The logic and challenge behind the FDA and CDC’s decision to temporarily halt the one-shot vaccine.
The US rollout of Johnson & Johnson’s single-dose Covid-19 vaccine was halted Tuesday as regulators race to investigate rare blood clotting complications linked to the shot. The move may force thousands of people scheduled to receive the shot this week to scramble for an alternative.
Both the Food and Drug Administration and the Centers for Disease Control and Prevention recommended a pause in distributing the vaccine after six reported cases of cerebral venous sinus thrombosis (CVST). These clots block blood flowing out of the brain and can quickly turn deadly.
The complications were found in women between the ages of 18 and 48, and they arose between six and 13 days after receiving the Johnson & Johnson vaccine. “Of the clots seen in the United States, one case was fatal, and one patient is in critical condition,” said Peter Marks, the head of the FDA’s Center for Biologics Evaluation and Research, during a Tuesday press conference.
However, the fact that so few cases led to a nationwide pause of the vaccine has raised questions about a possible overreaction.
Speaking at the White House on Tuesday, Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases, argued that the CDC and FDA were acting “out of an abundance of caution” and emphasized that their Tuesday decision was a “pause,” implying that it is meant to be temporary.
“I don’t think that they were pulling the trigger too quickly,” Fauci said.
But the move has nonetheless created confusion for people slated to receive the Johnson & Johnson shot and raised fears that it could fuel hesitancy around Covid-19 vaccines.
Johnson & Johnson itself was already reeling from a manufacturing error at one of its suppliers that ruined 15 million doses. And in Colorado, three mass vaccination sites stopped administering the Johnson & Johnson vaccine last week after 11 people reported feelings of nausea and dizziness.
For regulators, the episode highlights the tricky challenge of balancing caution against an urgent need for a vaccine in a still-raging pandemic. And as they investigate the problem, they also have to try to maintain public confidence in the vaccination program. The pause helps show that regulators are taking potential problems seriously, but if they botch the messaging, that could make people less likely to get vaccinated.
What is cerebral venous sinus thrombosis and how is it connected to Johnson & Johnson’s Covid-19 vaccine?
Cerebral venous sinus thrombosis is a condition that blocks blood from leaving the brain. In the general population, it occurs in about five out of a million people. Symptoms of CVST include headache, blurred vision, seizures, and a loss of control of the body.
However, there are several factors that made regulators pay close attention to the recent cases following vaccinations with the Johnson & Johnson shot. Marks explained that patients with these clots also had thrombocytopenia, a condition where platelets in the blood drop to very low levels, leading to bleeding and bruising. The combination of blood clots and low platelets means that patients cannot receive conventional blood clot therapies like heparin, a blood thinner. That’s why health officials want to wait to resume vaccinations with the Johnson & Johnson vaccine until they can investigate the concern and come up with new guidelines if necessary.
Another factor is that these cases occurred in younger women, who normally don’t face a high risk of these types of clots.
Very rare side effects, but right decision by @CDCgov @US_FDA to check the data and use science to guide next steps. pic.twitter.com/DWruhZRtUk
— Ali H. Mokdad (@AliHMokdad) April 13, 2021
The pause of the Johnson & Johnson vaccine mirrors a similar halt in Europe of another Covid-19 vaccine, one developed by the University of Oxford and AstraZeneca, because of concerns about blood clots. In March, the European Union’s pharmaceutical regulator halted the AstraZeneca/Oxford vaccine before allowing distribution to resume. Regulators concluded the vaccine didn’t cause an increase in overall risk of blood clots.
“This is a safe and effective vaccine. Its benefits in protecting people from Covid-19 with the associated risks of deaths and hospitalizations outweigh the possible risks,” said Emer Cooke, executive director of the European Medicines Agency, during a press conference last month.
Both the AstraZeneca/Oxford vaccine and the Johnson & Johnson vaccine are based on a modified adenovirus vector. The adenovirus is a separate virus engineered to deliver DNA instructions to cells for making the spike protein of SARS-CoV-2, the virus that causes Covid-19. Nearly 7 million people in the US have already received the Johnson & Johnson vaccine. The AstraZeneca/Oxford vaccine is still under review and has not begun distribution in the US, although the US government has already purchased millions of doses.
The mechanism connecting these vaccines to CVST isn’t clear just yet, but there are some hypotheses.
Robert Brodsky, director of the hematology division at Johns Hopkins University, said last month that the spike proteins built using the instructions from these vaccines could, in rare cases, trigger an immune system response that interferes with the regulation of blood clots. That immune response could also damage platelets, accounting for the symptoms presented. More evidence is needed to verify that is causing the problem, but it could help scientists develop ways to treat or prevent the issue.
But if a spike protein can trigger this reaction, then it’s likely that a whole intact virus could also trigger CVST in people who are vulnerable. The question is how best to protect those individuals from infection while also mitigating the risks of complications.
Rare complications with Covid-19 vaccines pose a massive challenge for public health messaging
It’s always tricky to communicate risk, but having to study and explain uncommon problems with vaccines was foreseeable. The Covid-19 vaccines were tested in tens of thousands of people in clinical trials, and all three that have begun distribution in the US — from Moderna, Pfizer/BioNTech, and Johnson & Johnson — were shown to be safe, with mild to moderate side effects.
But when vaccines make the jump from thousands of carefully screened trial participants to millions of people in the general population, rare problems — the one-in-a-million complications — start to emerge.
That already happened with the Pfizer/BioNTech vaccine after it started to roll out. Several recipients suffered severe allergic reactions to the vaccine. Similar problems emerged with the Moderna vaccine. The CDC estimated in January that the rate of allergic reactions to the Pfizer/BioNTech Covid-19 vaccine was 11.1 per million vaccinations, while the rate was 2.5 per million for Moderna. Both the Pfizer/BioNTech and the Moderna vaccine use mRNA as their means to deliver instructions to cells for making viral spike proteins. That mRNA is encased in a lipid nanoparticle, which may be what’s triggering the allergic reactions.
While researchers are still investigating the connection, the mRNA vaccines have continued distribution. Health officials modified the vaccine protocol to screen people with a history of severe allergies. They also added a 15-minute waiting period for recipients post-vaccination, since most allergic reactions arose in that window.
Regulators could, then, take a similar approach with the Johnson & Johnson shot to the one they used for allergies and the mRNA vaccines, adding a screening criterion for people at highest risk of these blood clots before they receive the Johnson & Johnson vaccine.
It’s too soon to say whether regulators did everything right when it comes to handling the pause and the public messaging around the vaccine. The willingness to wait and study potential problems may boost overall confidence in vaccinations, or the confusion and fears around complications could make more people wary. Or it may end up as a minor bump in the vaccine rollout.
And what about people who have already received the Johnson & Johnson vaccine?
Fauci said that for people who received the vaccine more than a month ago, they’re out of the woods. But people who have had the shot more recently and start to experience symptoms associated with CVST should alert their physician about their vaccination record.
“If you look at the time frame where this occurs, it’s pretty tight, from six to 13 days from the time of the vaccination,” Fauci said.
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