TAK-003 dengue vaccine as a new tool to mitigate dengue in countries with a high disease burden
Authors: Annelies Wilder-Smith
Journal: The Lancet Global Health (2024)

Dengue, an arboviral disease of the tropics and subtropics, is caused by infection with one of four distinct serotypes of the dengue virus (DENV-1, DENV-2, DENV-3, and DENV-4).1Wilder-Smith A Ooi EE Horstick O Wills B Dengue.Lancet. 2019; 393: 350-363Summary Full Text Full Text PDF PubMed Scopus (383) Google Scholar We have seen an exponential increase in dengue incidence over the past few decades, surpassing the growth rate of other communicable diseases, a trend anticipated to continue, fuelled by urbanisation with high population densities, global mobility, and climate change.2Yang X Quam MBM Zhang T Sang S Global burden for dengue and the evolving pattern in the past 30 years.J Travel Med. 2021; 28: taab146Crossref PubMed Scopus (74) Google Scholar Dengue incidence is concentrated in southeast and south Asia, with Latin America following closely. The proportion of dengue-related febrile episodes necessitating hospitalisation is 19% in Asia and 11% in Latin America.1Wilder-Smith A Ooi EE Horstick O Wills B Dengue.Lancet. 2019; 393: 350-363Summary Full Text Full Text PDF PubMed Scopus (383) Google Scholar The quest for an effective dengue has encountered substantial obstacles, primarily due to the immunological interaction between the four dengue virus serotypes. Therefore, phase 3 clinical trial designs require baseline blood samples of all trial participants to enable determination of serostatus before vaccination. Determining vaccine efficacy for dengue vaccines is complex because there are eight possible scenarios, with four serotypes in combination with seronegative versus seropositive baseline status. This is further complicated by stratification of efficacy against disease severity (virologically confirmed dengue of any severity versus hospitalisation and severe dengue). TAK-003 is a live attenuated tetravalent dengue vaccine developed by Takeda Vaccines (Cambridge, MA, USA). Chimeric serotype 1, 3, and 4 dengue viruses were created by substituting pre-membrane and envelope genes of the DENV-2 backbone with those of the corresponding serotype. TAK-003 generates both humoral and cross-reactive T-cell-mediated immune responses. 12-month and 36-month evaluations of the trial have already been published.4Rivera L Biswal S Sáez-Llorens X et al.Three-year efficacy and safety of Takeda's dengue vaccine candidate (TAK-003).Clin Infect Dis. 2022; 75: 107-117Crossref PubMed Scopus (64) Google Scholar, 5López-Medina E Biswal S Saez-Llorens X et al.Efficacy of a dengue vaccine candidate (TAK-003) in healthy children and adolescents 2 years after vaccination.J Infect Dis. 2022; 225: 1521-1532Crossref Scopus (27) Google Scholar Those interim analyses revealed that vaccine performance depended on baseline serostatus and serotype, and on the choice of the clinical endpoint. In The Lancet Global Health, Vianney Tricou and colleagues report conclusive outcomes of their 5-year study on TAK-003.6Tricou 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-e270Google Scholar These findings played a crucial role in its approval by the European Medicine Agency in December, 2022. The efficacy trial was done over 5 years, recruiting more than 20 000 children and adolescents (4–16 years of age) residing in dengue-endemic countries in Asia and Latin America. The dengue seroprevalence (the proportion of dengue seropositive people) in the study population before vaccination was approximately 70%, and the predominant circulating strains were serotypes 1 and 2. Despite the 5 year observation period, there was low circulation of serotypes 3 and 4, so that some of the uncertainties identified regarding serotype-stratified efficacy in seronegative people in the earlier interim analyses could not be addressed. In this study population and study setting, the cumulative vaccine efficacy of TAK-003 over 5 years against virologically confirmed dengue was 61·2% (95% CI 56·0–65·8) and against dengue-related hospitalisations was 84·1% (77·8–88·6). Vaccine efficacy varied by serostatus and serotype, with higher vaccine efficacy in people with a baseline seropositive serostatus compared with people with baseline seronegative serostatus. Vaccine efficacy was highest against DENV-2, both in seropositive and seronegative people. For individuals who were seropositive at baseline, TAK-003 demonstrated safety and efficacy against all four DENV serotypes, showing the greatest vaccine efficacy against DENV-2, and even higher vaccine efficacy against severe dengue. In those who were seronegative at baseline, the vaccine offered protection against DENV-1 and particularly good protection against DENV-2, in terms of both virologically confirmed dengue and dengue-related hospital admissions. The vaccine did not show a reduction in virologically confirmed dengue and dengue hospitalisations caused by DENV-3 in dengue-naive participants, with further uncertainties around DENV-4. There were higher rates of symptomatic as well as hospitalised DENV-3 cases among seronegative vaccinated people than among seronegative unvaccinated people, but this excess was small and not statistically significant. Therefore, despite conducting a well-designed trial according to WHO guidance, the relative low circulation of DENV-3 and DENV-4 during the 5 year trial did not allow the assessment of vaccine efficacy in seronegative people exposed to DENV-3 and DENV-4; a safety signal can neither be ruled out nor ruled in. Acknowledging that such a risk is plausible given the experience of the first licensed tetravalent live attenuated dengue vaccine, Dengvaxia (Sanofi Pasteur),7Wilder-Smith A Hombach J Ferguson N et al.Deliberations of the Strategic Advisory Group of Experts on Immunization on the use of CYD-TDV dengue vaccine.Lancet Infect Dis. 2019; 19: e31-e38Summary Full Text Full Text PDF PubMed Scopus (104) Google Scholar the question arises whether pre-vaccination screening would be necessary. In September, 2023, WHO's Strategic Advisory Group of Experts on Immunization (SAGE) addressed this question.8WHO SAGE meeting. Sept 25–29, 2023.https://terrance.who.int/mediacentre/data/sage/SAGE_eYB_Sept2023.pdfDate accessed: December 1, 2023Google Scholar Given that a statistically significant safety signal was not identified in the trial setting, SAGE came to the conclusion that pre-vaccination screening would significantly reduce the public health impact of TAK-003. Pre-vaccination screening has limited sensitivity and would exclude seropositive people who would benefit from vaccination. More importantly, in contrast to Dengvaxia where all seronegative people were at increased risk for severe dengue,7Wilder-Smith A Hombach J Ferguson N et al.Deliberations of the Strategic Advisory Group of Experts on Immunization on the use of CYD-TDV dengue vaccine.Lancet Infect Dis. 2019; 19: e31-e38Summary Full Text Full Text PDF PubMed Scopus (104) Google Scholar with TAK-003 there is a statistically significant protection in seronegative people for two of the four serotypes (DENV-1 and DENV-2). Pre-vaccination screening would unnecessarily increase the complexities and costs of roll-out and, hence, vaccine uptake. SAGE endorsed the use of TAK-003 without pre-vaccination screening. However, the policy recommendation is targeted for use in high disease burden settings only, as vaccine performance is higher in such populations and any potential, not yet proven, risk in a subset of seronegative people exposed to DENV-3 and DENV-4, would be mitigated. SAGE recommended a roll-out of the vaccine with a transparent communication strategy. In 2023, dengue has again caused major societal upheaval in the tropics and subtropics, and will continue to do so in the future. It is time to act and offer vaccination to mitigate the pressure on already overwhelmed health-care systems. TAK-003 is a new tool that countries with high burden of dengue, determined as a seroprevalence of approximately 60% and above by the age of 9 years,8WHO SAGE meeting. Sept 25–29, 2023.https://terrance.who.int/mediacentre/data/sage/SAGE_eYB_Sept2023.pdfDate accessed: December 1, 2023Google Scholar, 9Freedman DO A new dengue vaccine (TAK-003) now WHO recommended in endemic areas; what about travellers?.J Travel Med. 2023; 30: taad132Crossref Scopus (0) Google Scholar should consider using. AWS is a WHO employee. This was an invited comment, and written on a personal basis. The opinions shared here are those of the author and do not necessarily reflect those of WHO. 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 trialTAK-003 demonstrated long-term efficacy and safety against all four DENV serotypes in previously exposed individuals and against DENV-1 and DENV-2 in dengue-naive individuals. Full-Text PDF Open Access