Cardiac injury after vaccine administration : the smallpox experience

The eradication of the brutal smallpox virus is, rightfully so, regarded as one of the great achievements of modern man. But the lesser known story of the smallpox vaccine after smallpox was eradicated is an informative story with lots of lessons that pertain to vaccine safety monitoring and mass vaccination campaigns that were clearly forgotten, or ignored over the last 2 years.

Resuscitating the smallpox vaccine

Eradicating smallpox involved using a less virulent cousin of the virus called the vaccinia virus. The vaccine derived from this virus named Dryvax® was prepared by harvesting live virus from lesions that were grown on the skin of infected cows. The vaccine, while very effective at preventing and suppressing smallpox , had a number of adverse effects that included generalized vaccinia, eczema, encephalitis, and even death.

As the risk to the population from the smallpox virus shrank to near zero, the known risks from the vaccine became too great to subject the population to, and the smallpox vaccination campaign ended for the public in 1972 and for the military in 1989.

But in the aftermath of the 9/11 attack, the nation found itself on a war footing. One of the great fears at the time was an enemy nation may release smallpox into the population. To mitigate this risk, then President George W. Bush launched another smallpox vaccination program because it was feared that the mortality of smallpox attack in a vaccine/infection naive population would approach 25%. But because of the small but serious adverse event profile of the Dryvax® vaccine and because there wasn’t any actual smallpox circulating, the decision was made to only vaccinate potential civilian healthcare first responders, and military personnel. By June of 2004, 39,566 civilians had been vaccinated, and by September 2006, more than 1.1 million soldiers were vaccinated with Dryvax®.

To everyone’s surprise, while the historical experience with the live vaccinia virus had not suggested a significant rate of cardiac complications, this campaign revealed rates of myocardial inflammation that were ~7.5x expected background rates of myocarditis. Clustering of the cases after vaccine administration strongly suggested a causal link.

While the overwhelming majority of cases occurred in men, the single fatality related to myocarditis was female. There were also 7 cases of dilated cardiomyopathy (heart failure) reported after initiation of the vaccination program, 2 were sufficiently severe enough to require heart transplantation. There was not enough information to know if the cases of heart failure were related to the vaccinations or to myocarditis. Other than the one fatal case of myocarditis, everyone else that was followed up with myocarditis recovered and did not progress to develop heart failure.

The report of the Joint Smallpox Vaccine Safety Working Group noted :

The increased risk of smallpox vaccination–associated in- flammatory cardiac events was an important unanticipated event. Although vaccinees who developed inflammatory cardiac disease observed during this experience have largely recovered, concern remains that disease in some vaccinees could progress to DCM. These cardiac observations deserve further study.

Notably, the historical experience of cardiac injury and the smallpox vaccine had been fairly benign. Only five cases of myopericarditis were reported in the literature between 1955 and 1986 utilizing Dryvax. The Finnish strain of smallpox vaccine was reported to have an estimated incidence of post-vaccination clinical myopericarditis of 1 in 10,000 among Finnish military conscripts in 1983, and only 8 suspected cases out of 5,000,000 vaccinees were reported in the Australian experience.

Separate from these concerns, health officials were anxious to move away from the Dryvax vaccine for other reasons. Growing a vaccine on the skin of a cow was not exactly sterile, and there were theoretical concerns of selection pressures for a more virulent strain related to growing a mixed population of the virus.

The government decided to contract with Acambis, Inc (Cambridge, MA) to make a vaccine derived from a single viral clone named ACAM2000 that would use a cell culture based mode of viral production and hopefully be cleaner and safer than Drywax.

Given the higher rate of cardiac complications seen with DoD/DHHS Dryvac vaccination program, 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. Using routine ECG and laboratory tests that test for cardiac cell damage, 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 DOD/HHS vaccination experience. 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® vaccines respectively.

The current Frequently Asked Question page from the FDA about the ACAM2000™ vaccine notes “the vaccine may cause myocarditis and/or pericarditis… and can be very serious”

There were additional problems with the ACAM2000™ vaccine related to the fact it was a live replicating virus. Vaccinated individuals could spread the virus, and it could cause severe problems if spread to individuals with weakened immune systems, or individuals with a certain skin condition.

As a result, the US government then contracted with drug manufacturer Bavarian-Nordic to produce a live, non-replicating version of the smallpox vaccine called Modified Vaccinia Ankara (MVA-BN), trade name JYNNEOS that could be given to the immunosuppressed. Because of the prior cardiac issues that had been noted with prior versions of the smallpox vaccine, the trials for approval of JYNNEOS also required surveillance ECGs and blood tests to measure for cardiac damage (cardiac troponin).

Cardiac adverse events were noted to occur in 1.3% (95/7903) JYNNEOS recipients and 0.2% of placebo recipients (16/766). However, these cardiac events were extraordinarily mild. There were no cases of clinical myocarditis, and there were 28 cases of asymptomatic post vaccine elevation of troponins that were 2x the upper limit of normal. An additional 127 cases of asymptomatic post vaccination elevated troponins were noted but were not above 2x normal.

Cardiac troponins : When do they matter?

Cardiac Troponins are proteins that are only found in cardiac cells. The detection of cardiac troponins in the blood stream are indicative of egress of this particular protein out of the cardiac cell. While there are some notable reasons to have a false positive troponin, in the absence of these reasons, the only reason to have cardiac troponins exiting cells is because of cardiac injury to these cells. With regards to whether this injury is reversible or irreversible there is every reason to believe that the native configuration of the cardiac troponin protein in the cardiac cell is to be intertwined with the contractile apparatus of the cell. The main function of the cardiac cell is to contract, so release of this protein from the cell is very likely to represent irreversible injury to a portion of the contractile apparatus of the cell or cells.

Newer generation troponin tests have become ever more sensitive to small amounts of damage, and it is unclear what the long term clinical significance is of small elevations in troponins, but there is little question that the amount of cardiac troponin release tracks closely with prognosis. A peak high sensitivity cardiac troponin of 20 is highly unlikely to affect heart function or an athlete’s ability to eventually regain function at a high level, but a high sensitivity troponin of 100,000 means lots of irreversible damage that is probably not survivable without a heart transplant.

There is little doubt that there are cases of cardiac injury being discovered now, that were never picked up in an era before the existence of highly sensitive markers of injury like cardiac troponins. Once reports of myocarditis start circulating and the wider community becomes aware of the side effect, vaccinees become more likely to present to health care system with complaints that then prompt the ordering of high sensitivity tests which in turn help boost myocarditis rates. But this doesn’t mean the adverse event isn’t real, or that cardiac injury after administration of the vaccine should be waved away as important.

Casually dismissing elevations in troponins is just as bad a mistake as over-reacting to them. The degree of elevation and the context of the elevation matters. Well before Wuhan was the most recognized city in the world, there has been a concern that sudden cardiac death seen in young athletes could, in part, be related to subclinical myocarditis - cardiac injury with minimal/no symptoms. In this context, a vaccine that is known to cause clinically symptomatic myocarditis that is also associated with asymptomatic troponin elevations more than 2x the upper limit of normal in a window of time cardiac injury is expected to be seen isn’t the same thing as checking troponins after running 30 miles. Its also the case that no one is forcing you to run 30 miles, while the apparatus of the government, and wider society has been used explicitly to mandate vaccines.

The wider context and reasons a particular therapeutic is being considered is also of paramount importance. If the actual smallpox virus was circulating, and the only vaccine available was the Dryvax® vaccine, I would give it my 18 year old son myself, even with the knowledge of the attendant risk of myocarditis! If the smallpox virus was not circulating, I would hope the public health overlords would leave it to me to decide whether the risks of the vaccine was worth it. But this would require an understanding of what the risks of the vaccine were to my child - an answer that requires a careful study of the risks of the vaccine.

Remarkably, the COVID experience tells us that there are quite a few “intellectuals” that would rather no one know anything. They would rather issue blind reassurances of safety when very recent history tells us safety as it relates to the mass administration of a therapeutic to a healthy population isn’t something that just happens.. it takes years of unexpected twists and turns to navigate.

Those who would make light of troponin elevations after vaccine administration, should be aware of the markedly different rates of cardiac injury that were seen between the original Dryvax® vaccine, the ACAM2000 vaccine and the JYNNEOS vaccine. The improvement was an iterative process that is unlikely to have occurred if society had decide to normalize the adverse events of the earlier vaccine versions.

When a patient contacted my office to ask about the JYNNEOS vaccine because he had a heart condition, it was a relief to read the studies that had been performed specifically looking at this question. I could tell him that while there was low levels of cardiac injury noted in the trials in a small percentage of patients, and that none of the thousands of patients developed large enough elevations to cause clinical myocarditis. If he was at higher risk for contracting monkey-pox with its attendant severe complications, the cardiac adverse events reported in the trials should not deter him from taking the vaccine. Knowing about the cardiac events studied in the trial did not make me less likely to recommend the vaccine in this case, it made it more likely.

High quality knowledge in the hands of high quality people leads to better decision making. Unfortunately, the COVID pandemic has made clear that the public health institutions under times of stress can be persuaded to not produce high quality information, and sideline high quality people. The steps taken with regards to the COVID vaccines appear to break with fairly recent precedent for unclear reasons.

It appears that until very recently, public health programs were very familiar with the concept of focusing protection to high risk groups as well as the proper management of unexpected adverse events during a vaccination program. Regaining public trust begins with individuals and institutions rediscovering these basic principles. It may not be enough, but it sure is a start.

Anish Koka is a cardiologist. Follow him @anish_koka