AstraZeneca’s new clinical trial results are positive but confusing, leaving many experts wanting to see more data before passing final judgment on how well the vaccine will work.
A volunteer participating in the AstraZeneca vaccine trial having blood drawn in Oxford, England, last week.Credit…Andrew Testa for The New York Times
- Nov. 24, 2020
This month has seen a torrent of news about experimental vaccines to prevent Covid-19, with the latest development from AstraZeneca and the University of Oxford. On Monday they announced that a preliminary analysis showed their vaccine was effective — especially when the first dose was mistakenly cut in half.
The announcement came on the heels of stunning reports from Moderna, as well as Pfizer and BioNTech. But AstraZeneca’s news was murkier, leaving many experts wanting to see more data before passing final judgment on how effective the vaccine may turn out to be.
Researchers at the University of Oxford built the vaccine using a kind of virus, called an adenovirus, that typically causes colds in chimpanzees. They genetically altered the virus so that it carried a gene for a coronavirus protein, which would theoretically train a person’s immune system to recognize the real coronavirus.
Adenovirus-based vaccines are also being tested by Johnson & Johnson, as well as by labs in China, Italy and elsewhere. An adenovirus-based vaccine called Sputnik V is already being distributed in Russia on an emergency basis, although researchers have yet to release detailed results from their late-stage trial.
Scientists have been testing adenovirus-based vaccines for decades, but it wasn’t until July of this year that the first one was licensed, when Johnson & Johnson got approval from European regulators for an Ebola vaccine.
In the spring, AstraZeneca and Oxford started running clinical trials, first in Britain and then in other countries including the United States. The first round of trials showed that the vaccine prompted volunteers to produce antibodies against the coronavirus — a good sign.
On Monday, AstraZeneca and Oxford released details about the first 131 volunteers to get Covid-19 in late-stage trials in the United Kingdom and Brazil. All of the volunteers got two doses about a month apart, but in some cases the first dose was only at half strength.
Surprisingly, the vaccine combination in which the first dose was only at half strength was 90 percent effective at preventing Covid-19 in the trial. In contrast, the combination of two, full-dose shots led to just 62 percent efficacy.
No one knows. The researchers speculated that the lower first dose did a better job of mimicking the experience of an infection, promoting a stronger immune response. But other factors, like the size and makeup of the groups that got different doses, may also be at play.
It was a lucky mistake. Researchers in Britain had been meaning to give volunteers the initial dose at full strength, but they made a miscalculation and accidentally gave it at half strength, Reuters reported. After discovering the error, the researchers gave each affected participant the full strength booster shot as planned about a month later.
Fewer than 2,800 volunteers got the half-strength initial dose, out of the more than 23,000 participants whose results were reported on Monday. That’s a pretty small number of participants on which to base the spectacular efficacy results — far fewer than in Pfizer’s and Moderna’s trials.
For years, Oxford researchers have been testing their chimpanzee adenovirus vaccine, ChAdOx1, on a number of other diseases including Ebola and Zika. Although none of those studies have reached the final, so-called Phase 3 trials, they have allowed researchers to examine the safety of the vaccine platform. The researchers have not found any serious side effects.
When the researchers adapted ChAdOx1 for Covid-19, their early clinical trials also did not turn up any adverse reactions. In Phase 3 trials, however, the testing had to be paused twice when volunteers experienced neurological problems. The Food and Drug Administration did not directly tie the vaccine to the problems, but when the agency allowed the trial to resume in the United States, it advised the company to be vigilant for any signs of similar problems.
In their announcement on Monday, AstraZeneca and Oxford said that no serious safety issues were confirmed related to the vaccine.
AstraZeneca’s vaccine has a number of advantages over other leading vaccine candidates: It’s easier to mass produce and store, and it’s also cheaper, at $3 to $4 per dose. That reflects the prices paid by governments like the United States that have placed orders for tens or even hundreds of millions of doses of the vaccine. U.S. health officials have promised that Covid-19 vaccines will be available free of charge to any American who wants one.
The Road to a Coronavirus Vaccine
Words to Know About Vaccines
Confused by the all technical terms used to describe how vaccines work and are investigated? Let us help:
- Adverse event: A health problem that crops up in volunteers in a clinical trial of a vaccine or a drug. An adverse event isn’t always caused by the treatment tested in the trial.
- Antibody: A protein produced by the immune system that can attach to a pathogen such as the coronavirus and stop it from infecting cells.
- Approval, licensure and emergency use authorization: Drugs, vaccines and medical devices cannot be sold in the United States without gaining approval from the Food and Drug Administration, also known as licensure. After a company submits the results of clinical trials to the F.D.A. for consideration, the agency decides whether the product is safe and effective, a process that generally takes many months. If the country is facing an emergency — like a pandemic — a company may apply instead for an emergency use authorization, which can be granted considerably faster.
- Background rate: How often a health problem, known as an adverse event, arises in the general population. To determine if a vaccine or a drug is safe, researchers compare the rate of adverse events in a trial to the background rate.
- Efficacy: A measurement of how effective a treatment was in a clinical trial. To test a coronavirus vaccine, for instance, researchers compare how many people in the vaccinated and placebo groups get Covid-19. The real-world effectiveness of a vaccine may turn out to be different from its efficacy in a trial.
- Phase 1, 2, and 3 trials: Clinical trials typically take place in three stages. Phase 1 trials usually involve a few dozen people and are designed to observe whether a vaccine or drug is safe. Phase 2 trials, involving hundreds of people, allow researchers to try out different doses and gather more measurements about the vaccine’s effects on the immune system. Phase 3 trials, involving thousands or tens of thousands of volunteers, determine the safety and efficacy of the vaccine or drug by waiting to see how many people are protected from the disease it’s designed to fight.
- Placebo: A substance that has no therapeutic effect, often used in a clinical trial. To see if a vaccine can prevent Covid-19, for example, researchers may inject the vaccine into half of their volunteers, while the other half get a placebo of salt water. They can then compare how many people in each group get infected.
- Post-market surveillance: The monitoring that takes place after a vaccine or drug has been approved and is regularly prescribed by doctors. This surveillance typically confirms that the treatment is safe. On rare occasions, it detects side effects in certain groups of people that were missed during clinical trials.
- Preclinical research: Studies that take place before the start of a clinical trial, typically involving experiments where a treatment is tested on cells or in animals.
- Viral vector vaccines: A type of vaccine that uses a harmless virus to chauffeur immune-system-stimulating ingredients into the human body. Viral vectors are used in several experimental Covid-19 vaccines, including those developed by AstraZeneca and Johnson & Johnson. Both of these companies are using a common cold virus called an adenovirus as their vector. The adenovirus carries coronavirus genes.
- Trial protocol: A series of procedures to be carried out during a clinical trial.
There’s still a long way to go.
It is not yet clear whether the results announced on Monday are enough for AstraZeneca to take the first formal step of the regulatory process: submitting an application to the F.D.A. to get emergency authorization to distribute its vaccine. AstraZeneca plans to start testing the half-strength initial dose in its continuing United States trial and to ask the agency for guidance on how to proceed. The agency is likely to advise the company to collect more data on its promising dosing plan before submitting a formal application to authorization, several vaccine experts said.
Collecting more data might mean waiting for more results from participants in Britain who got the half dose. It might also mean waiting for the first results from the American study, which aren’t expected until next year.
Outside experts have plenty of unanswered questions.
“The only thing that you can really say right now is that the vaccine seems to work,” Florian Krammer, a virologist at the Icahn School of Medicine at Mount Sinai in New York City. “It’s just hard to say how well it works compared to others.”
Experts have had a hard time parsing the results because of the way they were announced. Like the results from Pfizer and Moderna, the data on AstraZeneca’s vaccine was summarized in a news release.
Although the announcement gave efficacy rates, it left out details that would have helped outside researchers independently assess the data: It did not say how many cases of Covid-19 were found in the group that got the half-strength initial dose, or in the group that got the regular-strength initial dose, or in the group that got a placebo. It also did not say how many severe cases were found in the placebo group.
The results were pooled from across the two studies in Britain and Brazil, which have slightly different designs. To complicate matters further, details weren’t available on exactly how those trials were designed, because AstraZeneca and Oxford haven’t publicly released the protocol documents that serve as a road map for how those trials are evaluating the vaccine. (AstraZeneca has, however, released the protocol for its continuing trial in the United States.) That means we don’t know, for example, how many Covid-19 cases will need to turn up in order to prompt the end of the British and Brazilian studies.
Some of these questions may be answered when the results are published in a peer-reviewed journal, which is expected soon.