Prospective Surveillance for Cardiac Adverse Events in
Healthy Adults Receiving Modified Vaccinia Ankara
Vaccines: A Systematic Review
Marnie L. Elizaga1, Sandhya Vasan2¤, Mary A. Marovich3, Alicia H. Sato4, Dale N. Lawrence5,
Bernard R. Chaitman6, Sharon E. Frey7, Michael C. Keefer8*, for the MVA Cardiac Safety Working Group"
1Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America, 2Aaron Diamond AIDS Research
Center, New York, New York, United States of America, 3United States Military HIV Research Program, Walter Reed Army Institute of Research, Rockville, Maryland, United
States of America, 4Statistical Center for HIV/AIDS Research and Prevention (SCHARP), Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of
America, 5Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America, 6Division of
Cardiology, Saint Louis University School of Medicine, St. Louis, Missouri, United States of America, 7Clinical Research Division of Infectious Diseases, Allergy and
Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, United States of America, 8University of Rochester School of Medicine and Dentistry,
Rochester, New York, United States of America
Background: 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.
Methods: 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.
Results: 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.
Conclusions: Prospective surveillance of MVA recipients for myo/pericarditis did not detect cardiac adverse reactions in 382
Trial Registration: ClinicalTrials.gov NCT00082446 NCT003766090 NCT00252148 NCT00083603 NCT00301184 NCT00428337
Citation: Elizaga ML, Vasan S, Marovich MA, Sato AH, Lawrence DN, et al. (2013) Prospective Surveillance for Cardiac Adverse Events in Healthy Adults Receiving
Modified Vaccinia Ankara Vaccines: A Systematic Review. PLoS ONE 8(1): e54407. doi:10.1371/journal.pone.0054407
Editor: Vasee Moorthy, World Health Organization, Switzerland
Received August 2, 2012; Accepted December 13, 2012; Published January 17, 2013
Copyright: ? 2013 Elizaga et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the National Institutes of Health grant numbers N01 AI25464, UM1 AI069511, UM1 AI068614, UM1 AI046747, UM1
AIO68614, UM1 AI068635. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: Michael_Keefer@URMC.Rochester.edu
¤ Current address: United States Army Medical Component, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand
" Membership of the MVA Cardiac Safety Working Group is provided in the Acknowledgements.
Modified vaccinia Ankara (MVA) is a highly attenuated strain of
vaccinia virus derived from the replication-competent Ankara
vaccinia strain, chorioallantois vaccinia Ankara (CVA) , and
was administered as a priming smallpox vaccine to over 120,000
people in Germany in the 1970s without significant side effects ,
. In contrast, replication-competent vaccinia was administered
to one-third of the world’s population during the World Health
Organization’s (WHO) smallpox eradication program  and has
well-recognized side-effects , although cardiac complications
were rare in the US compared to Europe and Australia,
presumably due to differences in the vaccinia strains employed
. Since the global eradication of smallpox in 1980, replication-
competent vaccinia continued to be used as a vector for
PLOS ONE | www.plosone.org1January 2013 | Volume 8 | Issue 1 | e54407
experimental vaccines [7–9]. However, attenuated poxviruses
(MVA [10–11], NYVAC, canarypox and fowlpox) have subse-
quently gained favor as safer vectors for vaccines against multiple
Concerned about potential bioterrorism, 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. By 2005,
approximately 39,500 civilians and 730,500 military personnel
had been vaccinated  and use in the military has continued
with 2.2 million people vaccinated to date .
Shortly after the US campaign began, several cases of myo/
pericarditis were reported among primary vaccines , [19–21]
and revaccinees [6–19] and the US Centers for Disease Control
(CDC) released a warning on March 28, 2003 . Cases typically
presented 1–2 weeks after receipt of DryVax with acute chest pain,
dyspnea, or palpitations, ECG changes, elevated cardiac enzymes,
depressed left ventricular function and/or abnormal cardiac
imaging indicating myocardial inflammation. By the end of
2003, 67 cases of myo/pericarditis were reported among
540,824 vaccinees (12.4 cases per 100,000 vaccinees [or 1 case
per 8065 vaccinees]) in the DoD program  and 21 cases
among 37,901 vaccinees (550 cases per 100,000 vaccinees [or 1
case per 182 vaccinees]) in the DHHS program . In both
groups, the clinical course of myo/pericarditis was generally mild
or moderate, with full recovery the most frequent outcome.
Consequently, the US FDA required prospective cardiac moni-
toring in a phase III trial comparing replication-competent
vaccinia produced in cell culture, ACAM2000 (Sanofi Pasteur,
Swiftwater, PA [formerly Acambis]) to DryVax. Ten cases of
myo/pericarditis occurred among 1675 vaccinia-naı ¨ve partici-
pants receiving either vaccine (1 case per 168 vaccinees), with no
significant difference in incidence between the two preparations
and importantly, about half of these events were subclinical,
detected only by ECG or cardiac troponin abnormalities [17–23].
While the mechanism of cardiotoxicity is unclear, limited
published data suggests an immunologically-mediated rather than
a direct cytotoxic effect .
Although MVA’s replication in mammalian cells is limited 
anditisavirulent inimmunosuppressed animals,,itremains
unclear whether it can induce myo/pericarditis. Consequently the
FDA extended the requirement for prospective cardiac monitoring
to clinical trials employing MVA. In order to investigate the rate of
vaccine-related cardiac adverse events from investigational 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. We describe the
frequency of reported cardiac symptoms, cardiac enzyme abnor-
malities, and clinically significant changes in ECGs, in participants
who received MVA vaccines compared to placebo recipients. We
determine the number of participants who met the CDC-case
definition for vaccinia-related myo/pericarditis or who experienced
cardiac adverse events related to these study agents, and propose an
approach to cardiac surveillance for future clinical trials of highly
attenuated vaccinia vectors.
Data from 1 Phase I trial of MVA vaccine (National Institute of
Allergy and Infectious Diseases [NIAID] –supported Division of
Microbiology and Infectious Diseases Saint Louis University
Vaccine and Treatment Evaluation Unit [SLU-DMID] )
and 5 Phase I trials of MVA-HIV vaccines (NIAID-supported
HIV Vaccine Trials Network [HVTN] [27–29], US Military HIV
Research Program [MHRP] , and the Aaron Diamond AIDS
Research Center, in collaboration with the International AIDS
Vaccine Initiative [ADARC-IAVI] ) were analyzed (Figure 1).
All clinical trials were approved by the sites’ institutional review
boards and institutional biosafety committees.
Eligibility Criteria and Follow-up
All six protocols enrolled healthy HIV-negative participants with
similar eligibility criteria and post-vaccination cardiac surveillance.
troponin I. Exclusionary ECG findings encompassed: 1) conduction
disturbance (complete left or right bundle branch block, intraventric-
ular conduction disturbance with QRS .120 ms, AV block of any
degree, and QTc prolongation .440 ms; 2) repolarization (ST
segment or T wave) abnormality; 3) significant atrial or ventricular
arrhythmia, including frequent ectopy (e.g., 2 premature ventricular
contractions in a row); and 4) evidence of past myocardial infarction.
All ECGs were obtained with GE MAC 1200 ECG machines (GE
Healthcare, Chalfont St. Giles, UK), and transmitted electronically to
the Saint Louis University Core ECG Laboratory for interpretation.
People with any history of, or known active cardiovascular disease,
stroke/transient ischemic attack, or risk factors for cardiac disease (2 or
more of hyperlipidemia, hypertension, tobacco use, family history of
cardiac disease) were excluded.
Participants were vaccinated with MVA or MVA-HIV-1
recombinants or placebo according to protocol-specific vaccination
schedules and were questioned about interval symptoms suggestive
of myo/pericarditis (such as chest pain, shortness of breath,
palpitations, unexplained fatigue, fever or flu-like symptoms) at all
visits. Additional routine assessment of serum troponin I was
conducted for all participants 2 weeks after each MVA vaccination
and all had routine ECGs 2 weeks after initial MVA vaccinations
(plus other per protocol time-points indicated in Figure 1). The two-
week post-vaccination time-point was chosen for routine cardiac
safety assessments because it corresponded well with the CDC case-
definition of myo/pericarditis following smallpox vaccination (4–30
days post-vaccination) . MVA dosage ranged from 16106to
16109pfu/ml and was administered intramuscularly in all studies,
but also subcutaneously in the SLU-DMID protocol and intrader-
mally in the MHRP protocol. Symptoms suggestive of myo/
pericarditis reported at or between visits were promptly evaluated
(symptom-driven cardiac investigations) by ECG and troponin I
(some studies included creatine phosphokinase-MB [CK-MB]). If
suspicion of cardiac involvement remained after initial work-up,
participants were referred to a cardiologist for further evaluation.
Data Management, Analysis Plan and Statistics
Cardiac safety data from the four research programs were
merged into a central database which included, 1) participant
demographics, 2) results of routine ECGs and cardiac troponin I
testing performed 2-weeks post-MVA injections, 3) cardiac
symptoms reported at 2-week post-vaccination visits and 4) results
of additional symptom-driven cardiac investigations, conducted at
any other time during the studies.
Vaccinations for which 2-week follow-up data was not collected
due to missed visits or visits outside the 30-day post-vaccination
window were excluded from this analysis. If the ECG was repeated
due to artifact, data were included only if the repeat test was within
30 days of vaccination. Data obtained after vaccinations with
other live-vector vaccines were excluded. As cardiac and ECG
abnormalities were uncommon in these populations, data was
Cardiac Safety after MVA Vaccination
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pooled across studies to gain efficiency in measuring outcomes.
Demographics, ECG and non-ECG cardiac assessments were
summarized using proportions. Unadjusted Fisher’s exact tests
were used to compare treatment arms for each of the cardiac
indicators. All analyses were performed in SAS.
The demographic data of participants with cardiac assessments
are shown in Table 1. Age and gender were balanced between
treatment arms of a given study. The mean age ranged from 24–
33 years, with MHRP having slightly older participants and the
DMID and MHRP studies had slightly more males than females
(62–67% male). The majority of trial participants were Caucasian,
Figure 1. Overview of clinical trial designs. 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] , B) National Institutes of Health Division of Microbiology and Infectious
Disease/St. Louis University study [NCT00082446] , C) Aaron Diamond AIDS Research Center/International AIDS Vaccine Initiative study
[NCT00252148] , D) HIV Vaccine Trials Network 055 study [NCT00083603] , E) HIV Vaccine Trials Network 065 study [NCT00301184] , and F)
HIV Vaccine Trials Network 067 study [NCT00428337] . ‘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).
Cardiac Safety after MVA Vaccination
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except for the MHRP trial, in which the majority were African-
American. Only one trial included participants who previously
received smallpox vaccination; eight (17%) and two (18%) such
participants in the ADARC-IAVI trial received MVA and
A total of 848 individuals across all trials had screening ECGs
for eligibility (Figure 2); 11% were excluded due to baseline ECG
findings. Of those meeting ECG eligibility, 478 (55%) enrolled in a
trial; of these 429 (90%) participants received MVA, an MVA-
HIV recombinant vaccine, or saline at 1 to 5 time-points
(median=2). Ninety-nine percent of these participants had cardiac
follow-up. In total, 916 MVA-containing and 105 placebo
vaccinations were administered to 382 and 43 participants,
Symptom-driven cardiac investigations apart from routine 2-
week post-vaccination time-points were initiated by at least one of
three conditions: 1) volunteer report of clinical symptoms
suggestive of myo/pericarditis, 2) an increase in laboratory
markers, and/or 3) a significant change on routine ECG. Overall,
47 participants had symptom-driven cardiac investigations,
including 12% (45/382) of MVA-vaccinated participants, versus
5% (2/43) of placebo recipients (p=0.20). Among MVA
recipients, 22 investigations were for reported cardiac symptoms,
19 for ECG/laboratory changes, and 4 for cardiac symptoms with
an ECG or laboratory change. The two placebo recipients had
investigations for cardiac symptoms. In most cases, the repeat
ECG and troponin were normal, however 18 participants were
referred for more intensive cardiac evaluation: 10 who had
symptoms alone, 1 for abnormal troponin, and 7 for ECG
changes, which resulted in 15 echocardiograms, 3 Holter monitor
tests, 2 cardiac MRIs, and one thallium treadmill stress test being
performed. Subsequently, only one participant in the MVA group
was diagnosed with a cardiac condition, supraventricular tachy-
cardia (SVT), which was an undisclosed pre-existing condition (see
below). Ultimately, no participant was diagnosed with myo/
Solicited Symptoms Suggestive of Myocarditis or
The percentage of participants with cardiac symptoms sugges-
tive of possible myo/pericarditis 2 weeks post-vaccination was
17.8% (68/382) among MVA recipients and 7.0% (3/43) among
placebo recipients (p=0.084) (Table 2). The most common
symptoms in MVA versus placebo recipients were fatigue, chest
pain and flu-like symptoms, but only fatigue was statistically
significant (p=0.044). There was no clear relationship between
any individual symptom and timing of vaccination (Table 2). Of
the 12 participants with chest pain, none had cardiac troponin
elevations and 2 had significant ECG changes from baseline (one
with incomplete right bundle branch block and one with voltage
criteria for left ventricular hypertrophy). In addition, 3 participants
reported chest pain at days 7, 24 and 36 days following
vaccination, respectively, all without ECG or troponin changes.
In all, 7 participants with chest pain, including the 2 with ECG
changes, were further evaluated by echocardiography without
Two MVA recipients reported palpitations at the 2 weeks post-
vaccination visits (Table 2), while 4 additional MVA recipients
reported palpitations at days 22, 47, 56 (normal echo), and 91
following vaccination and 2 placebo recipients reported palpita-
tions, at day 4 and at days 7 and 67 after injection. All participants
had normal troponin values and ECGs were unchanged from
baseline, except for one who had an elevated troponin (0.15 mcg/
L; normal #0.04 mcg/L) with prolonged exercise-induced palpi-
tations 22 days after receiving an MVA-HIV vaccine. This
participant underwent cardioversion for SVT and subsequently
had a normal ECG, echocardiogram and gadolinium-enhanced
cardiac MRI. After recurrent episodes of exercise-induced SVT,
the participant underwent radiofrequency ablation of an accessory
conduction pathway. Although this event met the case definition of
suspected vaccinia-induced myocarditis, the person had failed to
Table 1. Demographics of participants with cardiac safety assessments.
MHRP ADARC-IAVI SLU-DMIDHVTN Total
Vaccine PlaceboVaccine Placebo Vaccine Placebo VaccinePlaceboVaccinePlacebo
N 33 (9%)6 (14%) 46 (12%) 11 (26%) 74 (19%)– 229 (60%)26 (60%) 382 (90%) 43 (10%)
Age in years Mean (SD)31 (8.1) 33 (6.8) 28 (7.6)26 (6.4) 24 (3.7)– 25 (4.9)27 (5.8)26 (5.7) 27 (6.3)
Range(18, 48) (22, 41) (19, 52)(18, 40)(18, 33)–(18, 40)(19, 39)(18, 52)(18, 41)
GenderMale22 (67%)4 (67%)23 (50%)6 (55%)46 (62%)–109 (48%)12 (46%)200 (52%) 22 (51%)
Female11 (33%)2 (33%)23 (50%)5 (45%) 28 (38%)–120 (52%)14 (54%)182 (48%) 21 (49%)
RaceCaucasian11 (33%)0 (0%)25 (54%)6 (55%)67 (91%)–178 (78%)21 (81%)281 (74%) 27 (63%)
African American18 (55%)6 (100%)10 (22%)1 (9%)4 (5%)–30 (13%)3 (12%)62 (16%)10 (23%)
Asian3 (9%)0 (0%)3 (7%)1 (9%)1 (1%)–3 (1%)0 (0%)10 (3%) 1 (2%)
0 (0%)0 (0%)1 (2%)0 (0%)0 (0%)–2 (1%) 0 (0%)3 (1%) 0 (0%)
Hawaiian/Pacific Islander0 (0%) 0 (0%)1 (2%)0 (0%)1 (1%)– 8 (3%) 1 (4%)10 (3%)1 (2%)
More Than One Race1 (3%)0 (0%)0 (0%)0 (0%)1 (1%)– 8 (3%) 1 (4%)10 (3%)1 (2%)
Unknown or Not Reported0 (0%)0 (0%)6 (13%)3 (27%)0 (0%)–0 (0%)0 (0%)6 (2%)3 (7%)
Yes0 (0%) 0 (0%)8 (17%)2 (18%) 0 (0%)–0 (0%)0 (0%)8 (2%)2 (5%)
No33 (100%)6 (100%)38 (83%)9 (82%) 74 (100%) – 229 (100%) 26 (100%) 374 (98%) 41 (95%)
Cardiac Safety after MVA Vaccination
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Figure 2. Participant Flow. 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
Table 2. Cross-sectional frequency of solicited, self-reported symptoms suggestive of myo/pericarditis at visits 2 weeks post-
Days post Vaccination
Symptom First Reportedb
Any Cardiac SymptomMVA68 17.8%2.964.86.8612.0–
Placebo3 7.0%7.367.84.362.5 0.084
FeverMVA6 1.5% 4.765.11.660.9–
Placebo1 2.3%260160 0.53
Chest Pain MVA 123.1% 8.966.1 12.0625.3–
Placebo0 0.0% n/a n/a 0.62
Shortness of BreathMVA7 1.8% 5.866.33.663.0–
Placebo0 0.0% n/an/a 1.00
Placebo0 0.0%n/a n/a 1.00
FatigueMVA 48 12.5% 1.463.3 5.166.0–
Placebo 1 2.3%160260 0.044
MVA9 2.9% 4.364.7 6.264.1–
Placebo2 4.6%10.567.8 5.562.1 0.63
atotal number of participants who received: MVA=382; placebo=43.
bexpressed in mean 6 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.
cpalpitations and flu-like symptoms not collected for SLU-DMID study.
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disclose similar exercise-induced palpitations prior to enrollment
and it was concluded to be a pre-existing condition, unrelated to
Only 3 (0.8%) MVA recipients, all from one study site, had self-
limited mild elevations (0.06–0.08 ng/mL; normal ,0.05 ng/mL)
of cardiac troponin I values at any time-point, versus none among
placebo recipients. One participant was training for a marathon,
one had sinus arrhythmia and early repolarization and a third
reported dehydration and dizziness due to exertion and alcohol
intake (a cardiac MRI with gadolinium 33 days later was normal.)
CK values were also checked in some studies and were abnormal
in 4% (10/234) and 0% (0/26) of MVA versus placebo recipients,
respectively. Their occurrence was distributed across treatments
and no abnormal CK-MB values were seen.
New onset abnormalities found at any time on post-enrollment
ECGs are shown in Table 3.
Among the 425 participants, 8 had QTc intervals exceeding the
predefined 440 ms upper limit of normal. One participant was
inadvertently enrolled with a baseline QTc value of 474 ms; all
subsequent QTc intervals in this person were ,474 ms. The
remaining 7 participants (including one placebo recipient) had
QTc intervals exceeding 440 ms only after randomization, but the
incremental increases were ,60 ms. One participant was taking
clonazepam and escitalopram, which are associated with QTc
ST-T Wave Abnormalities
Eleven MVA recipients had new ST-T wave abnormalities after
enrollment. Of these, four reported fatigue in the 2-week period
following vaccination. Participants were otherwise asymptomatic
and troponin results were normal. In all cases but one the ST-T
wave changes were described as minor according to Minnesota
code criteria. Three participants were evaluated with echocardi-
ography with no significant findings. In one 30 year old
hypertensive participant, new asymptomatic ST-T wave changes
were observed 2 weeks after a second MVA vaccination and again
4 weeks after the third vaccination. Troponins were normal and
the ECG changes resolved within 1 day each time. Six months
after the final vaccination the participant reported chest pain, and
ST-T wave changes were again seen, with a normal troponin and
CK-MB. An exercise SPECT study revealed an abnormal
hypertensive blood pressure response to exercise, with nondiag-
nostic exercise-induced ST segment changes, normal myocardial
perfusion and left ventricular function. The cardiologist at the site
who evaluated the participant noted that the participant previously
had left ventricular hypertrophy documented on an echocardio-
gram and concluded that the ECG changes and atypical chest
pain were due to poorly controlled hypertension. In long term
follow-up contacts 1 and 2 years later, the participant has reported
no cardiac problems.
Thirteen asymptomatic participants (including 1 placebo
recipient) with normal troponin values developed T-wave changes;
one also had a new ST segment abnormality (described above).
The remaining 12 participants had minor T-wave changes; in one
it was present at baseline. Three participants with T wave changes
were evaluated with echocardiography with no significant cardiac
This report describes 6 phase I clinical trials administering
MVA or MVA-recombinant candidate HIV vaccines to 382
primarily healthy young adult (median age 25 years) participants
without a history of cardiac conditions or significant cardiac risk
factors. These participants were similar to those in recent US
military reports of symptomatic myo/pericarditis with respect to
age, rare history of pre-existing heart disease, and the majority
having not previously received vaccinia. Unlike the surveillance of
the military and civilian smallpox vaccination campaigns, our
studies employed prospective cardiac safety monitoring: longitu-
dinal questioning about cardiac symptoms, and monitoring of
serial serum troponin levels and ECGs, the latter of which were
interpreted at a single ECG facility. These prospective assessments
allow optimal evaluation of the potential of MVA vaccination to
induce both subclinical and clinically apparent myo/pericardial
Table 3. New onset ECG changes from routine and symptom-driven cardiac investigations.
(MVA vs placebo)
Total N participantsNo. of participants with analyzable ECG 38243425–
No. of participants with abnormalities listed
in this table
62 (16%) 5 (12%)67 (16%)0.51
ECG events Early Repolarization 15 (4%)1 (2%)16 (4%)1.0
Non-specific ST-T wave changes11 (3%)0 11 (3%)0.61
Non-specific T wave changes13 (3%)1 (2%) 14 (3%) 1.0
QTc .440 ms6 (2%) 1 (2%) 7 (2%)0.53
Voltage criteria for LVHb
7 (2%)0 7 (2%) 1.0
Premature atrial contractions0 1 (2%) 1 (,1%) 0.10
Other change 15 (4%)2 (5%)17 (4%) 0.69
ap-values are calculated from Fisher’s exact test for association between variable and onset.
bLeft ventricular hypertrophy.
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Among the 6 studies, 916 MVA vaccinations were adminis-
tered, of which 382 were primary vaccinations. No cases of
confirmed symptomatic or subclinical myo/pericarditis were
detected. All participants were selected to be at low-risk for
cardiac disease and were questioned regularly about cardiac
symptoms of any degree or duration during the studies. In spite of
their good general health, 17.8% of vaccinees, and 7.0% of
placebo recipients (16.7% of participants overall) reported at least
one occurrence of symptoms possibly indicative of mild myo/
pericarditis at routine visits. Although self-limited fatigue was more
frequently reported by MVA recipients than placebo recipients,
most were from a single study that did not have a placebo group
and were not indicative of cardiac involvement , 
(adjustment for study effect was not done due to the lack of events
reported in two studies). Of note, no one in any of the 6 studies
reported symptoms highly suggestive of myo/pericarditis, such as
dyspnea interfering with activity or positional pleuritic chest pain.
Troponin I levels were within normal limits in all participants
except 3 who had transient mild elevations. In one the elevation
was concluded to be due to distance running, which has been
reported to cause minor asymptomatic troponin I elevations ;
in another it normalized within 2 days before any additional
investigation; and in the third myo/pericarditis was ruled out by a
normal cardiac MRI scan. Importantly, even in this healthy young
volunteer population minor non-specific abnormalities were
frequently seen on ECGs, which on occasion led to additional
cardiac diagnostic testing. Moreover, 93 of 848 (11%) of potential
participants screened for the studies were excluded due to ECG
abnormalities that could complicate the assessment of myo/
pericarditis by ECG criteria.
As mentioned, the reported incidence of symptomatic myo/
pericarditis after receipt of replication-competent vaccinia in the
US military and civilian vaccination campaigns varied between 1
case per 8065 and 182 vaccinees, respectively. However, it is
possible that additional cases of mild myo/pericardial involvement
occurred that escaped detection. The best estimate of the
incidence of subclinical myo/pericarditis can be derived from
clinical trials conducted by Acambis, Inc. (now Sanofi-Pasteur), in
which single vaccinations with ACAM2000 vs DryVax were
administered with prospective cardiac safety monitoring .
These studies identified 10 cases of myo/pericarditis among 1675
primary vaccinees (1 case per 168 vaccinees). Seven of the 10
participants had received ACAM2000 (incidence of 5.73 events/
1000 vaccinations,) whereas 3 had received DryVax (10.38 events/
1000 vaccinations). Of note, 4 of 7 ACAM2000 recipients and 2 of
3 DryVax recipients with myo/pericarditis were asymptomatic,
with abnormalities found only on ECGs and/or cardiac enzyme
testing. Thus, this study indicated that for every case of
symptomatic myo/pericarditis after receiving replication-compe-
tent vaccinia, there could be one or more additional subclinical
Although our report provides information from the largest
collection of MVA studies monitored prospectively with similar
methods, our experience is still too limited to completely rule out
rare events in healthy people that may be observed with more
extensive experience or in people with pre-existing cardiac disease.
Our finding of no events in 382 MVA recipients has a 2-sided
upper 95% confidence bound of 0.96% (9.6 cases/1000 vaccinees
or 1 case per 104 vaccinees), which is not significantly different
than the rate reported by Acambis of 1 case per 168 vaccinees
(p=0.22). However, a number of studies with attenuated
recombinant poxvirus vaccines (MVA or NYVAC), conducted
without prospective monitoring of ECGs or cardiac enzymes, have
been reported over the past decade and none have reported events
consistent with myo/pericarditis [12–16], [35–40].
The use of attenuated forms of poxviruses including MVA and
NYVAC is likely to increase over the coming decades, either for
protection from variola as a bioweapon, or as recombinant
vaccines for infectious agents such as HIV, malaria and
tuberculosis. Although limited by small numbers of MVA
recipients, our report demonstrates that MVA is not associated
with asymptomatic or symptomatic myo/pericarditis at an
unexpectedly high rate (i.e., more than 1 case per 104 vaccinees
per the upper 95% CI bound) compared with replication-
competent vaccinia and that solicitation of symptoms that could
be caused by myo/pericarditis and conducting serial ECGs in a
population who is at low-risk for cardiac disease can lead to a
variety of non-specific findings that are not clinically significant.
Of note, the ongoing experience of the US DoD program, which
has now administered replication-competent vaccinia to over 1.2
million people, provides additional assurance that cardiac
involvement is rare and when it does occur it is mild and self-
limited in vast majority of cases . Specifically, vaccinia-related
sudden cardiac death (SCD), which is the primary safety concern
should asymptomatic cases of myo/pericarditis fail to be detected,
has not been documented in the DoD experience, although one
case of SCD was reported it was confirmed to be due to parvovirus
B19 by its detection in cardiac tissue on autopsy . In
conclusion, we feel that continued awareness of possible cardiac
adverse events related to MVA is prudent; however, sound clinical
judgment should be the mainstay of assessment of potential
cardiac adverse events among recipients of attenuated poxviruses.
PRISMA 2009 Checklist.
The authors wish to thank Mary Allen, RN, National Institute of Allergy
and Infectious Diseases, National Institutes of Health and Harriet L.
Robinson, Ph.D., GeoVax Labs, Inc. for critically reviewing the
manuscript and Allison Mitchell, Vaccine and Infectious Disease Division,
Fred Hutchinson Cancer Research Center for editorial assistance in
preparation of the manuscript. We gratefully acknowledge the participa-
tion and support of many colleagues and staff at each site and are
particularly grateful for the participation of the study participants.
The members of the MVA Cardiac Safety Working Group are:
David D. Ho, MD (manuscript review) and Sarah J. Schlesinger, MD
(manuscript review), Aaron Diamond AIDS Research Center, New York,
NY; Paul Chaplin, PhD (manuscript review), Bavarian Nordic GmbH,
Martinsried, Germany; Robert Johnson, PhD (manuscript review),
National Institute of Allergy and Infectious Diseases, Division of
Microbiology and Infectious Diseases; Artur Kalichman, MD, MPH (data
acquisition), Centro de Referencia e Treinamento em DST/AIDS, Sao
Paulo, Brazil; Ann Duerr, MD, PhD, MPH (manuscript review), Julie
McElrath, MD, PhD (data acquisition), Li Qin, PhD (administrative,
technical or material support) and Molly Swenson, RN, MSN, MPH
(administrative, technical or material support), Fred Hutchinson Cancer
Research Center, Seattle, WA; Lindsey Baden, MD (data acquisition),
Harvard Medical School, Brigham and Women’s Hospital, Boston, MA;
Massimo Cardinali, MD (administrative, technical, material support),
Henry M Jackson Foundation at the Division of AIDS, NIAID, NIH,
Bethesda, MD; Phumla Adesanya (manuscript review), Patricia Fast, MD,
PhD (data acquisition, manuscript review), Arlene Hurley, RN (data
acquisition), Claudia Schmidt, MD, MPH, DTMH (data acquisition,
manuscript review) and Soe Than, MD, PhD (manuscript review),
International AIDS Vaccine Initiative, New York, NY; Viseth Ngauy,
MD (data acquisition, manuscript review), Bonnie Slike, MSc (manuscript
review), and Lei Zhu, RN (manuscript review), US Military HIV Research
Cardiac Safety after MVA Vaccination
PLOS ONE | www.plosone.org7 January 2013 | Volume 8 | Issue 1 | e54407
Program; Geoffrey Gorse, MD (data acquisition), Gwendolyn Pendleton, Download full-text
RN, BSN (data acquisition), Karen Stocke, MBA (administrative, technical
or material support) and Janice Tennant, RN, BSN, MPH (data
acquisition), Saint Louis University School of Medicine; Jonathan Fuchs,
MD (data acquisition), San Francisco Department of Public Health, San
Francisco, CA; Paul Goepfert, MD (data acquisition), University of
Alabama, Birmingham, Birmingham, AL; Paulo Barroso, MD, PhD (data
acquisition), Universidade Federal do Rio de Janeiro, Rio de Janeiro,
Brazil; William Blattner, MD (data acquisition), University of Maryland
Institute of Human Virology, Baltimore, MD; Mhorag Hay, MD (data
acquisition), and Catherine Bunce, RN, MSN (data acquisition), University
of Rochester School of Medicine and Dentistry; Spyros Kalams, MD (data
acquisition), Vanderbilt University School of Medicine, Nashville, TN.
Conceived and designed the experiments: MLE SV MAM DNL SEF
MCK. Performed the experiments: MLE SV MAM BRC SEF MCK.
Analyzed the data: AHS MLE SV. Contributed reagents/materials/
analysis tools: BRC MLE DNL. Wrote the paper: MLE SV MAM AHS
DNL BRC SEF MCK.
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Cardiac Safety after MVA Vaccination
PLOS ONE | www.plosone.org8 January 2013 | Volume 8 | Issue 1 | e54407