Safety and Immunogenicity of Modified Vaccinia Ankara-Bavarian Nordic Smallpox Vaccine in Vaccinia-Naive and Experienced Human Immunodeficiency Virus-Infected Individuals: An Open-Label, Controlled Clinical Phase II Trial

Edgar Turner Overton, Jack Stapleton, Ian Frank, Shawn Hassler, Paul A Goepfert, David Barker, Eva Wagner, Alfred von Krempelhuber, Garth Virgin, Thomas Peter Meyer, Jutta Müller, Nicole Bädeker, Robert Grünert, Philip Young, Siegfried Rösch, Jane Maclennan, Nathaly Arndtz-Wiedemann, Paul Chaplin, Edgar Turner Overton, Jack Stapleton, Ian Frank, Shawn Hassler, Paul A Goepfert, David Barker, Eva Wagner, Alfred von Krempelhuber, Garth Virgin, Thomas Peter Meyer, Jutta Müller, Nicole Bädeker, Robert Grünert, Philip Young, Siegfried Rösch, Jane Maclennan, Nathaly Arndtz-Wiedemann, Paul Chaplin

Abstract

Background. First- and second-generation smallpox vaccines are contraindicated in individuals infected with human immunodeficiency virus (HIV). A new smallpox vaccine is needed to protect this population in the context of biodefense preparedness. The focus of this study was to compare the safety and immunogenicity of a replication-deficient, highly attenuated smallpox vaccine modified vaccinia Ankara (MVA) in HIV-infected and healthy subjects. Methods. An open-label, controlled Phase II trial was conducted at 36 centers in the United States and Puerto Rico for HIV-infected and healthy subjects. Subjects received 2 doses of MVA administered 4 weeks apart. Safety was evaluated by assessment of adverse events, focused physical exams, electrocardiogram recordings, and safety laboratories. Immune responses were assessed using enzyme-linked immunosorbent assay (ELISA) and a plaque reduction neutralization test (PRNT). Results. Five hundred seventy-nine subjects were vaccinated at least once and had data available for analysis. Rates of ELISA seropositivity were comparably high in vaccinia-naive healthy and HIV-infected subjects, whereas PRNT seropositivity rates were higher in healthy compared with HIV-infected subjects. Modified vaccinia Ankara was safe and well tolerated with no adverse impact on viral load or CD4 counts. There were no cases of myo-/pericarditis reported. Conclusions. Modified vaccinia Ankara was safe and immunogenic in subjects infected with HIV and represents a promising smallpox vaccine candidate for use in immunocompromised populations.

Keywords: HIV infection; MVA; immunocompromised; smallpox; vaccination.

Figures

Figure 1.
Figure 1.
Disposition of subjects and data sets analyzed. Of 1108 screened volunteers, 581 subjects were assessed eligible for enrolment, 579 subjects were allocated to 1 of 4 study groups, and all 579 subjects received at least 1 vaccination (full analysis set [FAS]). One hundred eighty-five subjects were excluded from the per-protocol analysis set ([PPS] n = 394). 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. Only 164 from 501 subjects came to an on-site visit for the Follow-up, for 337 of 501 subjects the safety-relevant information was gathered by telephone. For all other subjects, the safety-relevant information was gathered by telephone FU. In case any serious safety issues were detected via telephone, the subject was asked to appear for an onsite visit. Abbreviation: vacc., vaccinia.
Figure 2.
Figure 2.
Kinetics of humoral immune responses after 2 vaccinations with Modified vaccinia Ankara-Bavarian Nordic. Total and neutralizing antibody responses were analyzed by enzyme-linked immunosorbent assay ([ELISA] A and B) and plaque reduction neutralization test ([PRNT] C and D) using the Per Protocol Set. Abbreviation: GMT, geometric mean titer.
Figure 3.
Figure 3.
Kinetics of humoral immune responses after 2 vaccinations with Modified vaccinia Ankara-Bavarian Nordic. Total and neutralizing antibody responses were analyzed by enzyme-linked immunosorbent assay ([ELISA] A and B) and plaque reduction neutralization test ([PRNT] C and D) using the Full Analysis Set. Abbreviation: GMT, geometric mean titer.

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