Abstract

This study defined the genetic epidemiology of dengue viruses (DENV) in two pivotal phase III trials of the tetravalent dengue vaccine, CYD-TDV, and thereby enabled virus genotype-specific estimates of vaccine efficacy (VE). Envelope gene sequences (n = 661) from 11 DENV genotypes in 10 endemic countries provided a contemporaneous global snapshot of DENV population genetics and revealed high amino acid identity between the E genes of vaccine strains and wild-type viruses from trial participants, including at epitope sites targeted by virus neutralising human monoclonal antibodies. Post-hoc analysis of all CYD14/15 trial participants revealed a statistically significant genotype-level VE association within DENV-4, where efficacy was lowest against genotype I. In subgroup analysis of trial participants age 9-16 years, VE estimates appeared more balanced within each serotype, suggesting that genotype-level heterogeneity may be limited in older children. Post-licensure surveillance is needed to monitor vaccine performance against the backdrop of DENV sequence diversity and evolution.

Highlights

  • Dengue is the commonest arboviral disease of humans and has been a major public health problem in tropical Asia and Latin America for decades (Stanaway et al, 2016)

  • 433 acute serum samples from 595 virologically-confirmed dengue (VCD) cases in CYD14 and 512 samples from 662 VCD cases in CYD15 were selected for investigation on the basis of subject consent, viremia level and sample volume considerations (Figure 1A and B, respectively)

  • The probability of acquiring an E gene sequence from serum samples was positively associated with the dengue viruses (DENV) viremia level (Figure 1—figure supplement 1)

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Summary

Introduction

Dengue is the commonest arboviral disease of humans and has been a major public health problem in tropical Asia and Latin America for decades (Stanaway et al, 2016). Reducing the population of competent mosquito vectors of dengue viruses has been the central aim of disease control efforts, but these have had little success in eliminating or stopping the spread of dengue globally. Effective dengue vaccines will be essential tools to achieving dengue control. The licensure of the first tetravalent dengue vaccine (chimeric yellow fever–dengue virus tetravalent dengue vaccine (CYD-TDV), Sanofi Pasteur) together with recommendations from The World Health Organisation’s Strategic Advisory Group of Experts (SAGE) on Immunization on its use in highly endemic countries, Rabaa et al eLife 2017;6:e24196.

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