Neutralizing antibody correlates of sequence specific dengue disease in a tetravalent dengue vaccine efficacy trial in Asia

In the CYD14 trial of the CYD-TDV dengue vaccine in 2–14 year-olds, neutralizing antibody (nAb) titers to the vaccine-insert dengue strains correlated inversely with symptomatic, virologically-confirmed dengue (VCD). Also, vaccine efficacy against VCD was higher against dengue prM/E amino acid sequences closer to the vaccine inserts. We integrated the nAb and sequence data types by assessing nAb titers as a correlate of sequence-specific VCD separately in the vaccine arm and in the placebo arm. In both vaccine and placebo recipients the correlation of nAb titer with sequence-specific VCD was stronger for dengue nAb contact site sequences closer to the vaccine (p = 0.005 and p = 0.012, respectively). The risk of VCD in vaccine (placebo) recipients was 6.7- (1.80)-fold lower at the 90th vs 10th percentile of nAb for viruses perfectly matched to CYD-TDV, compared to 2.1- (0.78)-fold lower at the 90th vs 10th percentile for viruses with five amino acid mismatches. The evidence for a stronger sequence-distance dependent correlate of risk for the vaccine arm indicates departure from the Prentice criteria for a valid sequence-distance specific surrogate endpoint and suggests that the nAb marker may affect dengue risk differently depending on whether nAbs arise from infection or also by vaccination. However, when restricting to baseline-seropositive 9–14 year-olds, the correlation pattern became more similar between the vaccine and placebo arms, supporting nAb titers as an approximate surrogate endpoint in this population. No sequence-specific nAb titer correlates of VCD were seen in baseline-seronegative participants. Integrated immune response/pathogen sequence data correlates analyses could help increase knowledge of correlates of risk and surrogate endpoints for other vaccines against genetically diverse pathogens.Trial registration: EU Clinical Trials Register 2014-001708-24; registration date 2014-05-26.