# Omicron KP.3 RBD-Containing Spike mRNA Vaccine Induces Broadly Neutralizing Antibodies with Protection Against SARS-CoV-2 Omicron Infection in Mice

## TL;DR

A new mRNA vaccine targeting the Omicron KP.3 variant induces strong, broad protection against multiple Omicron subvariants in mice.

## Contribution

A novel mRNA vaccine encoding the Omicron KP.3 RBD is shown to elicit broadly neutralizing antibodies and protective immunity against multiple Omicron subvariants.

## Key findings

- The KP3 mRNA vaccine is stable at various temperatures and elicits potent antibody responses.
- The vaccine provides broad neutralizing activity against multiple Omicron subvariants in mice.
- Immune serum from vaccinated mice protects against subsequent virus challenge.

## Abstract

Background/Objectives: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the global COVID-19 pandemic, which led to hundreds of millions of human infections and more than seven million deaths worldwide. Major variants of concern, particularly the Omicron variant and its associated subvariants, can escape the vaccines developed so far to target previous strains/subvariants. Therefore, effective vaccines that broadly neutralize different Omicron subvariants and show good protective efficacy are needed to prevent further spread of Omicron. The spike (S) protein, including its receptor-binding domain (RBD), is a key vaccine target. Methods: Here, we designed a unique mRNA vaccine encoding Omicron-KP.3 RBD based on RBD-truncated S protein backbone of an earlier Omicron subvariant EG.5 (KP3 mRNA), and evaluated its stability, immunogenicity, neutralizing activity, and protective efficacy in a mouse model. Results: Our data showed that the nucleoside-modified, lipid nanoparticle-encapsulated mRNA vaccine was stable at various temperatures during the period of detection. In addition, the vaccine elicited potent antibody responses with broadly neutralizing activity against multiple Omicron subvariants, including KP.2, KP.3, XEC, and NB.1.8.1. This mRNA vaccine protected immunized transgenic mice from challenge with SARS-CoV-2 Omicron-KP.3. Immune serum also protected against subsequent virus challenge, with the level of protection associating positively with the serum neutralizing antibody titer. Conclusions: Taken together, the data presented herein suggest that this newly designed mRNA vaccine has potential against current and future Omicron subvariants.