Abstract
More than half of the world's population lives in areas at risk for dengue virus infection. A vaccine will be pivotal to controlling spread, however, the only licensed vaccine, Dengvaxia, has been shown to increase the risk of severe disease in a subset of individuals. Vaccine efforts are hampered by a poor understanding of antibody responses, including those generated by vaccines, and whether antibody titers can be used as a marker of protection from infection or disease. Here we present the results of an ancillary study to a phase III vaccine study (n = 611). All participants received three doses of either Dengvaxia or placebo and were followed for 6 years. We performed neutralization tests on annual samples and during confirmed dengue episodes (n = 16,508 total measurements). We use mathematical models to reconstruct long-term antibody responses to vaccination and natural infection, and to identify subclinical infections. There were 87 symptomatic infections reported, and we estimated that there were a further 351 subclinical infections. Cumulative vaccine efficacy was positive for both subclinical and symptomatic infection, although the protective effect of the vaccine was concentrated in the first 3 years following vaccination. Among individuals with the same antibody titer, we found no difference between the risk of subsequent infection or disease between placebo and vaccine recipients, suggesting that antibody titers are a good predictor of both protection and disease risk.
Highlights
IntroductionThe four dengue virus serotypes (DENV1-4) cause 50 million symptomatic infections each year1
In the six years post the third dose of the vaccine, there were 87 symptomatic infections (12 DENV1, 43 DENV2, 16 DENV3, 6 DENV4, 10 where the serotype was unknown), of which 9 led to hospitalisation (Table S3)
When considering vaccine efficacy over discrete windows of two years rather than cumulatively over the study period, we find that there was no significant protection from symptomatic infection after 3 years and no protection from subclinical infection after 5 years (Figure 2C-D)
Summary
IntroductionThe four dengue virus serotypes (DENV1-4) cause 50 million symptomatic infections each year. The relevance of these findings to vaccine-induced immunity remains unclear It is unknown whether the antibody response to Dengvaxia is comparable to natural infection, and provides comparable levels of protection from infection and disease. A major complication in answering these questions is that most infections are subclinical and not detected in phase III trials that only measure symptomatic disease10 These subclinical infections change the underlying antibody titers within an individual, changing their risk of future infection and disease. We need to measure the effect of vaccines on the risk of infection rather than just symptomatic disease These analyses require the long-term follow-up of vaccinated individuals and placebo controls that exceed the normal durations of Phase III trials
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