Epidemiological conditions to support dengue vaccine introduction in Asia using data from traditional and novel sources
Dengue, an Aedes mosquito-borne flavivirus, is the most common vector-borne viral infection worldwide. Infections result in around 100 million (95% credible interval: 67 - 136 million) clinical episodes and 10.5 million (95% uncertainty intervals: 4.1 – 22.7 million) hospitalizations annually, mostly within the Asia Pacific region. There are four closely related viral serotypes, all of which cause severe disease. First infections are often mild/asymptomatic but subsequent infections with heterologous serotypes more frequently result in severe episodes and hospitalisations. National surveillance systems are not designed to estimate the full disease burden and the value of preventive measures is therefore poorly defined. In 2014 the first dengue vaccine, CYD-TDV, was licensed having demonstrated significant efficacy against all four serotypes in study participants aged 2 – 16 years. Subsequent analyses after 5 years’ follow-up revealed a more complex vaccine profile with superior protection in individuals seropositive for dengue, but an elevated risk of hospitalized dengue in seronegative vaccine recipients. Population-level benefit-risk is therefore dependent on epidemiological criteria and WHO recommends its use only under certain conditions or following confirmation of individual serostatus. This thesis describes a body of epidemiological research designed to improve understanding of these conditions. Studies were intended to fill important knowledge gaps identified following discussions with local vaccine policymakers and experts. My role, working within a multidisciplinary team, was to understand identified gaps and develop and implement a corresponding research agenda to fill them. I designed and contributed to protocols, provided oversight to their implementation working with local research teams, analysed and interpreted the resulting data and drafted the manuscripts included in this thesis which were published between 2016 and 2020. These studies used different methods: we analysed existing data sources to improve estimates of symptomatic dengue disease burden; measured age-stratified dengue seroprevalence in children in India and Indonesia; estimated force-of-infection (the annual rate at which seronegative individuals acquire infection) as an indicator of endemicity in seven Asian countries; and conducted a prospective surveillance study to plan future dengue vaccine effectiveness research. After refining these methods for dengue, we extended them to Japanese encephalitis, another mosquito-borne flavivirus. Using data derived from active case ascertainment from the placebo arm of a paediatric clinical trial, wherein parents were contacted weekly and reminded to report to study sites in case of febrile illness in their children, we identified a crude dengue attack rate of 4.6%/year. Only 29% of these events were clinically diagnosed as dengue by study investigators, indicating that most symptomatic disease fails to satisfy existing case definitions. This active case ascertainment captured a greater proportion of symptomatic dengue than national passive surveillance systems. The ratio between these two rates (“expansion factor”) can be used to estimate the full disease burden from passive surveillance reports and we calculated factors ranging from 0.5 – 31.7, depending on country and case definition. Large seroprevalence surveys in India and Indonesia confirmed very high rates of paediatric infection: by the age of 10 years, 73% of children in India and 79% in Indonesia had been infected at least once. We also identified serological evidence for circulation of multiple dengue serotypes in both countries. We used these and other serological data to estimate force-of-infection which varied widely between countries from 1.7% (Singapore) to 24.1% (the Philippines), with significant heterogeneity within countries. The force of infection of Japanese encephalitis was much lower (varying from 0.8% in Malaysia to 5.2% in Vietnam) but this demonstration of transmission in urban areas was an important finding in areas where Japanese encephalitis vaccination is not routine. After conducting a hospital-based surveillance study to plan future dengue vaccine effectiveness studies in Malaysia, we concluded that test-negative case control studies are not feasible due to small numbers of test-negative controls; and that case control studies for dengue vaccines could be significantly biased by underlying differences between cases and controls. In summary, these studies demonstrated intense but heterogeneous dengue transmission across multiple Asia-pacific countries. These levels of transmission are broadly compatible with recommendations for dengue vaccine introduction at the national level but, due to heterogeneity in endemicity, more local approaches would likely be needed before implementation of mass vaccination programmes.