A session at the American Heart Association Scientific Sessions covered the data behind concerns about mRNA vaccines for COVID-19 and myocarditis. Then, leaders from Pfizer and Moderna discussed opportunities the technology offers.
Cases of myocarditis following a COVID-19 vaccine are rare, typically mild, and tend to resolve quickly—a far cry from myocarditis and other complications that stem from the virus itself, according to an expert taking part in a discussion on mRNA vaccines and cardiovascular (CV) health Saturday during the 2021 American Heart Association (AHA) Scientific Sessions.
Biykem Bozkurt, MD, PhD, FAHA, a cardiologist and heart failure specialist from Baylor College of Medicine, offered an overview of myocarditis data before the AHA session turned to experts from Pfizer and Moderna, the 2 companies that have developed and distributed mRNA vaccines worldwide. The companies are the largest producers of COVID-19 vaccine in the United States, where 439 million doses have been distributed.
Mikhael Dolsten, MD, PhD, chief scientific officer and president, Worldwide Research, Development and Medical for Pfizer, first discussed the “end-to-end” approach that the company has taken with COVID-19, by being first to get a vaccine to the US market then focusing on a therapy to dramatically cut the risk of hospitalization or death.
“The comprehensive approach was … that to control the pandemic, vaccine will be crucial,” Dolsten said. “But our experience is also that when you supplement the vaccine with a therapeutic, you get the maximal opportunity of medical management.”
Then, Stéphane Bancel, MBA, CEO of Moderna, discussed how the company’s focus on mRNA since 2011 had not only paid off with a COVID-19 vaccine, but also will revolutionize vaccine and therapeutic innovation. The company now has dozens of vaccines in development. “What is very fundamental about mRNA is that it is an information molecule,” he said. “It just changes how you can do things in terms of speed.”
Because the same chemical components are used to make the mRNA from vaccine to vaccine, time to market should increase, and failure rates in drug development could fall, Bancel said.
Data on myocarditis. Bozkurt explained that myocarditis, an inflammation of the middle heart wall, had been seen in tiny numbers with other vaccines, but is also seen in the general population—about 20 cases per 100,000 people occur each year, she said.
Because cases linked to the vaccine have been more concentrated among young males—late teens and young adults—there has been alarm about the safety of the vaccine in this group. But Bozkurt said that the overall incidence of myocarditis—even before COVID-19—was more common in this group; researchers believe the higher numbers may be linked to testosterone, and Bozkurt said there’s a need to examine genetics put some at higher risk.
Still, the incidence of myocarditis is uncommon. Multiple data sets, including registry data from Israel and Department of Defense (DOD) data that tracked vaccine reactions among the military, show that the overall incidence of post-vaccine myocarditis about 1 per 100,000 people; but the rate is higher among young males. DOD reported 23 males developed myocarditis after 2.8 million doses were administered, Bozkurt said. An analysis of cases from Israel published in the New England Journal of Medicine1earlier this fall found the rate among older male teens (age 16-19) was 1 case per 6637 male recipients.
However, she said, the cases that stem from a vaccine are rarer and milder than those that arise from developing COVID-19 itself.
“There were other cardiovascular complications related to the infection itself, including DVT, myocardial infarction, intracranial hemorrhage, pulmonary embolism, that far exceeded the myocarditis risk that is seen with mRNA vaccination,” Bozkurt said. “The risk of myocarditis due to COVID-19 infection is also further confirmed by the CDC data reflecting that overall risk of myocarditis with the infection itself is 16-fold higher in the general population, and in children with age less than 16. The risk of myocarditis with COVID infection is 37-fold higher, and this underlines the necessity for us to recognize that the risk is markedly higher with the infection itself.”
When myocarditis was present after a COVID-19 vaccine, she said, some patients experienced chest pain, and EKG and cardiac troponin levels were typically abnormal. “Symptoms and findings resolved within a couple of days and the benefits of vaccinations significantly outweigh the risk,” she said.
Pfizer’s “comprehensive” approach. Even for a huge pharmaceutical company like Pfizer, being on track to deliver 3 billion COVID-19 vaccine doses worldwide by the end of 2021, while simultaneously working on an oral therapeutic that has produced phase 2/3 interim results is no small feat.
“What does this mean?” Dolsten said. “As we generate that encouraging early clinical data, at the same time, we were in parallel at risk investing thousands of scientists and of course, the funds to prepare for potential success with putting our large manufacturing and pharmaceutical site network into play….”
But, Dolsten said, that wasn’t the end. Pfizer deployed its decades of experience with vaccines to think “far beyond” the FDA emergency use authorization. “We worked with, for example, real-world evidence from Israel that we heard recently [as well as] a program with multiple stages beyond the first emergency use authorization, followed by a full approval,” which he said increased trust, but added scrutiny.
From the start, he said, Pfizer studied the durability of the vaccines and was able to show through real-world evidence the need for and value of a booster shot. Pfizer then conducted a randomized controlled trial on booster shots, using some of the population that had been the first phase of the original vaccine trial. “Again, [this] showed very favorable benefit rates,” Dolsten said.
Today, the World Health Organization estimates that up to 25% of the 28.5 million doses given daily are boosters. This is not without controversy, as WHO officials say boosters are being distributed in wealthy countries while many poor countries still cannot get everyone an initial dose.
Still, Dolsten said, the process of moving through the population from the oldest adults to those in middle age, to younger adults and finally the 12-17 and 5-11 age groups was “a creative approach that I feel really good about.”
Having an oral therapeutic is just as important. “There will be individuals that are unvaccinated or individuals that do not gain maximum vaccination due to them being immunocompromised,” he said. “I hope that gave you a bit of a feeling of what was really our comprehensive and intended approach. And it continues to be rolled out with science and data.”
Moderna’s plans beyond COVID-19. The success of its COVID-19 vaccine has put Moderna on the map—AHA President Nancy Brown noted that before the pandemic, Moderna was not a household name, but that has changed.
Bancel said it’s important to understand the versatility of the mRNA technology and the possibilities that exist for both infectious and chronic disease. Already, the company has announced that it has dosed its first participant in a phase 3 trial for a cytomegalovirus (CMV) vaccine. “As you know, for 20 years, this has been the number one priority of the National Academy of Medicine for vaccine, and large vaccine companies have not been able to make such a vaccine, because it's a very complex herpes family virus.”
He touted phase 2 to be presented at AHA by AstraZeneca involving a vaccine for the heart in those who have suffered a heart attack. “That mRNA coding is for human VEGF. And the idea here is to drive vascularization of a heart muscle after the fact,” he said. A phase 1 study showed the approach was well-tolerated, he said.
The company envisions a “pan respiratory” vaccine, with the expectation that COVID-19 will become “endemic,” and people will need an annual COVID shot in addition to a flu shot. But the good news is the new technology developed to battle COVID-19 is going to lead to better vaccines for strains of flu. “So, one shot and you'll be set for the winter,” Bancel said.
Borzkut circled back with Bancel and asked if the company would entertain a partnership with AHA or other societies to tweak the vaccine and address the lingering issues with myocarditis, however uncommon they may be.
“I would say we would be very interested,” Bancel said. “As you know, the only thing we do at Moderna is mRNA. And we are very curious to always go to mechanistic understanding, because as you say, not only it allows us to potentially tweak this product, if we figure out what is causing the observation, even though it's very rare. It will help us, because we will have a product not only in vaccine, but also in therapeutic areas.”
Mevorach D, Anis E, Cedar N, et al. Myocarditis after BNT162b2 mRNA vaccine against COVID-19 in Israel. N Engl J Med. Published online October 6, 2021. doi: 10.1056/NEJMoa2109730