The curious case of AstraZeneca’s Covid-19 vaccine

AstraZeneca’s Covid-19 vaccine is facing a crisis of confidence, with one European country after another, as if seized by a fit of panic, temporarily suspending its use over concerns about reports of blood clots in people who received it.

Denmark, Iceland, and Norway had earlier said they would temporarily stop using the two-dose vaccine. On Sunday, Ireland announced a similar decision. France, Germany, and Italy followed on Monday.

Experts and Europe’s regulatory body insist that the vaccine’s benefit — preventing Covid-19 and helping to stop the pandemic — outweighs its risks. They note that the number of people to report the side effect is relatively small, and no causal link has been established.

But experts are also now worried that the decisions by multiple countries to suspend the vaccine’s use could make it harder to convince people to receive it should the concerns turn out, as they expect, to be a false alarm.

“When there are choices, I think the inclination would be that you aren’t stuck, so to speak, with a vaccine if you have questions,” said Sue Desmond-Hellmann, the former CEO of the Bill & Melinda Gates Foundation and a Pfizer board member. She said the concerns may be overstated, and that she is surprised how quickly European countries decided to act.

The decisions, even if temporary, are likely to have other ripple effects.  They put extraordinary pressure on a large clinical trial of the AstraZeneca vaccine being conducted in the United States, which has not authorized the vaccine’s use. And they raise questions about the rollout of a product that, globally, was expected to be produced most inexpensively and distributed most broadly.

In the wake of the decisions by more countries to suspend the vaccine’s use, the European Medicines Agency called an “extraordinary meeting” on Thursday to analyze the risks of the vaccine.

“While its investigation is ongoing, EMA currently remains of the view that the benefits of the AstraZeneca vaccine in preventing COVID-19, with its associated risk of hospitalisation and death, outweigh the risks of side effects,” the agency said in a statement.

The EMA said that the concern is related to blood clots with “unusual features” including low levels of platelets, which are involved in creating clots. Still both the EMA and AstraZeneca emphasized that the number of blood clot-related events, which could include clots in the legs and also more severe outcomes like heart attacks or strokes, seem not to be higher than the rate seen in the general population.

Sir Richard Peto, an emeritus professor of statistics at the University of Oxford, said that there was no good evidence of a hazard, and that he worried that the Norwegian medical agency, which first raised concerns, is not taking into account the underlying risk of clots. Even if vaccine decreased the risk of blood clots in older people, Peto points out, some blood clots would be expected to occur.

“Unless they’ve got serious evidence of hazard, they shouldn’t put out press statements that will very clearly be taken as evidence of hazard,” Peto said.

Side effect scares are common with vaccines, but they also very often do not pan out. The reason is that so many people receive vaccines that some will experience what seems like a side effect by chance when, really, it is not related to the vaccine at all.

“Vaccines protect against one thing: the infection or the infection plus disease,” said Susan Ellenberg, a biostatistician at the University of Pennsylvania who once tracked vaccine side effects at the FDA. “They don’t protect you against everything else that might possibly happen to you.”

That means that right after the vaccine is given to people, some will come down with cancer, or have heart attacks, or suffer falls. “There’s no reason to think that somehow there’s a magical period of time like, you know, four days or a week or two weeks after you get vaccinated, when none of those other horrible things are going to happen to you,” Ellenberg said.

But for some people, and even for some doctors and health ministers, seeing a strange health occurence happen right after a vaccine is given can make it hard to believe that the vaccine did not cause the problem.

“That’s something that’s very hard for people to process,” Ellenberg said. “That temporal association just gets them every time.”

The risk, she said, is losing an effective and safe vaccine that could help stop the pandemic to a coincidence. It’s happened before, she notes. 

She points to the story of the first vaccine for Lyme disease, developed by SmithKline Beecham in the late 1990s. The clinical trials for the vaccine showed that arthritis occurred at similar rates in both the vaccine and placebo groups. But media reports and suits by plaintiff’s lawyers led to fears among members of the public. Even after a panel of outside advisers to the FDA voted that the vaccine’s benefits outweighed its risks, sales fell so low that the company withdrew the vaccine from the market.

But part of what is feeding the actions taken by individual countries may be that there is less confidence about the AstraZeneca vaccine than for vaccines developed by other companies that are quickly becoming available.

Approvals for the AstraZeneca vaccine are based on clinical trials that were conducted in the U.K., Brazil, and South Africa. Published analyses of the data pool these clinical trials, an unusual strategy. The trial also included information on a second dosing strategy, which used a lower first dose and waited longer between the two doses.

The EMA’s report on the results says “the dossier suffers from a lack of sponsor oversight which impacts the reporting of data and therefore data integrity.” However, it concludes that “the data are sufficiently robust to allow conclusions regarding efficacy and safety.” The EMA estimated the vaccine was about 60% effective, and the data presented show no signs that patients receiving the vaccine were any more likely to develop blood clots than those on placebo.

AstraZeneca has not filed with the U.S. Food and Drug Administration, which likely means the FDA wants to wait for U.S. results, which could come any day.

Desmond-Hellmann, who ran drug development at Genentech, said she believes concerns about AstraZeneca’s vaccine stem at least in part from its rollout.  

She described as “unfortunate” “how it was carried out and how it was communicated. The clinical trial for the AstraZeneca vaccine was extremely confusing and led to, I think, an overall lack of confidence.” 

The AstraZeneca studies, she said, seemed to include “experimental tinkering.” And normally, in a late-stage study, the goal is to have no tinkering at all, but show a clear, definitive result. She emphasized that having many active and safe vaccines is good for the world.

The U.S. study, started last September and including 30,000 patients, is, like the studies for the Moderna and Johnson & Johnson vaccines, being run with the U.S. National Institutes of Health. It’s the best hope for settling any questions or concerns about the AstraZeneca vaccine once and for all.

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