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

Abstract

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 https://github.com/pdgcam/DengueTiters.git. 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 https://github.com/pdgcam/DengueTiters.git.

References

  1. 1.

    Stanaway, J. D. et al. The global burden of dengue: an analysis from the Global Burden of Disease Study 2013. Lancet Infect. Dis. 16, 712–723 (2016).

    Article  Google Scholar 

  2. 2.

    Hadinegoro, S. R. et al. Efficacy and long-term safety of a dengue vaccine in regions of endemic disease. N. Engl. J. Med. 373, 1195–1206 (2015).

    CAS  Article  Google Scholar 

  3. 3.

    Wilder-Smith, A. et al. Deliberations of the Strategic Advisory Group of Experts on Immunization on the use of CYD-TDV dengue vaccine. Lancet Infect. Dis. 19, e31–e38 (2019).

    CAS  Article  Google Scholar 

  4. 4.

    Moi, M. L., Takasaki, T. & Kurane, I. Human antibody response to dengue virus: implications for dengue vaccine design. Trop. Med. Health 44, 1 (2016).

    Article  Google Scholar 

  5. 5.

    Salje, H. et al. Reconstruction of antibody dynamics and infection histories to evaluate dengue risk. Nature 557, 719–723 (2018).

    CAS  Article  Google Scholar 

  6. 6.

    Katzelnick, L. C. et al. Antibody-dependent enhancement of severe dengue disease in humans. Science 358, 929–932 (2017).

    CAS  Article  Google Scholar 

  7. 7.

    Reich, N. G. et al. Interactions between serotypes of dengue highlight epidemiological impact of cross-immunity. J. R. Soc. Interface 10, 20130414 (2013).

    Article  Google Scholar 

  8. 8.

    Sabin, A. B. Research on dengue during World War II. Am. J. Trop. Med. Hyg. 1, 30–50 (1952).

    CAS  Article  Google Scholar 

  9. 9.

    Ferguson, N. M. et al. Benefits and risks of the Sanofi-Pasteur dengue vaccine: modeling optimal deployment. Science 353, 1033–1036 (2016).

    CAS  Article  Google Scholar 

  10. 10.

    Halstead, S. B. Dengue. Lancet 370, 1644–1652 (2007).

    Article  Google Scholar 

  11. 11.

    Russell, P. K., Nisalak, A., Sukhavachana, P. & Vivona, S. A plaque reduction test for dengue virus neutralizing antibodies. J. Immunol. 99, 285–290 (1967).

    CAS  PubMed  Google Scholar 

  12. 12.

    Thomas, S. J. et al. Dengue plaque reduction neutralization test (PRNT) in primary and secondary dengue virus infections: how alterations in assay conditions impact performance. Am. J. Trop. Med. Hyg. 81, 825–833 (2009).

    Article  Google Scholar 

  13. 13.

    Sridhar, S. et al. Effect of dengue serostatus on dengue vaccine safety and efficacy. N. Engl. J. Med. 379, 327–340 (2018).

    Article  Google Scholar 

  14. 14.

    Olivera-Botello, G. et al. Tetravalent dengue vaccine reduces symptomatic and asymptomatic dengue virus infections in healthy children and adolescents aged 2–16 years in Asia and Latin America. J. Infect. Dis. 214, 994–1000 (2016).

    CAS  Article  Google Scholar 

  15. 15.

    Chotpitayasunondh, T. et al. Post-licensure, phase IV, safety study of a live attenuated Japanese encephalitis recombinant vaccine in children in Thailand. Vaccine 35, 299–304 (2017).

    Article  Google Scholar 

  16. 16.

    Fried, J. R. et al. Serotype-specific differences in the risk of dengue hemorrhagic fever: an analysis of data collected in Bangkok, Thailand from 1994 to 2006. PLoS Negl. Trop. Dis. 4, e617 (2010).

    Article  Google Scholar 

  17. 17.

    Katzelnick, L. C. et al. Dengue viruses cluster antigenically but not as discrete serotypes. Science 349, 1338–1343 (2015).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

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.

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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.

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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). https://doi.org/10.1038/s41591-021-01392-9

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