Abstract
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.
Highlights
In recent decades dengue has expanded in tropical and subtropical areas around the world to become one of the most important vectorborne diseases of humans, with around 2.5 billion people living in regions where the disease is transmitted [1]
This vaccine – the CYD tetravalent dengue vaccine has been developed in compliance with World Health Organization (WHO) guidelines for the production and quality control of candidate tetravalent dengue vaccine [6], guidelines for the clinical evaluation of dengue vaccines in endemic areas [7], and guidelines for plaque reduction neutralization testing of human antibodies to dengue viruses [8]
Dengue and Japanese encephalitis (JE) viruses are the primary vector-borne flaviviruses in the country, [13] and while JE vaccine is included in the national immunization program this had only been partially implemented in the South of Viet Nam at the time of the study
Summary
This randomized, controlled, blind-observer, monocenter, phase II study took place in Long Xuyen city, An Giang province of Viet Nam. Cases of fever with body temperature ≥ 38°C for ≥ 48 hours within 28 days after vaccination were assessed for CYD-TDV viremia by quantitative RT-PCR. The neutralizing antibody titer was calculated and expressed as the highest reciprocal serum dilution (l/dil) reducing the mean plaque count by 50% as compared with the mean virus plaque number obtained from the control wells. In the event of a febrile episode with a body temperature of ≥ 38°C for ≥ 48 hours and suspected dengue, participants/parents were instructed to return to the study center for laboratory diagnosis using quantitative dengue RT-PCR, and by commercial ELISA kits: NS1Ag ELISA (PlateliaTM, Biorad Laboratories, Marnes-La-Coquette, France), and Dengue IgM and IgG ELISA (EL1500M and EL1500G respectively, Focus Diagnostics Inc, CA, USA).
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