# Enhanced reverse zoonotic potential and immune evasion by omicron JN.1 variant

## TL;DR

The JN.1 variant of SARS-CoV-2 has a higher risk of spreading to animals and evades the immune system more effectively due to a specific mutation.

## Contribution

This study identifies the L455S mutation as a key driver of increased infectivity and immune evasion in the JN.1 variant.

## Key findings

- JN.1 shows higher reverse zoonotic potential compared to other variants like BA.2.86.
- The L455S mutation increases fusogenicity and infectivity by lowering S protein thermostability.
- XBB breakthrough infection boosts neutralization antibodies against JN.1.

## Abstract

SARS-CoV-2 infects not only humans but also animals, posing reverse zoonotic risks. As SARS-CoV-2 rapidly evolves, JN.1 has become dominant globally. In this study, we determined the susceptibility of XBB.1.16, EG.5.1, BA.2.86, and JN.1 to 27 different animal angiotensin-converting enzyme 2 (ACE2) orthologs using pseudoviruses, and found that JN.1 displayed substantially higher overall reverse zoonotic risk potential compared to other variants except for EG.5.1. Live virus infection experiments further confirmed higher infectivity of JN.1 than BA.2.86. Mechanistic analyses revealed that L455S might be responsible for substantial increase in overall fusogenecity and infectivity by lowering S protein thermostability. Additionally, we also found that L455S mutation enhanced immune evasion of SARS-CoV-2, and XBB breakthrough infection increased levels of neutralization antibodies against JN.1. Together, our findings offer a better mechanistic understanding of CoV entry, host range, evolution, and immunogenicity and highlight the importance of surveillance of susceptible hosts to prevent potential outbreaks.

•JN.1 exhibits a higher potential for reverse zoonotic transmission risk compared to BA.2.86•The L455S mutation decreases receptor binding while increasing fusogenicity and infectivity•Mechanistically, the L455S mutation enhances viral infectivity by reducing S protein stability•Breakthrough infection with XBB strengthens protection against JN.1 infection

JN.1 exhibits a higher potential for reverse zoonotic transmission risk compared to BA.2.86

The L455S mutation decreases receptor binding while increasing fusogenicity and infectivity

Mechanistically, the L455S mutation enhances viral infectivity by reducing S protein stability

Breakthrough infection with XBB strengthens protection against JN.1 infection

Immunology; Virology