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 AS03B-adjuvanted dengue-purified inactivated vaccine (DPIV+AS03B). In this phase 1/2, observer-blind, placebo-controlled study (NCT02421367), 140 healthy adults were randomized 1:1:2 to receive DPIV+AS03B according to the following regimens: 0-1 month (M), 0-1-6 M, or 0-3 M. Participants received DPIV+AS03B or placebo at M0, M1, M3, and M6 according to their dosing schedule. Primary objectives were 1) to evaluate the safety of DPIV+AS03B 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+AS03B doses than placebo; the number of grade 3 AEs was low (≤ 4.5% after DPIV+AS03B; ≤ 2.9% after placebo), with no obvious differences across groups. Within 28 D following each dose, the frequency of unsolicited AEs after DPIV+AS03B 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.

Conflict of interest statement

Disclosures: P. M. and R. M. P. are currently employees of the GSK group of companies. E. L., D. W. V., and A. C. S. were employees of the GSK group of companies during the conduct of the study. P. M., R. M. P., and A. C. S. hold shares in the GSK group of companies. L. L., M. K., R. G. J., K. H. E., J. R. C., H. F., P. K., R. D. L. B., and S. J. T. received financial and other support without any personal financial benefit from the GSK group of companies as part of the CRADA between the U.S. Army and the GSK group of companies. M. A. M. received consulting fees from Takeda outside of the submitted work. K. E. reports having a licensed patent for which he received royalties. K. L. declares no financial and non-financial relationships and activities and no conflicts of interest. All authors had full access to the data and gave final approval before submission. GlaxoSmithKline Biologicals SA was involved in all stages of the study conduct and analysis, and also took charge of all costs associated with the development and publishing of this manuscript. Dengvaxia is a trademark of Sanofi Pasteur.

Disclaimer: The opinions or assertions contained herein are the private views of the authors and are not to be construed as reflecting the official views of the U.S. Army or the U.S. Department of Defense.

Figures

Figure 1.

Study design. AEs = adverse events; D = day(s); DPIV+AS03B = adjuvant system 03B-adjuvanted inactivated tetravalent dengue virus vaccine; M = month; MAEs = medically attended AEs; N = number of participants in each group included in the total vaccinated cohort; pIMDs = potential immune-mediated diseases; SAEs = serious AEs; 0–1 M = participants receiving two doses of DPIV+AS03B administered 1 M apart, at M0 and M1; 0–3 M = participants receiving two doses of DPIV+AS03B administered 3 M apart, at M3 and M6; 0–1–6 M = participants receiving three doses of DPIV+AS03B with the first two given 1 M apart and the third given 6 M after the first, at M0, M1, and M6. Only immunogenicity blood samples for analyses described here are shown in this figure.

Figure 2.

Flow diagram of study participants. AE = adverse event; ATP = according-to-protocol; DPIV+AS03B = adjuvant system 03B-adjuvanted inactivated tetravalent dengue virus vaccine; M = month; N = number of participants in each group; 0–1 M = participants receiving two doses of DPIV+AS03B administered 1 M apart, at M0 and M1; 0–3 M = participants receiving two doses of DPIV+AS03B administered 3 M apart, at M3 and M6; 0–1–6 M = participants receiving three doses of DPIV+AS03B with the first two given 1 M apart and the third given 6 M after the first, at M0, M1, and M6. *Non-compliance by participant and outside of window for visit (participation discontinued).

Figure 3.

Overall per dose incidence of solicited injection-site (A) and general (B) adverse events during the 7-D post-vaccination period (TVC). DPIV+AS03B = adjuvant system 03B-adjuvanted inactivated tetravalent dengue virus vaccine; GI symtoms = gastrointestinal symptoms (nausea, vomiting, diarrhea, and/or abdominal pain); M = month; TVC = total vaccinated cohort; 0–1 M = participants receiving two doses of DPIV+AS03B administered 1 M apart, at M0 and M1; 0–3 M = participants receiving two doses of DPIV+AS03B administered 3 M apart, at M3 and M6; 0–1–6 M = participants receiving three doses of DPIV+AS03B with the first two given 1 M apart and the third given 6 M after the first, at M0, M1, and M6. Error bars indicate 95% CIs.

Figure 4.

Kinetics of neutralizing antibody responses against DENV-1–4 (ATP cohort for immunogenicity). ATP = according-to-protocol; DENV = dengue virus; GMT = geometric mean titer; N = number of participants in each group; M = month; 0–1 M = participants receiving two doses of adjuvant system 03B-adjuvanted inactivated tetravalent dengue virus vaccine (DPIV+AS03B) administered one M apart, at M0 and M1; 0–3 M = participants receiving two doses of DPIV+AS03B administered 3 M apart, at M3 and M6; 0–1–6 M = participants receiving three doses of DPIV+AS03B with the first two given 1 M apart and the third given 6 M after the first, at M0, M1, and M6. Error bars depict 95% CIs.

Figure 5.

Seroconversion rates to DENV types at peak response and at study end (ATP cohort for immunogenicity). ATP = according-to-protocol; DENV = dengue virus; N = number of participants in each group; 0–1M = participants receiving two doses of adjuvant system 03B-adjuvanted inactivated tetravalent dengue virus vaccine (DPIV+AS03B) administered 1 M apart, at M0 and M1; 0–3 M = participants receiving two doses of DPIV+AS03B administered 3 M apart, at M3 and M6; 0–1–6 M = participants receiving three doses of DPIV+AS03B with the first two given 1 M apart and the third given 6 M after the first, at M0, M1, and M6. *Peak, 1 M after dose two for groups 0–1 M and 0–3 M and 1 M after dose 3 for group 0–1–6 M.

Figure 6.

Kinetics for the median (Q1/Q3) frequency (%) of DENV-type–specific memory B cells (by ELISpot) up to study end (ATP cohort for immunogenicity). ATP = according-to-protocol; DENV = dengue virus; ELISpot = enzyme-linked immunospot assay; N = number of participants in each group; M = month; Q1/Q3 = first and third quantiles; 0–1 M = participants receiving two doses of adjuvant system 03B-adjuvanted inactivated tetravalent dengue virus vaccine (DPIV+AS03B) administered 1 M apart, at M0 and M1; 0–3 M = participants receiving two doses of DPIV+AS03B administered 3 M apart, at M3 and M6; 0–1–6 M = participants receiving three doses of DPIV+AS03B with the first two given 1 M apart and the third given 6 M after the first, at M0, M1, and M6. Error bars depict interquartile ranges.