Safety, immunogenicity, and surrogate markers of clinical efficacy for modified vaccinia Ankara as a smallpox vaccine in HIV-infected subjects

Abstract

Background: Human immunodeficiency virus (HIV)-infected persons are at higher risk for serious complications associated with traditional smallpox vaccines. Alternative smallpox vaccines with an improved safety profile would address this unmet medical need.

Methods: The safety and immunogenicity of modified vaccinia Ankara (MVA) was assessed in 91 HIV-infected adult subjects (CD4(+) T-cell counts, ≥350 cells/mm(3)) and 60 uninfected volunteers. The primary objectives were to evaluate the safety of MVA and immunogenicity in HIV-infected and uninfected subjects. As a measure of the potential efficacy of MVA, the ability to boost the memory response in people previously vaccinated against smallpox was evaluated by the inclusion of vaccinia-experienced HIV-infected and HIV-uninfected subjects.

Results: MVA was well tolerated and immunogenic in all subjects. Antibody responses were comparable between uninfected and HIV-infected populations, with only 1 significantly lower total antibody titer at 2 weeks after the second vaccination, while no significant differences were observed for neutralizing antibodies. MVA rapidly boosted the antibody responses in vaccinia-experienced subjects, supporting the efficacy of MVA against variola.

Conclusions: MVA is a promising candidate as a safer smallpox vaccine, even for immunocompromised individuals, a group for whom current smallpox vaccines have an unacceptable safety profile.

Trial registration: ClinicalTrials.gov NCT00189904.

Figures

Figure 1.

Disposition of subjects and data sets analyzed. Of 208 screened volunteers, 151 subjects were assessed eligible for enrollment, allocated to 1 of 4 study groups, and received at least 1 vaccination (full analysis set [FAS]). Sixteen subjects were excluded from the per-protocol analysis set (PPS; n = 135). The active phase of the study is up to the visit for the last vaccination, and the follow-up (FU) phase is at least 26 weeks after last vaccination. Abbreviations: exp, experienced; HIV, human immunodeficiency virus. aTwo of these subjects completed the follow-up phase.

Figure 2.

Kinetics of humoral immune responses following vaccination(s) with modified vaccinia Ankara. Total and neutralizing antibody responses were analyzed by an enzyme-linked immunosorbent assay (ELISA; A and B) and plaque reduction neutralization test (PRNT; C and D) following vaccination(s). All vaccinia-naive subjects received 2 vaccinations, at weeks 0 and 4, while all vaccinia-experienced subjects only received a single vaccination, at week 0. The graphs illustrate the seroconversion rates (A: ELISA; C: PRNT) and the geometric mean titers (GMTs), calculated by the antilogarithm of the mean log10 titer, together with the 95% confidence interval (CI; B: ELISA; D: PRNT). Seroconversion was defined as a postvaccination titer greater than or equal to the assay cutoff (50 in ELISA, 10 in PRNT) or, for previously seropositive subjects, a ≥2-fold increase in titer as compared to the prevaccination value.