Prospective surveillance for cardiac adverse events in healthy adults receiving modified vaccinia Ankara vaccines: a systematic review.

Marnie L Elizaga,Sharon E Frey,Bernard R Chaitman,Dale N Lawrence,Alicia H Sato,Mary A Marovich,Sandhya Vasan,Michael C Keefer,Vasee Moorthy

doi:10.1371/journal.pone.0054407

Abstract

BackgroundVaccinia-associated myo/pericarditis was observed during the US smallpox vaccination (DryVax) campaign initiated in 2002. A highly-attenuated vaccinia strain, modified vaccinia Ankara (MVA) has been evaluated in clinical trials as a safer alternative to DryVax and as a vector for recombinant vaccines. Due to the lack of prospectively collected cardiac safety data, the US Food and Drug Administration required cardiac screening and surveillance in all clinical trials of MVA since 2004. Here, we report cardiac safety surveillance from 6 phase I trials of MVA vaccines.MethodsFour clinical research organizations contributed cardiac safety data using common surveillance methods in trials administering MVA or recombinant MVA vaccines to healthy participants. ‘Routine cardiac investigations’ (ECGs and cardiac enzymes obtained 2 weeks after injections of MVA or MVA-HIV recombinants, or placebo-controls), and ‘Symptom-driven cardiac investigations’ are reported. The outcome measure is the number of participants who met the CDC-case definition for vaccinia-related myo/pericarditis or who experienced cardiac adverse events from an MVA vaccine.ResultsFour hundred twenty-five study participants had post-vaccination safety data analyzed, 382 received at least one MVA-containing vaccine and 43 received placebo; 717 routine ECGs and 930 cardiac troponin assays were performed. Forty-five MVA recipients (12%) had additional cardiac testing performed; 22 for cardiac symptoms, 19 for ECG/laboratory changes, and 4 for cardiac symptoms with an ECG/laboratory change. No participant had evidence of symptomatic or asymptomatic myo/pericarditis meeting the CDC-case definition and judged to be related to an MVA vaccine.ConclusionsProspective surveillance of MVA recipients for myo/pericarditis did not detect cardiac adverse reactions in 382 study participants.Trial RegistrationClinicalTrials.gov NCT00082446 NCT003766090 NCT00252148 NCT00083603 NCT00301184 NCT00428337

Highlights

Modified vaccinia Ankara (MVA) is a highly attenuated strain of vaccinia virus derived from the replication-competent Ankara vaccinia strain, chorioallantois vaccinia Ankara (CVA) [1], and was administered as a priming smallpox vaccine to over 120,000 people in Germany in the 1970s without significant side effects [2], [3]
Replication-competent vaccinia was administered to one-third of the world’s population during the World Health Organization’s (WHO) smallpox eradication program [4] and has well-recognized side-effects [5], cardiac complications were rare in the US compared to Europe and Australia, presumably due to differences in the vaccinia strains employed [6]
In order to investigate the rate of vaccine-related cardiac adverse events from investigational modified vaccinia Ankara (MVA) vaccines in Phase I trials, we review the cumulative experience of 4 clinical research organizations that employed uniform methods of prospective cardiac monitoring in 6 clinical trials of MVA and/or MVA-vectored recombinant HIV-1 vaccines

Summary

Introduction

Modified vaccinia Ankara (MVA) is a highly attenuated strain of vaccinia virus derived from the replication-competent Ankara vaccinia strain, chorioallantois vaccinia Ankara (CVA) [1], and was administered as a priming smallpox vaccine to over 120,000 people in Germany in the 1970s without significant side effects [2], [3]. In 2002–2004 the US Department of Defense (DoD) and Department of Health and Human Services (DHHS) initiated a smallpox vaccination campaign with the New York City Board of Health (NYCBOH) vaccinia strain (DryVax, Wyeth Laboratories Inc, Marietta, PA) to protect military personnel and civilian first-responders. A highly-attenuated vaccinia strain, modified vaccinia Ankara (MVA) has been evaluated in clinical trials as a safer alternative to DryVax and as a vector for recombinant vaccines. We report cardiac safety surveillance from 6 phase I trials of MVA vaccines

Methods

Results

Conclusion