Neutralizing Antibody Correlates Analysis of Tetravalent Dengue Vaccine Efficacy Trials in Asia and Latin America

Abstract

Background: In the CYD14 and CYD15 Phase 3 trials of the CYD-TDV dengue vaccine, estimated vaccine efficacy (VE) against symptomatic, virologically confirmed dengue (VCD) occurring between months 13 and 25 was 56.5% and 60.8%, respectively.

Methods: Neutralizing antibody titers to the 4 dengue serotypes in the CYD-TDV vaccine insert were measured at month 13 in a randomly sampled immunogenicity subcohort and in all VCD cases through month 25 (2848 vaccine, 1574 placebo) and studied for their association with VCD and with the level of VE to prevent VCD.

Results: For each trial and serotype, vaccinees with higher month 13 titer to the serotype had significantly lower risk of VCD with that serotype (hazard ratios, 0.19-0.43 per 10-fold increase). Moreover, for each trial, vaccinees with higher month 13 average titer to the 4 serotypes had significantly higher VE against VCD of any serotype (P < .001).

Conclusions: Neutralizing antibody titers postdose 3 correlate with CYD-TDV VE to prevent dengue. High titers associate with high VE for all serotypes, baseline serostatus groups, age groups, and both trials. However, lowest titers do not fully correspond to zero VE, indicating that other factors influence VE.

Keywords: case cohort; immune correlate of protection; neutralizing antibodies; surrogate endpoint; vaccine efficacy trial.

© The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Sample selection for the case-cohort studies. Participants enrolled in the CYD14 and CYD15 studies were vaccinated at months 0, 6, and 12, and neutralizing antibody titers at month 13 were evaluated as correlates of risk and protection. The analysis datasets consisted of all participants at risk at month 13 who did not experience symptomatic, virologically confirmed dengue (VCD) before month 13 and who had month 13 neutralizing antibody data. Cases refer to participants with documented symptomatic VCD that occurred between month 13 and month 25; controls refer to participants with no documented symptomatic VCD throughout the first 25 months of the trials.

Figure 2.

Distributions of serotype-specific month 13 50% plaque reduction neutralization test (PRNT50) neutralization titer variables in dengue cases and controls among vaccine and placebo recipients in the month 13 at-risk cohorts in CYD14 for all age groups. Neutralization titers to (A) DENV-1, (B) DENV-2, (C) DENV-3, (D) DENV-4 in CYD14. Box plots show the 25th percentile (lower edge of the box), 50th percentile (horizontal line in the box), and 75th percentile (upper edge of the box), with participants stratified according to dengue case/control status and treatment assignment. The whiskers indicate the most extreme data points, which are no more than 1.5 times the interquartile range from the box. Low, medium, and high are the bottom, middle, and upper third of the month 13 PRNT50 titers of the month 13 at-risk cohort pooling over DENV1-4 and over the vaccine and placebo groups within each trial. Medium response is indicated by the gray horizontal bar (medium response titer = 58.0–266.0 in CYD14). Case = symptomatic, virologically confirmed dengue (VCD) primary endpoint between month 13 and month 25; Control = no VCD primary endpoint through month 25.

Figure 3.

Distributions of serotype-specific month 13 50% plaque reduction neutralization test (PRNT50) neutralization titer variables in dengue cases and controls among vaccine and placebo recipients in the month 13 at-risk cohorts in CYD15 for all age groups. Neutralization titers to (A) DENV-1, (B) DENV-2, (C) DENV-3, (D) DENV-4 in CYD15. Box plots show the 25th percentile (lower edge of the box), 50th percentile (horizontal line in the box), and 75th percentile (upper edge of the box), with participants stratified according to dengue case/control status and treatment assignment. The whiskers indicate the most extreme data points, which are no more than 1.5 times the interquartile range from the box. Low, medium, and high are the bottom, middle, and upper third of the month 13 PRNT50 titers of the month 13 at-risk cohort pooling over DENV1-4 and over the vaccine and placebo groups within each trial. Medium response is indicated by the gray horizontal bar (medium response titer = 135.0–631.0 in CYD15). Case = symptomatic, virologically confirmed dengue (VCD) primary endpoint between month 13 and month 25; Control = no VCD primary endpoint through month 25.

Figure 4.

Cumulative incidence of symptomatic, virologically confirmed dengue (VCD) of any serotype (DENV-Any) by month 13 average titer subgroups (low, medium, high) for the vaccine and placebo groups in CYD14 for all age groups (A and B) and CYD15 for all age groups (C and D). Two-sided P values test for different hazard rates (HR) of dengue across the 3 subgroups. Low, medium, and high are the bottom, middle, and upper third of the month 13 50% plaque reduction neutralization test (PRNT50) titers of the month 13 at-risk cohort pooling over DENV1-4 and over the vaccine and placebo groups within each trial. Medium response titer = 58.0–266.0 in CYD14 and 135.0–631.0 in CYD15.

Figure 5.

Estimated vaccine efficacy (VE) against symptomatic, virologically confirmed dengue of any serotype (DENV-Any) between months 13 and 25 by month 13 average titer with 95% pointwise and simultaneous confidence intervals (CI) and histogram of average titer in the vaccine group for the month 13 at-risk cohort. The following estimated VE curves are shown: (A) CYD14 all age groups; (B) CYD15 all age groups; (C) CYD14 + CYD15 9- to 16-year-olds. For A–C, 0.14%, 0.21%, 0.19% vaccine recipients, respectively, had no seroresponse (month 13 titer less than the lower limit of quantitation for all available serotypes).

Figure 6.

Estimated vaccine efficacy (VE) against symptomatic, virologically confirmed dengue of any serotype (DENV-Any) between months 0 and 25 by baseline average titer with 95% pointwise and simultaneous confidence intervals (CI) and histogram of baseline average titer in the vaccine and placebo groups combined. The following estimated VE curves are shown: (A) CYD14 all age groups; (B) CYD15 all age groups; (C) CYD14 + CYD15 9- to 16-year-olds; D, CYD14 + CYD15 all age groups. For A–D, 32.9%, 20.5%, 20.6%, 26.6% participants, respectively, were baseline seronegative (month 0 titer less than the lower limit of quantitation for all available serotypes).