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Epitope Classification and RBD Binding Properties of Neutralizing Antibodies Against SARS-CoV-2 Variants of Concern.

ABSTRACT: Severe acute respiratory syndrome coronavirus-2 (SAR-CoV-2) causes coronavirus disease 2019 (COVID19) that is responsible for short and long-term disease, as well as death, in susceptible hosts. The receptor binding domain (RBD) of the SARS-CoV-2 Spike (S) protein binds to cell surface angiotensin converting enzyme type-II (ACE2) to initiate viral attachment and ultimately viral pathogenesis. The SARS-CoV-2 S RBD is a major target of neutralizing antibodies (NAbs) that block RBD - ACE2 interactions. In this report, NAb-RBD binding epitopes in the protein databank were classified as C1, C1D, C2, C3, or C4, using a RBD binding profile (BP), based on NAb-specific RBD buried surface area and used to predict the binding epitopes of a series of uncharacterized NAbs. Naturally occurring SARS-CoV-2 RBD sequence variation was also quantified to predict NAb binding sensitivities to the RBD-variants. NAb and ACE2 binding studies confirmed the NAb classifications and determined whether the RBD variants enhanced ACE2 binding to promote viral infectivity, and/or disrupted NAb binding to evade the host immune response. Of 9 single RBD mutants evaluated, K417T, E484K, and N501Y disrupted binding of 65% of the NAbs evaluated, consistent with the assignment of the SARS-CoV-2 P.1 Japan/Brazil strain as a variant of concern (VoC). RBD variants E484K and N501Y exhibited ACE2 binding equivalent to a Wuhan-1 reference SARS-CoV-2 RBD. While slightly less disruptive to NAb binding, L452R enhanced ACE2 binding affinity. Thus, the L452R mutant, associated with the SARS-CoV-2 California VoC (B.1.427/B.1.429-California), has evolved to enhance ACE2 binding, while simultaneously disrupting C1 and C2 NAb classes. The analysis also identified a non-overlapping antibody pair (1213H7 and 1215D1) that bound to all SARS-CoV-2 RBD variants evaluated, representing an excellent therapeutic option for treatment of SARS-CoV-2 WT and VoC strains.

SUBMITTER: Deshpande A

PROVIDER: S-EPMC8212047 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background The receptor-binding domain (RBD) variants of SARS-CoV-2 could impair antibody-mediated neutralization of the virus by host immunity; thus, prospective surveillance of antibody escape mutants and understanding the evolution of RBD are urgently needed. Methods Using the single B cell cloning technology, we isolated and characterized 93 RBD-specific antibodies from the memory B cells of four COVID-19 convalescent individuals in the early stage of the pandemic. Then, global RBD alanine scanning with a panel of 19 selected neutralizing antibodies (NAbs), including several broadly reactive NAbs, was performed. Furthermore, we assessed the impact of single natural mutation or co-mutations of concern at key positions of RBD on the neutralization escape and ACE2 binding function by recombinant proteins and pseudoviruses. Results Thirty-three amino acid positions within four independent antigenic sites (1 to 4) of RBD were identified as valuable indicators of antigenic changes in the RBD. The comprehensive escape mutation map not only confirms the widely circulating strains carrying important immune escape RBD mutations such as K417N, E484K, and L452R, but also facilitates the discovery of new immune escape-enabling mutations such as F486L, N450K, F490S, and R346S. Of note, these escape mutations could not affect the ACE2 binding affinity of RBD, among which L452R even enhanced binding. Furthermore, we showed that RBD co-mutations K417N, E484K, and N501Y present in B.1.351 appear more resistant to NAbs and human convalescent plasma from the early stage of the pandemic, possibly due to an additive effect. Conversely, double mutations E484Q and L452R present in B.1.617.1 variant show partial antibody evasion with no evidence for an additive effect. Conclusions Our study provides a global view of the determinants for neutralizing antibody recognition, antigenic conservation, and RBD conformation. The in-depth escape maps may have value for prospective surveillance of SARS-CoV-2 immune escape variants. Special attention should be paid to the accumulation of co-mutations at distinct major antigenic sites. Finally, the new broadly reactive NAbs described here represent new potential opportunities for the prevention and treatment of COVID-19. Supplementary Information The online version contains supplementary material available at 10.1186/s13073-021-00985-w.

Project description:During the COVID-19 pandemic, several SARS-CoV-2 variants of concern (VOC) emerged, bringing with them varying degrees of health and socioeconomic burdens. In particular, the Omicron VOC displayed distinct features of increased transmissibility accompanied by antigenic drift in the spike protein that partially circumvented the ability of pre-existing antibody responses in the global population to neutralize the virus. However, T cell immunity has remained robust throughout all the different VOC transmission waves and has emerged as a critically important correlate of protection against SARS-CoV-2 and its VOCs, in both vaccinated and infected individuals. Therefore, as SARS-CoV-2 VOCs continue to evolve, it is crucial that we characterize the correlates of protection and the potential for immune escape for both B cell and T cell human immunity in the population. Generating the insights necessary to understand T cell immunity, experimentally, for the global human population is at present a critical but a time consuming, expensive, and laborious process. Further, it is not feasible to generate global or universal insights into T cell immunity in an actionable time frame for potential future emerging VOCs. However, using computational means we can expedite and provide early insights into the correlates of T cell protection. In this study, we generated and revealed insights on the T cell epitope landscape for the five main SARS-CoV-2 VOCs observed to date. We demonstrated using a unique AI prediction platform, a significant conservation of presentable T cell epitopes across all mutated peptides for each VOC. This was modeled using the most frequent HLA alleles in the human population and covers the most common HLA haplotypes in the human population. The AI resource generated through this computational study and associated insights may guide the development of T cell vaccines and diagnostics that are even more robust against current and future VOCs, and their emerging subvariants.

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Epitope Classification and RBD Binding Properties of Neutralizing Antibodies Against SARS-CoV-2 Variants of Concern.

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