Phase I Randomized Study of a Tetravalent Dengue Purified Inactivated Vaccine in Healthy Adults from Puerto Rico

Abstract

The safety and immunogenicity of four adjuvanted formulations of an investigational tetravalent dengue purified inactivated vaccine (DPIV) were evaluated in a predominantly dengue-primed population in Puerto Rico. In this placebo-controlled, randomized, observer-blind, phase I trial, 100 healthy adults were randomized 1:1:1:1:1 to receive DPIV at Day (D)0 and D28 (1 μg per dengue virus [DENV] type 1-4 adjuvanted with either alum, AS01_E or AS03_B, or 4 μg per DENV type adjuvanted with alum) or saline placebo. Functional antibody responses were assessed using a microneutralization assay at D56, Month (M)7, and M13. All DPIV formulations were well tolerated and no safety signals were identified through M13. The M13 according-to-protocol (ATP) immunogenicity cohort included 83 participants. The ATP analysis of immunogenicity was performed only on the 78 subjects seropositive for ≥ 1 DENV type at baseline: 69 tetravalent, three trivalent, two bivalent, and four monovalent. In all DPIV groups, geometric mean antibody titers (GMTs) increased from D0 to D56 and waned modestly through M13, while remaining well above prevaccination levels. The 4 μg + alum and the AS01_E- and AS03_B-adjuvanted formulations were highly immunogenic, with M13-neutralizing antibody GMTs against all four DENV types above 1,000. M13/D0 GMT ratios were highest in the 1 μg + AS03_B group (ranging 3.2-3.7 depending on the DENV type). These results encourage continued clinical development of DPIV (ClinicalTrials.gov: NCT01702857).

Figure 1.

Disposition of study participants and reasons for exclusion from ATP cohort for immunogenicity. ATP = according-to-protocol; M13 = 12 months after dose 2; N = number of subjects in each group/cohort; * Withdrawals.

Figure 2.

Overall per dose incidence of any grade solicited local (A) and general (B) adverse events during the 7-day postvaccination period (total vaccinated cohort). Error bars indicate exact 95% confidence intervals; GI = gastro-intestinal; Temperature = oral temperature ≥ 37.5°C (99.5°F).

Figure 3.

Geometric mean titers to DENV types 1–4 up to 1 year postdose 2 (according-to-protocol cohort for immunogenicity M13). Participants with a titer below the assay cutoff were attributed the arbitrary value of half the cutoff; D56 = Day 56 (1 month postdose 2); DENV = dengue virus type; M7 = month 7 (6 months postdose 2); M13 = month 13 (12 months postdose 2); PRE = prevaccination. This figure appears in color at www.ajtmh.org.

Figure 4.

Focus on patient section.