Neurologists are getting queries from anxious patients in the aftermath of a nationwide “temporary" pause in administration of the single-shot Janssen/Johnson & Johnson COVID-19 vaccine. As of April 12, more than 6.8 million doses of the Janssen vaccine were administered around the country. Two days later, it climbed to 7.2 million doses.
The pause, requested by both the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA) on April 13, came in the wake of reports that six young women, ages 18 to 48, had developed serious blood clotting problems after receiving the vaccine. One woman has died, four others have not recovered yet, and one woman was discharged home.
The CDC and FDA said the pause was in effect until more is known about the unusual risk for cerebral venous sinus thrombosis (CVST) and thrombocytopenia, or low levels of blood platelets.
All of the six cases of CVST and low platelets involved such symptoms as headache, nausea, vision problems, abdominal pain and malaise, seizures, and stroke that occurred between six and 13 days after receiving the vaccination. All of these women tested negative for a COVID-19 infection, and it was unclear which risk factors might have led to these serious blood clots that triggered stroke and other serious problems.
“It makes me nervous when trials are fast-tracked, but this was critical in the pandemic situation. We are probably seeing safety signals that have not been identified because of the warp-speed of this process," said Jennifer Armstrong, MD, MPH, FAHA, an associate professor of pediatrics in the section of neurology at University of Colorado who specializes in neurovascular disease. That said, she added: “The amount of COVID-19 disabilities and death, including CVST and stroke, is higher than what we are seeing in the adverse events with the vaccine."
So what should be done? “We figure out what is going on. The vaccine has still been a good, needed option for people, and most who have been vaccinated did not experience adverse events."
She and her colleagues have already received a dozen calls from worried patients, and the university has decided not to offer the Janssen vaccine until the “pause" is lifted. She is telling patients who have already had the vaccine to contact their health care provider if they develop headaches or visual changes that could be a red flag for CVST and a low platelet count.
“The risk is rare, but it is enough of a signal that we need to be cautious and pay attention to new-onset headaches or strokes in people who have recently gotten the vaccine," added Ryan Felling, MD, PhD, assistant professor of neurology at Johns Hopkins Medicine who specializes in pediatrics and stroke. “I don't think we know yet why this is happening, but it may be that the person's body is creating antibodies against the virus and that the antibodies are recognizing and attacking normal parts of the blood. I am cautioning all my patients until more is known."
Avindra Nath, MD, FAAN, clinical director of the division of intramural research at the National Institute of Neurological Disorders and Stroke, also feels that these events may be an antibody-mediated phenomena. “That there are only six people identified so far suggests that there has to be some susceptibility factor that we haven't identified yet," he said. “It is like the perfect storm. These are all young women, and they have high levels of estrogen. Other known risk factors for cerebral venous thrombosis include dehydration, obesity, and use of birth control pills. In these cases, it might be the body's immune response to the vaccine that may be the straw that broke the camel's back."
Dr. Nath, a neurovirologist, added that he believes that the federal pause is the right thing to do. It could be an unusual antibody response to the spike proteins and not due to the viral vector itself. At this point, scientists don't have a clue.
He and others stressed the importance of vaccination to prevent serious COVID-19 infections. “These vaccines have been a godsend; their success has been mind-boggling. I think these vaccines are safe given the risk of COVID-19 infection."
Stephan Mayer, MD, professor of neurology and neurosurgery at New York Medical College and director of neurocritical care and emergency neurology for the Westchester Health Network, agreed. “It is appropriate to stop and pause and let epidemiologists figure it out," he said. “What if there is something about this vaccine that can activate coagulation? If you have clots in large venous channels that drain out of the brain and this channel is blocked, the pooled blood gets backed up. The surrounding tissue gets swollen and congested. The symptoms are typical of ischemic stroke.
Meanwhile, federal officials warn that health professionals should be advised that patients who show up with symptoms of CVST and thrombocytopenia—and are assessed as having a vaccine-induced clotting event and low platelet count—should not receive low molecular weight heparin or heparin for the treatment of CVST. This class of drugs could make matters worse when vaccine-induced thrombocytopenia (or heparin-induced thrombocytopenia) is added to the mix.
Mary Cushman, MD, a vascular hematologist at the University of Vermont Medical Center, professor of medicine and pathology at the Larner College of Medicine at University of Vermont, and medical director of the Thrombosis and Hemostasis Program, conducts research on risk factors for blood clotting disorders. She has also become a COVID-19 clinical trialist as vascular problems can occur in patients with COVID-19.
“Neurologists need to be on the lookout for vaccine-induced CVST and thrombocytopenia," she said. “The federal pause on use of the vaccine means that our system is working, and this pause will allow the medical community to be aware and educated about what to do. People on the frontlines can't afford to miss this."
A quick and accurate assessment is the first step. Gustavo Saposnik, MD, PhD, MPH, associate professor of neurology at St. Michael's Hospital and University of Toronto and editor-in-chief of the World Stroke Academy for the World Stroke Organization, said that many people may be worried that they may have a vaccine-induced clot disorder following the Janssen or AstraZeneca vaccines, but it is very rare. Assessing this rare but serious adverse event requires a team approach that often begins with a person showing up at the emergency room with a persistent headache, visual problems, and maybe stroke-like symptoms. In addition, patients with vaccine-induced thrombocytopenia may also complain of abdominal pain, as clots can develop in the deep veins in the legs, pelvis, or lungs.
He said that doctors should take a medical and vaccine history, and if there is suspicion of CVST and low platelets, the work-up should include blood tests and markers such as a D-dimer test that is generally elevated in CVST (but also in COVID-19 and other infections.) Dr. Saposnik recommends that physicians follow the guidelines for the management of CVST by ordering an MRI and MRV to look for clots in the veins. They should also determine whether the platelet count is within the normal range or not and consult a hematologist.
The role of the hematologist should be to confirm this diagnosis with testing like PF4 antibodies, advise on the use of intravenous immunoglobulin, and direct alternative anticoagulation treatments to heparin. Dr. Cushman said the antibody test may take a few days to get the results back, and they need to make clinical decisions before they know the test results.
Treatments must be quickly administered, which is why the CDC and FDA sent out letters to health care practitioners throughout the country so that they are aware of the rare side effect, how to treat it, and how to report the events to the CDC's Vaccine Adverse Event Reporting System (VAERS).
The CDC's Advisory Committee on Immunization Practices (ACIP) is investigating the cases involving the six young women who experienced adverse events. The FDA and CDC held public hearings with the ACIP on April 14, at which time Janssen's chief medical officer and head of global safety, Aran Maree, MD, shared data with the committee about these events and others identified in their clinical trials.
The company has already completed one phase 3 clinical trial of the single-dose vaccine, which is built on a human adenovirus vector delivery system. The study included data on 43,783 people who received vaccine or a placebo injection. The second study that includes another 28,277 people and calls for two doses is ongoing and thus is still blinded. The company is also overseeing an open-label study in South Africa where they have delivered vaccines to 272,438 people and plan to treat and follow a total of half a million.
Janssen also had recent data on a 25-year old man who developed CVST and hemorrhage eight days after receiving his vaccine.
The April 14 meeting of the CDC's ACIP committee ended after more than four hours without a vote as to whether they have enough information to answer these two questions: Does ACIP have enough information to make interim age or risk factor recommendations for use of the vaccine? What recommendations does ACIP feel are appropriate given the current available information available on the Janssen vaccine?
The group will reconvene in seven to 10 days to see whether enough information will become available to answer these questions.
This is not the first time this serious vaccine-related side effect has come up. In the United Kingdom and Europe, AstraZeneca, a company that also uses an adenovirus vector (from a chimp), has reported the same serious side effects. For instance, in the United Kingdom, where more than 20 million doses have been administered, there were 79 cases of serious blood clots (CVST and other types of clots) and 19 deaths, according to the European Medicines Agency. Fifty-one vaccine recipients were women and 28 men. Many European countries, including Germany, Denmark, Norway, and Austria, have put a temporary suspension on use of AstraZeneca's two-dose vaccine.
According to the CDC and FDA, the combination of CVST and low platelet counts has not been observed in the mRNA-based vaccines developed by Moderna and Pfizer, which became available in December. Most of the people in the US who have been vaccinated have received the mRNA vaccines. UVM's Dr. Cushman said that she is receiving calls from people worried about these adverse events after taking the Moderna or Pfizer vaccines, and she is doing a lot of reassuring that they have not seen these problems with these vaccines.
Janssen scientists are continuing to study these serious adverse events. “While causality has not been fully established between these very rare events and our vaccine, we recognize that these events could represent an important potential risk with Janssen vaccine," said Dr. Maree.
Henry H. Bernstein, DO, MHCM, FAAP, an ACIP/CDC member and professor of pediatrics at the Zucker School of Medicine at Hofstra/Northwell, said that it is a “credit to the VAERS, co-managed by the CDC and FDA, that this signal was identified. There is a real concern that the CVST and low platelets may be attributed to the vaccine, but we will need more information and do a risk/benefit analysis to come to any decision about how to address these potential problems and decide if and when the temporary pause should be lifted."
He added that “these events are incredibly serious and have even resulted in death. Although extremely rare, the initial safety data suggest that these events are three times higher than the expected rates of these conditions in women 20-50 years of age."
“We need as many people as possible vaccinated with a COVID-19 vaccine to develop an appropriate level of herd immunity and help put this pandemic behind us," said Dr. Bernstein.
Acting FDA Commissioner Janet Woodcock, MD, said that they have hypotheses about why these rare events are occurring on the heels of the vaccine in some patients. “It may be a similar mechanism that we see with other adenovirus vector vaccines. This may be an immune response that occurs very rarely and leads to activation of platelets and these extremely rare blood clots." The vaccination triggers an autoimmune response and leads to the body's immune system attacking its own platelets or other parts of the coagulation system.
“Neurologists need to tell their patients to get vaccinated," Dr. Mayer emphasized. “Moderna and Pfizer vaccines are readily available, and their safety profile has been good."