aamc.org does not support this web browser.
  • AAMCNews

    Is it safe? How experts assessed J&J’s suspended COVID-19 vaccine

    The pause of the Johnson & Johnson vaccine after six cases of serious illness among 7 million vaccinated people shows how a federal panel weighs the risks and benefits of medical protection that might also cause severe harm.

    COVID-19 Vaccine Side Effects

    Editor’s note: On April 23 the federal advisory panel described in this article recommended the resumption of J&J vaccinations, with an update to the vaccine label about risks of a rare, but serious, blood clotting condition in women under 50.

    One in a million doesn’t sound like a lot. But what if you’re on a committee that has to decide whether your country should use a vaccine that protects people from a potentially fatal disease — yet in some cases appears to cause a rare blood clotting condition that could be deadly? What if that appears to only happen to people of certain ages, but you suspect that you don’t know about all the cases?

    Those are among the questions facing doctors on the Advisory Committee on Immunization Practices (ACIP) that meets on April 23 to recommend whether to continue using one of the three COVID-19 vaccines that have been authorized for use in the United States. At least six Americans have fallen critically ill, including one who died, after receiving the vaccine made by Johnson & Johnson (J&J), prompting federal officials to halt the vaccinations while ACIP assesses the danger — as well as the harm of removing a vaccine amid a pandemic that has killed more than 560,000 people in the United States in just over a year.

    “We’re going to have to balance the risks and benefits of vaccinating people” with the J&J vaccine, says ACIP member Henry Bernstein, DO, a professor of pediatrics at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell in New York. “Any health intervention has some risk.”

    The deliberations of ACIP has shed light on how the federal government checks on the safety of vaccines in the real world after approving them as safe based on clinical trials. Once a vaccine is approved or authorized for public use, Bernstein explains, “the evaluation doesn’t stop.”

    How do regulators find out about serious side effects?

    The Food and Drug Administration (FDA) licenses vaccines, while the Centers for Disease Control and Prevention (CDC) makes recommendations about their specific use, and both watch for safety concerns thereafter. ACIP advises the CDC about how to use vaccines to control diseases.

    Several systems inform federal health officials about possible safety issues arising from vaccines that are on the market. For the J&J vaccine, alerts sprung from the Vaccine Adverse Event Reporting System (VAERS) — an early warning system to which anyone, from patients to doctors, can submit a report about side effects.

    VAERS reports have set off investigations before that led federal officials to withdraw vaccines from public use. For instance, a vaccine for rotavirus — a gastrointestinal virus that kills an estimated 215,000 young children worldwide each year — was pulled in 1999 on recommendations from ACIP because it sometimes caused intestinal blockage in infants.

    As explained by the CDC’s Immunization Safety Office, staff at the CDC and FDA code each VAERS report, marking as “serious” those that involve death, life-threatening illness, hospitalization or the prolonging of a hospitalization, permanent disability, congenital anomalies, or birth defects.

    For “serious” reports, the CDC uses medical records to assess each case and analyzes cumulative data to “determine if a statistically meaningful association exists between the vaccine and the adverse event,” according to the safety office. If so, the CDC conducts a deeper review that can include referring the issue to ACIP, which is currently composed of 15 voting members (13 doctors, a nurse, and a lawyer).

    How did the J&J vaccine raise concerns?

    Americans started getting the J&J vaccine on March 2. Later that month and into April, FDA evaluators grew alarmed by six reports of people who got the vaccine and developed a rare combination of two potentially fatal disorders: a severe type of blood clot in the brain (cerebral venous sinus thrombosis, or CVST) along with low levels of blood platelets (thrombocytopenia). This was out of about 7 million doses administered by April 12, the day before the FDA and CDC asked states to stop using the vaccine. One of the patients died, two were released from the hospital, and three remained hospitalized (two of them in intensive care) by the time ACIP met to discuss the cases on April 14.

    Adding to the concerns was that the J&J reactions were nearly identical to side effects attributed to the AstraZeneca COVID-19 vaccine that has been distributed in several other countries. The J&J and AstraZeneca vaccines use the same basic technology: The vaccines include a modified version of a common virus (an adenovirus) that prompts cells to create a protein similar to the spike protein from the virus that causes COVID-19. That protein triggers the body’s immune response so that it can more effectively fight a subsequent infection.

    The European Union and the United Kingdom have reported at least 106 cases of CVST with thrombocytopenia — including 32 fatalities — among the more than 25 million AstraZeneca doses that have been administered, according to the agency that monitors vaccines in the European Union. The agency concluded that blood clots and low blood platelets “should be listed as very rare side effects” of the AstraZeneca vaccine.

    Health officials also looked at side effects reported from the two other vaccines that the FDA has authorized to combat COVID-19. No cases of CVST have been reported to VAERS among those who received a vaccine made by Pfizer, according to the CDC. The agency says that three cases have been reported for a vaccine made by Moderna — none of them in combination with low platelets and none of them fatal. Those vaccines fundamentally differ from the J&J and AstraZeneca vaccines: They use messenger RNA, not forms of other viruses, to ignite immune responses.

    How do experts know if a vaccine made people sick?

    CDC and FDA staff, along with ACIP, look more deeply at individual cases and the overall data to assess if there’s a cause-and-effect link. Among the key factors they consider:

    How often does the illness occur?

    Some have criticized the FDA and CDC for pausing the vaccine over a handful of cases (the six reported in VAERS) among about 7 million inoculations. CDC staff and ACIP members note that another nonfatal case was reported in a man who got the vaccine during one of the J&J clinical trials, and they point to the more than 100 cases from a similar vaccine in Europe. They also believe more reports might emerge because:

    • Public awareness about side effects might prompt reports from doctors and patients who had not alerted authorities to such reactions before — a common phenomenon called “stimulated reporting.”

      “My suspicion is that events like stroke” caused by blood clots “might not get flagged” as related to the vaccine, ACIP member Helen Talbot, MD, MPH, associate professor of medicine at Vanderbilt University School of Medicine, told the committee.
    • Millions of people got the J&J vaccine so recently that the side effects might not have appeared by the April 14 meeting. Symptoms of CVST (including headache, left arm weakness, and abdominal pain) typically emerge six to 13 days after vaccination, according to the CDC.

    “The true incidence of this condition needs to be revealed,” ACIP member Pablo Sanchez, MD, director of clinical and translational research at the Center for Perinatal Research at Nationwide Children’s Hospital in Ohio, said at the meeting.

    That’s why the committee delayed making recommendations at that time, opting instead to get more information from the CDC and FDA in time for a committee meeting on April 23.

    Does the illness happen more than expected?

    One of the first questions scientists ask about people getting a certain illness after being vaccinated is how often people sharing the same characteristics (such as age and health condition) contract the same illness without being vaccinated. That kind of comparison might not be possible for the J&J vaccine.

    All six people who were afflicted with CVST and thrombocytopenia after receiving the publicly released J&J vaccine were women from ages 18 through 48. Tom Shimabukuro, MD, MPH, MBA, a member of the CDC’s COVID-19 Vaccine Task Force, told the committee that the combination of CVST and thrombocytopenia is so unusual that there might not be data about its prevalence among women of that age group in the general population.

    “It’s always good to know what the baseline rate of any particular condition is,” says ACIP member Wilbur Chen, MD, a professor of medicine at the Center for Vaccine Development and Global Health at the University of Maryland School of Medicine. But the limited data that does exist convinces him that CVST with thrombocytopenia is an “extremely rare” condition in the general population, making its appearance among certain vaccine recipients stand out.

    How do experts decide whether to act?

    Several ACIP members referred to the need to conduct a risk-benefit analysis.

    “Everyone acknowledges that risk is an inherent part of life,” committee member Grace Lee, MD, MPH, associate chief medical officer for practice innovation at Lucile Packard Children’s Hospital Stanford in California, said at the April 14 meeting. “The role of ACIP is mitigating that risk” associated with a vaccine.

    The committee considers:

    How severe is the potential harm from the vaccine?

    The harm is severe, Bernstein says: “The outcome was death, persons in intensive care, everyone needing to be hospitalized.”

    How severe is the potential harm from halting the vaccine?

    That harm is also severe, according to ACIP members. Estimated death rates from the disease in the United States are exponentially higher than the rates of the most severe side effects from the J&J vaccine. Removing the vaccine could make more people vulnerable to the potentially fatal disease.

    In addition, evaluators consider if the removal of a vaccine will disproportionately harm specific populations. ACIP member Camille Kotton, MD, told the committee that because the J&J vaccine is easier to manage than the two other authorized vaccines — it doesn’t need to be stored in freezers and requires one dose instead of two — it is more suitable for delivery to homebound and transient people. “Putting this vaccine on pause would be devastating” for those populations, said Kotton, clinical director of transplant and immunocompromised host infectious diseases at Massachusetts General Hospital.

    What are the options?

    The choices include continuing the pause, lifting it, and restricting the use of the vaccine to certain populations. Regulators could also issue guidance to physicians and patients to help them decide whether to use the vaccine and to recognize and treat side effects. 

    ACIP Executive Secretary Amanda Cohn, MD, a senior advisor for vaccines at the CDC, told the committee at the April 14 meeting that it could recommend that the vaccine not be used for specific populations — meaning it could steer the vaccine away from women age 50 and below. Most members were not willing to take that step then, but Chen and Bernstein say there might be enough information this week about the age and gender characteristics of more patients to recommend limiting the vaccine to certain populations. (The European vaccine monitoring agency recommended that written warnings be issued with the vaccine; France has limited the vaccine to people over the age of 55.)

    Among complicating factors for ACIP: The afflicted person in the J&J trial was male, as were more than two dozen of those who developed severe complications after receiving the AstraZeneca vaccine. All six women who got the publicly released vaccine in the United States were White, but that might be because 64% of those who received the vaccine were White, according to CDC data.

    What are other factors to consider?

    Immediate need

    Weighing the risks and benefits of a drug for a disease that has been around for a while allows for more of a go-slow approach than assessing a vaccine in the midst of a new disease that kills thousands daily, Chen explains. “We’ve got a pandemic going on,” he says. “We need more vaccines, not less.”

    Alternative vaccines

    The CDC told the committee that the J&J vaccine accounts for less than 5% of the U.S. vaccinations against COVID-19. Moderna and Pfizer have committed to provide enough vaccines to cover the entire U.S. population by the end of July.

    Public confidence

    Evaluators worry about hesitancy over COVID-19 vaccines overall and don’t want to fuel doubts about their safety. Pausing one vaccine might make some people more skeptical about the safety of them all, while letting a vaccine continue to roll out amid safety concerns might make others doubt how well the government protects them. (In one recent survey of 1,000 registered voters, 23% said the pause of the J&J vaccine made them less likely to get any COVID-19 vaccine; another survey, of 1,500 adults, found that the pause reduced confidence only in the J&J vaccine.)

    “This is confusing to the public,” Chen explains. He and others on the committee have sought more information so that they can make a decision that stands — rather than taking an action now that they will reverse later based on new information.

    They must do that, Chen says, while recognizing that “there are no perfect solutions.”