Safety and immunogenicity of IMVAMUNE® smallpox vaccine using different strategies for a post event scenario

Abstract

Introduction: Reintroduction of Variola major as an agent of bioterrorism remains a concern. A shortened dosing schedule of Bavarian Nordic's (BN) IMVAMUNE(®) (modified vaccinia Ankara vaccine against smallpox) was compared to the currently recommended 0- and 28-day schedule for non-inferiority by evaluating the magnitude and kinetics of the immune responses.

Methods: Subjects were assigned to receive IMVAMUNE or placebo administered subcutaneously on Days 0 and 7, Days 0 and 28, or Day 0. Blood was collected for antibody and cell-mediated immune assays. Subjects were followed for safety for 12 months after last vaccination.

Results: The primary endpoint of this study was the geometric mean antibody titers (GMT) at 14 days post last vaccination. Of 208 subjects enrolled, 191 received vaccine (Group: 0+7, Group: 0+28 and Group: 0) and 17 received placebo. Moderate/severe systemic reactogenicity after any vaccination were reported by 31.1%, 25.4%, and 28.6% of the subjects for Group: 0+7, Group: 0+28, and Group: 0, respectively (Chi-square test, P=0.77). Based on BN's Plaque Reduction Assay GMTs, Group: 0+7 was non-inferior to Group: 0+28 at Day 4, 180, and 365 after the second vaccination. On Day 14, Group: 0+7 and Group: 0+28 GMT were 10.8 (CI: 9.0, 12.9) and 30.2 (CI: 22.1, 41.1), respectively. Based on BN's Enzyme-linked immunosorbent assay, the proportion of subjects with positive titers for Group: 0+28 was significantly greater than that for Group: 0+7 after second vaccination at Days 4 and 180. By Day 14 after the second dose, the IFN-γ enzyme-linked immunosorbent spot (ELISPOT) responses were similar for Group: 0+28 and Group: 0+7.

Conclusion: Overall, a standard dose of IMVAMUNE (0.5 mL of 1 x 10(8) TCID/mL) administered subcutaneously was safe and well tolerated. A second dose of IMVAMUNE at Day 28 compared to Day 7 provided greater antibody responses and the maximal number of responders. By Day 14 after the second dose, IFN-γ ELISPOT responses were similar for Group: 0+28 and Group: 0+7.

Trial registration: ClinicalTrials.gov NCT00437021.

Figure 1

Percent of Subjects Reporting by Vaccination and Group: The percentage of subjects with local and systemic reactogenicity is shown by vaccination group and vaccination number. The highest grade for each event is reported. Subjects were vaccinated on Days 0 and 28. Placebo recipient data is not shown. Solicited and unsolicited events were graded according to the following scale: Grade 0= Not present: Grade 1= Mild (present, but easily tolerated); Grade 2= Moderate (able to tolerate routine activity with effort); Grade 3= Severe (unable to continue routine activity) and Grade 4 = Life-threatening. Erythema or induration at the vaccination site was measured in millimeters: Grade 1= Mild (≤15mm); Grade 2= Moderate (>15-≤30mm) and Grade 3= Severe (>30mm).

Figure 2

a-d. PRNT Assays: 2.a-b. Plaque Reduction Neutralizing Antibody Geometric Mean Titers (GMT) conducted at Bavarian Nordic using Bavarian Nordic’s MVA as the assay antigen, positive titer ≥15. Time points represent the number of days after the first vaccination for all three groups (2.a.) and after last vaccination for all three groups, i.e. after the single vaccination in Group:0, and after the second vaccination for the other two groups (Group:0+7 and Group:0+28) (2.b.). Placebo recipient data is not shown. 2.c-d. Plaque Reduction Neutralizing Antibody Geometric Mean Titers (GMT) conducted at Saint Louis University using ATCC MVA (VR-1508) as the assay antigen, positive titer ≥20. Time points represent the number of days after the first vaccination for all three groups (2.c.) and after last vaccination for all three groups, i.e. after the single vaccination in Group:0, and after the second vaccination for the other two groups (Group:0+7 and Group:0+28) (2.d.). Placebo recipient data is not shown.

Figure 3

a-d. ELISA: 3.a-b. ELISA conducted at Bavarian Nordic using BN MVA as the assay antigen, positive titer ≥50. Time points represent the number of days after the first vaccination for all three groups (3.a.) and after last vaccination for all three groups, i.e. after the single vaccination in Group:0, and after the second vaccination for the other two groups (Group:0+7 and Group:0+28) (3.b.) vaccinations. Placebo recipient data is not shown. 3.c-d. ELISA Antibody conducted at Saint Louis University using ATCC MVA (VR-1508) as the assay antigen, positive titer > 50. Time points represent the number of days after the first vaccination for all three groups (3.c.) and after last vaccination for all three groups, i.e. after the single vaccination in Group:0, and after the second vaccination for the other two groups (Group:0+7 and Group:0+28) (3.d.). Placebo recipient data is not shown.

Figure 4

a-b. ElISPOT Results: Mean spot forming units with confidence intervals. Time points represent the number of days after the first vaccination for all three groups (4.a.) and after last vaccination for all three groups, i.e. after the single vaccination in Group:0, and after the second vaccination for the other two groups (Group:0+7 and Group:0+28) (4.b.). Vaccinia-Western Reserve was used as the assay antigen. Placebo recipient data is not shown.