Safety and Immunogenicity of an AS03B-Adjuvanted Inactivated Tetravalent Dengue Virus Vaccine Administered on Varying Schedules to Healthy U.S. Adults: A Phase 1/2 Randomized Study

Abstract

Dengue disease and its causative agents, the dengue viruses (DENV-1-4), cause high morbidity in tropical and subtropical regions. We evaluated three dosing regimens of the investigational tetravalent AS03 B-adjuvanted dengue-purified inactivated vaccine (DPIV+AS03 B). In this phase 1/2, observer-blind, placebo-controlled study (NCT02421367), 140 healthy adults were randomized 1:1:2 to receive DPIV+AS03 B according to the following regimens: 0-1 month (M), 0-1-6 M, or 0-3 M. Participants received DPIV+AS03 B or placebo at M0, M1, M3, and M6 according to their dosing schedule. Primary objectives were 1) to evaluate the safety of DPIV+AS03 B for 28 days (D) after each dose; 2) to demonstrate the added value of a booster dose (0-1-6 M versus 0-1 M) based on neutralizing antibody titers to each DENV type (DENV-1-4) at 28 D after the last dose; and, if this objective was met, 3) to demonstrate the benefit of a longer interval between the first and second doses (0-1 M versus 0-3 M). Adverse events (AEs) within 7 D after vaccination tended to be more frequent after DPIV+AS03 B doses than placebo; the number of grade 3 AEs was low (£ 4.5% after DPIV+AS03 B ; £ 2.9% after placebo), with no obvious differences across groups. Within 28 D following each dose, the frequency of unsolicited AEs after DPIV+AS03 B appeared higher for three-dose (0-1-6 M) than two-dose (0-1 M and 0-3 M) regimens. No serious AEs were considered related to vaccination, and no potential immune-mediated diseases were reported during the study. All three schedules were well tolerated. Both primary immunogenicity objectives were demonstrated. The 0-3 M and 0-1-6 M regimens were more immunogenic than the 0-1 M regimen.

Characterization of B-cell and T-cell responses to a tetravalent dengue purified inactivated vaccine in healthy adults

“…Similarly, in a previous study, administration of the AS01 B -adjuvanted formulation according to a 0-, 1-, and 6-month schedule induced higher peak neutralizing antibody response than 2-dose schedules at 1-month post-last vaccination. However, after 12 months, similar memory B cells frequencies and neutralizing antibody levels were observed for the 0-, 1-, and 6-month and the 0-, and 3-month schedules 15 . A limitation of the memory B-cell ELISPOT assay employed here is that it does not distinguish DENV serotype-specific versus DENV serotype-cross-reactive memory B cells.…”

“…However, the promise of DPIV was that it would induce an immune response in dengue-naive individuals that is tetravalent, balanced, and durable-three important features that are critical requirements for a dengue vaccine 26 . While published studies have confirmed that the neutralizing antibody response generated by DPIV is tetravalent and balanced 12,15 , a concern raised by these same studies is that the neutralizing antibody response demonstrated rapid waning and poor durability in dengue-naive adults. The data presented here show that durable B and T-cell immunity is established following DPIV vaccination in dengue-naive adults 12 and can be boosted in previously vaccinated and dengue seropositive adults.…”

“…Studies with DPIV have demonstrated a very good safety and tolerability profile 12 , 13 , 15 . Immunogenicity assessments in terms of neutralizing antibody have shown that DPIV induces robust and balanced tetravalent peak titers.…”

Controlled Human Infection Models To Accelerate Vaccine Development

“…Three clinical studies comparing various dose levels, adjuvants, and schedules have been completed. These included Phase 1 (172) and Phase 1/2 (173) studies in denguenaïve adults, and a Phase 1 study in Puerto Rican adults (174,175), most of whom were previously exposed to dengue. In the dengue-naïve populations, two doses of DPIV adjuvanted with GSK's proprietary AS03B adjuvant given intramuscularly one month apart induced a tetravalent neutralizing antibody response in 100 percent of subjects at one month after the second dose.…”

Vaccine-Associated Enhanced Viral Disease: Implications for Viral Vaccine Development

“…On challenge with live DENV, low levels of viremias or RNAemias were detected. Because viremia levels were considered to be lower than levels in diseased humans while antibody responses were fairly robust, vaccines were advanced to phase I in susceptibles and partial dengue-immunes [ 55 – 57 ]. The Walter Reed Army Institute of Research (WRAIR), GSK and the Oswaldo Cruz Foundation produced and tested a candidate tetravalent PIV formulated with aluminum hydroxide (AlOH) or a GSK proprietary Adjuvant System.…”