India's First Dengue Vaccine Receives Approval-Visiting the Evidence Journey Behind QDENGA :From Clinical Trial Efficacy to Real World Effectiveness- Dr Puneet Kalra

India has marked a major milestone in its fight against dengue with the approval of QDENGA (TAK-003) by the Central Drugs Standard Control Organisation (CDSCO), making it the country's first licensed dengue vaccine. The live-attenuated tetravalent vaccine is approved for individuals aged 4–60 years and offers protection against all four dengue virus serotypes (DENV-1 to DENV-4). It is noteworthy that QDENGA® can be administered irrespective of prior dengue infection and pretesting of serostatus is not required prior to vaccination (1,2).

The approval comes at a time when dengue continues to pose a major public health challenge with its evolving epidemiological landscape. India accounts for a substantial proportion of the global dengue burden, with seasonal outbreaks resulting in significant morbidity, hospitalisations and economic losses. The availability of a vaccine backed by robust clinical evidence could complement existing vector control and surveillance measures in reducing disease-related burden (1).

Global Clinical Development Programme: Overview

QDENGA® (TAK-003) has undergone a comprehensive clinical development program that includes 5 Phase I, 6 Phase II, and 8 Phase III studies (some of which are ongoing), with over 28,000 participants from 14 countries in both dengue-endemic and non-endemic settings (3). The program included a diverse population ranging in age from 18 months to 60 years, and it assessed safety, tolerability, reactogenicity, immunogenicity, and efficacy across age groups, geographic contexts, and levels of past dengue exposure (3). Early Phase I and II trials influenced crucial areas of vaccine development, vaccine composition, formulation, and dosing schedule, ultimately leading to the adoption of the two-dose subcutaneous regimen administered three months apart for later clinical testing (3). The program culminated in the pivotal Phase III Tetravalent Immunization against Dengue Efficacy Study (TIDES; NCT02747927), which enrolled 20,099 healthy children and adolescents aged 4-16 years across eight dengue-endemic countries in Asia and Latin America. The study included prospective determination of baseline dengue serostatus, allowing efficacy and safety to be assessed in both seropositive and seronegative participants (4,5). The TIDES study included a 4.5-year follow-up period following the second dose, which provided information on the durability of protection and long-term safety across baseline serostatus groups (6).

Collectively, the clinical development programme generated extensive evidence on the safety, immunogenicity and efficacy of QDENGA® across a wide age group and diverse epidemiological settings, providing the evidence base for its regulatory development and subsequent WHO recommendations on its use for dengue prevention (3,6,7).

TIDES: The Landmark Phase III Trial Including 20,000+ Individuals

The Tetravalent Immunisation against Dengue Efficacy Study (TIDES; DEN-301) was the pivotal Phase III trial that established the efficacy and safety of QDENGA® (TAK-003). This randomised, double-blind, placebo-controlled study enrolled 20,099 healthy children and adolescents aged 4–16 years across eight dengue-endemic countries—Brazil, Colombia, the Dominican Republic, Nicaragua, Panama, the Philippines, Sri Lanka, and Thailand. Participants received two doses of QDENGA® (TAK-003) or placebo administered three months apart, with active surveillance for both hospitalised and non-hospitalised virologically confirmed dengue (VCD) (4). The trial achieved its primary endpoint, demonstrating an overall vaccine efficacy (VE) of 80.2% against virologically confirmed dengue 12 months after the second dose.(4) A key secondary endpoint was vaccine efficacy against VCD leading to hospitalisation, a particularly relevant outcome for dengue given that epidemic outbreaks can result in substantial surges in hospitalisations and place considerable strain on healthcare systems, providing the key measure against which the two-dose regimen was evaluated (4,7).

Follow-up analyses showed that protection against severe disease was sustained, with 90.4% efficacy against dengue-related hospitalisation over 18 months (8). Long-term data further confirmed durable protection, with cumulative efficacy of 61.2% against virologically confirmed dengue and 84.1% against hospitalised dengue through 4.5 years after vaccination, irrespective of baseline serostatus (6).

Importantly, the TIDES trial demonstrated a favourable long-term safety profile, with no vaccination-related deaths, no evidence of increased disease severity, and no increased risk of hospitalisation among vaccine recipients (6). The substantial efficacy and safety data obtained by TIDES served as the scientific foundation for QDENGA®'s regulatory approval in various countries, as well as informed evaluations by international regulatory bodies such as the European Medicines Agency and the World Health Organisation (WHO) stance on dengue vaccines (7,9).

Figure 1: QDENGA® (TAK-003) – Global Clinical Development Program Journey

QDENGA® (TAK-003) – Global clinical development program journey Effect of QDENGA® (TAK-003) on Clinical & Hospitalisation Outcomes: Clinical trial findings of QDENGA® (TAK-003) vaccines are increasingly being supported by real-world evidence. In a test-negative, case-control study conducted among adolescents (n=92,621) aged 10–14 years during the 2024 dengue outbreak in São Paulo, Brazil, effectiveness of one dose of TAK-003 against symptomatic dengue reduced the risk by 50.2% (adjusted vaccine effectiveness; 95% CI 45.0–54.9) and reduced dengue-related hospitalisation by 67.5%. Among adolescents who had received two doses, vaccine effectiveness against symptomatic dengue increased to 61.7%, although estimates were limited by the small number of cases. The study concluded that TAK-003 was effective against both symptomatic dengue and hospitalisation during a large outbreak., supporting the real-world effectiveness of the vaccine beyond clinical trials (10).

Real-World Safety Evidence with QDENGA® (TAK-003) on 1 Lakh+ vaccinated Individuals: Real-world safety data from Argentina further supports the favourable safety profile of QDENGA®. In a retrospective, multicentre passive surveillance study conducted across private vaccination centres in metropolitan Buenos Aires, 156,676 doses of QDENGA® were administered to 112,345 individuals aged 4–102 years. A total of 303 adverse events following immunisation (AEFIs) were reported, corresponding to an incidence of 1.9 per 1,000 doses. Most AEFIs (95.1%) were non-serious, commonly presenting as rash, myalgia, pyrexia, and headache, and were reported more frequently after the first dose than the second. Serious AEFIs were rare (1.3%), with very low rates of anaphylaxis and hypersensitivity, reinforcing the vaccine's favourable safety profile under routine clinical use (11).

The robust clinical evidence supporting QDENGA® (TAK-003) has led to its regulatory approval in 43 countries, including the European Union. WHO recommends that countries consider introducing QDENGA® (TAK-003) in children aged 6–16 years in geographical areas where dengue transmission intensity is high and dengue poses a significant public-health problem. Such recommendations are intended to guide national and subnational immunisation-policy decisions and should be considered alongside local epidemiology and national guidance. (6,7).

Global and Regional Recommendations for QDENGA® (TAK-003)

• In October 2022, the EMA recommended TAK-003 (QDENGA®) for preventing dengue in individuals aged four years and older, irrespective of previous dengue exposure; the European Commission subsequently granted EU marketing authorisation in December 2022 [15].
• In September 2023, the WHO Strategic Advisory Group of Experts on Immunization (SAGE) recommended that QDENGA® (TAK-003) be considered for introduction in children aged 6-16 years living in areas with a high dengue disease burden and high transmission intensity, with the goal of maximizing public-health benefit while minimizing potential risks in seronegative individuals [12]. This recommendation was later reflected in the WHO position paper on dengue vaccines, which recommends a two-dose schedule given three months apart and advises countries to consider routine or targeted subnational introduction in areas where dengue transmission is a major public-health concern [8].
• The Pan American Health Organization Technical Advisory Group (TAG), 2023 on Vaccine-Preventable Diseases approved the SAGE recommendation to use TAK-003 in areas with a high dengue burden and transmission intensity. PAHO recommends that such introductions be carefully studied, preferably as targeted or pilot programs followed by comprehensive post-marketing surveillance, [14].
• On May 10, 2024, QDENGA® (TAK-003) became the second dengue vaccine to gain WHO prequalification, an important regulatory milestone that enables procurement by United Nations agencies and promotes vaccine access in qualifying countries [13].

QDENGA® - Marking A New Era with Potential to Reform India’s Fight Against Dengue

The approval of QDENGA® represents an important advance in India's dengue prevention strategy. While vector control, early diagnosis and supportive clinical management remain essential, vaccination provides an additional evidence-based intervention capable of reducing symptomatic disease and preventing severe dengue requiring hospitalisation. Backed by an extensive global clinical development programme, robust Phase I, II and III clinical evidence, and long-term follow-up from the TIDES study, QDENGA® has the potential to significantly strengthen India's efforts to reduce the public health burden of dengue.

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