Ngoc Huu Tran, Chan Quang Luong, Thi Que Huong Vu, Remi Forrat, Jean Lang, Quoc Dat Vu, Alain Bouckenooghe and Tram Anh Wartel
Background: Dengue viruses (DENV1-4) are estimated to infect 50-100 million individuals per year worldwide including an estimated 500,000 people with severe dengue who require hospitalization every year. The live, attenuated, tetravalent dengue vaccine (CYD-TDV) candidate, containing four recombinant dengue viruses (CYD1- 4), is in clinical phase III. Methods: In an observer-blind, phase II trial in Long Xuyen, Vietnam, 180 children and adults (range: 2-45 years) were randomized 2:1 to receive 3 CYD-TDV vaccinations at months (M) 0, 6 and 12 or meningococcal polysaccharide A+C at M0, placebo at M6, and typhoid Vi polysaccharide at M12. Serum antibody responses against the CYD1-4 parental wild-type dengue viruses were assessed using plaque-reduction neutralization test (PRNT50). Safety and reactogenicity were assessed using conventional methods. Febrile episodes lasting ≥ 48 h with suspicion of dengue (passive surveillance) were virologically confirmed. (ClinicalTrials.gov: NCT00875524). Results: At baseline 139(77%) were seropositive (titer ≥ 10 l/dil) against dengue or Japanese encephalitis; 36% were seropositive to all four dengue serotypes. After the first CYD-TDV vaccination, 53% were seropositive to all four serotypes, increasing to 72% and 92% after the second and third vaccinations. In the control group seropositivity against all four dengue serotypes was 28% at baseline and slightly increased at 36% after the third injection 13 months later. After the third CYD-TDV vaccination, 96% were seropositive to at least 3 serotypes, and geometric mean titers against DENV1-4 were respectively 129, 216, 169, and 146. Six serious adverse events (SAEs), unrelated to vaccination, were reported including 2 virologically-confirmed dengue cases after the second vaccination in the control group. Reactogenicity of CYD-TDV decreased after each vaccination, was slightly higher than placebo, but not higher than either active control. Conclusions: Safety and reactogenicity of CYD-TDV were satisfactory and consistent with results from phase I and other phase II studies. Three doses of CYD-TDV induced a balanced neutralizing antibody response against the four dengue serotypes in children and adults living in a dengue endemic country.