Immunogenicity and safety of three consecutive production lots of the non replicating smallpox vaccine MVA: A randomised, double blind, placebo controlled phase III trial

PLoS One. 2018 Apr 13;13(4):e0195897. doi: 10.1371/journal.pone.0195897. eCollection 2018.

Abstract

Background: Modified Vaccinia Ankara (MVA) is a live, viral vaccine under advanced development as a non-replicating smallpox vaccine. A randomised, double-blind, placebo-controlled phase III clinical trial was conducted to demonstrate the humoral immunogenic equivalence of three consecutively manufactured MVA production lots, and to confirm the safety and tolerability of MVA focusing on cardiac readouts.

Methods: The trial was conducted at 34 sites in the US. Vaccinia-naïve adults aged 18-40 years were randomly allocated to one of four groups using a 1:1:1:1 randomization scheme. Subjects received either two MVA injections from three consecutive lots (Groups 1-3), or two placebo injections (Group 4), four weeks apart. Everyone except personnel involved in vaccine handling and administration was blinded to treatment. Safety assessment focused on cardiac monitoring throughout the trial. Vaccinia-specific antibody titers were measured using a Plaque Reduction Neutralization Test (PRNT) and an Enzyme-Linked Immunosorbent Assay (ELISA). The primary immunogenicity endpoint was Geometric Mean Titers (GMTs) after two MVA vaccinations measured by PRNT at trial visit 4. This trial is registered with ClinicalTrials.gov, number NCT01144637.

Results: Between March 2013 and May 2014, 4005 subjects were enrolled and received at least one injection of MVA (n = 3003) or placebo (n = 1002). The three MVA lots induced equivalent antibody titers two weeks after the second vaccination, with seroconversion rates of 99·8% (PRNT) and 99·7% (ELISA). Overall, 180 (6·0%) subjects receiving MVA and 29 (2·9%) subjects in the placebo group reported at least one unsolicited Adverse Event (AE) that was considered trial-related. Vaccination was well tolerated without significant safety concerns, particularly regarding cardiac assessment.

Conclusions: The neutralizing and total antibody titers induced by each of the three lots were equivalent. No significant safety concerns emerged in this healthy trial population, especially regarding cardiac safety, thus confirming the excellent safety and tolerability profile of MVA.

Trial registration: ClinicalTrials.gov NCT01144637.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibodies, Viral / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Healthy Volunteers
  • Humans
  • Immunization, Secondary
  • Immunogenicity, Vaccine*
  • Male
  • Seroconversion
  • Smallpox Vaccine / adverse effects*
  • Smallpox Vaccine / immunology*
  • Smallpox Vaccine / standards
  • United States
  • Vaccination
  • Viral Vaccines / adverse effects*
  • Viral Vaccines / immunology*
  • Viral Vaccines / standards
  • Young Adult

Substances

  • Antibodies, Viral
  • MVA vaccine
  • Smallpox Vaccine
  • Viral Vaccines

Associated data

  • ClinicalTrials.gov/NCT01144637

Grant support

The trial was funded by the Biomedical Advanced Research and Development Authority (BARDA, http://www.phe.gov/about/BARDA/Pages/default.aspx). Bavarian Nordic was the sponsor receiving the fund (BARDA Contract No.: HHSO100200700034C). Bavarian Nordic reimbursed the clinical trial investigators (i.e. ETO and SJL) for their efforts. Bavarian Nordic provided support in form of salaries for authors EW, KN, SR, PY, DS, CK, SDC, TPM, HW, NS and PC. The statistical analysis plan was written by PY (Bavarian Nordic). Data collection, management and analysis were performed by Chiltern International Inc. (Bristol, TN). The specific roles of the authors are articulated in the "author contributions" section. Bavarian Nordic did not have any additional role in the data collection and analysis, decision to publish or preparation of the manuscript.