Quadrivalent dengue-virus vaccines: challenges and opportunities for India
Authors: Guruprasad R Medigeshi, Farzana Islam, Rakesh Lodha
Journal: The Lancet Infectious Diseases (2024)

An estimated 12·9 million primary dengue-virus infections occurred in India in 2017, according to the constant force of infection model.1Murhekar MV Kamaraj P Kumar MS et al.Burden of dengue infection in India, 2017: a cross-sectional population based serosurvey.Lancet Glob Health. 2019; 7: e1065-e1073Summary Full Text Full Text PDF PubMed Scopus (65) Google Scholar Vaccine-efficacy studies for quadrivalent dengue-virus vaccines conducted in other endemic countries2Capeding MR Tran NH Hadinegoro SR et al.Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial.Lancet. 2014; 384: 1358-1365Summary Full Text Full Text PDF PubMed Scopus (771) Google Scholar, 3Kallás EG Cintra MAT Moreira JA et al.Live, attenuated, tetravalent butantan-dengue vaccine in children and adults.N Engl J Med. 2024; 390: 397-408Crossref PubMed Scopus (3) Google Scholar, 4Tricou V Yu D Reynales H et al.Long-term efficacy and safety of a tetravalent dengue vaccine (TAK-003): 4·5-year results from a phase 3, randomised, double-blind, placebo-controlled trial.Lancet Glob Health. 2024; 12: e257-e270Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar have provided an excellent plan to guide the progress of phase 3 trials in India, which contributes to about 30% of the global burden of dengue.5Bhatt S Gething PW Brady OJ et al.The global distribution and burden of dengue.Nature. 2013; 496: 504-507Crossref PubMed Scopus (6566) Google Scholar One of the dengue-virus vaccines developed by the US National Institutes of Health (NIH), is licensed to Indian companies under the Indo–US Vaccine Action Programme, a collaboration between the NIH and the two organisations of the Government of India. Phase 3 trials for this vaccine in India are proposed to begin in 2024. The efficacy of dengue-virus vaccines depends on the baseline serostatus of participants, serotype of infecting virus, and titres of neutralising antibodies. The three quadrivalent dengue-virus vaccines have shown high efficacy in participants who are seropositive.2Capeding MR Tran NH Hadinegoro SR et al.Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial.Lancet. 2014; 384: 1358-1365Summary Full Text Full Text PDF PubMed Scopus (771) Google Scholar, 3Kallás EG Cintra MAT Moreira JA et al.Live, attenuated, tetravalent butantan-dengue vaccine in children and adults.N Engl J Med. 2024; 390: 397-408Crossref PubMed Scopus (3) Google Scholar, 4Tricou V Yu D Reynales H et al.Long-term efficacy and safety of a tetravalent dengue vaccine (TAK-003): 4·5-year results from a phase 3, randomised, double-blind, placebo-controlled trial.Lancet Glob Health. 2024; 12: e257-e270Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 6Biswal S Reynales H Saez-Llorens X et al.Efficacy of a tetravalent dengue vaccine in healthy children and adolescents.N Engl J Med. 2019; 381: 2009-2019Crossref PubMed Scopus (199) Google Scholar, 7Forrat R Dayan GH DiazGranados CA et al.Analysis of hospitalized and severe dengue cases over the 6 years of follow-up of the tetravalent dengue vaccine (CYD-TDV) efficacy trials in Asia and Latin America.Clin Infect Dis. 2021; 73: 1003-1012Crossref PubMed Scopus (11) Google Scholar The NIH vaccine (Instituto Butantan, São Paulo, Brazil) showed efficacy for dengue virus type 1 (DENV-1) and dengue virus type 2 (DENV-2), which were reported to be circulating during the study period in Brazil.6Biswal S Reynales H Saez-Llorens X et al.Efficacy of a tetravalent dengue vaccine in healthy children and adolescents.N Engl J Med. 2019; 381: 2009-2019Crossref PubMed Scopus (199) Google Scholar Efficacy data could not be generated for dengue virus type 3 (DENV-3) and dengue virus type 4 (DENV-4). There is currently a massive dengue-virus outbreak in Brazil; DENV-3 has resurfaced after 15 years and is implicated in this outbreak. Another dengue-virus vaccine, TAK-003 (Takeda Pharmaceutical, Tokyo, Japan), was not efficacious against DENV-3 and the incidence of DENV-4 was too low during the study period to reliably estimate vaccine efficacy against this serotype.4Tricou V Yu D Reynales H et al.Long-term efficacy and safety of a tetravalent dengue vaccine (TAK-003): 4·5-year results from a phase 3, randomised, double-blind, placebo-controlled trial.Lancet Glob Health. 2024; 12: e257-e270Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar Considering the re-emergence of DENV-3 in Brazil and its association with severe primary infections in southeast Asia,8Soo KM Khalid B Ching SM Chee HY Meta-analysis of dengue severity during infection by different dengue virus serotypes in primary and secondary infections.PLoS One. 2016; 11e0154760Crossref Scopus (140) Google Scholar these two vaccines need to protect against DENV-3 and DENV-4 as all four dengue-virus serotypes co-circulate in India. India needs to establish clinical trial sites with reliable seroprevalence data, including the profile of neutralising antibody titres, and to track the dynamics of circulating dengue-virus serotypes. In 2023, we reported seroprevalence for dengue virus in patients with acute febrile illness—52% of children younger than 15 years and 89% of adults older than 45 years were seropositive for dengue virus.9Anantharaj A Agrawal T Shashi PK et al.Neutralizing antibodies from prior exposure to dengue virus negatively correlate with viremia on re-infection.Commun Med (Lond). 2023; 3: 148Crossref PubMed Google Scholar Results of a phase 2 study of TV005 (National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA) in Bangladesh published in 2024 reported waning of antibody titres in children aged 1–4 years who were seronegative at the time of vaccination. Only 22–28% of children in this age group remained seropositive for DENV-1, DENV-3, and DENV-4 after 3 years of follow-up compared with 69% seropositivity for DENV-2,10Walsh MR Alam MS Pierce KK et al.Safety and durable immunogenicity of the TV005 tetravalent dengue vaccine, across serotypes and age groups, in dengue-endemic Bangladesh: a randomised, controlled trial.Lancet Infect Dis. 2024; 24: 150-160Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar which is a concern. The long-term safety and efficacy in seronegative populations will understandably be a challenge in India. As a majority of participants who are seronegative are likely to be children in India, monitoring safety and estimating the risk of hospitalisation due to dengue virus in this group is of paramount importance. As phase 3 trials for dengue-virus vaccines require many participants, generating data on the neutralisation titres of thousands of samples via a standardised protocol is crucial. Developing a high-throughput, validated assay to measure neutralising antibody titres might provide information on the correlation between baseline neutralising antibody titres, the threshold for antibody titres to prevent virologically confirmed dengue, and waning of antibody responses. Phase 3 trial designs also need to standardise hospitalisation criteria for virologically confirmed dengue across study sites to avoid any effects on efficacy data, as was observed for TAK-003 in Sri Lanka.4Tricou V Yu D Reynales H et al.Long-term efficacy and safety of a tetravalent dengue vaccine (TAK-003): 4·5-year results from a phase 3, randomised, double-blind, placebo-controlled trial.Lancet Glob Health. 2024; 12: e257-e270Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar Overall, phase 3 trials of dengue-virus vaccines in India might provide further impetus for efforts to control the spread of dengue virus to new regions and to strategise reducing the disease burden in endemic countries. We declare no competing interests. We thank all the members of the bioassay laboratory, the Translational Health Science and Technology Institute (THSTI), and the Department of Community Medicine at the Hamdard Institute of Medical Sciences and Research for technical support. This work was supported by grants from the Department of Biotechnology at the THSTI through the Ind-CEPI Mission (BT/MB/CEPI/2016) Translational Research Program (BT/PR30159/MED/15/188/2018).