Complexity of Viral Epitope Surfaces as Evasive Targets for Vaccines and Therapeutic Antibodies

Abstract

The dynamic interplay between virus and host plays out across many interacting surfaces as virus and host evolve continually in response to one another. In particular, epitope-paratope interactions (EPIs) between viral antigen and host antibodies drive much of this evolutionary race. In this review, we describe a series of recent studies examining aspects of epitope complexity that go beyond two interacting protein surfaces as EPIs are typically understood. To structure our discussion, we present a framework for understanding epitope complexity as a spectrum along a series of axes, focusing primarily on 1) epitope biochemical complexity (e.g., epitopes involving N-glycans) and 2) antigen conformational/dynamic complexity (e.g., epitopes with differential properties depending on antigen state or fold-axis). We highlight additional epitope complexity factors including epitope tertiary/quaternary structure, which contribute to epistatic relationships between epitope residues within- or adjacent-to a given epitope, as well as epitope overlap resulting from polyclonal antibody responses, which is relevant when assessing antigenic pressure against a given epitope. Finally, we discuss how these different forms of epitope complexity can limit EPI analyses and therapeutic antibody development, as well as recent efforts to overcome these limitations.

Overcoming Variants Resistance in Monoclonal Antibody for Antiviral Therapy

“…Another mechanism of variant resistance is epitope masking or conformational changes. Epitope masking occurs when a variant antigen undergoes structural changes that prevent monoclonal antibodies from binding to their target epitopes [17]. This can happen due to post-translational modifications or protein-protein interactions that alter the conformation of the antigen.…”

Investigation of Reasons for the Reluctance to get Vaccinated with COVID-19 in the General Population in the South of Kerman Province (A Cross-sectional Study)

“…For instance, the influenza vaccine targets hemagglutinin, a key surface protein, while the measles vaccine targets the measles virus envelope protein. In contrast, the COVID-19 vaccine development has had to account for the novel nature of the spike protein, a unique surface protein of SARS-CoV-2, which mediates viral entry into host cells [8,9]. This required researchers to work swiftly to understand the structural and functional aspects of this protein, which is essential for developing an effective vaccine.…”

Learned features of antibody-antigen binding affinity

“…This was one of the early success stories for a computational method that was built using basic machine learning principles of featurization and regression to achieve such a drastic improvement in the binding affinity of an antibody ( Wong et al, 2018 ). Of note, these physicochemical and geometric interface properties were likewise found to be useful for modeling viral escape from neutralizing antibodies, including instances where escape was conferred by combinations of epistatic mutations as occurred for the BA.1 Omicron variant of SARS-CoV-2 ( Tharakaraman et al, 2014 ; Miller et al, 2021a ; Miller et al, 2022a ; Miller et al, 2022b ).…”