Dengue fever, caused by 4 distinct dengue virus serotypes (DENV-1, -2, -3 and -4), is the most rapidly spreading mosquito-borne viral disease globally.1 With a yearly estimate of up to 400 million infections, it poses a severe public health challenge, particularly for children and adults living in or traveling to endemic regions. Dengue virus (DENV) infections cause a broad clinical spectrum from inapparent infection to severe dengue with plasma leakage and shock.2 Global dengue incidence has increased over recent decades, involving previously nonendemic countries, and remains a leading cause of febrile illness and hospitalization throughout endemic regions. Vaccination is a key prevention strategy because vector control alone has proven insufficient to control cyclical epidemics. The complex, 4-serotype nature of the virus and the phenomenon of antibody-dependent enhancement (ADE)—where preexisting, non-neutralizing antibodies from a prior infection can paradoxically increase the risk of severe disease upon subsequent infection with a different serotype—have historically made vaccine development profoundly difficult.3 In addition, there is no suitable animal model to study viral replication and full-blown disease to extrapolate findings into humans. The primary goal for pediatric vaccination is a tetravalent vaccine that provides balanced, long-lasting and safe immunity against all 4 DENV serotypes, regardless of a subject’s prior exposure (serostatus).4 DENV infection, however, poses a multifaceted challenge to global public health due to its complex virology, immunopathogenesis and the paradoxical nature of the immune response (Table 1). TABLE 1. - Knowledge Gaps in Dengue Prevention • Which virus–host interactions are critical for dengue immune pathogenesis?• Do viral serotype and genotype differences explain vaccination protection and potential adverse safety signals?• Can a humoral or cellular correlation of protection against dengue infection or severe disease be defined, and are these correlates serotype-specific?• Does lack of vaccine efficacy in seronegative subjects necessarily translate into an increased risk of disease exacerbation?• How should dengue vaccination adapt to changing population demographics and the increasing burden of disease in small children and older adults?• Can heterologous prime-boost strategies or mixed vaccination schedules with different products or technological platforms optimize tetravalent prevention, regardless of serostatus? LICENSED AND LATE-STAGE DENGUE VACCINES CYD-TDV (Dengvaxia)—Sanofi Pasteur Dengvaxia was the first dengue vaccine to be licensed and introduced, first approved in Mexico and Brazil in 2015. It is a chimeric vaccine that uses a yellow fever virus backbone to carry the genes encoding the structural proteins (premembrane and envelope) of the 4 DENV serotypes. Current evidence: Clinical trials demonstrated that while the vaccine offered protection for individuals who had a prior dengue infection (seropositive), it significantly increased the risk of severe dengue and hospitalization (around 2–4 years after the first dose) in immunologically naïve children (seronegative) at the time of vaccination. This safety concern stems from the ADE mechanism: in seronegative recipients, the vaccine essentially mimics a primary, mild infection, and the subsequent natural wild-type infection acts as a severe secondary infection. Recommendations for children: Due to the ADE risk, its use is strictly limited. The WHO and various regulatory bodies, including the US Food and Drug Administration and the Advisory Committee on Immunization Practices, recommend Dengvaxia only for children 9–16 years of age who have a laboratory-confirmed history of previous DENV infection and reside in endemic areas. This requirement for prevaccination screening to determine serostatus presents a significant logistical and cost challenge for mass immunization programs in resource-limited settings. Manufacturing status: In late 2024, the manufacturer announced the discontinuation of this vaccine, citing a lack of global market demand, which further shifts the focus toward newer candidates. TAK-003 (Qdenga)—Takeda Qdenga is considered a “second-generation” live-attenuated tetravalent vaccine. It utilizes a genetically modified DENV-2 virus as the backbone for all 4 serotypes. This design is believed to induce a more balanced immune response, encompassing both humoral and cell-mediated responses to the DENV. Current evidence: Data from the pivotal phase 3 Tetravalent Immunization against Dengue Efficacy Study in children 4–16 years old has shown promising results, particularly in terms of long-term protection. Over nearly 5 years of follow-up, the vaccine demonstrated an overall efficacy of approximately 61% against symptomatic virologically confirmed dengue and 84% against dengue-related hospitalizations. Vaccine efficacy against serotype 3 in dengue-naïve participants was lower compared to the other serotypes, with higher rates of symptomatic and dengue cases among this population, but it was not statistically significant. The low incidence of virologically confirmed cases prevented assessment of efficacy against serotype 4; however, no increase in disease severity was observed during follow-up.4 A recent real-world effectiveness trial conducted in São Paulo, Brazil, confirmed the usefulness of the TAK-003 vaccine in a huge outbreak setting.5 Crucially, unlike Dengvaxia, it is approved for use regardless of a child’s prior dengue exposure, greatly simplifying its implementation. The vaccine is administered as a 2-dose series, 3 months apart. Current evidence suggests that a booster dose may not be necessary; however, more information on its impact on seronegative individuals is required and is currently under analysis. Further investigation is needed to consider a flexible interval for second dose administration (ie, between 3 and 12 months after the first dose), based on the risk of infection, circulating serotypes, the individual’s serological status and epidemiologic patterns, among other factors. Recommendations for children: The WHO prequalified TAK-003 and recommended its use in children 6–16 years old residing in areas with a high intensity of dengue transmission.6 Bridging immunogenicity studies suggest efficacy up to 60 years of age. High transmission is typically defined by a 60% seroprevalence rate by age 9 or a mean age of peak dengue hospitalizations below age 16. This age restriction (6–16 years) is based on slightly lower observed efficacy in children under 6 years old and the generally lower seropositivity rate in that group. The recommendation also emphasizes that the vaccine is part of an integrated control strategy, not a standalone solution.6 Regulatory status: Qdenga has been approved in Europe in children from 4 years of age7 and in numerous endemic countries across Asia and Latin America, quickly becoming the primary vaccine candidate for national immunization programs. Other Promising Emerging Candidates (TV003/Butantan, etc.) Butantan-DV—Instituto Butantan: This single-dose, live-attenuated tetravalent vaccine (TV003) is a significant advancement. Its phase 3 trial in Brazil, involving children and adults 2–59 years old, demonstrated a robust efficacy of 67%–79% against infection caused by serotypes 1 and 2 (serotypes 3 and 4 did not circulate during the trial), regardless of baseline serostatus, although a slightly lower protection was observed against serotype 2 in seronegative subjects.8 The simplicity of a single-dose schedule would dramatically improve logistical feasibility and compliance in mass pediatric vaccination campaigns. Registration approval is currently pending in Brazil. TV003/TV005—National Institutes of Health/various manufacturers: Developed by the US National Institutes of Health, this live-attenuated vaccine is also tetravalent and single-dose. It has shown promising immunogenicity in young children and is currently in late-stage clinical trials across multiple countries, including an advanced Phase 3 trial in India (in collaboration with Panacea Biotec) and an Asia-Pacific V181-005 phase 3 study conducted by MSD.9 KEY EFFICACY AND SAFETY FINDINGS Efficacy Against Symptomatic and Severe Disease Across recent trials, the newer tetravalent live vaccines demonstrated moderate to high efficacy against virologically confirmed symptomatic dengue (estimates varying by vaccine, serotype, age and follow-up interval). Importantly, TAK-003 showed stronger and more consistent protection against hospitalization and severe dengue than earlier vaccines in most age groups studied—an essential public health endpoint given the burden of severe disease in children.4 Longitudinal analyses also indicate that protection may wane for certain serotypes or age strata, underlining the need for continued postlicensure effectiveness studies. Safety, Serostatus Effects and Age Dependency Dengvaxia’s safety signal in seronegative children reshaped policy: the vaccine is now typically recommended only for seropositive individuals. In contrast, TAK-003’s clinical program reported no comparable increased risk in seronegative recipients in primary analyses. Nonetheless, effectiveness and safety varied by age and serostatus in secondary analyses. The WHO recommends restricting routine use in children under the age of 6 due to lower point estimates of efficacy in younger age groups and lower baseline seropositivity. Consequently, WHO and national advisory bodies emphasize robust surveillance, case confirmation and program-level risk–benefit assessment when introducing dengue vaccination for children.6 The Challenge of Antibody-dependent Enhancement ADE remains the fundamental hurdle in dengue vaccinology. Ideally, for a vaccine to be safe for universal use, it must provide high and sustained neutralizing antibody titers against all 4 serotypes simultaneously in both seronegative and seropositive individuals. Any vaccine that falls short on one or more serotypes could theoretically put the vaccine recipient at risk for enhanced disease upon future natural exposure. The new TAK003 vaccine, however, has not shown any safety signal of ADE in long-term follow-ups after 7 years, conferring robustness to the effect of the vaccine in individuals, irrespective of their serostatus. Therefore, the lack of vaccine efficacy against serotype 3 in seronegative individuals could be attributed to vaccine failure, which was detected even early after the first dose. It is believed that the lack of this adverse phenomenon is due to the induction of NS1 antibodies and cell-mediated immunity to DENV, which was not present in previous CYD-TDV vaccination. More real-world studies in settings with circulation of all serotypes are needed to refute that there are potential risks. Defining Correlates of Protection A major scientific gap is the lack of a clear, validated correlate of protection—a measurable immune response, humoral and/or cellular, that reliably predicts protection against dengue disease. Identifying this correlate would significantly expedite vaccine development and licensure by reducing the reliance on massive, costly and protracted phase 3 efficacy trials. IMPLEMENTATION CHALLENGES IN IMMUNIZATION PROGRAMS Age Targeting and Transmission Intensity Because age-specific seroprevalence varies greatly between and within countries, optimal age groups for vaccination differ. WHO’s current programmatic advice (eg, recommending TAK-003 for children 6–16 years of age in high-transmission settings) reflects these complexities. Models and empirical effectiveness studies should guide decisions on whether to target school-age children, broader pediatric cohorts or integrate vaccination with routine health services for all ages. In some Asian and Latin American countries, morbidity and case-fatality rates have become higher in small children and older adults, so there is an urgent need to properly evaluate vaccines in these high-risk populations.10 Surveillance, Registries, and Safety Monitoring To detect rare safety signals and monitor the real-world impact of vaccines on hospitalizations and severe disease, robust surveillance systems and vaccination registries are essential. The WHO stresses the importance of active surveillance, sentinel hospital networks and laboratory confirmation to distinguish vaccine effects from natural fluctuations in dengue epidemiology. Recommendations for Travelers The WHO states the vaccine is for frequent or long-term travelers and expatriates from nonendemic areas who have had a prior dengue infection (seropositive) before retraveling to endemic areas, as it can help prevent a more severe second dengue infection; the vaccine’s benefit is lower for those who have never been infected (seronegative).6 During the phase 3 TAK003 study efficacy of the first dose was 81% during the subsequent 3 months, before administration of the second dose. A real-world evidence study in Brazilian adolescents (10–14 years), mostly seronegative, conducted during a dengue outbreak in 2024 showed that after 1 dose, the effectiveness was 50.2%.5 Although new evidence on the persistence of antibody levels could be helpful for travelers, some countries recommend that travelers with a documented previous dengue infection receive the full vaccination series before travel.11–13 FUTURE DIRECTIONS AND RESEARCH PRIORITIES Improved Vaccines and Schedules Further vaccine refinement aims to increase the breadth and durability of protection across all 4 serotypes, improve immunogenicity in younger children, and minimize the risk of ADE. Heterologous prime-boost strategies, dose-optimization and new platforms (eg, recombinant subunits, inactivated formulations, virus-like particles, viral vectors and nucleic acid-based approaches) are under investigation and could broaden options for pediatric use. Head-to-head Effectiveness and Combination Strategies Comparative effectiveness studies across vaccines (and against different serotypes) are needed to inform policy choices. Evaluations of combined approaches—vaccination plus intensified vector control, rapid diagnostics and therapeutic strategies—will clarify the role of vaccines within integrated dengue control. Long-term Monitoring and Modeling Longitudinal cohort studies and modeling are needed to anticipate serotype or genotype replacement, long-term herd effects and optimal revaccination schedules. Continuous postlicensure data will also help refine age and serostatus recommendations and identify whether booster doses are required for sustained protection. CONCLUSIONS Recent years have brought meaningful advances in dengue vaccines. The introduction and WHO prequalification of TAK-003 (Qdenga) provides a new, programmatically useful tool with demonstrated protection against symptomatic and severe dengue in children, adolescents and potentially adults. Meanwhile, the experience with Dengvaxia underscores the importance of considering baseline serostatus, age and robust surveillance in vaccine policy. Continued development of diverse vaccine platforms, improved diagnostics for serostatus and careful monitoring of real-world effectiveness and safety are high priorities to maximize the public health impact of vaccination and protect children in endemic regions. Local epidemiology, feasible delivery strategies and strong safety/surveillance infrastructure should guide policy decisions.
Sáez-Llorens et al. (Mon,) studied this question.