A randomized phase 3 trial of the immunogenicity and safety of coadministration of a live-attenuated tetravalent dengue vaccine (TAK-003) and an inactivated hepatitis a (HAV) virus vaccine in a dengue non-endemic country

Background: Vaccination against hepatitis A virus (HAV) is largely recommended for travelers worldwide. Concurrent dengue and HAV vaccination may be desired in parallel for travelers to countries where both diseases are endemic. This randomized, observer-blind, phase 3 trial evaluated coadministration of HAV vaccine with tetravalent dengue vaccine (TAK-003) in healthy adults aged 18-60 years living in the UK.Methods: participants were randomized (1:1:1) to receive HAV vaccine and placebo on Day 1, and placebo on Day 90 (Group 1), TAN-003 and placebo on Day 1, and TAK-003 on Day 90 (Group 2), or TAK-003 and HAV vaccine on Day 1, and TAK-003 on Day 90 (Group 3). The primary objective was non-inferiority of HAV sero- protection rate (anti-HAY> 12.5 mIU/mL) in Group 3 versus Group 1. one month post-urst vaccination (Day 30) in HAV-naive and dengue-naive participants. Sensitivity analyses were performed on combinations of baseline HAV and dengue serostatus. Secondary objectives included dengue seropositivity one month post- second vaccination (Day 120), HAV geometric mean concentrations (GMCs), and safety.
Results: 900 participants were randomized. On Day 30, HAV seroprotection rates were non-inferior follow- ing coadministration of HAV and TAK-003 (Group 3: 98.7%) to HAV administration alone (Group 1:97.1%%% difference: -1.68, 95 % CI: -8.91 to 4.28). Sensitivity analyses including participants who were neither HAV-naive nor DENV-rive at baseline supported this finding. Anti-HAV GMCs on Day 30 were 82.1 (95% CI: 62.9-107.1) mIU/mL in Group 1 and 93.0 (76.1-113.6) mIU/mL in Group 3. By Day 120, 90.9- 96.8 % of TAK-003 recipients were seropositive (neutralizing antibody titer > 10) to all four dengue sero- types. Coadministration of HAV vaccine and TAK-003 was well tolerated, with no important safety risks
identified. Conclusion: Immune responses following coadministration of HAV vaccine and TAK-003 were non-inferior to administration of HAV vaccine alone. The results support the coadministration of HAV vaccine and TAK- 003 with no adverse impact on immunogenicity, safety, and reactogenicity of either vaccine.