Safety and durable immunogenicity of the TV005 tetravalent dengue vaccine, across serotypes and age groups, in dengue-endemic Bangladesh: a randomised, controlled trial.

BACKGROUND: Morbidity and mortality from dengue virus (DENV) is rapidly growing in the large populations of south Asia. Few formal evaluations of candidate dengue vaccine candidates have been undertaken in India, Pakistan, or Bangladesh. Tetravalent vaccines must be tested for safety and immunogenicity in all age groups and in those previously exposed and naive to DENV infections. TV005 is a live, attenuated tetravalent dengue vaccine. We evaluated the safety and immunogenicity of a single dose of TV005 across age groups in dengue-endemic Bangladesh. METHODS: We performed a randomised, placebo-controlled age de-escalating clinical trial of TV005 at a single clinical site in dengue-endemic Dhaka, Bangladesh, following a technology transfer from the USA. Healthy (as determined by history, clinical examination, and safety laboratory test results) volunteers aged 1-50 years were randomly assigned 3:1 (stratified by four age groups) to receive a single dose of TV005 vaccine or placebo. Participants were followed up for 3 years. The study was double blind and was unmasked at day 180; outcome assessors, clinic staff, and volunteers remained blind throughout. Primary outcomes were safety, evaluated per-protocol as proportion of volunteers with solicited related adverse events of any severity through 28 days post dosing, and post-vaccination seropositivity by day 180 using serotype-specific neutralising antibodies (PRNT50 ≥10). Secondary outcomes included viremia, impact of past dengue exposure, and durability of antibody responses. This study is registered with Clinicaltrials.gov, NCT02678455, and is complete. FINDINGS: Between March 13, 2016, and Feb 14, 2017, 192 volunteers were enrolled into four age groups (adults [18-50 years; 20 male and 28 female], adolescents [11-17 years; 27 male and 21 female], children [5-10 years; 15 male and 33 female], and young children [1-4 years; 29 male and 19 female]) with 48 participant per group. All participants were Bangladeshi. Vaccination was well tolerated and most adverse events were mild. Rash was the most common vaccine-associated solicited adverse event, in 37 (26%) of 144 vaccine recipients versus six (12%) of 48 placebo recipients; followed by fever in seven (5% of 144) and arthralgias in seven (6% of 108), which were only observed in vaccine recipients. Post-vaccine, volunteers of all ages (n=142) were seropositive to most serotypes with 118 (83%) seropositive to DENV 1, 141 (99%) to DENV 2, 137 (96%) to DENV 3, and 124 (87%) to DENV 4, overall by day 180. Post-vaccination, viraemia was not consistently found and antibody titres were higher (10-15-fold for DENV 1-3 and 1·6-fold for DENV 4) in individuals with past dengue exposure compared with the dengue-naive participants (DENV 1 mean 480 [SD 4·0] vs 32 [2·4], DENV 2 1042 [3·2] vs 105 [3·1], DENV 3 1406 [2·8] vs 129 [4·7], and DENV 4 105 [3·3] vs 65 [3·1], respectively). Antibody titres to all serotypes remained stable in most adults (63-86%) after 3 years of follow-up. However, as expected for individuals without past exposure to dengue, titres for DENV 1, 3, and 4 waned by 3 years in the youngest (1-4 year old) cohort (69% seropositive for DENV 2 and 22-28% seropositive for DENV 1, 3, and 4). INTERPRETATION: With 3 years of follow-up, the single-dose tetravalent dengue vaccine, TV005, was well tolerated and immunogenic for all four serotypes in young children to adults, including individuals with no previous dengue exposure. FUNDING: National Institutes of Health-National Institute of Allergy and Infectious Diseases Intramural Research Program and Johns Hopkins University. TRANSLATION: For the Bangla translation of the abstract see Supplementary Materials section.