Efficacy, public health impact and optimal use of the Takeda dengue vaccine – Nature

Report on the Efficacy, Public Health Impact, and Optimal Use of the Takeda Dengue Vaccine (Qdenga) with Emphasis on Sustainable Development Goals (SDGs)

Abstract

Dengue, the most prevalent arboviral infection worldwide, causes significant morbidity and mortality, challenging global health systems. The recent licensing of Qdenga, a second-generation dengue vaccine developed by Takeda Pharmaceuticals, offers a timely intervention aligned with the Sustainable Development Goal 3 (Good Health and Well-being). This report evaluates Qdenga’s efficacy across diverse transmission settings using mathematical modeling calibrated to clinical trial data. Findings indicate that vaccine efficacy varies by dengue serotype, serological status, and age. Vaccination of children over 6 years in moderate-to-high transmission areas (seroprevalence in 9-year-olds > 60%) could reduce hospitalized dengue cases by 10–22% over ten years. However, potential vaccine-induced disease enhancement risks in seronegative recipients, particularly children under 6 years, necessitate cautious deployment and further long-term efficacy data, supporting SDG 3’s target to combat communicable diseases.

Main Findings

Background and Challenges in Dengue Vaccination

Over half of the global population is at risk of dengue infection, underscoring the urgent need for effective control measures, including vaccines. The complexity of dengue virus (DENV) serotypes (DENV1–4) and antibody-dependent enhancement mechanisms have historically complicated vaccine development. The first licensed vaccine, Dengvaxia, revealed increased hospitalization risks in seronegative individuals, limiting its use and highlighting the need for vaccines that can be safely administered without pre-vaccination serological screening.

Qdenga Vaccine Profile and Clinical Trial Data

• Qdenga is a tetravalent live-attenuated vaccine using DENV2 as the backbone, substituting pre-membrane and envelope proteins for DENV1, 3, and 4.
• Phase III trials enrolled ~21,000 participants aged 4–16 years across Asia and South America, randomized 2:1 to receive Qdenga or placebo.
• Vaccine efficacy (VE) was evaluated by baseline serostatus, serotype, age, and clinical outcome up to 54 months post-second dose.
• Average VE was 61.2% against symptomatic dengue and 84.1% against hospitalization, with waning efficacy over time.
• Highest and most durable neutralizing antibody titers were observed against DENV2 and in seropositive individuals.

Vaccine Efficacy and Risks

• High VE against symptomatic and hospitalized DENV2 across all ages and serostatuses.
• Moderate protection against other serotypes in seropositive individuals.
• Evidence of potential disease enhancement in seronegative children aged 4–5 years for DENV1, DENV3, and DENV4, with increased hospitalization risk for DENV3 and DENV4.
• No significant protection against DENV3 and DENV4 in seronegative individuals beyond 3 years post-vaccination.
• Modeling suggests vaccine-associated disease enhancement risk is highest in seronegative children under 6 years.

Population-Level Impact of Routine Qdenga Vaccination

Using a stochastic dengue transmission model integrated with VE estimates, the public health impact of Qdenga was simulated across various scenarios:

1. Transmission settings characterized by seroprevalence in 9-year-olds (SP9) from 10% to 90%.
2. Vaccination coverage levels from 20% to 80% among children aged 6–12 years.
3. Vaccine efficacy decay scenarios over 5 or 15 years.
4. Protection assumptions against disease only or both infection and disease.

Key outcomes include:

• In moderate-to-high transmission settings (SP9 > 60%), vaccination could reduce hospitalized dengue cases by up to 22% over 10 years.
• Population impact is modest overall, with symptomatic cases averted ranging from 1.6% to 17.2%, depending on assumptions.
• Positive impact primarily driven by prevention of DENV2 cases; small negative impacts possible for DENV1, DENV3, and DENV4 in low-to-moderate transmission settings.
• Optimal vaccination age decreases with increasing transmission intensity, supporting targeted vaccination strategies.

Individual-Level Impact and Risk Assessment

• Seropositive vaccinees consistently benefit from vaccination, with 40–75% of symptomatic and hospitalized cases averted.
• Seronegative vaccinees may experience negative impacts in low-to-moderate transmission settings, reflecting uncertainty in VE and circulating serotypes.
• Vaccination in high transmission settings yields positive individual benefits, reducing disease burden substantially.
• Pre-vaccination serological screening reduces population impact by 29–85% depending on transmission intensity but increases individual benefit by targeting seropositive individuals.

Impact on Dengue Serotype Dynamics

Modeling indicates that routine Qdenga vaccination minimally alters serotype dominance patterns in moderate-to-high transmission settings, with potential reductions in DENV2 dominance and modest increases in DENV3 dominance in low transmission settings.

Discussion and Implications for Sustainable Development Goals (SDGs)

Summary of Efficacy and Safety Profile

Qdenga demonstrates high efficacy against DENV2 and moderate efficacy against other serotypes in seropositive individuals, aligning with SDG 3 by contributing to the reduction of communicable diseases. However, potential risks of vaccine-associated disease enhancement in seronegative children, especially under 6 years, necessitate careful age-targeted vaccination strategies and ongoing safety monitoring.

Recommendations for Vaccine Deployment

• Vaccination programs should prioritize children aged 6 years and above in moderate-to-high transmission settings to maximize benefits and minimize risks.
• Pre-vaccination screening is not currently recommended by WHO for Qdenga due to test limitations and impact on population-level benefits.
• Continuous post-licensure surveillance is essential to monitor long-term efficacy and safety, particularly for DENV3 and DENV4.
• Consideration of booster doses may mitigate waning immunity and potential risks.

Contribution to Global Health and SDGs

The introduction and optimized use of Qdenga support the achievement of SDG 3 (Good Health and Well-being) by reducing dengue morbidity and mortality. By decreasing dengue hospitalizations and symptomatic cases, the vaccine contributes to strengthening health systems and reducing economic burdens associated with dengue outbreaks, thereby advancing equitable health outcomes and sustainable development.

Future Research and Integration with Other Interventions

• Further research is needed to refine correlates of protection and understand vaccine efficacy against infection.
• Integration of Qdenga vaccination with other dengue control measures, such as Wolbachia-infected mosquito deployments and antivirals, aligns with SDG 3 targets for comprehensive disease management.
• Modeling frameworks developed can be adapted to evaluate new dengue vaccines and combined intervention strategies.

Methods Overview

Data Sources

Phase III clinical trial data for Qdenga were extracted from published reports covering up to 54 months post-second dose, including symptomatic and hospitalized dengue cases stratified by serotype, age, and baseline serostatus.

Vaccine Efficacy Modeling

• A Bayesian cohort survival model linked neutralizing antibody titers to vaccine efficacy against symptomatic disease and hospitalization.
• Model accounted for serotype-specific, age-specific, and serostatus-specific variations in efficacy and potential vaccine-associated disease enhancement.
• Model parameters were estimated using Hamiltonian Monte Carlo methods implemented in Stan.

Dengue Transmission Modeling

• A stochastic compartmental model simulated dengue transmission dynamics across four serotypes, incorporating mosquito population dynamics, human demography, and vaccination effects.
• Model scenarios varied transmission intensity, vaccination coverage, age at vaccination, vaccine efficacy decay, and protection mechanisms.
• Population and individual-level impacts of vaccination were estimated by comparing scenarios with and without vaccination over a 10-year horizon.

Sensitivity Analyses

Robustness of findings was assessed by varying assumptions on heterotypic immunity duration, serotype transmissibility, vaccine efficacy parameters, and pre-vaccination screening test performance.

Data and Code Availability

• All data used in the modeling study are publicly available on GitHub: https://github.com/mrc-ide/qdenga_impact.
• Code for the analyses is also available at the same repository.

1. Sustainable Development Goals (SDGs) Addressed or Connected

1. SDG 3: Good Health and Well-being
   • The article focuses on dengue, a significant global health issue causing morbidity and mortality.
   • Development, efficacy, and public health impact of the Takeda dengue vaccine (Qdenga) are central themes.
   • Efforts to reduce disease burden, hospitalizations, and improve vaccine safety align with SDG 3.
2. SDG 9: Industry, Innovation and Infrastructure
   • The article discusses the development and evaluation of a second-generation dengue vaccine using advanced modeling techniques.
   • It highlights innovation in vaccine development and modeling to optimize vaccine deployment.
3. SDG 17: Partnerships for the Goals
   • The research involves collaboration among international organizations, pharmaceutical companies, and WHO.
   • Data sharing and use of global demographic and epidemiological data reflect partnerships to achieve health goals.

2. Specific Targets Under the Identified SDGs

1. SDG 3: Good Health and Well-being
   • Target 3.3: By 2030, end the epidemics of AIDS, tuberculosis, malaria and neglected tropical diseases and combat hepatitis, water-borne diseases and other communicable diseases.
     • The article’s focus on dengue vaccine development and impact directly contributes to controlling a neglected tropical disease.
   • Target 3.8: Achieve universal health coverage, including access to quality essential health-care services and access to safe, effective, quality and affordable essential medicines and vaccines for all.
     • Evaluation of Qdenga’s efficacy and safety supports access to effective vaccines.
   • Target 3.b: Support the research and development of vaccines and medicines for communicable and non-communicable diseases that primarily affect developing countries.
     • The article details research and modeling supporting vaccine development and deployment strategies.
2. SDG 9: Industry, Innovation and Infrastructure
   • Target 9.5: Enhance scientific research, upgrade the technological capabilities of industrial sectors and encourage innovation.
     • Use of mathematical and transmission models to evaluate vaccine efficacy and impact exemplifies innovation.
3. SDG 17: Partnerships for the Goals
   • Target 17.6: Enhance North-South, South-South and triangular regional and international cooperation on and access to science, technology and innovation.
     • The article references collaboration between WHO, pharmaceutical companies, and research institutions.
   • Target 17.18: Enhance capacity-building support to developing countries to increase significantly the availability of high-quality, timely and reliable data.
     • Use of global demographic data and sharing of clinical trial data supports this target.

3. Indicators Mentioned or Implied to Measure Progress

1. Incidence and Hospitalization Rates of Dengue
   • Number and proportion of symptomatic virologically confirmed dengue cases.
   • Number and proportion of hospitalized dengue cases.
   • These indicators measure disease burden and vaccine impact on health outcomes.
2. Vaccine Efficacy (VE) Indicators
   • VE against symptomatic dengue and hospitalization, stratified by serotype, age, and serostatus.
   • VE waning over time (e.g., from 1 to 54 months post-vaccination).
   • Risk ratios (RR) of disease and hospitalization comparing vaccinated vs. unvaccinated individuals.
3. Seroprevalence in Population
   • Average seroprevalence in 9-year-olds (SP9) as a measure of transmission intensity.
   • Used to stratify transmission settings and optimize vaccination strategies.
4. Neutralizing Antibody Titers
   • Correlates of protection measured by neutralizing antibody titers against dengue serotypes.
   • Used as immunogenicity metrics to predict vaccine protection and risk of enhancement.
5. Vaccination Coverage
   • Proportion of target population vaccinated (e.g., 20%, 40%, 60%, 80%).
   • Used to model population-level impact of vaccination.
6. Population and Individual-Level Impact Metrics
   • Proportion and absolute number of dengue cases and hospitalizations averted over 10 years.
   • Individual benefit-risk measured as cases averted in vaccinated cohorts.
7. Diagnostic Test Performance
   • Sensitivity and specificity of serological tests used for pre-vaccination screening.
   • Important for evaluating strategies to mitigate risks in seronegative individuals.

4. Table of SDGs, Targets, and Indicators

SDGs	Targets	Indicators
SDG 3: Good Health and Well-being	3.3: End epidemics of communicable diseases including neglected tropical diseases. 3.8: Achieve universal health coverage including access to vaccines. 3.b: Support research and development of vaccines for communicable diseases.	Incidence of symptomatic dengue cases. Incidence of hospitalized dengue cases. Vaccine efficacy against symptomatic disease and hospitalization. Neutralizing antibody titers as immunogenicity markers. Vaccination coverage rates.
SDG 9: Industry, Innovation and Infrastructure	9.5: Enhance scientific research and innovation.	Development and application of mathematical and transmission models for vaccine impact assessment. Evaluation of vaccine efficacy profiles and optimization of deployment strategies.
SDG 17: Partnerships for the Goals	17.6: Enhance international cooperation on science, technology and innovation. 17.18: Increase availability of high-quality, timely and reliable data.	Collaborative data sharing and joint research efforts. Use of global demographic and epidemiological data in modeling. Availability and use of clinical trial data and seroprevalence surveys.

Source: nature.com