Second Dose of Tetravalent Dengue Vaccine Candidate Shows Enhanced Immunogenicity

A new dosing schedule for a tetravalent candidate vaccine showed enhanced immunogenicity to the dengue virus — one of the most common and uncontrolled mosquito-borne diseases affecting humans — in endemic regions of Asia and Latin America.

Six-month interim data from a randomized controlled study of the tetravalent dengue vaccine (TDV) published recently in Lancet Infectious Disease showed that a second dose was both safe and conferred enhanced protection against 2 of the 4 dengue strains (DENV1-4) in children age 2 to 17 who were seronegative before vaccination.¹

For the double-blind placebo-controlled phase 2 study (ClinicalTrials.gov identifier: NCT02302066; funded by the Takeda Pharmaceutical Company, LTD), investigators enrolled 1800 participants (mean age 7.3) from 3 hospital clinics in the Dominican Republic, Panama, and the Philippines between December 2014 and February 2015. The participants were randomly assigned to 1 of 3 dosing schedules of TDV involving 1 dose at baseline, followed by 1 dose at 3 months (group 1, n=200); no other dose (group 2, n=398); a booster at 12 months (group 3, n=998); or placebo (group 4, n=198).

Neutralizing antibodies to all 4 dengue serotypes peaked at 1 month post-baseline. At 6 months, 85% of children in group 1 tested positive for neutralizing antibodies to DENV1-4 serotypes after 2 doses of the vaccine, with particularly high geometric mean titres (GMTs) against DENV-2. In group 2 participants who had only a single dose, GMT response to all 4 serotypes was 68%. In children who were seronegative at baseline, a second dose at 3 months elicited a higher GMT response at 6 months to DENV-3 and DENV-4. As these were interim results of a longer study, the impact of a booster at 12 months could not be yet be assessed.

“The levels of immunogenicity induced by TAK-003 against all four dengue serotypes, even in seronegative participants, are encouraging because seropositivity after vaccination may be an important measure of vaccine performance,” explained lead investigator Xavier Sáez-Llorens, MD, head of infectious diseases and director of clinical research at the Panama Children’s Hospital, in Panama City, in a Takeda press release.² “Infection with one dengue serotype makes subsequent infection with a different serotype a major risk factor for severe disease, hence the need for a safe and effective vaccine that simultaneously protects against all four serotypes,” he said.

The published results of the TDV clinical phase 2 trial showed broad and strong dengue immunogenicity at 6 months, irrespective of previous dengue exposure, the investigators reported, which was enhanced by a second dose in children who were seronegative prior to vaccination. “These and other phase 1 and phase 2 safety and immunogenicity data support continued development of this important vaccine candidate,^1,3,4” said Derek Wallace, MBBS, Takeda Global Dengue Program Head, in the Company press release.²

References

1. Sáez-Llorens X, Tricou V, Yu D, et al. Safety and immunogenicity of one versus two doses of Takeda’s tetravalent dengue vaccine in children in Asia and Latin America: interim results from a phase 2, randomised, placebo-controlled study. Lancet Infect Dis. 2017;17:615-625.
2. Takeda’s dengue vaccine candidate elicited broad immune responses in children and adolescents living in dengue-endemic areas; interim phase 2 analysis published in The Lancet Infectious Diseases [press release]. Osaka, Japan: Takeda Pharmaceutical Company Limited. Published March 30, 2017. Accessed August 3, 2017.
3. Osorio JE, Velez I, Thomson C, et al. Safety and immunogenicity of a recombinant live attenuated tetravalent dengue vaccine (DENVax) in flavivirus-naive healthy adults in Colombia: a randomised, placebo-controlled, phase 1 study. Lancet Infect Dis. 2014;14:830-838.
4. 4. Wallace D. Persistence of neutralizing antibodies one year after two doses of a candidate recombinant tetravalent dengue vaccine in subjects aged from 1.5 to 45 years. Presented at the American Society of Tropical Medicine and Hygiene 64th Annual Meeting, October 25-29, 2016, Philadelphia, Pennsylvania.