Dengue is the most rapidly spreading mosquito-borne viral disease in the world. Past 50 y have witnessed 30-fold increase in its incidence with increasing geographic expansion to new countries and, in the present decade, from urban to rural settings. The incidence of dengue increased greatly between 1990 and 2013, with the number of cases more than doubling every decade, from 8·3 million (3.3 million–17.2 million) apparent cases in 1990, to 58·4 million (23.6 million–121.9 million) apparent cases in 2013 .
Dengue, a mosquito-borne flavivirus disease is caused by four closely related viruses, the Dengue viruses (DV) 1–4. Massive urbanization, overcrowding and poor living conditions; increased human migration; failure of vector control programs; and the global emergence of more virulent genotypes of DV have made eradication of dengue difficult. A dengue vaccine would therefore, be a major tool in controlling the disease. The first successful dengue vaccine was reported in 1945 by Sabin and Schlesinger, who attenuated the “Hawaiian” strain (serotype DEN-1) of DV in mouse brain by serial passage and then used this mouse brain vaccine to protect 16 volunteers against the bites of infected A. aegypti mosquitoes . The most advanced approaches are live attenuated vaccines (LAVs) followed by inactivated/recombinant adjuvanted vaccines and DNA vaccines . Various dengue vaccines are in clinical and preclinical stage of development .
The first licensed dengue vaccine, Dengvaxia (CYD-TDV) by Sanofi Pasteur, was first registered in Mexico in December, 2015. The vaccine is also licensed in the Philippines, Brazil, El Salvador and Paraguay . The Philippines has included this vaccine in its National Immunization Program (NIP) but India is yet to do so as Phase III trial has not started in India so far.
WHO has recommended introduction of the dengue vaccine CYD-TDV in countries with epidemiologically high burden of disease i.e., seroprevalence of approximately 70% or greater in the age group targeted for vaccination to maximize public health impact and cost-effectiveness.
Populations with seroprevalence between 50% and 70% can be vaccinated but the impact of the vaccination programme may be lower. WHO does not recommend vaccination when seroprevalence is below 50% .
It is a live recombinant vaccine containing 4 live attenuated recombinant viruses representing serotypes 1, 2, 3, and 4. Each monovalent CYD recombinant is obtained separately by replacing the genes encoding the prM and E proteins of the attenuated yellow fever (YF) 17D virus genome with the corresponding genes of the 4 wild-type dengue viruses. The final formulation contains 4.5–6.0 log10 median cell-culture infectious doses (CCID50) of each of the live attenuated dengue serotype 1, 2, 3 and 4 vaccine viruses .
Dose and Schedule
It is administered as a 3-dose series given as a 0, 6, and 12-mo schedule. It has been registered for use in individuals 9–45 y of age living in endemic areas. Co-administration with other vaccines is permissible. Recent study in Mexico showed that co-administration of the DTaP-IPV/Hib booster vaccine with CYD-TDV does not affect immunogenicity or safety profile of either vaccine . Co-administration with YF vaccine and MMR also did not identify any safety concerns. Trials with human papillomavirus (HPV) and tetanus toxoid and reduced-dose diphtheria (TdaP) vaccines are underway.
Godói et al. in their systemic review and meta-analysis have derived vaccine efficacy of 60% in participants aged 2–16 y old, with DENV4 and DENV2 presenting the best and worst results, respectively .
Erythema and swelling were frequently associated but systemic adverse events were few.
Other Candidate Vaccines
There are at least five more candidates in clinical development but not yet licensed. TV003 and TV005 are most advanced vaccines developed by the U.S National Institutes of Health (US NIH) that are licensed. They are attenuated wild-type virus strains containing serotypes 1, 3, and 4 as complete viruses, and serotype 2 as recombinant virus. TV003 or TV005 has been licensed to Butantan, VaBiotech, Panacea, Serum Institute of India and Merck pharmaceuticals. A single dose of either TV003 or TV005 induced upto 90% seroconversion in flavivirus seronegative adults and elicited near-sterilizing immunity to a second dose of vaccine administered 6–12 mo later. Another live recombinant tetravalent vaccine, TDV (formerly DENVax) using a whole attenuated DEN2 virus and recombinant DEN1, DEN3, and DEN4 having DEN2 backbone is being developed by Takeda. Many Phase 1 and Phase 2 trials are undergoing and multicenter Phase 3 study is being planned. A tetravalent purified inactivated vaccine (GSK/Walter Reed Army Institute of Research), a tetravalent recombinant subunit vaccine based on the dengue wild-type pre-membrane and truncated envelope protein (Merck), a monovalent plasmid DNA vaccine (US Navy Medical Research Center), and an inactivated vaccine/live attenuated vaccine heterologous prime boost (Walter Reed Army Institute of Research) are in Phase 1 trial .