A computational method to design broad-spectrum T cell-inducing vaccines applied to Betacoronaviruses.

Antigenically diverse pathogens such as coronaviruses pose substantial global health threats, highlighting the need for broad-spectrum vaccines. Here, we introduce Spectravax, a computational method that designs broad-spectrum vaccines accounting for genetic diversity in both host and pathogen populations. Using Spectravax, we designed a nucleocapsid (N) antigen to elicit cross-reactive immune responses to viruses from the Sarbecovirus and Merbecovirus subgenera of Betacoronaviruses. In silico analyses demonstrated superior predicted host and pathogen coverage for Spectravax compared to wild-type sequences and existing computational designs. Experimental validation in mice supported these predictions: Spectravax N elicited robust immune responses to SARS-CoV, SARS-CoV-2, and MERS-CoV-the three coronaviruses responsible for major outbreaks in humans since 2002-while wild-type and existing computational designs elicited limited responses. Furthermore, we identified the MERS-CoV N epitopes responsible for Spectravax's cross-reactivity, advancing the rational design of broad-spectrum vaccines for pandemic preparedness.