Departments of the Army and Defense and National Institute of Allergy and Infectious Diseases.

The safety and immunogenicity of four formulations of an investigational tetravalent dengue purified inactivated vaccine (DPIV), formulated at 1 or 4 μg with aluminum hydroxide (alum) or at 1 μg with an adjuvant system (AS01E or AS03B), were evaluated in a first-time-in-human, placebo-controlled, randomized, observer-blind, phase 1 trial in the continental United States. Two doses of vaccine or placebo were administered intramuscularly 4 weeks apart to 100 healthy adults 18–39 years of age, randomized 1:1:1:1:1 to receive one of four DPIV formulations or saline placebo. The response to a third dose was evaluated in a subset of nine participants remote from primary vaccination. Humoral immunogenicity was assessed using a 50% microneutralization assay. All DPIV formulations were well tolerated. No vaccine-related serious adverse events were observed through 12 months after the second vaccine dose. In all DPIV groups, geometric mean antibody titers peaked at Day 56, waned through 6 months after the second vaccine dose, and then stabilized. In the nine subjects where boosting was evaluated, a strong anamnestic response was observed. These results support continuation of the clinical development of this dengue vaccine candidate (clinicaltrials.gov: NCT01666652).

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, AS01E or AS03B, 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 AS01E- and AS03B-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 + AS03B group (ranging 3.2–3.7 depending on the DENV type). These results encourage continued clinical development of DPIV (ClinicalTrials.gov: NCT01702857).

Background Dengue human infection models (DHIM) have been used as a safe means to test the viability of prophylaxis and therapeutics. Methods A phase I study of 12 healthy adult volunteers using a challenge virus, DENV-1-LVHC, strain 45AZ5, was performed. A dose escalating design was used to determine the safety and performance profile of the challenge virus. Subjects were evaluated extensively until 28 days and then out to 6 months. Results 12 subjects received the challenge virus; 6 with 0.5 mL of 6.5 x 103 PFU/mL (low-dose group) and 6 with 0.5 mL of 6.5 x 104 PFU/mL (mid-dose group). All except one in the low-dose group developed detectable viremia. For all subjects the mean incubation period was 5.9 days (range 5 to 9 days) and mean time of viremia was 6.8 days (range 3 to 9 days). Mean peak for all subjects was 1.6 x 107 GE/mL (range 4.6 x 103 to 5 x 107 GE/mL). There were no serious adverse events or long-term safety signals noted. Conclusions We conclude that DENV-1-LVHC was well-tolerated, resulted in an uncomplicated dengue illness, and may be a suitable DHIM for therapeutic and prophylactic product testing.

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