[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]
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, and Peter B. Gilbert
PNAS August 20, 2018. 201714250; published ahead of print August 20, 2018. https://doi.org/10.1073/pnas.1714250115
Edited by Rafi Ahmed, Emory University, Atlanta, GA, and approved July 17, 2018 (received for review December 21, 2017)
Dengue virus (DENV) vaccine development is complicated by the existence of four genetically diverse DENV serotypes. A high degree of antigenic match between vaccine strains and circulating DENVs may be important to achieve high vaccine efficacy (VE). Using data from two phase 3 trials of the CYD-TDV vaccine, we assessed whether and how VE against virologically confirmed dengue varied with amino acid sequence characteristics and genotypes of the disease-causing DENVs. VE decreased with the degree of amino acid dissimilarity between the vaccine insert and disease-causing DENVs. After accounting for differential VE by serotype, this effect seemed to occur only for younger children, who also had lower baseline seropositivity and potentially a less broadly protective immune response.
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.
amino acid position signatures – CYD-TDV – dengue virus – sieve analysis – vaccine efficacy
1 P.T.E. and P.B.G. contributed equally to this work.
2 To whom correspondence should be addressed. Email: firstname.lastname@example.org.
Author contributions: M.J., C.A.M., B.G., N.J., P.T.E., and P.B.G. designed research; Y.G.-C., E.L., C.F., B.G., N.J., K.D.T.H., and C.P.S. performed research; K.D.T.H. led the operational aspects of the DENV prM/E sequencing; C.P.S. provided oversight of the dengue prM/E sequencing; Y.G.-C. and C.F. acquired data; M.J., C.A.M., J.S., A.J.F.-G., D.B., P.T.E., and P.B.G. analyzed data; C.A.M., Y.G.-C., and E.L. curated data; M.J., C.A.M., J.S., L.N.C., A.J.F.-G., D.B., Y.G.-C., B.G., N.J., P.T.E., and P.B.G. interpreted data; P.B.G. provided oversight of the statistical analyses; and M.J., L.N.C., and P.B.G. wrote the paper.
Conflict of interest statement: Y.G.-C., E.L., C.F., B.G., and N.J. are employees of Sanofi Pasteur. M.J., C.A.M., J.S., L.N.C., A.J.F.-G., P.T.E., and P.B.G. received a contract from Sanofi Pasteur to conduct the statistical analysis work. This work was supported by Sanofi Pasteur and the US National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under award number R37AI054165.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1714250115/-/DCSupplemental.
Published under the PNAS license.
Keywords: Dengue Fever; Vaccines.