Metabolite-Tfh axis as a key modulator of protective humoral immunity to the historical SA14-14-2 Japanese encephalitis vaccine 3685

Abstract Description Japanese encephalitis (JE) is the leading cause of viral encephalitis globally, with approximately 100,000 cases annually, a high fatality rate of 30%, and neurological sequelae in 50% of survivors. The live attenuated SA14-14-2 vaccine is widely used and regarded as the gold standard for JE vaccine development. However, its durability and immunological effectiveness remain uncertain. This study assessed the magnitude and longevity of humoral and T-cell immunity in a longitudinal cohort of 87 young adults vaccinated with SA14-14-2. Samples were collected at baseline and at five time points over three years post-vaccination. Among seronegative individuals, only 36% seroconverted, while 18% remained non-seroconverters. Of the vaccinees, 41 achieved seroprotection (FRNT50 ≥ 10), but these levels declined drastically within two years. Interestingly, we observed that non-seroconverters exhibited significantly lower frequencies of JEV-specific T follicular helper (Tfh) cells and impaired T-B cell interactions, leading to poor class-switching and a likely failure to seroconvert. Metabolomics analyses identified unique metabolites enriched in non-seroconverters. Further studies revealed that a metabolite suppressed Tfh responses, disrupting GC-activity and abrogating vaccine-induced humoral immunity. These findings highlight a novel mechanism of metabolite-mediated modulation of vaccine efficacy and emphasize the need for optimizing JE and related flavivirus vaccination strategies. Funding Sources Supported by Department of Biotechnology Grants - BT/PR30223/MED/2018; BT/PR25335/NER/2017 Topic Categories Vaccines and Immunotherapy (VAC)