AstraZeneca’s U.S. Study May Answer Some of the Lingering Questions About Its Vaccine

AstraZeneca announced the long-awaited results of the U.S. and South American study of its COVID-19 vaccine, and it was the first bit of positive news about the shot in recent weeks, after a parade of countries halted its use due to reports of blood clot complications.

In the Phase 3 study involving more than 32,000 people, AstraZeneca found that its vaccine was 79% efficacious in protecting against symptoms of COVID-19. In the trial, the two-dose shot—developed by the British-Swedish multinational pharmaceutical company in conjunction with Oxford University—was also 100% efficacious in protecting people from severe symptoms and hospitalization from the disease.

Those results differ slightly from the company’s earlier late-stage human trial, released in February, which was conducted in the U.K., U.S., South Africa, and Brazil. In that study, the overall efficacy of the vaccine was 66%. In part, that difference might be due to the fact that more of the people in that earlier study were likely exposed and infected with new, mutant versions of SARS-CoV-2, particularly one first discovered in South Africa—against which the vaccine provides slightly less protection—compared to those in the U.S., Chile and Peru, where the later trial took place.

Still, those earlier findings indicate an effective vaccine, and led many countries, as well as the European Union and the World Health Organization, to authorize its use. Then, in mid-March, reports of blood clots emerged, and many of these countries decided to suspend vaccination with the AstraZeneca regimen while they investigated the reports. On March 18, the European Medicines Agency determined after reviewing the cases that there was no increased risk of clotting or other related issues due to the vaccine, but said it would continue to monitor vaccinated people for any side effects.

In the new, U.S.-based study, the data safety monitoring board also found no increased risk of blood clots among people who were vaccinated compared to those who were given placebo. “This study puts to bed any doubts that this isn’t a highly effective vaccine against COVID-19 disease and COVID-19 symptoms,” says Mene Pangalos, executive vice president for biopharmaceuticals research and development at AstraZeneca.

AstraZeneca’s vaccine is based on technology developed by scientists at Oxford University’s Jenner Institute, and involves using a chimpanzee adenovirus modified so it cannot cause the cold infection it normally does. The chimp virus acts as a vehicle to deliver genes into the body, where it encodes the SARS-CoV-2 spike protein; cells then process the protein so the immune system can recognize it as foreign and mount a strong response against it.

The decisions by countries to halt vaccination with the AstraZeneca shot were likely “premature,” says Dr. Ann Falsey, professor of medicine at the University of Rochester and one of the coordinating investigators of the U.S. trial. The latest study bears that out, since it revealed no increased risk for blood clotting issues among people who were vaccinated than would normally occur even without the shot. Nevertheless, the reports of blood clotting and the choices of European countries to stop using the vaccine will likely factor into discussions about the safety of the shot when AstraZeneca submits its request for emergency-use authorization to the U.S. Food and Drug Administration in what Pangalos expects will be “a very small number of weeks.”

In the public’s view, the difference in efficacy data between the newer U.S.-based and the older U.K.-based studies might only add to confusion over understanding how safe and effective the AstraZeneca vaccine is. “That is the challenge of looking at different trials with different populations in different age groups and with different endpoints,” says Pangalos. “That’s why we [at AstraZeneca] have always said that inter-trial comparison is difficult and dangerous.”

The U.K.-based trial, for example, included different dosing regimens, with some people getting the planned two full doses, about a month apart, while some received a half dose and then a full dose due to a dosing mistake. Some people in that study also received their second dose up to three months after the first. The U.S. study was more consistent. “Having a well designed and consistent protocol with consistent dosing intervals is enormously helpful,” says Falsey, who is hopeful the results will allay concerns about the vaccine’s safety and efficacy.

How well the vaccine protects against the new variants of SARS-CoV-2, however, remains unclear. In a disappointing study published in the New England Journal of Medicine on March 16, researchers in South Africa found that the AstraZeneca vaccine was only about 10% efficacious against the mutated virus circulating there, following other reports that the vaccine generated lower levels of virus-fighting antibodies against the South African variant. In fact, variants may explain the difference in efficacy between the U.K.- and U.S.-based studies. The U.S.-based study began in September, and involved people in the U.S., Chile and Peru, where mutated versions of SARS-CoV-2 haven’t been dominant. The U.K.-based study, on the other hand, included people in the three countries where new variants have quickly taken over new infections—in the U.K., South Africa and Brazil—as well as in the U.S.. While the overall efficacy of the vaccine in the U.K.-based study was 66%, when the scientists looked specifically at different countries in that study, they found that in the U.S., where the variants hadn’t spread widely yet, the efficacy was 72% (close to overall 79% found in the more recent study), while in South Africa, where the new variant is relatively common, the efficacy was 47%.

Pangalos notes that the vaccine’s efficacy may improve the longer people wait between doses; the U.K. study found that levels of virus-fighting antibodies were higher among people who got their second dose up to three months after the first, compared to those getting it a month later. That’s why, he says, the company will provide FDA with data from a subset of that study who were vaccinated 12 weeks apart, as well as real-world data on people in Europe who have also been vaccinated 12 weeks apart, all showing that the immune responses are stronger then.

In any case, Pangalos says, the data on those received two doses a month apart is “perfectly good enough” for the public to feel confident about the shots. These results should reassure nations that have been relying on the 3 billion doses of the vaccine that the company committed to providing by the end of 2021. That includes doses manufactured for COVAX, the global vaccine procurement program that provides COVID-19 vaccines for more than 100 lower resource countries at reduced or no cost. Unlike the vaccines made by Pfizer-BioNTech and Moderna, AstraZeneca’s shot can be shipped and stored at refrigerated temperatures, which makes it easier for countries with less robust infrastructure to manage. Pangalos said the company is ready to provide 30 million doses to the U.S. immediately upon receiving emergency use authorization, and another 50 million within a month after that.