Gene-deletion attenuated live vaccines for Streptococcus suis: Advances, challenges, and future directions

This review consolidates recent advances in the development of gene-deletion attenuated live vaccines (ALVs) against Streptococcus suis, a pathogen causing substantial economic losses in swine production and zoonotic infections. We critically evaluate the protective efficacy, immune mechanisms, and safety profiles of rationally designed ALVs, drawing insights from 13 pivotal studies (1990-2025). Key findings demonstrate that multi-gene deletions targeting virulence factors (e.g., sly, ssnA, scpA) or metabolic pathways (e.g., aro, mtsABCD) confer robust homologous protection and emerging cross-serotype efficacy. These findings underscore opsonophagocytic antibodies (OPA) as the cardinal immune correlate for next-gen SS2 vaccines. Nevertheless, virulence reversion risks necessitate further optimization through multi-gene attenuation and standardized safety assessments. Future research should focus on improving safety profiles through multi-gene deletions, standardizing challenge protocols, and developing differentiating infected from vaccinated animals (DIVA) compatible vaccines to enhance practical application. It is essential to note that all gene-deletion ALVs discussed here remain in the experimental stage and have not yet been deployed in field settings.