convalescent and vaccinated individuals and comprises several antigenic sites recognized by neutralizing Abs with a range of neutralization potencies and breadth (15)(16)(17)(18)(49)(50)(51). The B.1.617.1 S and B.1.617.2 S structures resolve the complete RBD and provide high-resolution blueprints of the residue substitutions found in these two variants (Fig 2C-D).…”

Apropos of Universal Epitope Discovery for COVID-19 Vaccines: A Framework for Targeted Phage Display-Based Delivery and Integration of New Evaluation Tools

“…6,7 A recent massive analysis of more than 300,000 viral genomes has suggested that mutations within the S protein represent one of the main pathways of adaptive evolution in SARS-CoV-2, 8 thereby raising concerns about potential for resistance to neutralizing antibodies acquired through either vaccination or previous COVID-19 infection. [9][10][11] Recent developments have supported the concept of "inescapable" monoclonal antibodies with broad activity against multiple variants of SARS-CoV-2 12 ; however the ongoing genetic evolution of the virus raises uncertainty regarding the possibility of new viral mutations that allow immune escape. Moreover, given that some proportion of the viral mutations may also alter infectivity, disease severity, interaction with host immunity, and resistance to antiviral drugs, 13 both the World Health Organization (WHO) 14 and the United States Centers for Disease Control & Prevention (CDC) 15 have actively been monitoring at least 21 new variants of SARS-CoV-2.…”

“…26 Collectively, these empirical results suggest that C662-C671 epitope might represent a privileged motif for vaccine development and perhaps even a potential target for inescapable antibodies. 12 To gain further insight into the structural properties of C662-C671, we performed comparative structural analysis (Fig. 1b) and molecular simulations (Fig.…”