Streptococcus suis manganese transporter mutant as a live attenuated vaccine: Safety, efficacy, and virulence reversion mechanisms

Streptococcus suis is the leading cause of mortality in piglets and is responsible for severe economic losses in the global pork industry. Severe invasive diseases caused by S. suis include sepsis, meningitis, arthritis, and endocarditis. S. suis disease prevention is hampered by the lack of safe and efficacious vaccines. In this study, we constructed an S. suis live attenuated vaccine candidate lacking the major streptococcal manganese transporter, a known virulence determinant of this organism. The safety and efficacy of this live vaccine were evaluated in swine. Our clinical study results showed that when administered at a dose of 10¹⁰ CFU, the vaccine strain was safe and efficacious. However, a lower dose of 10⁹ CFU failed to generate significant immune protection. To investigate if an adjuvant could enhance the efficacy of the vaccine at a lower dose, we spiked the vaccine with a polymeric adjuvant and evaluated its performance. Surprisingly, four pigs receiving the adjuvanted vaccine died during the vaccination phase. Pathology, microbiology, and genetic analyses suggested that the vaccine strain reverted to virulence in these animals. Functional genetic analysis found that the vaccine strain acquired compensatory mutations that upregulated the expression of a secondary manganese transporter, which in turn restored the virulence of the vaccine strain. Our results provide a new understanding of S. suis host adaptation mechanisms and useful information for the design of future live-attenuated vaccines.