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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.

SUBMITTER: Juraska M 

PROVIDER: S-EPMC6130398 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Juraska Michal M   Magaret Craig A CA   Shao Jason J   Carpp Lindsay N LN   Fiore-Gartland Andrew J AJ   Benkeser David D   Girerd-Chambaz Yves Y   Langevin Edith E   Frago Carina C   Guy Bruno B   Jackson Nicholas N   Duong Thi Hue Kien K   Simmons Cameron P CP   Edlefsen Paul T PT   Gilbert Peter B PB  

Proceedings of the National Academy of Sciences of the United States of America 20180820 36


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, a  ...[more]

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