Viral genetic diversity and protective efficacy of a tetravalent dengue vaccine in two phase 3 trials

Abstract

Two phase 3 placebo-controlled trials of the CYD-TDV vaccine, evaluated in children aged 2-14 y (CYD14) and 9-16 y (CYD15), demonstrated vaccine efficacy (VE) of 56.5% and 60.8%, respectively, against symptomatic virologically confirmed dengue (VCD). Sieve analyses were conducted to evaluate whether and how VE varied with amino acid sequence features of dengue viruses (DENVs). DENV premembrane/envelope amino acid sequences from VCD endpoint cases were aligned with the vaccine insert sequences, and extensions of the proportional hazards model were applied to assess variation in VE with amino acid mismatch proportion distances from vaccine strains, individual amino acid residues, and phylogenetic genotypes. In CYD14, VE against VCD of any serotype (DENV-Any) decreased significantly with increasing amino acid distance from the vaccine, whereas in CYD15, VE against DENV-Any was distance-invariant. Restricting to the common age range and amino acid distance range between the trials and accounting for differential VE by serotype, however, showed no evidence of VE variation with distance in either trial. In serotype-specific analyses, VE against DENV4 decreased significantly with increasing amino acid distance from the DENV4 vaccine insert and was significantly greater against residue-matched DENV4 at eight signature positions. These effects were restricted to 2- to 8-y-olds, potentially because greater seropositivity of older children at baseline might facilitate a broader protective immune response. The relevance of an antigenic match between vaccine strains and circulating DENVs was also supported by greater estimated VE against serotypes and genotypes for which the circulating DENVs had shorter amino acid sequence distances from the vaccine.

Keywords: CYD-TDV; amino acid position signatures; dengue virus; sieve analysis; vaccine efficacy.

Fig. 1.

Marginal and serotype-adjusted VE against DENV-Any by residue mismatch proportion in all aligned sites (A and D; see footnote “^†” in the figure), NAb contact sites (B and E), and surface-exposed sites on the mature virion in the ITT cohort (C and F; see footnote “^‡” in the figure) of CYD14 2- to 14-y-olds (A–C) and CYD15 9- to 16-y-olds (D–F). The saffron-shaded area represents the 95% pointwise CI for the marginal VE. P, placebo; V, vaccine.

Fig. 2.

VE against DENV4 by residue mismatch proportion of various amino acid sets in the ITT cohort of 2- to 8-y-olds in CYD14. (A) All aligned sites (see footnote “^†” in the figure). (B) NAb contact sites. (C) Surface-exposed sites on the mature virion. The saffron-shaded area represents the 95% pointwise CI. P, placebo; V, vaccine.

Fig. 3.

VE by serotype and genotype in the ITT cohorts of CYD14 and CYD15. (A) VE against the serotype-specific dengue endpoints and evidence for differential VE between serotypes in CYD14. (B) VE against the serotype-specific dengue endpoints and evidence for differential VE between serotypes in CYD15. (C) VE against the primary dengue endpoint of any serotype (DENV-Any) and the serotype-specific dengue endpoints with a matched and mismatched genotype to the vaccine strain of the same serotype in CYD14. (D) VE against DENV4 with the vaccine-matched DENV4-II and vaccine-mismatched DENV4-I genotype in 2- to 8-year-olds and 9- to 14-y-olds in CYD14.

Fig. 4.

VE against DENV4 with a vaccine-matched and -mismatched residue at signature amino acid positions in the ITT cohort of 2- to 8-y-olds in CYD14.

Fig. 5.

The amino acid residue distribution by genotype and study group at DENV4 signature positions in the ITT cohort of 2- to 8-y-olds in CYD14. Counts show numbers of VCD DENV4 endpoints; residues in the DENV4-II vaccine sequence are shown at the top. Each color represents a different residue. P, placebo; V, vaccine.

Fig. 6.

(A and B) Amino acid sequence distances to the vaccine insert sequences among placebo group cases in the ITT cohort of CYD14 (2- to 14-y-olds) (A) and CYD15 (9- to 16-y-olds) (B). (C and D) VE (on the log relative risk scale) versus median amino acid sequence distance from the vaccine insert sequence among placebo group cases in the ITT cohort of CYD14 (2- to 14-y-olds) (C) and CYD15 (9- to 16-y-olds) (D). The vertical bars show 95% CIs.

Fig. 7.

Locations of DENV4 signature amino acid sites and the epitopes of DENV4-neutralizing monoclonal antibodies. The amino acids at the five DENV4 signature sites located in the ectodomain and the residues in the footprint of one or more DENV4-specific monoclonal antibodies (D4-126, D4-131, and 5H2) (23, 24) are shown on one monomer of the DENV E protein dimer (Protein Databank ID code 1OAN). Residues common to both the D4-126 and D4-131 epitopes are shown in orange, and the amino acids at signature sites present in the 5H2 epitope are shown in light blue. This figure was generated using MacPyMOL.