Vaccination against smallpox using live vaccinia virus has historically caused a number of different adverse events.2
The adverse reactions range in severity and typically involve skin, eye, cardiac tissue, or in extremely rare cases, the nervous system. Cutaneous reactions include uticaria, rash, autoinoculation, eczema vaccinatum, generalized vaccinia, and progressive vaccinia (previously termed “vaccinia necrosum”). Ocular vaccinia is a common manifestation of auto-inoculation. Post-vaccinial encephalitis is a rare but potentially fatal complication. The rates of complications vary by age, with serious adverse events (SAEs) generally occurring at a greater rate among the very young, particularly those less than 12 months old, than in older children and adults.
Whereas cardiac events had been reported in the literature before 2003, they were largely unrecognized during the worldwide eradication campaign and were thought to occur very rarely. Only six cases of cardiac complications after smallpox vaccination with the NYCBH strain of vaccinia had been reported in the US before 2003.36
In the past decade, cardiac complications following live vaccinia vaccination have been detected more often. This increase in detection is because of the availability of more sophisticated diagnostic techniques. Cardiac complications resulting from live vaccinia vaccination range in severity from mild to fatal and include myocarditis, pericarditis, arrhythmias, and dilated cardiomyopathy (DCM). Myocarditis is an inflammation of the heart muscle without blockage of the coronary arteries, and pericarditis is an inflammation of the fibrous sack surrounding the heart muscle. DCM is characterized by an enlarged and weakened heart muscle. Myocarditis and pericarditis, also collectively referred to as myopericarditis, can cause palpitations, shortness of breath, fever, sweats, or chest pain and can be diagnosed by an abnormal electrocardiogram (ECG), imaging studies ( echocardiogram), histopathology, or elevated cardiac enzymes. These inflammatory processes can be caused by a number of viral infections and autoimmune disorders, and have sequelae ranging from self-limiting asymptomatic disease to DCM, resulting in fulminant congestive heart failure and possibly death. Interestingly, myocarditis is blamed for causing up to 20% of all cases of sudden death among military recruits.37
To enhance preparedness in the event of an intentional release of smallpox, a 2002 presidential initiative recommended vaccination of enlisted military members, and voluntary participation for civilian health care workers with potential to be first responders. Military and civilian populations were vaccinated with Dryvax®
under the guidance of the Department of Defense (DOD) and the Department of Health and Human Services (HHS), respectively.38
By June of 2004, 39,566 civilians had been vaccinated, and by September 2006, more than 1.1 million soldiers were vaccinated. The occurrence of adverse events in both civilian and military populations was carefully monitored. 39
Compared with the historical rates of SAEs in the US reported before the 1970s, the rates of events such as generalized vaccinia and autoinoculation were comparable. Cases of progressive vaccinia, eczema vaccinatum, and fetal vaccinia were completely avoided by careful screening of potential vaccinees, and attempting to limit vaccination to those without immunodeficiencies, eczema, or pregnancy. Among 730,580 DOD vaccinees, three cases of post-vaccinial encephalitis and 43 cases of mild generalized vaccinia occurred.41
Complications from vaccination were much less frequent in previously vaccinated individuals than those that were vaccinia-naïve.
While the frequencies of most SAEs were anticipated based on historical findings, a surprisingly large number of cardiac complications were reported in both civilian and military cohorts in the 2003 vaccination campaign. One study that compared US soldiers who received live vaccinia vaccination with unvaccinated soldiers from South Korea showed a similar number of hospitalizations and cases of chest pain between the two groups, suggesting that the high rate of cardiac events was no greater than the baseline of a population.39
However, the occurrence of the vast majority of cardiac adverse events within 30 days of vaccination, and clustering within 7–12 days post-vaccination, suggests a direct link between vaccination with live vaccinia virus and incidence of cardiac complications.40
Of 730,580 US armed forces personnel vaccinated with Dryvax®
, 86 cases of myopericarditis with moderate or severe clinical presentation occurred in otherwise healthy vaccinees.42
The single fatal case of myocarditis was in a female. An earlier report calculated a rate of myopericarditis 7.5-fold higher than the expected background rate among 347,516 primary vaccinees (56 cases, at a rate of 161 per million).43
Of 37,901 HHS vaccinees, 21 civilians were diagnosed with myopericarditis (at a rate of 554 per million), all of which were mild cases that resolved without further complications.36
Additionally, four DOD and three HHS cases of DCM occurred among previously healthy subjects, with two requiring heart transplants. 40
Ten patients among HHS vaccinees experienced ischemic cardiac events (ICEs), which are characterized as cardiac damage by a mechanism of constriction or blockage of blood flow. Seven of these patients had pre-existing cardiac risk factors, and two cases resulted in death.44
Of DOD vaccinees, 16 cases of ICE occurred with three fatalities. The rates of cardiac events were so high within the first two months of the HHS vaccination program, the CDC formed a cardiac team to specifically monitor cardiac-related SAEs. From the time this correlation was recognized, patients were pre-screened and those with at least three cardiac risk factors were deferred from vaccination. Possibly because of this screening, no additional ICEs were reported in the final 6638 HHS vaccinees.
Serious and nonserious adverse events following vaccination of 2983 people with ACAM2000™ (1307 naïve and 1676 experienced) were compared with that of Dryvax®
With regard to overall common adverse events such as flu-like symptoms, lymph node pain, and reaction at the vaccination site, 99% of ACAM2000™ vaccinees had at least one adverse event compared with 100% of those receiving Dryvax®
. In general, the individuals vaccinated with ACAM2000™ had a slightly lower, but statistically significant, incidence of several specific adverse events (including lymph node pain, injection site pain and pruritus). Additionally, the rates of flu-like symptoms among ACAM2000™-vaccinated subjects were lower for experienced vaccinees compared with the vaccinia-naïve group (55% versus 76%).5
With the higher than expected rate of cardiac complications in the HHS and DOD vaccination programs, the ACAM2000™ vaccine trials closely monitored patients by performing ECGs and serum tests for troponin I enzyme levels on all subjects in two Phase III clinical trials and in one Phase I clinical trial. The result was astounding in that people vaccinated with either ACAM2000™ or Dryvax®
had ECG and enzyme levels fitting a diagnosis of either myocarditis or pericarditis at a rate of more than 10 times that seen in the recent DOD and HHS vaccinations. In vaccinia-naïve subjects, myopericarditis occurred at a rate of 5730 per million (seven cases in 1307 subjects) in ACAM2000™ vaccinees, and 1038 per million (three cases in 363 subjects) in Dryvax®
No cases of myopericarditis occurred among 1819 vaccinia-experienced subjects vaccinated with either vaccine.40
The rates of myopericarditis for ACAM2000™ and Dryvax®
were not statistically different in these trials.5
Thus, ACAM2000™ does not offer a significant reduction in cardiac adverse events compared with Dryvax®
. A second important conclusion from these trials is that vaccination with either strain of NYCBH-derived live vaccinia virus results in a much higher rate of cardiac complications than previously thought, despite limiting enrollment into the studies to subjects with no known cardiac risk factors. The increased detection of adverse cardiac events can be attributed to the use of ECG and enzyme tests, as well as surveying for cardiac symptoms on post-vaccination questionnaires. Surveillance studies of adverse events after smallpox vaccination in the US in 1968 did not include questions related to possible cardiac events.45
Interestingly, many of the cases of myocarditis and pericarditis detected by the advanced screening were sub-clinical or asymptomatic.
In a Phase I clinical trial, 18.9% (17 of 90) of subjects vaccinated with Dryvax®
, ACAM1000 or ACAM2000™ had a biologic false positive (BFP) syphilis test.46
The association of smallpox vaccination with a BFP syphilis test result has long been known, and has been reported to occur in as few as 4% or as many as 45% of vaccine recipients.47
A BFP syphilis test result also occurs in many individuals with autoimmune disorders such as lupus, or infections such as HIV or parvovirus B19.49
Interestingly, patients with lupus or parvovirus B19 infections are predisposed to myocarditis and pericarditis as well as other cardiac complications.50
The BFP syphilis test result indicates an individual has developed autoimmune antiphospholipid antibodies. Only a subset of ACAM2000™ or Dryvax®
vaccinees with a BFP syphilis test result had myocarditis or pericarditis, and not all vaccinees with cardiac complications had a BFP syphilis test result. Thus, a direct correlation between antiphospholipid antibodies and myocarditis or pericarditis was not found among vaccinees; however, it is possible that the study was too small for the results to reach statistical significance. A causative role of antiphospholipid antibody responses and myocarditis and pericarditis has been reported for lupus.52
The possible association of vaccination, antiphospholipid antibodies, and cardiac adverse events could reveal a mechanism by which live vaccinia vaccination causes cardiac damage and warrants further study. Of particular concern is that acute infectious myocarditis has been reported to result in lasting cardiac damage.53
The antiviral compound ST-246 inhibits viral replication in ACAM2000™-vaccinated mice.54
Another antiviral compound, cidofovir, reduced Dryvax®
vaccination side effects in cynomolgus macaques, but also compromised the protection against monkeypox challenge.55
Thus, co-administration of antiviral drugs may help reduce the frequency and severity of SAEs following vaccination with ACAM2000™ or other live vaccinia strains, but may also interfere with protective efficacy. Alternatively, a vaccine with a stronger safety profile, possibly attenuated vaccinia vaccines such as modified vaccinia Ankara (MVA), LC16m8, or subunit vaccine formulations, could be used as a first vaccination, followed by vaccination with ACAM2000™.