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

Michal Juraska, Craig A. Magaret, Jason Shao, Lindsay N. Carpp, Andrew J. Fiore-Gartland, David Benkeser, Yves Girerd-Chambaz, Edith Langevin, Carina Frago, Bruno Guy, Nicholas Jackson, Kien Duong Thi Hue, Cameron P. Simmons, Paul T. Edlefsen, Peter B. Gilbert

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)E8378-E8387
Number of pages10
JournalProceedings of the National Academy of Sciences
Volume115
Issue number36
DOIs
Publication statusPublished - 4 Sep 2018

Keywords

  • Amino acid position signatures
  • CYD-TDV
  • Dengue virus
  • Sieve analysis
  • Vaccine efficacy

Cite this

Juraska, M., Magaret, C. A., Shao, J., Carpp, L. N., Fiore-Gartland, A. J., Benkeser, D., ... Gilbert, P. B. (2018). Viral genetic diversity and protective efficacy of a tetravalent dengue vaccine in two phase 3 trials. Proceedings of the National Academy of Sciences, 115(36), E8378-E8387. https://doi.org/10.1073/pnas.1714250115
Juraska, Michal ; Magaret, Craig A. ; Shao, Jason ; Carpp, Lindsay N. ; Fiore-Gartland, Andrew J. ; Benkeser, David ; Girerd-Chambaz, Yves ; Langevin, Edith ; Frago, Carina ; Guy, Bruno ; Jackson, Nicholas ; Hue, Kien Duong Thi ; Simmons, Cameron P. ; Edlefsen, Paul T. ; Gilbert, Peter B. / Viral genetic diversity and protective efficacy of a tetravalent dengue vaccine in two phase 3 trials. In: Proceedings of the National Academy of Sciences. 2018 ; Vol. 115, No. 36. pp. E8378-E8387.
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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.",
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Juraska, M, Magaret, CA, Shao, J, Carpp, LN, Fiore-Gartland, AJ, Benkeser, D, Girerd-Chambaz, Y, Langevin, E, Frago, C, Guy, B, Jackson, N, Hue, KDT, Simmons, CP, Edlefsen, PT & Gilbert, PB 2018, 'Viral genetic diversity and protective efficacy of a tetravalent dengue vaccine in two phase 3 trials' Proceedings of the National Academy of Sciences, vol. 115, no. 36, pp. E8378-E8387. https://doi.org/10.1073/pnas.1714250115

Viral genetic diversity and protective efficacy of a tetravalent dengue vaccine in two phase 3 trials. / Juraska, Michal; Magaret, Craig A.; Shao, Jason; Carpp, Lindsay N.; Fiore-Gartland, Andrew J.; Benkeser, David; Girerd-Chambaz, Yves; Langevin, Edith; Frago, Carina; Guy, Bruno; Jackson, Nicholas; Hue, Kien Duong Thi; Simmons, Cameron P.; Edlefsen, Paul T.; Gilbert, Peter B.

In: Proceedings of the National Academy of Sciences, Vol. 115, No. 36, 04.09.2018, p. E8378-E8387.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Viral genetic diversity and protective efficacy of a tetravalent dengue vaccine in two phase 3 trials

AU - Juraska, Michal

AU - Magaret, Craig A.

AU - Shao, Jason

AU - Carpp, Lindsay N.

AU - Fiore-Gartland, Andrew J.

AU - Benkeser, David

AU - Girerd-Chambaz, Yves

AU - Langevin, Edith

AU - Frago, Carina

AU - Guy, Bruno

AU - Jackson, Nicholas

AU - Hue, Kien Duong Thi

AU - Simmons, Cameron P.

AU - Edlefsen, Paul T.

AU - Gilbert, Peter B.

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N2 - 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.

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KW - Amino acid position signatures

KW - CYD-TDV

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