Abstract
In individuals with prior dengue virus (DENV) exposure, subsequent heterotypic infection can increase the risk of severe disease. A single-dose dengue vaccine that protects against the four DENV serotypes across a wide age range and regardless of DENV serostatus is needed. Here we report the long-term safety and efficacy of Butantan dengue vaccine (Butantan-DV), a live, attenuated, tetravalent dengue vaccine, among participants ages 2–59 who were randomized 2:1 in a double-blind, placebo-controlled, phase 3 trial in Brazil. A primary objective was to evaluate vaccine efficacy (VE) against reverse transcription–PCR-positive symptomatic dengue 28 days after vaccination because of any DENV serotype, regardless of serostatus. Prespecified secondary endpoints included VE by serotype, by serostatus and against severe dengue or dengue with warning signs (combined). The primary and secondary objectives were met if the lower bound of the two-sided 95% confidence interval (CI) for VE was above 25%. Between 2016 and 2019, 16,235 participants received Butantan-DV (n = 10,259) or placebo (n = 5,976). The trial met the primary and secondary objectives. During the 5 years of follow-up, between 2016 and 2024, overall VE (95% CI) was 65.0% (57.8–71.0%). Secondary VE endpoints (95% CI) were 77.1% (67.6–83.9%) in dengue-experienced participants, 58.9% (48.0–67.6%) in dengue-naive participants, 73.0% (64.3–79.7%) against DENV-1 and 55.7% (42.3–66.1%) against DENV-2. Cases of DENV-3 or DENV-4 were not observed. VE (95% CI) against dengue with warning signs or severe dengue (secondary endpoint) was 80.5% (50.8–92.4%). The most commonly reported solicited systemic adverse event (AE) was headache (36.7% of vaccine recipients and 31.1% of placebo recipients), most of which were grade 1. The proportions of participants with unsolicited vaccine-related AEs (including serious AEs) were comparable between intervention groups. A single dose of Butantan-DV was efficacious against symptomatic virologically confirmed dengue because of DENV-1 or DENV-2, regardless of dengue serostatus at baseline, with no safety concerns observed during the 5-year follow-up (ClinicalTrials.gov: NCT02406729).
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Data availability
Data will be made available after ANVISA’s approval to qualified scientific researchers with a specific purpose outlined in a proposal approved by Instituto Butantan. Complete deidentified aggregate patient data will be shared after the researcher enters into standard data sharing agreement and the proposal is approved. Researchers must commit to transparency in publication. Requests for data must be sent to ensaiosclinicos@fundacaobutantan.org and will be evaluated for scientific validity within 6 months.
Code availability
The underlying individual code for the results detailed in this manuscript can be requested from the corresponding author. If the request is deemed scientifically appropriate, code will be shared through a secure file transfer process. Requests for the code must be sent to ensaiosclinicos@fundacaobutantan.org and will be evaluated for scientific validity within 6 months.
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Acknowledgements
The trial was sponsored by Instituto Butantan. Funding support was provided, in part, by the Ministry of Health of Brazil, the Brazilian National Bank for Economic and Social Development, The São Paulo Research Foundation and Fundação Butantan. Instituto Butantan designed the study (with feedback from the investigators and site staff) and managed the study data. Statistical analyses and data management support were provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ USA (MSD) The sponsor had a role in the design and conduct of the study, the collection, management, analysis and interpretation of the data and the preparation, review and approval of the manuscript. We would like to thank the participants and their parents who enrolled in the study, the study investigators, study site staff, contract research organization team (IQVIA Brazil), the phase 3 Butantan-DV working group and the sponsor personnel for their contributions to the implementation and conduction of the trial, former and current Instituto Butantan employees who were crucial to bringing about the trial and G. Áñez of MSD for critically reviewing the manuscript. Medical writing assistance for the first draft of the manuscript under the guidance of the authors was provided by E. Anderson and editorial assistance was provided by K. Davis, both of MSD.
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Conceptualization, E.G.K., M.L.N., A.P.D. and S.S.W. Method design, E.G.P. and P.E.B. Data collection, E.G.K., D.B.P., J.C., E.E., I.C.-B., M.L.N., E.T.A.M., A.M.P.B., V.S.B., F.R., C.J.F.F., A.M.S., G.A.S.R., R.Q.G., M.M.T., A.J.d.F., C.F.E., A.C.F., C.L.S.d.S., M.C.S.T.T. and M.V.G.L. Data curation, D.S., F.C.B., J.A.M., J.C.V.T., L.B.O.A., M.A.T.C., V.I., J.L.M., A.E.-J., B.-A.G.C., J.M. and S.V. Data verification, M.L.N., F.C.B., J.A.M., J.C.V.T., L.B.O.A., E.G.P., V.I., J.L.M., A.E.-J., B.-A.G.C., J.M. and S.V. Formal analysis, E.G.P., P.E.B., J.-J.L., D.C. and T.S. All authors had access to all the relevant study data and related analyses, vouch for the completeness and accuracy of the data presented, critically reviewed the manuscript and approved the final version of the manuscript to be published.
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E.G.K., J.A.M., E.G.P., P.E.B., J.C.V.T., L.B.O.A., V.I., D.H.R.S., J.L.M. and F.C.B. are employees of Instituto Butantan. M.A.T.C. was an employee of Instituto Butantan when the trial took place. E.G.K. is the current director of Instituto Butantan. F.C.B. reports owning stock from Novartis. Instituto Butantan, a nonprofit public health institution, provided research grants used by the site institutions to fund the clinical trial. S.S.W. reports that the vaccine technology was licensed by Butantan Foundation/Institute from his employer (National Institutes of Health). A.P.D. is a consultant with Merck & Co., advising them on dengue vaccine development. A.E.-J., T.S., J.-J.L., D.C., S.V., J.M. and B.-A.G.C. are (or were) employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and may own stock and/or hold stock option in Merck & Co., Inc., Rahway, NJ, USA. D.B.P., A.J.d.F., R.Q.G., I.C.-B.C., C.J.F.F., E.T.A.M., G.A.S.R., M.M.T., A.M.S., V.S.B., F.R., E.E., J.C.M., C.F.E., A.C.F., C.L.S.d.S., M.C.S.T.T., M.L.N. and M.V.G.L. declare no competing interests.
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Extended data
Extended Data Fig. 1 VE against Symptomatic VCD: Age Subgroup Analysis by Baseline Serostatus.
Vaccine efficacy and 95% confidence intervals (CI) against VCD after Day 28 postvaccination due to any DENV serotype and by individual DENV serotype and by baseline serostatus for participants ages 18-59 years old (Panel A), 7-17 years old (Panel B), and 2-6 years old (Panel C). Five-year follow-up postvaccination for each participant. Data are presented as the point estimate with 95% CI. aVaccine efficacy was estimated based on the exact binomial method proposed by Chan and Bohidar, and the 95% CI was estimated using Blaker’s exact CI. The person-years at risk was the cumulative time (in years) until the participant was diagnosed with first symptomatic VCD episode or until the end of the follow-up, whichever came first. The person-years at risk calculation presented in the table is the sum of individual units of time for which the participants contributed to the analysis. Incidence rate was calculated as the number of symptomatic VCD cases divided by the cumulative person-years at risk. Only dengue virus serotype 1 (DENV-1) and serotype 2 (DENV-2) were detected in this study. Vaccine efficacy according to prior dengue exposure was calculated for participants with baseline dengue serostatus (those who had pre-vaccination VRNT60 results). Cases=number of participants with at least one symptomatic VCD episode after 28 days postvaccination until the end of the follow-up period; Incidence rate=cases per 100 person-years at risk.
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Kallás, E.G., Moreira, J.A., Patiño, E.G. et al. Long-term efficacy and safety of the single-dose tetravalent Butantan dengue vaccine. Nat Med (2026). https://doi.org/10.1038/s41591-026-04255-3
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DOI: https://doi.org/10.1038/s41591-026-04255-3
