# Pandemic-driven immune imprinting accelerates evolution of human coronavirus OC43

## TL;DR

The study shows that pandemic measures and immune responses may be driving rapid evolution in the human coronavirus OC43.

## Contribution

The study identifies accelerated genomic evolution in HCoV-OC43 post-2020 and links it to immune imprinting from pandemic interventions.

## Key findings

- HCoV-OC43's spike gene substitution rate increased 3.76-fold after 2020.
- Positively selected mutations in the spike protein overlap with antigenic epitopes.
- Structural modeling shows cross-binding of antibodies from SARS-CoV-2 to HCoV-OC43.

## Abstract

Global pandemic interventions have reshaped host-virus dynamics, potentially altering the evolution of endemic pathogens. Here, we report accelerated genomic evolution of human coronavirus OC43 (HCoV-OC43)—a close relative of pandemic-associated coronaviruses—following recent worldwide epidemiological shifts. Bayesian analysis of longitudinal surveillance data revealed a 3.76-fold increase (8.9403 × 10 ⁻ ⁴ nucleotide substitutions/site/year, 95% HPD: 4.9075 × 10 ⁻ ⁴, 1.3053 × 10 ⁻ ³) in the spike gene substitution rate of the currently dominant genotype K post-2020. Positively selected mutations were mainly located in the spike protein, and some colocalize with antigenic epitopes. Crucially, structural modeling demonstrated that broadly neutralizing antibodies targeting conserved stem-helix (S2P6) and fusion-peptide (COV44–62/79, 76E1) epitopes of high-pathogenicity betacoronaviruses cross-bind HCoV-OC43 spike protein, establishing a mechanistic basis for immune-driven selection. These findings suggest that population-level immune imprinting may play a potential driving role in mutations within key domains of HCoV-OC43, although further validation is required. Sustained co-surveillance of co-circulating coronaviruses is imperative to anticipate emergent variants with altered pathogenicity.

Since the global outbreak of COVID-19, extensive public health interventions—such as mask wearing, social distancing, and travel restrictions—along with widespread vaccination and antiviral treatments, have profoundly influenced the transmission dynamics of various respiratory viruses. HCoV-OC43 and SARS-CoV-2 both belong to the genus Betacoronavirus and share structural and antigenic similarities, which may lead to potential cross-reactivity and cross-protective immunity between them. The pandemic may have exerted immune selection pressures that drive adaptive mutations in HCoV-OC43, enabling it to maintain endemic circulation. However, current research on the molecular basis of cross-immunity between these coronaviruses and its impact on viral evolution remains limited. By comparing substitution rates and analyzing antigen–antibody interactions, our study revealed an accelerated evolutionary trend of HCoV-OC43 under potential immune selection pressure. These findings underscore the importance of ongoing joint surveillance of co-circulating coronaviruses to anticipate the emergence of new variants with altered pathogenicity.