Background: Sanofi-Pasteur’s CYD-TDV is the only licensed dengue vaccine. Two phase III trials showed higher efficacy in seropositive than seronegative recipients. Hospital follow-up revealed increased hospitalisation in 2-5-year-old vaccinees, where serostatus and age effects were unresolved.

Methods: We fit a survival model to individual-level data from both trials, including year one of hospital follow-up. We determine efficacy by age, serostatus, serotype and severity, and examine efficacy duration and vaccine action mechanism.

Results: Our modelling indicates that vaccine-induced immunity is long-lived in seropositive recipients, and therefore that vaccinating seropositives gives higher protection than two natural infections. Long-term increased hospitalisation risk outweighs short-lived immunity in seronegatives. Independently of serostatus, transient immunity increases with age, and is highest against serotype 4. Benefit is higher in seropositives, and risk enhancement is greater in seronegatives, against hospitalised disease than febrile disease.

Conclusions: Our results support vaccinating seropositives only. Rapid diagnostic tests would enable viable “screen-then-vaccinate” programs. Since CYD-TDV acts as a silent infection, long-term safety of other vaccine candidates must be closely monitored.

Funding: Bill and Melinda Gates Foundation, National Institute for Health Research, UK Medical Research Council, Wellcome Trust.