OBJECTIVES: Despite widespread vaccination programmes and consensus recommendations, the understanding of the durability of COVID-19 vaccination against ensuing infection and transmission at the individual level is incomplete. The objective of this study was to estimate the effects of time-varying covariates including time since vaccination and symptoms on subsequent positive SARS-CoV-2 test results and assess the stability of these effects between March 2020 and April 2022. DESIGN: Prospective cohort study. SETTING: Urban university in the USA. PARTICIPANTS: Drexel University students, faculty, and staff (n=15 527) undergoing mandatory COVID-19 symptom tracking, testing and vaccinations. INTERVENTION: Systematic symptom tracking and SARS-COV-2 testing starting in September 2020 and mandatory COVID-19 vaccination starting in September 2021. MAIN OUTCOMES AND MEASURES: COVID-19 vaccine effectiveness modified by time since vaccination and symptoms. RESULTS: Using fit-for-purpose digitally based symptom and vaccine tracking and mandatory comprehensive testing for SARS-CoV-2 infection, we estimate the time-dependent effects of vaccination, symptoms and covariates on the risk of infection with a Cox proportional hazards model based on calendar time scale. We found a strong protective effect of vaccination against symptomatic infection. However, there was strong evidence of a protective effect against infection only in the first 90 days after completed vaccination, and only against symptomatic versus asymptomatic infection. The overall estimated effect of vaccination within 30 days, including asymptomatic infections, was 37.3% (95% CI 26%, 47%). Vaccine effect modification by reported symptoms and time period was estimated, revealing the protective effect of vaccination within 90 days against symptomatic infection that varied from 90% (95% CI 84%, 94%) to 49%(95% CI -77%, 85%) across time periods. CONCLUSIONS: This study is among the first to prospectively capture complete COVID-19 symptom, testing and vaccination data over a multiyear period. Overall effectiveness of the COVID-19 vaccine against subsequent infection, including transmissible asymptomatic infections, is modest and wanes after 90 days. Vaccination policies may need to take these issues into account.