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THE NEED FOR DENGUE VACCINES

The dengue virus is a single positive-stranded RNA virus belonging to the Flavivirus genus and transmitted by Aedes mosquitos. Four antigenically distinct dengue viruses (DENVs), DENV-1 to DENV-4, are circulating.^[1] Although they are conventionally referred to as DENV serotypes, the genetic distance between them suggests they are 4 separate species of flavivirus.

The incidence of dengue has increased substantially over the last few decades.^[2] It is estimated that almost 400 million infections occur annually, although most are mild and asymptomatic.^[2,3] Dengue is not restricted to endemic regions and is the most frequent infection diagnosed in travelers returning from the tropics.^[4,5] The recent COVID-19 pandemic led to an increase in dengue hospitalizations and deaths in 2021 and 2022 in many countries in Asia.^[6]

Infection with DENV can result in a wide range of manifestations, from asymptomatic to severe disease, which includes dengue shock syndrome from uncontrolled plasma leakage, internal hemorrhage, and organ dysfunction. Several factors can increase the risk for severe disease, such as the DENV serotype and strain, age, and certain comorbidities.^[7,8] In addition, secondary infection with a heterologous DENV serotype can increase the risk of severe dengue^[9] due to a phenomenon known as antibody-dependent enhancement (ADE).^[10,11]

Currently, there is no licensed anti-dengue medication, and treatment relies on supportive fluid therapy.^[12] Measures for vector control and suppression (such as reducing the abundance of water containers that can constitute breeding sites for Aedes mosquitoes, the use of insecticide or screens/bed nets, or preventing bites/transmission) are not sufficient to sustainably prevent outbreaks. In Singapore, mosquito suppression measures in place since 1970 prevented dengue epidemics for around 2 decades, but dengue resurged in the early 1990s in the context of low population immunity^[13] and outbreaks continue to occur.^[14] Therefore, the prevention of disease through vaccination is an essential tool in combating dengue.

CURRENTLY LICENSED DENGUE VACCINES

Two dengue vaccines, CYD-TDV and TAK-003, are currently licensed for use in various countries worldwide. Both are tetravalent, live-attenuated vaccines. CYD-TDV is based on a yellow fever virus backbone in which the pre-membrane and envelope genes have been replaced with homologous genes from the 4 DENV serotypes.^[15] TAK-003 is constructed in a similar way, but is based on the attenuated PDK-53 DENV-2 strain backbone.^[16]

CYD-TDV was first approved for use in Mexico, in December 2015,^[17] and was initially introduced in public immunization programs in the Philippines and Brazil. Currently, CYD-TDV is approved in ≥ 20 countries worldwide for use in individuals with laboratory-confirmed previous infection with DENV and aged 9 to 45 years, although the targeted age group may vary by country from 6 to 60 years. For instance, the European Medicines Agency recommends it for individuals aged 6 to 45 years,^[18] while in the United States it is only licensed for children and adolescents aged 9 to 16 years of age (Table 1).^[19]

TAK-003 is a newer dengue vaccine that received its first approval in August 2022, in Indonesia, followed by the European Union in December 2022 and the United Kingdom in January 2023 (Table 1).^[20,21]

Table 1. Approval Status and Indication for CYD-TDV and TAK-003^[18-21]

EU, European Union.
*Targeted age group varies by country.

CLINICAL TRIAL DATA ON LICENSED DENGUE VACCINES

Both CYD-TDV and TAK-003 were licensed based on accumulated data from pivotal phase 3 trials.

CYD-TDV Vaccine

For CYD-TDV, efficacy data were generated from 2 large randomized phase 3 trials. CYD14 (NCT01373281) was conducted in children 2 to 14 years of age, with 6851 participants receiving 3 doses of CYD-TDV and 3424 participants receiving placebo.^[22] CYD15 (NCT01374516) was conducted in children and adolescents 9 to 16 years of age, of whom 13,920 received CYD-TDV and 6949 placebo.^[23] The pooled analysis of these data at 25 months post first CYD-TDV dose showed that efficacy varied with age group, DENV serotype, and baseline serostatus (Table 2).^[24] Available long-term data are limited: a pooled estimate for vaccine efficacy (VE) against virologically confirmed dengue (VCD) of 14.6% (95% CI: -74.7, 58.3) was reported from the CYD14 and CYD15 trials during the last 2 years of follow-up (years 5 and 6) after the initial dose in a subset of initially seropositive participants 6 to 16 years of age, suggesting waning of efficacy over time.^[18]

Stratification by serostatus also showed a higher incidence of hospitalization for VCD and severe VCD among initially seronegative vs seropositive recipients. In a post hoc, pooled analysis of data from the CYD14 and CYD15 trials and the phase 2 CYD23 trial and its extension study CYD57 conducted in Thailand, the cumulative 5-year incidence of hospitalization for VCD was 3.06% and 0.75% among CYD-TDV recipients and 1.87% and 2.47% among controls in dengue-seronegative and dengue-seropositive participants, respectively.^[25] A similar trend of higher risk in participants who were seronegative at baseline and receiving CYD-TDV was observed for severe dengue. The risk of hospitalization for VCD and severe dengue also tended to be higher in children aged 2 to 8 years than in those 9 to 16 years of age (Table 2).^[25] Based on these data, the World Health Organization subsequently changed its recommendation to restrict the use of CYD-TDV to individuals with prior, laboratory-confirmed dengue infection.^[26]

Table 2. Efficacy and Safety Data From Phase 3 Trials Evaluating CYD-TDV ^{[18,19,24,25,27]}

DHF, dengue hemorrhagic fever.

The most frequent adverse events observed after administration of CYD-TDV were headache (51%), injection site pain (49%), malaise (41%), myalgia (41%), asthenia (32%), and fever (14%).^[18]

TAK-003 Vaccine

The efficacy of TAK-003 was evaluated in the TIDES trial conducted in Brazil, Colombia, the Dominican Republic, Nicaragua, Panama, the Philippines, Sri Lanka, and Thailand in children and adolescents aged 4 to 16 years. Participants were randomized in a 2:1 ratio to receive TAK-003 according to a 2-dose schedule (13,380 individuals) or placebo (6687 individuals). The primary endpoint was VE against VCD; an overall efficacy of 80.2% (95% CI: 73.3, 85.3) was estimated from 30 days to 12 months post dose 2.^[28] Long-term data up to 4.5 years of follow-up are available (Table 3), showing variability in efficacy by DENV serotype and a trend for somewhat lower estimates in initially seronegative vs seropositive participants.^[21,28-31] VE against DENV-4 remains inconclusive due to an insufficient number of cases for statistical analysis. There was no clear evidence of ADE and no statistically supported conclusion for increased risk of hospitalization following vaccination with TAK003 up to 4.5 years after completion of the vaccination schedule.^[31]

Table 3. Efficacy Data From the Phase 3 TIDES Trial Evaluating TAK-003^[29-31]

No important safety risks were identified during the clinical development of TAK-003.^[31] The most frequent adverse events observed after administration of TAK-003 were injection site pain (50%), headache (35%), myalgia (31%), injection site erythema (27%), malaise (24%), asthenia (20%), and fever (11%).^[21]

Other Relevant Trial Data

Neither vaccine was evaluated in the adult population, but efficacy was inferred from the clinical efficacy demonstrated in children based on bridging of immunogenicity data.^[18,21]

Co-administration with other vaccines was shown to be safe for CYD-TDV.^[32] Data supporting the co-administration of TAK-003 with a hepatitis A vaccine have also become available recently.^[33] When not given simultaneously with other live-attenuated vaccines, it is recommended that administration is separated by at least 4 weeks to reduce or eliminate any interference.^[32]

Among the vaccines still in development, only 1 other, the tetravalent live attenuated TV003 vaccine, has reached phase 3 clinical trial evaluation, and preliminary data are now available in individuals 2 to 59 years of age from a study conducted in Brazil. After 2 years of follow-up, VE against symptomatic dengue was 89.3% and 73.5% in initially seropositive and seronegative participants, respectively.^[34]

WHAT ARE THE GOALS OF IMMUNIZATION AGAINST DENGUE?

The main goal of vaccination against dengue is the prevention of severe disease and hospitalization, which have the highest risk of fatal outcomes when not managed properly and place a high burden on the healthcare system. As no therapeutic antiviral treatments are yet available for dengue, prevention of severe forms of dengue remains key. Vaccines are also evaluated in terms of their efficacy against symptomatic dengue of any severity, which may be a more pragmatic clinical trials endpoint. Nevertheless, preventing symptomatic disease entirely becomes an important target of vaccination when considering long dengue. It was already known that severe dengue can lead to long-term persistence of symptoms (over 2 years from disease onset) in around 50% of affected individuals,^[35] but the COVID-19 pandemic also increased awareness about the possibility of chronic, potentially disabling dengue sequelae even after mild symptomatic disease. A recent study estimated that around 20% of patients with acute, nonsevere dengue experience symptoms persisting for at least 3 months.^[36] However, long dengue may even be prevented by generating immunity levels that would not necessarily prevent symptomatic disease; this hypothesis and the impact of vaccination on long dengue prevention should be tested in future clinical trials.

There is currently no evidence of a potential herd immunity effect of dengue vaccination, and this is not likely to be achieved because of the apparent imbalance in VE against the 4 DENV serotypes, especially in seronegative individuals, and the relatively high reproductive rate (R₀) of dengue virus, which requires high immunization uptake rates. Therefore, control of dengue is likely not fully achievable by vaccination alone. Indeed, vaccination is not intended to replace vector control and other preventive measures for dengue, which need to be implemented in parallel with vaccination. In addition to contributing to the control of other viruses transmitted by Aedes mosquitos, vector control can reduce the need for high vaccine coverage. A combined approach could not only address the weaknesses of each strategy, but could even lead to a synergistic effect when well planned.^[37,38]

Young children are the most susceptible population to dengue. The risk of severe dengue and death is higher in children than in adults.^[39] Other high-risk groups are people with comorbidities^[40] and the elderly, who can experience more severe complications, requiring longer hospitalization.^[41,42] Travelers from non-endemic to endemic regions are also at higher risk of dengue due to their lack of immunity.^[5] The approval of TAK-003^[21] is the first step in broadening the availability of vaccination to seronegative young children, older individuals, and international travelers. Dengue infection can also lead to complications during pregnancy and impact neonatal outcomes,^[43] but data on the efficacy of vaccination in pregnant women are still lacking.

CONCLUDING REMARKS

Prevention of dengue by vaccination is not without challenges. The lack of an established correlate of vaccine protection and ADE^[44] makes the evaluation of vaccine candidates difficult, and to date no vaccine has demonstrated consistent immunity/protection against all 4 DENV serotypes. For CYD-TDV, previous dengue infection needs to be confirmed via an appropriate serological test, which poses difficulties in low-income settings. A low vaccine uptake (due to several factors such as variable access to health care across endemic regions, low compliance to vaccination, vaccine hesitancy/fatigue, and a lack of awareness of the potential severity of the disease) reduces the effectiveness of vaccination programs. Therefore, both healthcare providers and patients must be educated on the benefits of vaccinating against dengue. While vaccination may not represent a complete solution to controlling the disease, it is still capable of preventing a large proportion of the millions of dengue cases that occur each year, as both licensed vaccines have demonstrated significant protection against the virus. The recent approval of TAK-003 has broadened the use of dengue vaccination in seronegative individuals, and various vaccines are still in the pipeline, bringing us a step closer to achieving control of the disease.

Vaccination is a powerful tool in preventing dengue, especially in the most vulnerable populations, young children and older adults. All eligible individuals should be aware of the protection offered by vaccination and its role in increasing population immunity to dengue, thus leading to improved control of a growing global health threat.