Immunological consequences of delayed exposure to hepatitis A virus: evidence consistent with CD8+ T-cell–mediated immunopathology

BACKGROUND: Hepatitis A virus (HAV) infection has traditionally occurred during early childhood in high-endemic settings but is increasingly affecting adolescents and adults in regions undergoing epidemiological transition, where improvements in sanitation delay primary exposure. Adult HAV infection is associated with more severe clinical disease, and prior work has implicated CD8 + cytotoxic T lymphocyte responses and cytokine-driven bystander immune activation in hepatocyte injury; however, the immunological correlates underlying age-dependent severity in populations undergoing active epidemiological transition remain incompletely characterised. METHODS: We analysed statewide surveillance data from Kerala, India (2020-2024), comprising 34,118 confirmed or probable HAV cases, to characterise temporal, seasonal, and geographic trends. Within this framework, we conducted an immunological substudy of 180 patients with confirmed acute HAV infection, stratified by age at infection used as an operational proxy for early (< 18 years) versus delayed (≥ 18 years) primary exposure in a population where improvements in sanitation have progressively shifted first infection to later ages. Clinical severity, hospitalisation, liver biochemistry, peripheral CD8 + T-cell responses (IFN-γ ELISPOT), plasma cytokines, and viral load were assessed. Multivariable logistic regression and sensitivity analyses were used to identify factors associated with moderate-to-severe disease. RESULTS: Surveillance data demonstrated a marked increase in reported HAV cases after 2021, with pronounced post-monsoon seasonality and geographic clustering. In the immunological cohort, individuals infected at ≥ 18 years had significantly higher odds of moderate-to-severe disease compared with those infected earlier (adjusted odds ratio 8.42, 95% CI 3.21-22.08). Moderate-to-severe disease occurred in 69.5% of participants with delayed exposure compared with 7.7% of those with early exposure. Delayed exposure was associated with stronger peripheral CD8 + T-cell IFN-γ responses and higher plasma IFN-γ and TNF-α concentrations, alongside higher aminotransferase levels and increased hospitalisation rates. Viral load did not differ significantly between age groups. Findings were robust across multiple sensitivity analyses. CONCLUSIONS: In this transitioning setting, adult primary HAV infection is associated with increased clinical severity and heightened peripheral cellular immune responses, independent of viral load. These peripheral immune findings are consistent with an immune-mediated contribution to liver injury during adult HAV infection. The findings support consideration of public health strategies aimed at preventing delayed exposure, including prioritisation of childhood hepatitis A vaccination in regions experiencing similar epidemiological transitions.