Consistency of immunogenicity in three consecutive lots of a tetravalent dengue vaccine candidate (TAK-003): A randomized placebo-controlled trial in US adults.

BACKGROUND: We conducted a trial to demonstrate immunogenic equivalence of three consecutive manufacturing lots of Takeda's tetravalent dengue vaccine candidate, TAK-003, and further assessed its safety and reactogenicity. METHODS: Healthy US adults (n = 923) randomized 2:2:2:1 to four groups received two doses of one of three TAK-003 lots or placebo on Days 0 and 90, with follow-up to Day 270. Primary endpoint evaluated lot-to-lot equivalence of geometric mean neutralizing titers at Day 120 against each of 4 dengue serotypes in baseline seronegative participants. Solicited local and systemic, and unsolicited adverse events (AEs) were assessed for 7, 14 and 28 days after each dose, respectively. Serious AEs (SAE) were monitored throughout the study. RESULTS: Eight of 12 prespecified equivalence comparisons were met in the per-protocol set but failed marginally in the other 4 mainly due to loss of statistical power following higher than anticipated baseline seropositivity and drop-out rates. All three TAK-003 lots elicited high rates of tetravalent dengue seropositivity (96.7 %, 93.0 % and 97.5 % at Day 120; 91.0 %, 80.5 % and 85.7 % at Day 270) and had similar reactogenicity profiles with no vaccine-related SAEs. CONCLUSIONS: The three lots of TAK-003 were immunogenic for all four dengue serotypes and well tolerated in healthy adults. Despite not meeting all equivalence comparisons, no major differences were observed between lots and the data support acceptable consistency of the manufacturing process. Trial registrationClinicalTrials.gov identifier: NCT03423173.

Bridging the immunogenicity of a tetravalent dengue vaccine (TAK-003) from children and adolescents to adults.

Immunobridging is an important methodology that can be used to extrapolate vaccine efficacy estimates to populations not evaluated in clinical studies, and that has been successfully used in developing many vaccines. Dengue, caused by a mosquito-transmitted flavivirus endemic to many tropical and subtropical regions, is traditionally thought of as a pediatric disease but is now a global threat to both children and adults. We bridged immunogenicity data from a phase 3 efficacy study of a tetravalent dengue vaccine (TAK-003), performed in children and adolescents living in endemic areas, with an immunogenicity study in adults in non-endemic areas. Neutralizing antibody responses were comparable in both studies following receipt of a two-dose TAK-003 schedule (months 0 and 3). Similar immune responses were observed across exploratory assessments of additional humoral responses. These data support the potential for clinical efficacy of TAK-003 in adults.