A prospective study of the incidence of myocarditis/pericarditis and new onset cardiac symptoms following smallpox and influenza vaccination

Renata J M Engler, Michael R Nelson, Limone C Collins Jr, Christina Spooner, Brian A Hemann, Barnett T Gibbs, J Edwin Atwood, Robin S Howard, Audrey S Chang, Daniel L Cruser, Daniel G Gates, Marina N Vernalis, Marguerite S Lengkeek, Bruce M McClenathan, Allan S Jaffe, Leslie T Cooper, Steve Black, Christopher Carlson, Christopher Wilson, Robert L Davis, Renata J M Engler, Michael R Nelson, Limone C Collins Jr, Christina Spooner, Brian A Hemann, Barnett T Gibbs, J Edwin Atwood, Robin S Howard, Audrey S Chang, Daniel L Cruser, Daniel G Gates, Marina N Vernalis, Marguerite S Lengkeek, Bruce M McClenathan, Allan S Jaffe, Leslie T Cooper, Steve Black, Christopher Carlson, Christopher Wilson, Robert L Davis

Abstract

Background: Although myocarditis/pericarditis (MP) has been identified as an adverse event following smallpox vaccine (SPX), the prospective incidence of this reaction and new onset cardiac symptoms, including possible subclinical injury, has not been prospectively defined.

Purpose: The study's primary objective was to determine the prospective incidence of new onset cardiac symptoms, clinical and possible subclinical MP in temporal association with immunization.

Methods: New onset cardiac symptoms, clinical MP and cardiac specific troponin T (cTnT) elevations following SPX (above individual baseline values) were measured in a multi-center prospective, active surveillance cohort study of healthy subjects receiving either smallpox vaccine or trivalent influenza vaccine (TIV).

Results: New onset chest pain, dyspnea, and/or palpitations occurred in 10.6% of SPX-vaccinees and 2.6% of TIV-vaccinees within 30 days of immunization (relative risk (RR) 4.0, 95% CI: 1.7-9.3). Among the 1081 SPX-vaccinees with complete follow-up, 4 Caucasian males were diagnosed with probable myocarditis and 1 female with suspected pericarditis. This indicates a post-SPX incidence rate more than 200-times higher than the pre-SPX background population surveillance rate of myocarditis/pericarditis (RR 214, 95% CI 65-558). Additionally, 31 SPX-vaccinees without specific cardiac symptoms were found to have over 2-fold increases in cTnT (>99th percentile) from baseline (pre-SPX) during the window of risk for clinical myocarditis/pericarditis and meeting a proposed case definition for possible subclinical myocarditis. This rate is 60-times higher than the incidence rate of overt clinical cases. No clinical or possible subclinical myocarditis cases were identified in the TIV-vaccinated group.

Conclusions: Passive surveillance significantly underestimates the true incidence of myocarditis/pericarditis after smallpox immunization. Evidence of subclinical transient cardiac muscle injury post-vaccinia immunization is a finding that requires further study to include long-term outcomes surveillance. Active safety surveillance is needed to identify adverse events that are not well understood or previously recognized.

Conflict of interest statement

Competing Interests: The authors of this manuscript have the following competing interests: Renata J. M. Engler: Study support as detailed under sources of funding. Allan S. Jaffe: Currently and in the past has consulted for most of the major diagnostic companies including the company that makes the assay used in this study. Leslie T. Cooper: Has consulted for Sanofi Pasteur, Inc. Christopher Carlson: Study support (NIH Grant) as detailed under sources of funding. Christopher Wilson: Study support (NIH Grant) as detailed under sources of funding. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Subject enrollment, exclusions and outcomes…
Fig 1. Subject enrollment, exclusions and outcomes for two prospective cohorts, post-smallpox and annual trivalent influenza vaccine.

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