PLoS ONE (Jan 2020)

Microneutralization assay titer correlates analysis in two phase 3 trials of the CYD-TDV tetravalent dengue vaccine in Asia and Latin America.

  • Lindsay N Carpp,
  • Youyi Fong,
  • Matthew Bonaparte,
  • Zoe Moodie,
  • Michal Juraska,
  • Ying Huang,
  • Brenda Price,
  • Yingying Zhuang,
  • Jason Shao,
  • Lingyi Zheng,
  • Laurent Chambonneau,
  • Robert Small,
  • Saranya Sridhar,
  • Carlos A DiazGranados,
  • Peter B Gilbert

DOI
https://doi.org/10.1371/journal.pone.0234236
Journal volume & issue
Vol. 15, no. 6
p. e0234236

Abstract

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We previously showed that Month 13 50% plaque reduction neutralization test (PRNT50) neutralizing antibody (nAb) titers against dengue virus (DENV) correlated with vaccine efficacy (VE) of CYD-TDV against symptomatic, virologically-confirmed dengue (VCD) in the CYD14 and CYD15 Phase 3 trials. While PRNT is the gold standard nAb assay, it is time-consuming and costly. We developed a next-generation high-throughput microneutralization (MN) assay and assessed its suitability for immune-correlates analyses and immuno-bridging applications. We analyzed MN and PRNT50 titers measured at baseline and Month 13 in a randomly sampled immunogenicity subset, and at Month 13 in nearly all VCD cases through Month 25. For each serotype, MN and PRNT50 titers showed high correlations, at both baseline and Month 13, with MN yielding a higher frequency of baseline-seronegatives. For both assays, Month 13 titer correlated inversely with VCD risk. Like PRNT50, high Month 13 MN titers were associated with high VE, and estimated VE increased with average Month 13 MN titer. We also studied each assay as a valid surrogate endpoint based on the Prentice criteria, which supported each assay as a valid surrogate for DENV-1 but only partially valid for DENV-2, -3, and -4. In addition, we applied Super-Learner to assess how well demographic, Month 13 MN, and/or Month 13 PRNT50 titers could predict Month 13-25 VCD outcome status; prediction was best when using demographic, MN, and PRNT50 information. We conclude that Month 13 MN titer performs comparably to Month 13 PRNT50 titer as a correlate of risk, correlate of vaccine efficacy, and surrogate endpoint. The MN assay could potentially be used to assess nAb titers in immunogenicity studies, immune-correlates studies, and immuno-bridging applications. Additional research would be needed for assessing the utility of MN titer in correlates analyses of other DENV endpoints and over longer follow-up periods.