A Randomized, Double-Blind, Placebo-Controlled Phase II Trial Investigating the Safety and Immunogenicity of Modified Vaccinia Ankara Smallpox Vaccine (MVA-BN®) in 56-80-Year-Old Subjects

Abstract

Background: Modified Vaccinia Ankara MVA-BN® is a live, highly attenuated, viral vaccine under advanced development as a non-replicating smallpox vaccine. In this Phase II trial, the safety and immunogenicity of Modified Vaccinia Ankara MVA-BN® (MVA) was assessed in a 56-80 years old population.

Methods: MVA with a virus titer of 1 x 108 TCID50/dose was administered via subcutaneous injection to 56-80 year old vaccinia-experienced subjects (N = 120). Subjects received either two injections of MVA (MM group) or one injection of Placebo and one injection of MVA (PM group) four weeks apart. Safety was evaluated by assessment of adverse events (AE), focused physical exams, electrocardiogram recordings and safety laboratories. Solicited AEs consisted of a set of pre-defined expected local reactions (erythema, swelling, pain, pruritus, and induration) and systemic symptoms (body temperature, headache, myalgia, nausea and fatigue) and were recorded on a memory aid for an 8-day period following each injection. The immunogenicity of the vaccine was evaluated in terms of humoral immune responses measured with a vaccinia-specific enzyme-linked immunosorbent assay (ELISA) and a plaque reduction neutralization test (PRNT) before and at different time points after vaccination.

Results: Vaccinations were well tolerated by all subjects. No serious adverse event related to MVA and no case of myopericarditis was reported. The overall incidence of unsolicited AEs was similar in both groups. For both groups immunogenicity responses two weeks after the final vaccination (i.e. Visit 4) were as follows: Seroconversion (SC) rates (doubling of titers from baseline) in vaccine specific antibody titers measured by ELISA were 83.3% in Group MM and 82.8% in Group PM (difference 0.6% with 95% exact CI [-13.8%, 15.0%]), and 90.0% for Group MM and 77.6% for Group PM measured by PRNT (difference 12.4% with 95% CI of [-1.1%, 27.0%]). Geometric mean titers (GMT) measured by ELISA two weeks after the final vaccination for Group MM were 804.1 and 605.8 for Group PM (with ratio of GMTs of 1.33 with 95% CI of [0.96, 1.84]). Similarly, GMTs measured by PRNT were 210.3 for Group MM and 126.7 for Group PM (with ratio 1.66 and 95% CI [0.95, 2.90]).

Conclusions: One or two doses of MVA were safe and immunogenic in a 56-80 years old vaccinia-experienced population. No cases of myopericarditis were observed following vaccinations with MVA. The safety, reactogenicity and immunogenicity were similar to that seen in younger (18-55 year old) healthy populations as investigated in other MVA trials. The results suggest that a single dose of MVA in a 56-80 years old population was well tolerated and sufficient to rapidly boost the long-term B cell memory response induced by a prior vaccination with a traditional smallpox vaccine.

Trial registration: ClinicalTrials.gov NCT00857493.

Conflict of interest statement

Competing Interests: The trial was funded by the National Institute of Allergy and Infectious Diseases US (NIAID) (N01-AI-40072). Bavarian Nordic was the sponsor receiving the fund (N01-AI-40072). Bavarian Nordic reimbursed the Clinical Trial Investigators and the design and conduct of the trial were managed by Bavarian Nordic A/S. Eva Wagner, Eva Kreitmeir, Siegfried Rösch, Alfred von Krempelhuber, Philip Young, Richard Nichols, Thomas P. Meyer, Darja Schmidt, Josef Weigl, Garth Virgin, Nathaly Arndtz-Wiedemann and Paul Chaplin are employed by Bavarian Nordic GmbH, the manufacturer of MVA-BN. Patents relevant to this study are part of the supporting information as there are too many to list. The Statistical Analysis Plan was written by Philip Young (PY, Bavarian Nordic). Data collection, data management and analysis were performed by Kendle International (Cincinnati, OH). Kendle International is now part of INC Research (Raleigh, NC). The specific roles of the authors are articulated in the ‘author contributions’ section. There are no further patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Fig 1. Disposition of Subjects and Data Sets analyzed.

Of 242 screened volunteers, 120 subjects were assessed eligible for enrollment, allocated to one of the two groups, Group MM (MVA/MVA) or Group PM (Placebo/MVA), respectively, and received at least one vaccination of MVA. All safety data for these 120 subjects were analyzed. * One subject, who didn’t complete the active trial phase returned for the FU visit. ** One subject was excluded from the Immunogenicity Analysis Set (IAS; N = 119), because baseline results were missing. 18 subjects were excluded from the Per-Protocol Set (PPS); N = 102). FU = Follow-up.

Fig 2. Vaccinia-specific ELISA GMTs by Week (IAS, N = 119).

Administrations at week 0 (Group MM: first MVA vaccination; Group PM: Placebo) and at week 4 (Group MM: second MVA vaccination; Group PM: first MVA vaccination). No samples were taken between week 8 and 32, therefore the graph was cut. IAS = Immunogenicity Analysis Set, GMT = geometric mean titer, ELISA = enzyme-linked immunosorbent assay, CI = confidence interval.

Fig 3. Vaccinia-specific PRNT GMTs by Week (IAS, N = 119).

Administrations at week 0 (Group MM: first MVA vaccination; Group PM: Placebo) and at week 4 (Group MM: second MVA vaccination; Group PM: first MVA vaccination). No samples were taken between week 8 and 32, therefore the graph was cut. IAS = Immunogenicity Analysis Set, GMT = geometric mean titer, PRNT = plaque reduction neutralization test, CI = confidence interval.