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.
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.


BACKGROUND
ClinicalTrials.gov NCT00857493.
University of Kentucky School of Medicine, MN663 Medical Science Bldg., 800 Rose Street, Lexington, KY, 40536, United States of America.
Richard N
RN
Greenberg
University of Iowa, SW54, GH, 200 Hawkins Drive, UHC, Iowa City, IA, 52242, United States of America.
Christine M
CM
Hay
University of Rochester Medical Center School of Medicine and Dentistry, 601 Elmwood Avenue, Box 689, Rochester, NY, 14642, United States of America.
Jack T
JT
Stapleton
Orlando Clinical Research Center, 5055 South Orange Avenue, Orlando, FL, 32809, United States of America.
Thomas C
TC
Marbury
Bavarian Nordic GmbH, Fraunhoferstrasse 13, 82152 Martinsried, Germany.
Eva
E
Wagner
Bavarian Nordic GmbH, Fraunhoferstrasse 13, 82152 Martinsried, Germany.
Eva
E
Kreitmeir
Bavarian Nordic GmbH, Fraunhoferstrasse 13, 82152 Martinsried, Germany.
Siegfried
http://orcid.org/0000-0002-6206-091X
S
Röesch
Bavarian Nordic GmbH, Fraunhoferstrasse 13, 82152 Martinsried, Germany.
Alfred
A
von Krempelhuber
Bavarian Nordic GmbH, Fraunhoferstrasse 13, 82152 Martinsried, Germany.
Philip
P
Young
Bavarian Nordic GmbH, Fraunhoferstrasse 13, 82152 Martinsried, Germany.
Richard
R
Nichols
Bavarian Nordic GmbH, Fraunhoferstrasse 13, 82152 Martinsried, Germany.
Thomas P
TP
Meyer
Bavarian Nordic GmbH, Fraunhoferstrasse 13, 82152 Martinsried, Germany.
Darja
http://orcid.org/0000-0001-8559-1302
D
Schmidt
Bavarian Nordic GmbH, Fraunhoferstrasse 13, 82152 Martinsried, Germany.
Josef
J
Weigl
Bavarian Nordic GmbH, Fraunhoferstrasse 13, 82152 Martinsried, Germany.
Garth
G
Virgin
Bavarian Nordic GmbH, Fraunhoferstrasse 13, 82152 Martinsried, Germany.
Nathaly
N
Arndtz-Wiedemann
Bavarian Nordic GmbH, Fraunhoferstrasse 13, 82152 Martinsried, Germany.
Paul
P
Chaplin
D000369:Aged, 80 and over; D003710:Demography; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos; D000069078:Seroconversion; D012900:Smallpox Vaccine / Q000009:adverse effects* / Q000276:immunology*; D019444:Vaccines, DNA; D010948:Viral Plaque Assay; D014765:Viral Vaccines / Q000009:adverse effects* / Q000276:immunology*
C560489:MVA vaccine; D010919:Placebos; D012900:Smallpox Vaccine; D019444:Vaccines, DNA; D014765:Viral Vaccines