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 value=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 Day 4 and 180. By Day 14 after the second dose, the IFN-y Enzyme-linked immunosorbent spot (ELISPOT) responses were similar for Group:0+28 and Group:0+7. Conclusion Overall, a standard dose of IMVAMUNE (0.5mL of 1×108 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-y ELISPOT responses were similar for Group:0+28 and Group:0+7.

Comparison of lyophilized versus liquid modified vaccinia Ankara (MVA) formulations and subcutaneous versus intradermal routes of administration in healthy vaccinia-naïve subjects

“…The immunogenicity and safety profiles of both formulations delivered SC were shown to be similar to each other and consistent with prior clinical trial data [8,35]. It is interesting that the proportion of subjects with moderate/severe functional local reactions after the first vaccination was significantly greater in the Lyophilized-SC group compared to the Liquid-SC group.…”

Innate and secondary humoral responses are improved by increasing the time between MVA vaccine immunizations

“…It may be tempting to shorten the vaccine schedule in face of a new emerging infectious disease or outbreak, and hence ensure faster protection of the population at risk, but an accelerated vaccination schedule appears to be detrimental for humoral immunity. Such a large impact of the time-interval between first and second immunizations on the intensity and quality of the specific Ab response is concordant with clinical studies showing that a delay between injections shorter than 3 weeks impaired the ability of individuals to develop protective immunity against smallpox after MVA immunizations 32,33 . As for recombinant MVA vaccine vectors, in a recent clinical trial evaluating an MVA-based influenza A H5N1 vaccine, a boosting immunization 1 year after the prime was shown to elicit higher neutralizing antibody titers compared to a boost at 1 month against influenza, although the level of sero-conversion was similar in both groups 34 .…”

Sex difference in immune response to vaccination: A participant-level meta-analysis of randomized trials of IMVAMUNE ® smallpox vaccine

“…Therefore, 3 studies were included in our analysis. Results of two studies were published (ClinicalTrials.gov NCT #00437021[20] and NCT #00879762[22]) and a manuscript for the third study (NCT #00914732) was in peer review at the time of this writing.…”

“…We focused our analysis on measurements taken after the second vaccination as this is the time period when IMVAMUNE is shown to elicit the strongest humoral immune response. [20] Antibody titers, measured by enzyme linked immunosorbent assay (ELISA) and plaque reduction neutralizing titer (PRNT), were extracted from each included study for several time points post-second vaccination (Table 1). The primary endpoint for our meta-analysis was the highest log 2 -transformed titer achieved for each individual, which we interpreted as an estimate of the peak titer.…”