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

Authors

Richard N. Greenberg, University of KentuckyFollow
Christine M. Hay, University of Iowa
Jack T. Stapleton, University of Rochester
Thomas C. Marbury, Orlando Clinical Research Center
Eva Wagner, Bavarian Nordic, Germany
Eva Kreitmeir, Bavarian Nordic, Germany
Siegfried Röesch, Bavarian Nordic, Germany
Alfred von Krempelhuber, Bavarian Nordic, Germany
Philip Young, Bavarian Nordic, Germany
Richard Nichols, Bavarian Nordic, Germany
Thomas P. Meyer, Bavarian Nordic, Germany
Darja Schmidt, Bavarian Nordic, Germany
Josef Weigl, Bavarian Nordic, Germany
Garth Virgin, Bavarian Nordic, Germany
Nathaly Arndtz-Wiedemann, Bavarian Nordic, Germany
Paul Chaplin, Bavarian Nordic, Germany

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.

Document Type

Article

Publication Date

6-21-2016

Notes/Citation Information

Published in PLOS ONE, v. 11, no. 6, e0157335, p. 1-15.

© 2016 Greenberg et al.

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Digital Object Identifier (DOI)

https://doi.org/10.1371/journal.pone.0157335

Funding Information

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).

Repository Citation

Greenberg, Richard N.; Hay, Christine M.; Stapleton, Jack T.; Marbury, Thomas C.; Wagner, Eva; Kreitmeir, Eva; Röesch, Siegfried; von Krempelhuber, Alfred; Young, Philip; Nichols, Richard; Meyer, Thomas P.; Schmidt, Darja; Weigl, Josef; Virgin, Garth; Arndtz-Wiedemann, Nathaly; and Chaplin, Paul, "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" (2016). Internal Medicine Faculty Publications. 98.
https://uknowledge.uky.edu/internalmedicine_facpub/98