Immunogenicity and safety of lyophilized and liquid dengue tetravalent vaccine candidate formulations in healthy adults: a randomized, phase 2 clinical trial

Abstract

Takeda has developed a live-attenuated dengue tetravalent vaccine candidate (TAK-003) which has been shown to be immunogenic with acceptable reactogenicity in phase 1 trials. In agreement with World Health Organization prequalification requirements for dengue vaccines, Takeda has manufactured a lyophilized formulation of TAK-003 that allows stable storage at +2°C to +8°C. This randomized, double-blind, phase 2 study (NCT02193087) was performed in 1002 healthy dengue-naïve adults, 18-49 years of age, across seven centers in the USA to compare the safety and immunogenicity of one or two doses of a lyophilized TAK-003 formulation with the liquid TAK-003 formulation used in previous phase 1 studies. The primary objective was to show immunologic equivalence in terms of geometric mean titers (GMT) of neutralizing antibodies to the four dengue serotypes one month after one dose of the lyophilized and liquid formulations. Secondary assessments were of safety and seropositivity rates, including after a second dose. The primary endpoint was not met, because immunologic equivalence after one dose was only shown for the DENV-2 serotype. Nonetheless, GMTs and seropositivity rates to all four serotypes were achieved with all formulations after two doses and are in line with what was observed in previous studies. Additionally, in view of the acceptable reactogenicity, with no vaccine-related serious adverse events reported, these data support continuing further clinical development of the lyophilized TAK-003 formulation.

Immunogenicity and safety of a tetravalent dengue vaccine in dengue-naïve adolescents in Mexico City

“…The safety findings in this study were consistent with reports from previous studies and the vaccine was well tolerated. The majority of solicited and unsolicited AEs were mild to moderate, with injection site pain and headache being the most frequently reported local and systemic AEs, respectively, as observed previously ( 22 , 23 , 28 , 29 ). Rash was infrequent and was reported by only a few participants.…”

“…This was the first study of TAK-003 specifically designed to assess responses to TAK-003 in seronegative adolescents in a non-endemic setting. As previous studies of TAK-003 immunogenicity and safety have focused predominantly on endemic areas ( 24 , 25 , 28 , 32 , 33 ), or in dengue-naïve adults in non-endemic areas ( 21 - 23 , 29 ), this study contributes important data on the vaccine effects in dengue-naïve adolescents for whom there is no currently recommended vaccine. Consistent with all previous studies of TAK-003, highest GMTs were observed against DENV-2 ( 24 - 26 , 28 , 32 , 33 ), which also corresponded with the highest efficacy against this serotype observed in the ongoing phase 3 efficacy study ( 27 ).…”

“…Previous clinical trials of TAK-003 have been conducted in both endemic and non-endemic areas. Across the clinical development program, studies in endemic areas have mostly enrolled children and adolescents, whereas studies in non-endemic areas have so far only been conducted in adults ( 21 - 29 ). Adolescents enrolled in the studies in endemic areas have been predominantly pre-exposed to dengue.…”

Dengue vaccine development by the year 2020: challenges and prospects

“…TAD-003 induces cross-reactive T cell-mediated responses that may be necessary for broad protection against dengue fever [ 31 , 32 ]. In agreement with WHO’s prequalification requirements for dengue vaccines, Takeda has manufactured a lyophilized formulation of TAK-003 that allows stable storage at +2 degrees C to +8 degrees C. In a randomized, double-blind, phase 2 study ( NCT02193087 ) in 1002 healthy dengue-naive adults, 18–49 years of age, GMTs and seropositivity rates to all four serotypes were achieved [ 33 ]. A Multi-Color FluoroSpot (MCF) assay enabled quantitation of serotype-specific and cross-reactive individual memory B cells (MBCs) secreting DENV-specific antibodies in a polyclonal mixture [ 34 ].…”

“…A Multi-Color FluoroSpot (MCF) assay enabled quantitation of serotype-specific and cross-reactive individual memory B cells (MBCs) secreting DENV-specific antibodies in a polyclonal mixture [ 34 ]. Using the MCF assay, type-specific and cross-reactive MBC responses were investigated; the results demonstrate that, unlike primary or secondary natural DENV infection, tetravalent vaccination elicits tetravalent type-specific MBCs, and thus all four components of TAK-003 contribute to the DENV-specific MBC response following vaccination [ 33 ].…”