Abstract
We previously showed that Month 13 50% plaque reduction neutralization test (PRNT50) neutralizing antibody (nAb) titers against dengue virus (DENV) correlated with vaccine efficacy (VE) of CYD-TDV against symptomatic, virologically-confirmed dengue (VCD) in the CYD14 and CYD15 Phase 3 trials. While PRNT is the gold standard nAb assay, it is time-consuming and costly. We developed a next-generation high-throughput microneutralization (MN) assay and assessed its suitability for immune-correlates analyses and immuno-bridging applications. We analyzed MN and PRNT50 titers measured at baseline and Month 13 in a randomly sampled immunogenicity subset, and at Month 13 in nearly all VCD cases through Month 25. For each serotype, MN and PRNT50 titers showed high correlations, at both baseline and Month 13, with MN yielding a higher frequency of baseline-seronegatives. For both assays, Month 13 titer correlated inversely with VCD risk. Like PRNT50, high Month 13 MN titers were associated with high VE, and estimated VE increased with average Month 13 MN titer. We also studied each assay as a valid surrogate endpoint based on the Prentice criteria, which supported each assay as a valid surrogate for DENV-1 but only partially valid for DENV-2, -3, and -4. In addition, we applied Super-Learner to assess how well demographic, Month 13 MN, and/or Month 13 PRNT50 titers could predict Month 13-25 VCD outcome status; prediction was best when using demographic, MN, and PRNT50 information. We conclude that Month 13 MN titer performs comparably to Month 13 PRNT50 titer as a correlate of risk, correlate of vaccine efficacy, and surrogate endpoint. The MN assay could potentially be used to assess nAb titers in immunogenicity studies, immune-correlates studies, and immuno-bridging applications. Additional research would be needed for assessing the utility of MN titer in correlates analyses of other DENV endpoints and over longer follow-up periods.
Highlights
40% of the world is at risk of infection with the four serotypes of dengue virus (DENV-1, -2, -3, and -4) [1]
Correlations were highest for the average titer at both time-points (baseline 0.96, 95% confidence intervals (CIs) 0.95–0.97; Month 13 0.95, 95% CI 0.93–0.96; Month 13 0.94, 95% CI 0.93–0.95), with high correlations for the DENV-1, -2, and -3 readouts (0.88–0.94 across both time-points)
We previously showed that estimated vaccine efficacy (VE) against DENV-Any was approximately 25% for vaccine recipients with no seroresponse at Month 13 and increased with average Month 13 PRNT50 titer in baseline seronegative vs. baseline seropositive subgroups in CYD14 and CYD15 9–16-year-old vaccine recipients (Fig 7A and 7B; reproduced with modification from [11])
Summary
40% of the world is at risk of infection with the four serotypes of dengue virus (DENV-1, -2, -3, and -4) [1]. The global health and economic burdens of DENV are significant, with about 400 million (including 500,000 hospitalized) infections annually worldwide [1, 3] and an estimated annual $8.9 billion cost of dengue disease [4]. Estimated vaccine efficacy (VE) of CYD-TDV against VCD caused by any serotype (DENV-Any) between Months 13 and 25 was 56.5% in CYD14 and 60.8% in CYD15 [6, 7], supporting licensing of CYD-TDV for individuals 9 years old in multiple dengue-endemic countries [8]. The World Health Organization (WHO)’s Strategic Advisory Group of Experts on Immunization has concluded: “a ‘pre-vaccination screening strategy’ would be the preferred option, in which only dengueseropositive persons are vaccinated” [10]
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