Vaccines and immunization: Dengue

There is a growing public health need for effective preventive interventions against dengue, a disease caused by four viruses, termed serotypes 1–4.

Two dengue vaccines have been licensed, Dengvaxia® (CYD-TDV), developed by Sanofi Pasteur, and Qdenga® (TAK-003), developed by Takeda.

Another dengue vaccine developed at the Laboratory of Infectious Diseases, at the National Institutes of Allergy and Infectious Diseases (NIAID) in the United States, is in the late stages of clinical development.

CYD-TDV was the first dengue vaccine to be licensed. CYD-TDV is a live recombinant tetravalent dengue vaccine, given as a 3-dose series with 6-month interval been doses, for individuals aged 9–45 years or 9–60 years (depending on the country-specific regulatory approvals) living in dengue-endemic countries or areas. It requires individuals to have pre-vaccination screening for previous dengue virus infection. Only those who test positive should receive the vaccine. Because of the requirement of pre-vaccination screening, this vaccine is currently not being widely used.

TAK-003 is the second dengue vaccine to be licensed. TAK-003 is a live-attenuated vaccine containing weakened versions of dengue virus serotypes 1, 2, 3 and 4 developed by Takeda. TAK-003 uses the DENV2 strain as the genomic backbone. The vaccine schedule is a 2-dose series three months apart, given to specific age groups and in specific circumstances according to WHO recommendations.

WHO recommends the use of TAK-003 in children aged 6–16 years in settings with high dengue transmission intensity. WHO does not currently recommend the programmatic use of TAK-003 in children aged <6 years because of the lower efficacy of the vaccine in this age group. Furthermore, the dengue seropositivity rate in this age group is generally low, even in high dengue transmission settings.

The vaccine is recommended as a 2-dose schedule with a minimum interval of 3 months between doses. It is not advised to reduce the interval between doses. If the second dose is delayed for any reason, it is not necessary to restart the series and the second dose should be administered at the first available opportunity.

WHO recommends that countries consider introducing TAK-003 into their routine immunization programmes in geographical locations where high transmission intensity of dengue poses a significant public health problem. Many countries may have a heterogeneous geographical distribution of dengue transmission intensity and could consider targeted subnational introduction.

Until the efficacy–risk profile for DENV3 and DENV4 in seronegative persons has been more thoroughly assessed, WHO does not recommend the programmatic use of TAK-003 vaccine in low to moderate dengue transmission settings.

Persons with comorbidities who live in dengue-endemic countries could be offered vaccination, even if they fall outside the recommended age range for programmatic use (6–16 years), provided that a substantial country-specific burden of severe dengue outcomes in these subpopulations has been documented. Until more data on efficacy-safety profiles become available, WHO recommends the lower age limit of 6 years, and the upper limit of 60 years for vaccination in persons with comorbitities.

To determine dengue transmission intensity, countries look at age-specific seroprevalence and age-specific hospital admissions for dengue. A seroprevalence rate (percentage of people in a population who have antibodies that show they have been exposed to dengue virus) of more than 60% by the age of 9 years or a mean age of peak dengue-associated hospitalizations below the age of 16 years could be considered as indicators of high dengue transmission.

The TAK-003 vaccine should not be administered to:

• people who are pregnant or planning to become pregnant at least 1 month following vaccination;
• people who are breastfeeding;
• people with congenital or acquired immune deficiency, including those receiving immunosuppressive therapies such as chemotherapy or high doses of systemic corticosteroids (for example 20 mg/day or 2 mg/kg body weight/day of prednisone for 2 weeks or more) within 4 weeks prior to vaccination; and
• people with symptomatic HIV infection or with asymptomatic HIV infection associated with evidence of impaired immune function.

Available evidence supports co-administration of TAK-003 with yellow fever and hepatitis A vaccines. Studies to assess co-administration with HPV vaccines are ongoing.

TAK-003 does not prevent all cases of dengue.

Vaccination against dengue should be viewed as part of an integrated strategy to control the disease, including vector control, proper case management, community education and community engagement. Comprehensive vector control must remain a critical component of dengue control programmes. Furthermore, the mosquito vectors of dengue transmit other important viruses, including yellow fever, chikungunya and Zika viruses.

Persons living in non-endemic countries who have previously been infected with any of the 4 dengue virus serotypes following travel to dengue-endemic countries may benefit from TAK-003 vaccination to prevent a second (and hence potentially more severe) dengue infection when travelling again to an endemic country.

Frequent travellers, long-term travellers, migrants and long-term expatriates have a higher likelihood of previous dengue infection (and are therefore more likely to be seropositive) compared to first-time or short-term travellers.

The benefits of vaccination with TAK-003 are lower for travellers who have never experienced dengue infection (and are therefore seronegative) compared to travellers who are seropositive.