Can AstraZeneca dispel doubts about its shots?

With the company caught up in murky data releases and public relations misfires, experts worry that the world may turn its back on a vaccine that still holds promise for combating the pandemic.

The AstraZeneca shot was supposed to be the vaccine for a couple of billion people. It is inexpensive at just a couple of dollars per dose and can be stored in an ordinary fridge unlike the mRNA vaccines. But after reports the shot may trigger a rare side effect, and the company’s string of communication blunders, public health officials worry that the people in some countries may have lost faith in the world’s most important vaccine.

Just one week after the news of a rare and potentially deadly blood clotting disorder led some countries to halt vaccinations, the NIH issued an unprecedented and very public reprimand over the company’s release of incomplete clinical trial results in the United States. Now many physicians and scientists fear the public’s response to AstraZeneca’s missteps—which included earlier reports of muddled test results and confusing dosing schedules. Could AstraZeneca’s actions undermine the public’s trust in what clinical trials showed is a safe and effective vaccine, one that many hope would be instrumental in ending the global pandemic?

It’s been quite a comedown for the vaccine that is considered the world’s most practical shot. One of the first vaccines to be tested in clinical trials, it was born of a unique partnership between University of Oxford scientists and the British-Swedish pharmaceutical giant, which promised to have the vaccine available by October—far ahead of its competitors. And it pledged to sell it at cost to ensure it would be available for poorer nations.

“I can’t remember the rollout of another vaccine that has run into so many difficulties,” says William Schaffner, a physician and professor of preventive medicine at the Vanderbilt University School of Medicine in Nashville, Tennessee, who has been an infectious disease specialist for half a century. “This one seems to be one of their own making.”

What is of greatest concern to experts is that AstraZeneca’s is one of the key vaccines being delivered by COVAX, the global vaccine facility aiming to reach mid-and low-income countries. “The world needs this vaccine, alongside others,” says Eric Topol, a physician-scientist and clinical trials expert at Scripps Research in La Jolla, California. “We’re cheering for the company to do right, and we need this vaccine to succeed because we need it for two to three billion people.”

When National Geographic asked AstraZeneca whether it was planning public education campaigns to ease some of the confusion, or other steps to address public fears about the vaccine, a company spokesperson replied, “The U.S. trial results add to the Oxford trial data and a growing body of real-world evidence that shows this vaccine is well tolerated and highly effective against all severities of COVID-19 and across all ethnic and age groups studied.”

The spokesperson didn’t comment specifically on the issue of blood clots but wrote that health regulators in the U.K. and Europe, “have reaffirmed the benefits of the vaccine continue to far outweigh the risks.”

Early blunders

The development of AstraZeneca’s vaccine (trade name: Vaxzevria) has been rife with hitches. Last August, worldwide tests were stopped when one of the test subjects developed a form of spinal inflammation, although a safety review later revealed the grave condition was not caused by the shot. Then initial results in November 2020, from its U.K. trial were confusing because two different dosing regimens were used in some participants. This made it difficult to determine the best way to administer the vaccine. There was also a mix-up that caused some volunteers to receive only half a dose, which further muddled the trial results. More recently, studies indicated the vaccine wasn't particularly effective against the South African variant of the virus, known as B.1.351, leading that country to stop its use.

Heidi Larson, a former UNICEF official and director of The Vaccine Confidence Project at the London School of Hygiene & Tropical Medicine, worries that “the continuing reports of safety concerns and precautions certainly provoke questions and seed hesitancy.”

A poll by YouGov, conducted in the wake of the potentially life-threatening blood clot news, revealed that a significant number distrust the vaccine. More than half of people surveyed in France, Germany, and Spain think the shot is unsafe.

And in Italy, which was hit hard early and is now undergoing another deadly surge, at least half of the patients that Roberto Burioni, a physician and professor of microbiology and virology at the Universita Vita-Salute San Raffaele in Milan, sees in his practice are refusing the AstraZeneca vaccine for themselves and their children. This is in large part because of the information they’re seeing on Facebook and other social media. “I’ve never seen this in my long career—people refusing a vaccine that has been proven safe, effective, and free of charge,” Burioni says. “AstraZeneca did a masterpiece in setting up this vaccine in a very short time. But they did everything wrong in communication. So there is a lot of confusion.”

Recent troubles

The most recent troubles began in early March when the vaccine seemed to be linked to at least 15 cases of a rare and potentially life-threatening blood disorder, causing blood clots and low platelet counts that resulted in internal bleeding and strokes. This report prompted 13 EU nations, including France, Spain, and Germany, to temporarily halt their vaccination campaigns. Inoculations were resumed when the European Medicines Agency (EMA) pronounced the vaccine to be generally safe; the benefits of being protected against COVID-19 far outweighed the risks of COVID-19, which can be deadly. The agency added that the incidence of blood clotting was about what would be expected in similar-sized populations in normal circumstances.

Since the initial report in early March, the number of cases has risen to 62 out of 9.2. million people who have received the vaccine in the European Economic Area (EEA), according to the latest figures from the EMA. Those cases resulted in 10 deaths, in Germany, the United Kingdom, and in Norway, which has seen five cases, three of which led to death. These five cases occurred after vaccinating 130,000 Norwegians with the AZ vaccine. That’s a high incidence with grave consequences in what was generally considered a previously healthy, young population, Sara Viksmoen Watle, chief physician at the Norway Institute of Public Health, told Science. These cases have prompted the German government to restrict the vaccine to people over 60 because the side effects seem confined to a younger population.

With the blood clotting issue unresolved, the European Medicines Agency is convening an expert panel to figure out what may be triggering these side effects. In the meantime, German scientists at the University of Greifswald doing preliminary work hypothesize that this condition resembles an unusual side effect of the blood thinner heparin, called heparin-induced thrombocytopenia, which is treatable if caught in time.

Figuring out whether the vaccine causes the severe reaction will enable physicians to diagnose and possibly treat it, and also predict who might be predisposed to this clotting issue before they receive their shot.

This is something entirely different from the garden variety type of blood clots, says Nigel Key, a hematologist and director of the hemophilia and thrombosis center at the University of North Carolina School of Medicine in Chapel Hill. The syndrome presents a unique combination of symptoms, including blood clots that occur in unusual places, and in seemingly contradictory fashion, it’s also associated with a drop in platelet counts, the substances that help blood coagulate. “It’s the peculiarity of this particular syndrome that is unusual,” he says. “Many had cerebral thrombosis [strokes and bleeds]. So it greatly narrows down the possibilities of what we’re seeing. But it’s really just a matter of time until this is nailed down in terms of frequency and mechanism.”

More bad news

On Monday, March 22, AstraZeneca released the much-anticipated results from its largest clinical trial, which involved more than 32,000 participants. The company reported that the efficacy of the vaccine was 79 percent. The U.S. Data Safety and Monitoring Board (DSMB), an independent group of experts that oversees patient safety and trial integrity, accused it of omitting data to make the vaccine look more effective.

In a harshly worded letter, which was obtained by several news outlets, the safety board charged that the company had used “outdated and potentially misleading” data in its analysis. “Decisions like this are what erode public trust in the scientific process,” noted the oversight board, prompting Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases, to call it “an unforced error” that could “contribute to a lack of confidence in the process.”

"This was egregious," agrees Topol of Scripps Research who has overseen more than a dozen clinical trials involving hundreds of thousands of people around the world. “I’ve never seen something like this. Never.”

AstraZeneca responded to the criticism by maintaining it was using preliminary data collected up until a February 17 cutoff. When the British-Swedish pharmaceutical giant released its final data two days later on March 24, - after all cases of COVID-19 contracted during the clinical trials were factored in - the efficacy of the vaccine was 76 percent, 3 percent lower than the figure released on Monday.

Early this month the company plans to apply to the U.S. Food and Drug Administration for emergency authorization, but the shot may face stiffer scrutiny because of all the controversies. “The FDA will look especially carefully at all of this data,” says Vanderbilt’s Schaffner. “But I still anticipate a favorable FDA response.” 

How will this play out in poorer nations? 

With the string of communications blunders and a rare side effect, the developing world may view the AstraZeneca vaccine as a second-rate substitute that’s being dumped on poorer nations. A lot of hopes were pinned on this vaccine because it is cheaper and easier to produce and can be stored for up to six months. Thailand and Indonesia temporarily halted its use, pending the outcome of the blood clotting investigations. The Democratic Republic of the Congo postponed its proposed rollout, and Cameroon has decided not to use the AstraZeneca vaccine because of safety concerns. However, the AstraZeneca vaccine is slated to be used in more than 140 countries, including Indonesia, the Philippines, Fiji, Ghana, and India.

But sub-Saharan Africa alone has over a billion people. To vaccinate the continent’s population, two billion doses will be needed of the AstraZeneca shot—two per individual—to ensure that everyone is fully vaccinated. If the world doesn’t reach herd immunity, the virus will continue to replicate and evolve, yielding new variants that would continue to circulate.

“The reality for most African countries is the AstraZeneca vaccine is the primary one,” says Shabir Madhi, a professor of vaccinology at the University of Witwatersrand in Johannesburg, South Africa. “African countries don’t have many choices in terms of which vaccines are available.” Other vaccines might not be available until the middle of May, by which time we might be facing another resurgence, says Madhi.

 Still, more than 20 million doses have been administered in the EU and the U.K., and another 27 million doses in India (where the vaccine is called Covishield), with relatively few blood clotting incidents.

The WHO is standing solidly behind the vaccine, which is still one of the only options for global health and has been approved for use in more than 70 countries. And it remains in high demand by members of COVAX, the WHO-led collaborative effort to deliver vaccines to the developing world. “The AstraZeneca COVID-19 vaccine (including Covishield) continues to have a positive benefit-risk profile, with tremendous potential to prevent infections and reduce deaths across the world,” according to a WHO statement released on March 19.

Schaffner, the Vanderbilt infectious disease specialist, is confident that once the FDA approves the vaccine, it will dispel a lot of the remaining skepticism. “Other ministers of health around the world will take some comfort that our FDA has given it the green light,” says Schaffner, “and it will make them more comfortable.”

Other vaccine controversies

This isn’t the first time a vaccine rollout has hit snags. And serious side effects can become evident when millions of people are getting a shot. This was true for the yellow fever vaccine, which in rare instances can cause an allergic reaction that triggers difficulty breathing or swallowing (anaphylaxis), brain or spinal cord swelling (encephalitis), or organ failure.

“There have been some serious confidence crises around different vaccines,” says Larson. “But it’s almost always because of a particular issue that creates concern and not this dribbling that slowly wears down confidence.”

The 1976 swine flu fiasco, for example, is a cautionary tale about how acting in haste can erode public trust. When a group of Army recruits in Fort Dix, New Jersey, were sickened by a virulent form of influenza, tests revealed that the virus had a similar genetic structure as the culprit behind the deadly 1918 Spanish flu epidemic that killed millions. Without waiting for evidence that the small outbreak could escalate into an epidemic, the Ford White House pushed for a widespread vaccine campaign that resulted in 45 million Americans receiving a swine flu shot.

But there was no epidemic and vaccinations were halted in 1976. But by then, the damage had been done: 450 Americans who received the vaccine developed a rare autoimmune condition called Guillain-Barre syndrome, which can cause muscle weakness and paralysis (although we still don’t know whether the shot was responsible for these adverse effects). The fallout included the firing of the director of the Centers for Disease Control (as it was called then) and congressional hearings, which undermined the credibility of the agency for years afterward.

But the so-called “Cutter incident” in 1955 had far more deadly consequences. After the successful introduction of the polio vaccine that April, Cutter Laboratories in Berkeley, California, produced a vaccine that contained polio viruses that hadn’t been completely killed. More than 120,000 children were given these shots, which were responsible for the deaths of five children and for paralyzing 51 others. While this man-made polio epidemic was a dark chapter in the annals of public health, vaccinations resumed in the fall of 1955 once the source of the outbreak was identified, and this disaster led to a better system of regulating vaccines.

“It was a different time then,” Paul Offit, a professor of vaccinology at the Perelman School of Medicine at the University of Pennsylvania, said. “People were less cynical and generally trusted pharmaceutical companies.”

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