Putting COVID-19 vaccine reactions into perspective

ByCaitlyn Stulpin

Experts have worked to reassure people that the benefits of COVID-19 vaccination outweigh the risks, which primarily include short-lived reactions.

The expected side effects include pain, swelling and redness at the injection site, fever, fatigue, headache, chills, muscle aches and joint pains, said Sandra Adamson Fryhofer, MD, an AMA trustee and member of the CDC Advisory Committee on Immunization Practices (ACIP) COVID-19 vaccines work group.

COVID-19 sign — More than 126 million people in the U.S. are fully vaccinated against COVID-19.
*Source: Adobe Stock*.

“We have three vaccines that are safe and highly effective that have been authorized by the FDA for COVID-19, and this is very, very exciting,” Fryhofer told Healio. “We are fortunate this happened so quickly.”

All three vaccines were tested in large phase 3 clinical trials — around 44,000 patients were included in the Pfizer-BioNTech clinical trial, 30,000 in the Moderna trial and 40,000 in the Johnson & Johnson trial — and all included diverse populations in terms of race, ethnicity and age, as well as patients with underlying medical conditions, Fryhofer noted.

Sandra Adamson Fryhofer

Anthony S. Fauci

“They set up their clinical trials in the right way, but even though they did it right and the trials were large, these phase 3 trials are often not large enough to detect rare adverse events,” she said. “This is why post-authorization safety surveillance is so important.”

Some side effects, including fever and muscle aches, are signs that the vaccine is working. More serious adverse effects — blood clots in combination with low platelet counts, and anaphylaxis — have also occurred and can be life threatening.

Healio spoke with Fryhofer to put reactions to the Pfizer-BioNTech, Moderna and Johnson & Johnson vaccines into perspective.

mRNA vaccines

More than 160 million people in the United States have received at least one dose of COVID-19 vaccine since the first FDA emergency use authorizations (EUAs) were issued in December, and more than 126 million people are fully vaccinated, according to tracking by the CDC. Globally, more than 1.5 billion doses have been administered, according to Our World in Data, a research group affiliated with the University of Oxford.

“I still remember watching with joy as 90-year-old Maggie Keenan and none other than William Shakespeare received the first of Great Britain’s Pfizer vaccine doses,” Fryhofer said. “It was so exciting.”

Shortly after the start of vaccinations, reports of anaphylaxis emerged — a side effect that had not showed up in either of the large messenger RNA vaccine trials, according to Fryhofer.

Data published in February in JAMA demonstrated that the reactions are rare: Just 4.7 cases per million doses of the Pfizer-BioNTech and 2.5 cases per million doses of the Moderna vaccine were reported among the first 17.5 million doses administered of the two mRNA vaccines.

“When considered in the context of morbidity and mortality from COVID-19, the benefits of vaccination far outweigh the risk of anaphylaxis, which is treatable,” the authors of the study wrote.

Last month, the NIH announced the start of a phase 2 clinical trial to determine whether people who are highly allergic or have a mast cell disorder are at increased risk for an immediate, systemic allergic reaction to either of the mRNA vaccines.

According to the NIH, 3,400 adults aged 18 to 69 years will be enrolled in the study at up to 35 academic allergy research centers nationwide. Approximately 60% of study participants will have either a history of severe allergic reactions or a diagnosis of a mast cell disorder, whereas 40% of participants will not. A second group will consist of people with no history of any allergic reactions or allergic disease and no history of a mast cell disorder.

The NIH said approximately two-thirds of participants in each group will be female because severe allergic reactions to vaccines in general and specifically to the Moderna and Pfizer-BioNTech COVID-19 vaccines have occurred mainly in women.

Data from the trial will likely be available late this summer.

“The public understandably has been concerned about reports of rare, severe allergic reactions to the Moderna and Pfizer-BioNTech COVID-19 vaccines. The information gathered during this trial will help doctors advise people who are highly allergic or have a mast cell disorder about the risks and benefits of receiving these two vaccines,” Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said in a release. “However, for most people, the benefits of COVID-19 vaccination far outweigh the risks.”

Johnson & Johnson vaccine

The Johnson & Johnson vaccine has been linked to a different and dangerous adverse effect — rare types of blood clots in unusual places, including cerebral venous sinuses thrombosis (CVST), in combination with thrombocytopenia. The CDC has named this syndrome TTS thrombosis with thrombocytopenia syndrome, Fryhofer noted.

Federal health officials called for a pause in the rollout of the vaccine after six reported CVST cases occurred out of the first 6.8 million doses of the vaccine that were administered as of April 12, all among women aged between 18 and 48 years. During the pause, more cases were identified and a total of 15 TTS cases were confirmed, Fryhofer said.

More cases have been reported since then. Among those patients — all female — 12 had CVST, none were pregnant or postpartum, none had a history of coagulation disorder and none were diabetic, Fryhofer said. Two patients did have high blood pressure, two had an underactive thyroid, seven had obesity, and two used oral contraceptives, but the only real risk factors identified across the board were gender and age, she said. Fryhofer noted that all cases were in people aged 18 to 59 years and all occurred between 1 to 2 weeks after receiving the Johnson & Johnson vaccine.

The ACIP reviewed available data at its April 23 emergency meeting, just 10 days after the pause was initiated, and determined that the benefits of vaccination outweighed the risks. It recommended the vaccine again for those aged 18 years and older, but under an amended EUA with an additional warning: Women under age 50 years should be made aware of a rare risk for blood clots and low platelets following vaccination.

“Women also need to know that there are other COVID-19 vaccines out there that don’t pose this small risk,” Fryhofer said. “There have been no reports of CVST with thrombocytopenia in 182 million mRNA COVID vaccine doses administered.”

According to a presentation during a recent ACIP meeting, per 1 million women taking oral contraceptives, the risk for ischemic stroke is 99 to 162, the risk for heart attack is 37 to 58, the risk for thrombotic stroke is 151 to 156, the risk for cerebral venous sinus thrombosis is 30 and the risk for venous thromboembolic events is 300 to 900, Fryhofer said.

However, she noted that the blood clots in TTS are not standard blood clots and differ from those seen in women on oral contraceptives.

“Usually when we detect blood clots, we turn to blood thinners like heparin, but for these types of blood clots, that standard treatment could cause tremendous harm. The clinical course is similar to HIT autoimmune heparin-induced thrombocytopenia,” Fryhofer said.

“We don't have our arms around a risk factor profile that can help us other than age and gender,” she said, adding that one TTS case occurred in a male during the phase 3 trial and several more cases in males have been reported since the pause was lifted. In total, Fryhofer said there have been 28 cases among 8.7 million doses administered, six of which were in males.

“There is risk, but we're in a pandemic and this vaccine is highly effective and it was tested at a time when the variants were out there,” Fryhofer said. “It is the only single-dose vaccine option available. There are some people who only are able to get one dose of vaccine, so, to me, this is an important vaccine to have as a tool for getting isolated, rural and transient populations vaccinated. This is a global pandemic. Its logistical advantages could greatly increase vaccination in other countries.”

When the pause was lifted, the reporting rate for women aged younger than age 50 years was higher, about seven cases per 1 million, as compared with less than 1 in a million (0.9 per million) for women aged 50 years or older, Fryhofer said. The reporting rate was highest for women in their 30s 11.8 per 1 million doses.

Fryhofer said the ACIP will continue to review vaccine safety surveillance reports from the CDC and FDA.

“The bottom line here is women under 50 need to be made aware that there's a rare risk of blood clots and low platelets following vaccination with the Johnson & Johnson vaccine. They should be made aware that there are other COVID-19 vaccines out there that don't pose these risks,” Fryhofer said. “The FDA has updated the emergency use authorizations with an additional warning, but having this effective, single-dose, easy-to-transport and -store vaccine available and making sure that our patients understand this, to me, will increase vaccination and empowers patient choice.”