Safety and immunogenicity of a purified inactivated Zika virus vaccine candidate in healthy adults: an observer-blind, randomised, phase 1 trial.

BACKGROUND

Zika virus, a flavivirus transmitted by Aedes aegypti and Aedes albopictus mosquitoes, is associated with cases of congenital malformations and neurological complications. Absence of specific treatment makes a prophylactic Zika virus vaccine an unmet medical need. We assessed safety and immunogenicity of three doses of a purified, inactivated, Zika virus vaccine candidate in healthy flavivirus-naive and flavivirus-primed adults.

METHODS

This two-part, multicentre, observer-blind, randomised, placebo-controlled, phase 1 trial was done at seven medical clinics in the USA and two in Puerto Rico. Eligible participants were healthy adults aged 18-49 years. Participants were randomly assigned (1:1:1:1), using a sponsor-supplied randomisation scheme, to four groups to receive two intramuscular injections, 28 days apart, of saline placebo or TAK-426 containing 2 μg, 5 μg, or 10 μg antigen. Participants, investigators, and vaccine administrating personnel were masked to group assignment. Part 1 of the study assessed flavivirus-naive participants and part 2 assessed flavivirus-primed participants. The primary outcomes were safety, tolerability, and immunogenicity based on solicited local reactions and solicited systemic adverse events in the 7 days after each dose; unsolicited adverse events and serious adverse events in the 28 days after each dose; and geometric mean titres (GMTs) of neutralising anti-Zika virus antibodies at 28 days after the second dose. Safety assessments were done in all participants who received at least one dose of vaccine. Immunogenicity assessments were in the per-protocol set, comprising all participants who received at least one dose of vaccine and provided valid serology results at baseline and at least one post-vaccination timepoint, with no major protocol violations. The trial is ongoing and is registered at ClinicalTrials.gov (NCT03343626).

FINDINGS

Between Nov 13, 2017, and Oct 24, 2018, 894 volunteers were screened and 271 enrolled (125 flavivirus-naive and 146 flavivirus-primed participants). All TAK-426 doses were well tolerated with no deaths, no vaccine-related serious adverse events, and similar rates of mainly mild to moderate adverse events. TAK-426 elicited dose-dependent increases in antibody GMTs in both flavivirus-naive and flavivirus-primed participants. 28 days after dose 2, plaque-reduction neutralisation test GMTs in flavivirus-naive participants were 1130 (95% CI 749-1703) in the 2 μg TAK-426 group, 1992 (1401-2833) in the 5 μg TAK-426 group, and 3690 (2677-5086) in the 10 μg TAK-426 group. In pairwise comparisons, responses after two vaccinations in the 10 μg group were significantly greater than in the 2 μg group (GMT ratio 3·27 [95% CI 1·98-5·39], p<0·0001) and the 5 μg group (GMT ratio 1·85 [1·15-2·98], p=0·012).

INTERPRETATION

TAK-426 was well tolerated, with an acceptable safety profile, and was immunogenic in both flavivirus-naive and flavivirus-primed adults. Based on the safety and immunogenicity profiles of all TAK-426 doses assessed, the 10 μg TAK-426 dose was selected for further clinical development.

FUNDING

Takeda Vaccines and the US Biomedical Advanced Research and Development Authority.

TRANSLATION

For the Spanish translation of the abstract see Supplementary Materials section.