Bayesian joint modelling of antibody kinetics and test-negative vaccine effectiveness to characterise hybrid immunity across epidemic waves

Vaccine effectiveness (VE) against symptomatic SARS-CoV-2 infection has shown marked temporal variation across epidemic waves, driven by a combination of waning immunity and immune escape by emerging variants. Test-negative case-control designs have been central to VE monitoring, but they operate at a population level and provide limited insight into the underlying immune mechanisms. In parallel, longitudinal serological studies have characterised antibody trajectories after vaccination and infection, and quantitative models have linked neutralising antibody levels to protection against infection and severe disease. These two streams of evidence are usually analysed separately. We propose a Bayesian joint model that links individual-level antibody kinetics to test-negative VE estimates across successive epidemic waves. The model represents hybrid immunity as the combined effect of vaccination and documented or undocumented infection, with antibody titres following a boost-and-decay process after each immunising event. A titre-protection curve maps latent antibody levels to the risk of symptomatic infection with each variant, extending the correlates-of-protection framework. This allows us to decompose observed VE into contributions from waning, immune escape, and differences in exposure. Using simulated data calibrated on realistic vaccination schedules, infection histories and assay performance, we show that the joint model can recover the underlying titre-protection relationship and separate variant-specific immune escape from pure waning. In scenarios with hybrid immunity, the model captures higher and more durable titres, consistent with empirical observations. When applied to test-negative surveillance data enriched with nested serology, the approach yields VE trajectories that are more interpretable and more stable across time than conventional analyses. This framework provides a coherent way to combine serology and VE to quantify hybrid immunity, and offers practical summary measures for comparing vaccine strategies in the presence of evolving variants.