Immunogenicity and safety of an investigational tetravalent recombinant subunit vaccine for dengue: results of a Phase I randomized clinical trial in flavivirus-naïve adults

Abstract

There is an unmet medical need for vaccines to prevent dengue. V180 is an investigational recombinant subunit vaccine that consists of truncated dengue envelope proteins (DEN-80E) for all 4 serotypes. Three dosage levels of the tetravalent DEN-80E antigens were assessed in a randomized, placebo-controlled, Phase I dose-escalation, first-in-human proof-of-principle trial in healthy, flavivirus-naïve adults in Australia (NCT01477580). The 9 V180 formulations that were assessed included either ISCOMATRIX™ adjuvant (2 dosage levels), aluminum-hydroxide adjuvant, or were unadjuvanted, and were compared to phosphate-buffered saline placebo. Volunteers received 3 injections of assigned product on a 0, 1, 2 month schedule, and were followed for safety through 1 year after the last injection. Antibody levels were assessed at 6 time-points: enrollment, 28 days after each injection, and 6 and 12 months Postdose 3 (PD3). Of the 98 randomized participants, 90 (92%) received all 3 injections; 83 (85%) completed 1-year follow-up. Immunogenicity was measured by a qualified Focus Reduction Neutralization Test with a 50% neutralization cutoff (FRNT50). All 6 V180 formulations with ISCOMATRIX™ adjuvant showed robust immunogenicity, while the 1 aluminum-adjuvanted and 2 unadjuvanted formulations were poorly immunogenic. Geometric mean antibody titers generally declined at 6 months and 1 year PD3. All 9 V180 formulations were generally well tolerated. Formulations with ISCOMATRIX™ adjuvant were associated with more adverse events than aluminum-adjuvanted or unadjuvanted formulations.

Keywords: dengue vaccine; immunogenicity; recombinant; safety; subunit.

Figures

Figure 1.

Participant disposition. Primary study period extended from receipt of the first injection through 28 days after the last injection.Completed primary study period means participant received all 3 injections and completed 28 days of safety and immunogenicity follow-up after each injection.Long-term follow-up period extended from the end of the primary study period through 1 year after the last injection. Participants who entered long-term follow-up included those who completed the primary study period, and those who did not receive all 3 injections during the primary study period and agreed to participate in long-term follow-up.Completed long-term follow-up means participant completed the long-term follow-up visits at 6 months and 1 year following the last injection.Completed trial means completed long-term follow-up.* Participant withdrew consent for participation for personal reasons after receiving 1 injection.† Investigator discontinued participant’s dosing after 1 injection due to adverse events of arthralgia (left knee and ankle) and injection-site swelling; participant completed long-term follow-up and the trial.‡4 participants withdrew consent for participation for personal reasons: 2 after receiving 1 injection, and 2 after receiving 2 injections.§ Participant received 3 injections but did not complete the primary study period prior to completing 28 days of primary safety follow-up due to relocating internationally. Participant completed long-term follow-up via telephone contacts, and thus completed the trial.¶ Participant received 2 injections; the third injection could not be administered due to receipt of medically-necessary vaccines outside of the protocol. The participant agreed to enter long-term follow-up, but was lost during this period.‖ Participant was lost to follow up after receiving 2 injections.

Figure 2.

Neutralizing antibody kinetics: GMTs through 1 Year postdose 3 (per-protocol population). DENV = Dengue Virus; GMT = Geometric Mean Titer; Panel A: Low-Dose V180 Cohort; Note: The arrows indicate when the study product (V180/placebo) was administered. Some data points for unadjuvanted V180 are

Figure 3A.

Proportions of participants with a tetravalent response, by study month (per-protocol population). Note: The arrows indicate when the study product (V180/placebo) was administered. The 0% data points for groups other than placebo are hidden by the placebo group. Tetravalent Response = FRNT50 titers ≥10 for all 4 DENV serotypes.Study Month 3 is 28 days Postdose 3.

Figure 3B.

Proportions of participants with a tetravalent response, by study month (per-protocol population). Note: The arrows indicate when the study product (V180/placebo) was administered. The 0% data points for groups other than placebo are hidden by the placebo group. Tetravalent Response = FRNT50 titers ≥10 for all 4 DENV serotypes.Study Month 3 is 28 days Postdose 3.

Figure 4.

Induction of B-cell memory to each of the four DENV serotypes in a subset of 18 high-dose cohort subjects who received 3 injections of study product (vaccine/placebo). Blood samples to assess B-cell memory were collected at 2 time points (at Study Month 0 immediately before the first injection, and at Study Month 3 [28 days Postdose 3]) in 18 high-dose cohort participants: 5 recipients of V180 with 30 ISCO™ units of ISCOMATRIX™ adjuvant, 5 recipients of V180 with 60 ISCO™ units of ISCOMATRIX™ adjuvant, 5 recipients of unadjuvanted V180, and 3 placebo recipients.Panel A: Change in Proportion of Dengue-specific memory B cells from Study Month 0 (prevaccination baseline) to Study Month 3 (28 days Postdose 3)Note: Each line represents the data for 1 participantPanel B: Dengue-specific memory B cell frequencies at Study Month 3 (28 days Postdose 3)Note: ASC = antibody secreting cells