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Evaluation of the extended efficacy of the Dengvaxia vaccine against symptomatic and subclinical dengue infection


More than half of the world’s population lives in areas at risk for dengue virus infection. A vaccine will be pivotal to controlling spread, however, the only licensed vaccine, Dengvaxia, has been shown to increase the risk of severe disease in a subset of individuals. Vaccine efforts are hampered by a poor understanding of antibody responses, including those generated by vaccines, and whether antibody titers can be used as a marker of protection from infection or disease. Here we present the results of an ancillary study to a phase III vaccine study (n = 611). All participants received three doses of either Dengvaxia or placebo and were followed for 6 years. We performed neutralization tests on annual samples and during confirmed dengue episodes (n = 16,508 total measurements). We use mathematical models to reconstruct long-term antibody responses to vaccination and natural infection, and to identify subclinical infections. There were 87 symptomatic infections reported, and we estimated that there were a further 351 subclinical infections. Cumulative vaccine efficacy was positive for both subclinical and symptomatic infection, although the protective effect of the vaccine was concentrated in the first 3 years following vaccination. Among individuals with the same antibody titer, we found no difference between the risk of subsequent infection or disease between placebo and vaccine recipients, suggesting that antibody titers are a good predictor of both protection and disease risk.

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Fig. 1: Antibody responses and detected infections during follow-up.
Fig. 2: Vaccine efficacy for individuals who are seropositive at baseline.
Fig. 3: Antibody titer response following vaccination or infection.
Fig. 4: Time-to-event analysis.

Data availability

Data used for this project are available at To preserve anonymity, date information has been removed. Instead all time periods, including all dates of illness and dates of blood draws, have been replaced with days since enrollment. Source data are provided with this paper.

Code availability

C++ code used in this study is available at


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This work was supported by the National Institutes of Health and National Institute of Allergy and Infectious Diseases (grant numbers P01AI034533, 5R01AI114703-05), the US Military Infectious Diseases Research Program and the European Research Council (grant number. 804744). The funders had no role in the study design, data collection or analysis, decision to publish or preparation of the manuscript. Material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official, or as reflecting the true views of the National Institutes of Health, Department of the Army or the Department of Defense. The investigators have adhered to the policies for protection of human subjects as prescribed in AR 70–25.

Author information




H.S. developed the methods and conducted the analysis. H.S. and A.L.R. wrote the first draft of the paper. M.T.A, M.N.C, D.E., R.G.J., L.M., I.-K.Y, S.F. and A.L.R. conducted or oversaw field data collection. S.C., I.R.-B. and D.A.T.C. helped with the development of the methods, and T.H., A.S. and G.D.G. conducted or oversaw the laboratory testing. A.L.R. and S.F. are principal investigators of the study. All authors contributed to the revision of the paper.

Corresponding author

Correspondence to Henrik Salje.

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The authors declare no competing interests.

Additional information

Peer review information Nature Medicine thanks Eng Eong Ooi, Alan Barrett and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Alison Farrell was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figures 1–4 and Supplementary Tables 1–5.

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Source data

Source Data Fig. 1

Values used in plots.

Source Data Fig. 2

Values used in plots.

Source Data Fig. 3

Values used in plots.

Source Data Fig. 4

Values used in plots.

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Salje, H., Alera, M.T., Chua, M.N. et al. Evaluation of the extended efficacy of the Dengvaxia vaccine against symptomatic and subclinical dengue infection. Nat Med 27, 1395–1400 (2021).

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