A phase I randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and immunogenicity of a live-attenuated quadrivalent dengue vaccine in flavivirus-naïve and flavivirus-experienced healthy adults

Abstract

Dengue (DENV) is a mosquito-borne virus with four serotypes causing substantial morbidity in tropical and subtropical areas worldwide. V181 is an investigational, live, attenuated, quadrivalent dengue vaccine. In this phase 1 double-blind, placebo-controlled study, the safety, tolerability, and immunogenicity of V181 in baseline flavivirus-naïve (BFN) and flavivirus-experienced (BFE) healthy adults were evaluated in two formulations: TV003 and TV005. TV005 contains a 10-fold higher DENV2 level than TV003. Two-hundred adults were randomized 2:2:1 to receive TV003, TV005, or placebo on Days 1 and 180. Immunogenicity against the 4 DENV serotypes was measured using a Virus Reduction Neutralization Test (VRNT 60 ) after each vaccination and out to 1 year after the second dose. There were no discontinuations due to adverse events (AE) or serious vaccine-related AEs in the study. Most common AEs after TV003 or TV005 were headache, rash, fatigue, and myalgia. Tri- or tetravalent vaccine-viremia was detected in 63.9% and 25.6% of BFN TV003 and TV005 participants, respectively, post-dose 1 (PD1). Tri- or tetravalent dengue VRNT 60 seropositivity was demonstrated in 92.6% of BFN TV003, 74.2% of BFN TV005, and 100% of BFE TV003 and TV005 participants PD1. Increases in VRNT 60 GMTs were observed after the first vaccination with TV003 and TV005 in both flavivirus subgroups for all dengue serotypes, and minimal increases were measured PD2. GMTs in the TV003 and TV005 BFE and BFN groups remained above the respective baselines and placebo through 1-year PD2. These data support further development of V181 as a single-dose vaccine for the prevention of dengue disease.

Dengue Virus: Molecular Biology and Recent Developments in Control Strategies, Prevention, Management, and Therapeutics

“…57 As compared to TV003, TV005 showed a greater tetravalent response in vaccinated participants. 62, 63 In a phase I trial, no difference in terms of adverse events (i.e., myalgias, fatigue, headaches, and rashes) was observed in the placebo, TV003, and TV005 groups with healthy adults (18–50 years) from Puerto Rico and the United States. Following the first dose, vaccine viremia was observed in 25.6% and 63.9% of baseline-flavivirus-naïve (BFN) TV005 and TV003 groups, respectively.…”

“…Moreover, seropositivity was found to be 74.2% and 92.6% after the first dose in BFN-given TV005 and TV003 groups, respectively, as well as 100% in both vaccine groups with flavivirus-experienced (BFE) healthy individuals. 62 Phase II trials (in Taiwan) and phase III trials (in Brazil) are currently ongoing, where immunogenicity against all strains, great safety profiles, and enhanced tolerability in the participants (50-70 years) have been reported so far. 63 Tetravalent Dengue Virus-Purified Inactivated Vaccine (TDENV-PIV)…”

Is new dengue vaccine efficacy data a relief or cause for concern?

“…Both the Sanofi and Takeda vaccines appear to have a dominant single vaccine virus which replicates after administration (Sanofi—DENV-4, Takeda—DENV-2) despite having all four DENV types included in the vaccine 71 – 73 . In contrast, MSD’s formulation of the NIH vaccine induced replication of three or more vaccine viruses in 64% of flavivirus non-immune recipients 74 . How this will translate into efficacy across the five years of follow up and DENV type-specific efficacy remains to be seen.…”

A dengue vaccine whirlwind update

“… 6 , 18 , 19 TV005 has shown a higher tetravalent response in vaccinated individuals compared to TV003. 18 , 20 Phase 1, three-arm, randomized, placebo-controlled, multicenter blinded trials have shown no difference in AEs (i.e rashes, headaches, fatigue, and myalgias) between TV003, TV005, and placebo groups with 18- to 50-year-old healthy adults from the United States and Puerto Rico. Vaccine viremia was detected in 63.9% and 25.6% of baseline-flavivirus-naïve (BFN) TV003 and TV005 group, respectively, after dose 1.…”

“…More importantly, seropositivity was 92.6% and 74.2% after dose 1 in BFN given TV003 and TV005, respectively, and 100% in both vaccine groups including flavivirus-experienced (BFE) healthy adults. 20 Currently, phase 2 and phase 3 trials are underway in Taiwan and Brazil, respectively, with very good safety profiles and immunogenicity against all strains and high tolerability in the 50- to 70-year-old populations. 18 …”