# The role of receptor binding and immunity in SARS-CoV-2 fitness landscape: A modeling study

## TL;DR

This study models how SARS-CoV-2 evolves by analyzing receptor binding and immune escape in relation to population immunity.

## Contribution

A novel model decomposes the effective reproduction number to explore how viral traits and immunity shape SARS-CoV-2 fitness.

## Key findings

- SARS-CoV-2 fitness peaks correspond to variants of concern like alpha, delta, and omicron.
- BA.2 achieved optimal fitness through high immune escape despite lower ACE2 binding than BA.1.1.
- Population immunity and viral traits together create a rugged fitness landscape for SARS-CoV-2.

## Abstract

Despite extensive research on SARS-CoV-2 ACE2 binding and transmissibility, their relationship concerning varying immunity remains unclear. SARS-CoV-2 receptor-binding domain (RBD) sequences from Italy in GISAID, combined with multiple deep mutational scanning data, were used to calculate ACE2 binding score and immune escape during the pandemic. We developed a COVID-19 transmission model that decomposed the effective reproduction number into three time-varying components: viral infectiousness (representing fitness), host susceptibility, and contact rate. After model fitting, a rugged fitness landscape, spanned by ACE2 binding score and virus-perceived effective immunity (adjusted for viral immune escape), was observed with peaks corresponding to individual variants of concern (VOCs) (alpha, delta, and omicron (BA.1∗ and BA.2∗)). Increasing effective immunity with reduced ACE2 binding corresponded to decreasing virus fitness peaks from alpha to delta. Among omicron sub-lineages, which exhibited enhanced immune escape, BA.2∗ reached a fitness optimum, with ACE2 binding slightly lower relative to BA.1.1. The findings help explain the evolution of SARS-CoV-2.

•The model estimated intrinsic viral fitness, adjusted for host susceptibility and contact•SARS-CoV-2 traits, together with population immunity, shaped a rugged viral fitness landscape•BA.2 reached optimal fitness via high immune escape despite lower ACE2 binding than BA.1.1

The model estimated intrinsic viral fitness, adjusted for host susceptibility and contact

SARS-CoV-2 traits, together with population immunity, shaped a rugged viral fitness landscape

BA.2 reached optimal fitness via high immune escape despite lower ACE2 binding than BA.1.1

Public health; Computational bioinformatics