Prospective Surveillance for Cardiac Adverse Events in Healthy Adults Receiving Modified Vaccinia Ankara Vaccines: A Systematic Review

<div><h3>Background</h3><p>Vaccinia-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.</p> <h3>Methods</h3><p>Four 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.</p> <h3>Results</h3><p>Four 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.</p> <h3>Conclusions</h3><p>Prospective surveillance of MVA recipients for myo/pericarditis did not detect cardiac adverse reactions in 382 study participants.</p> <h3>Trial Registration</h3><p>ClinicalTrials.gov <a href="http://clinicaltrials.gov/ct2/results?term=NCT00082446">NCT00082446</a> <a href="http://clinicaltrials.gov/ct2/results?term=NCT003766090">NCT003766090</a> <a href="http://clinicaltrials.gov/ct2/results?term=NCT00252148">NCT00252148</a> <a href="http://clinicaltrials.gov/ct2/results?term=NCT00083603">NCT00083603</a> <a href="http://clinicaltrials.gov/ct2/results?term=NCT00301184">NCT00301184</a> <a href="http://clinicaltrials.gov/ct2/results?term=NCT00428337">NCT00428337</a></p> </div

Cross-sectional frequency of solicited, self-reported symptoms suggestive of myo/pericarditis at visits 2 weeks post-vaccination/boost.

a<p>total number of participants who received: MVA = 382; placebo = 43.</p>b<p>expressed in mean ± standard deviation; for participants who had multiple reports of a given symptom, the minimum number of days post-vaccination and maximum duration of symptoms were used.</p>c<p>palpitations and flu-like symptoms not collected for SLU-DMID study.</p><p>n/a = not applicable.</p

Overview of clinical trial designs.

<p>Schema for each of the 6 clinical trials with prospective cardiac safety assessments included in this report, A) US Military HIV Research Program study [NCT00376090] <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054407#pone.0054407-Currier1" target="_blank">[30]</a>, B) National Institutes of Health Division of Microbiology and Infectious Disease/St. Louis University study [NCT00082446] <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054407#pone.0054407-Frey1" target="_blank">[11]</a>, C) Aaron Diamond AIDS Research Center/International AIDS Vaccine Initiative study [NCT00252148] <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054407#pone.0054407-Vasan1" target="_blank">[31]</a>, D) HIV Vaccine Trials Network 055 study [NCT00083603] <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054407#pone.0054407-Keefer1" target="_blank">[27]</a>, E) HIV Vaccine Trials Network 065 study [NCT00301184] <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054407#pone.0054407-Goepfert1" target="_blank">[28]</a>, and F) HIV Vaccine Trials Network 067 study [NCT00428337] <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054407#pone.0054407-Gorse1" target="_blank">[29]</a>. ‘Arrows’ indicate time of vaccination; ‘X’ indicates time of routine ECGs; ‘N’ indicates total number of study participants included in this analysis; ‘A:P’ indicates ratio of participants who received active vaccination (A) to placebo (P).</p

New onset ECG changes from routine and symptom-driven cardiac investigations.

a<p>p-values are calculated from Fisher’s exact test for association between variable and onset.</p>b<p>Left ventricular hypertrophy.</p

Demographics of participants with cardiac safety assessments.

<p>Demographics of participants with cardiac safety assessments.</p

Participant Flow.

<p>Flow diagram of participants screened, enrolled and followed with prospective cardiac safety assessments among the 6 trials included in this report. ‘MVA’ indicates MVA alone or an MVA-HIV recombinant candidate vaccine, whereas ‘Placebo’ was a buffered sterile saline solution.</p

Safety and tolerability of HIV-1 multiantigen pDNA vaccine given with IL-12 plasmid DNA via electroporation, boosted with a recombinant vesicular stomatitis virus HIV Gag vaccine in healthy volunteers in a randomized, controlled clinical trial.

BACKGROUND:The addition of plasmid cytokine adjuvants, electroporation, and live attenuated viral vectors may further optimize immune responses to DNA vaccines in heterologous prime-boost combinations. The objective of this study was to test the safety and tolerability of a novel prime-boost vaccine regimen incorporating these strategies with different doses of IL-12 plasmid DNA adjuvant. METHODS:In a phase 1 study, 88 participants received an HIV-1 multiantigen (gag/pol, env, nef/tat/vif) DNA vaccine (HIV-MAG, 3000 μg) co-administered with IL-12 plasmid DNA adjuvant at 0, 250, 1000, or 1500 μg (N = 22/group) given intramuscularly with electroporation (Ichor TriGrid™ Delivery System device) at 0, 1 and 3 months; followed by attenuated recombinant vesicular stomatitis virus, serotype Indiana, expressing HIV-1 Gag (VSV-Gag), 3.4 ⊆ 107 plaque-forming units (PFU), at 6 months; 12 others received placebo. Injections were in both deltoids at each timepoint. Participants were monitored for safety and tolerability for 15 months. RESULTS:The dose of IL-12 pDNA did not increase pain scores, reactogenicity, or adverse events with the co-administered DNA vaccine, or following the VSV-Gag boost. Injection site pain and reactogenicity were common with intramuscular injections with electroporation, but acceptable to most participants. VSV-Gag vaccine often caused systemic reactogenicity symptoms, including a viral syndrome (in 41%) of fever, chills, malaise/fatigue, myalgia, and headache; and decreased lymphocyte counts 1 day after vaccination. CONCLUSIONS:HIV-MAG DNA vaccine given by intramuscular injection with electroporation was safe at all doses of IL-12 pDNA. The VSV-Gag vaccine at this dose was associated with fever and viral symptoms in some participants, but the vaccine regimens were safe and generally well-tolerated. TRIAL REGISTRATION:Clinical Trials.gov NCT01578889

Phase 1 Safety and Immunogenicity Testing of DNA and Recombinant Modified Vaccinia Ankara Vaccines Expressing HIV-1 Virus-like Particles

Background. Recombinant DNA and modified vaccinia virus Ankara (rMVA) vaccines represent a promising approach to an HIV/AIDS vaccine. This Phase 1 clinical trial compared the safety and immunogenicity of a rMVA vaccine administered with and without DNA vaccine primin