Safety, Immunogenicity, and Surrogate Markers of Clinical Efficacy for Modified Vaccinia Ankara as a Smallpox Vaccine in HIV-Infected Subjects
ABSTRACT Background. 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 MVA was assessed in 91 HIV-infected adult subjects (CD4 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 uninfected subjects.Results. MVA was well tolerated and immunogenic in all subjects. Antibody responses were comparable between uninfected and HIV infected populations with only one significantly lower total antibody titer at 2 weeks post 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.Clinical Trial Registration. NCT00189904.
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ABSTRACT: Reintroduction of Variola major as an agent of bioterrorism remains a concern. Time to seroconversion and plaque reduction neutralizing antibody titers (PRNT) of 1 or 2 standard doses (SD) were compared to a single high dose (HD) of modified vaccinia Ankara (MVA). Ninety subjects were randomized 1:1 to receive 1 HD or 2 SD of MVA subcutaneously on Days 0 and 28 in a placebo-controlled trial. Serum was collected for PRNT and ELISA. Subjects were followed for safety for the entire study. The HD was well-tolerated. Using Bavarian Nordic's ELISA, subjects in both groups achieved seroconversion by Study Day 15 (HD) and Day 28 (SD). Before second vaccination, the hazard rate of seroconverting for the HD group was 1.7 times the SD group with a median time for seroconversion of 14 days for both groups. The peak titer of one HD vaccine was superior to one dose of SD vaccine but inferior to the peak titer after the second dose of the SD vaccination regimen. Using Saint Louis University's PRNT, peak titers were 95.8 and 65.2 for the HD and SD groups, respectively, prior to second vaccination. Non-inferiority of the SD group was not established. The proportions of positives were 93.3% (42/45) and 82.2% (37/45) for the HD and SD groups, respectively. The peak titer after two standard doses was superior to that of the HD. HD MVA was safe and well-tolerated. While the hazard rate for seroconverting was significantly higher in the HD group before second dose, the effect was small as the median time to seroconversion was identical. When comparing PRNT, non-inferiority of one SD was not established and the peak titers were low for both groups. The HD peak response was inferior to the standard two-dose regimen response based on ELISA and PRNT.Vaccine 03/2014; 32(23). DOI:10.1016/j.vaccine.2014.02.043 · 3.49 Impact Factor
PLoS Pathogens 05/2014; 10(5):e1004108. DOI:10.1371/journal.ppat.1004108 · 8.06 Impact Factor
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ABSTRACT: Background: Following vaccination with traditional smallpox vaccines or after exposure to vaccinated individuals, subjects with atopic dermatitis (AD) can develop eczema vaccinatum, a severe disease with disseminated eruption of pustular contagious lesions. Alternative smallpox vaccines with an improved safety profile would address this unmet medical need. Methods: An open-label controlled Phase I clinical trial was conducted to investigate the safety and immunogenicity of modified vaccinia Ankara (MVA) in 15 healthy subjects compared to 45 subjects with either mild allergic rhinitis, a history of AD or presenting with mild active AD. MVA was given (Week 0 and 4) by a subcutaneous injection during a 28-week observation period. Results: No serious adverse event was reported and vaccinations with MVA did not lead to any clinically relevant skin reactions in AD subjects. Unsolicited administration site reactions did not show any trends compared to the healthy subject group. The majority of adverse reactions were mild to moderate, and all reactions were transient and resolved without intervention. The majority of vaccinees had seroconverted by ELISA (80-93%) and PRNT (69-79%) already two weeks after the first vaccination, increasing to 100% after the second immunization, with peak GMT above 1000 and 145 for ELISA and PRNT, respectively. Conclusions: MVA was equally well tolerated and immunogenic in all enrolled subjects with mild to moderate pain and redness at the injection site being the most frequent adverse reactions. There were no differences in the safety or immunogenicity profile of MVA in healthy subjects or those with AD or allergic rhinitis. The study has confirmed MVA as a promising smallpox vaccine candidate and demonstrated in a small study population that the vaccine has a similar safety and immunogenicity profile in healthy subjects and people with active AD. Clinical trials registration: NCT00189917.Vaccine 08/2014; 32(43). DOI:10.1016/j.vaccine.2014.08.022 · 3.49 Impact Factor