The landscape of antibody binding affinity in SARS-CoV-2 Omicron BA.1 evolution
- Harvard University, United States
- Fred Hutchinson Cancer Research Center, United States
Abstract
The Omicron BA.1 variant of SARS-CoV-2 escapes convalescent sera and monoclonal antibodies that are effective against earlier strains of the virus. This immune evasion is largely a consequence of mutations in the BA.1 receptor binding domain (RBD), the major antigenic target of SARS-CoV-2. Previous studies have identified several key RBD mutations leading to escape from most antibodies. However, little is known about how these escape mutations interact with each other and with other mutations in the RBD. Here, we systematically map these interactions by measuring the binding affinity of all possible combinations of these 15 RBD mutations (215 = 32,768 genotypes) to four monoclonal antibodies (LY-CoV016, LY-CoV555, REGN10987, and S309) with distinct epitopes. We find that BA.1 can lose affinity to diverse antibodies by acquiring a few large-effect mutations and can reduce affinity to others through several small-effect mutations. However, our results also reveal alternative pathways to antibody escape that do not include every large-effect mutation. Moreover, epistatic interactions are shown to constrain affinity decline in S309 but only modestly shape the affinity landscapes of other antibodies. Together with previous work on the ACE2 affinity landscape, our results suggest that escape of each antibody is mediated by distinct groups of mutations, whose deleterious effects on ACE2 affinity are compensated by another distinct group of mutations (most notably Q498R and N501Y).
Data availability
Raw sequencing reads have been deposited in the NCBI BioProject database under accession number PRJNA877045.All associated metadata are available at https://github.com/desai-lab/omicron_ab_landscape. -
Article and author information
Author details
Funding
Human Frontier Science Program (Postdoctoral Fellowship)
- Thomas Dupic
Howard Hughes Medical Institute (Hanna H. Gray Postdoctoral Fellowship)
- Angela M Phillips
National Science Foundation (Graduate Research Fellowship Program)
- Jeffrey Chang
National Science Foundation (Simons Center DMS-1764269)
- Michael M Desai
National Science Foundation (Harvard Quantitative Biology Initiative DEB-1655960)
- Michael M Desai
National Institutes of Health (Harvard Quantitative Biology InitiativeGM104239)
- Michael M Desai
National Institutes of Health (NIH/NIAID R01AI141707)
- Jesse D Bloom
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, Moulana et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The landscape of antibody binding affinity in SARS-CoV-2 Omicron BA.1 evolution
eLife 12:e83442.
https://doi.org/10.7554/eLife.83442
Further reading
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The majority of highly polymorphic genes are related to immune functions and with over 100 alleles within a population, genes of the major histocompatibility complex (MHC) are the most polymorphic loci in vertebrates. How such extraordinary polymorphism arose and is maintained is controversial. One possibility is heterozygote advantage (HA), which can in principle maintain any number of alleles, but biologically explicit models based on this mechanism have so far failed to reliably predict the coexistence of significantly more than 10 alleles. We here present an eco-evolutionary model showing that evolution can result in the emergence and maintenance of more than 100 alleles under HA if the following two assumptions are fulfilled: first, pathogens are lethal in the absence of an appropriate immune defence; second, the effect of pathogens depends on host condition, with hosts in poorer condition being affected more strongly. Thus, our results show that HA can be a more potent force in explaining the extraordinary polymorphism found at MHC loci than currently recognised.
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Understanding the origins of novel, complex phenotypes is a major goal in evolutionary biology. Poison frogs of the family Dendrobatidae have evolved the novel ability to acquire alkaloids from their diet for chemical defense at least three times. However, taxon sampling for alkaloids has been biased towards colorful species, without similar attention paid to inconspicuous ones that are often assumed to be undefended. As a result, our understanding of how chemical defense evolved in this group is incomplete. Here, we provide new data showing that, in contrast to previous studies, species from each undefended poison frog clade have measurable yet low amounts of alkaloids. We confirm that undefended dendrobatids regularly consume mites and ants, which are known sources of alkaloids. Thus, our data suggest that diet is insufficient to explain the defended phenotype. Our data support the existence of a phenotypic intermediate between toxin consumption and sequestration — passive accumulation — that differs from sequestration in that it involves no derived forms of transport and storage mechanisms yet results in low levels of toxin accumulation. We discuss the concept of passive accumulation and its potential role in the origin of chemical defenses in poison frogs and other toxin-sequestering organisms. In light of ideas from pharmacokinetics, we incorporate new and old data from poison frogs into an evolutionary model that could help explain the origins of acquired chemical defenses in animals and provide insight into the molecular processes that govern the fate of ingested toxins.
