The first peer-reviewed results, describing clinical studies with a COVID-19 vaccine developed by Oxford University and pharmaceutical company AstraZeneca, were released Tuesday after a preliminary announcement in late November caused confusion and criticism among scientists.
The paper, published in the medical journal Lancet, described trials of the vaccine being carried out by Oxford in the UK, Brazil and South Africa. Overall, data from the UK and Brazil show that the vaccine was 70% effective in preventing symptomatic COVID-19. No serious safety issues were reported in the three countries.
The results announced in the November press release had shown that the vaccine could be up to 90% effective when given in half a dose for the first shot. However, the group did not disclose that the data was obtained because of a dosing error, and scientists subsequently criticized the investigators for a lack of transparency and accuracy.
Andrew Pollard, head of the Oxford team, told BuzzFeed News that he hoped the newspaper would allay concerns about the process. “Most of that was the assumption that we were trying to pick dates to get good results,” he said. “But that is not the case. We agreed in advance with the regulators how to proceed.”
Still, scientists confused by the earlier press releases are not convinced that their concerns have been completely addressed.
“In terms of policy making, the 70% figure is still hard to interpret,” said Natalie Dean, a biostatistician at the University of Florida who specializes in developing strategies for vaccine testing against emerging diseases BuzzFeed News.
“It’s a mess,” John Moore, a virologist at Weill Cornell Medical College in New York who works on vaccine development for HIV, told BuzzFeed News. “The vaccine clearly works, but we still don’t know how well.”
Developed by Oxford University and its spin-off company Vaccitech, the vaccine is being launched in collaboration with the British-Swedish pharmaceutical company AstraZeneca. It’s made up of a chimpanzee adenovirus – a group of viruses that can cause colds in humans – that make the “spike” protein from SARS-CoV-2, the virus that causes COVID-19.
Scientists and public health officials have been eagerly awaiting these results as the Oxford AstraZeneca vaccine is the most widely pre-ordered COVID-19 vaccine that governments hope will finally bring the pandemic under control.
The appeal lies in the low cost and easy delivery of the vaccine. Supply deals announced so far suggest that the Oxford-AstraZeneca vaccine will be marketed for less than $ 4 per dose, compared to around $ 20-25 for the other vaccines with results from large-scale clinical trials by rival drug giants Pfizer and Moderna a biotech company based in Cambridge, Massachusetts.
In addition, the Oxford-AstraZeneca vaccine can be stored at normal refrigeration temperatures, unlike those of Pfizer and Moderna, which must be frozen until just before use – in the case of the Pfizer vaccine at around -70 degrees Celsius.
However, claims about the vaccine’s effectiveness have been under a cloud since November 23, when AstraZeneca issued a confusing press release describing the combined results of studies from Oxford University in the UK and Brazil involving around 23,000 volunteers. Based on the distribution of 131 COVID-19 cases across the vaccine and placebo arms of the study, AstraZeneca claimed an “average effectiveness of 70%”.
This suggested the vaccine was less effective than its main competitors, as Pfizer and Moderna each announced in early November that studies for their vaccines showed they were more than 90% effective.
However, AstraZeneca and Oxford claimed their vaccine was also 90% effective when given to participants a half dose followed by a full dose. Two full doses, meanwhile, resulted in only 62% effectiveness. The more successful outcome played a major role in their advertising boost.
“Excitingly, we have found that one of our dosing schedules can be about 90% effective. If that dosing schedule is used, more people could be vaccinated with the planned vaccine supply,” Pollard said in the press release.
Scientists were initially puzzled by these results. “I found the results presented difficult to interpret,” Dean told BuzzFeed News last week.
And as more details emerged, experts became increasingly skeptical of the 90% requirement. First Mene Pangalos, head of non-oncology research and development at AstraZeneca, admitted to Reuters that half the dose was actually the result of a mistake – made by Italian manufacturer Advent and first revealed by Mirror newspaper in June.
On November 24, Moncef Slaoui, senior scientist at Operation Warp Speed, the U.S. federal government’s partnership to accelerate the development of COVID-19 vaccines, told reporters that the volunteers who were mistakenly given the initial half dose were all younger than 55 years of age – not representative of the age of the volunteers during the entire study.
The fact that the dosage error affected an unrepresentative group reflects another confusing aspect of the UK study: since it was first listed on ClinicalTrials.gov in late May, the number of specific patient groups in the study has steadily increased, resulting in one Confusion has led to the arrangement of 12 experimental groups and 25 subgroups, each of which received subtly different treatments.
“What do these attempts mean? We don’t know, ”Moore told BuzzFeed News last week.
In the new Lancet publication, the Oxford team statistically controlled the age differences between the groups given the different doses and found that the improved efficacy was retained for the half-dose and full-dose treatment. However, other scientists remain concerned that there is as yet no data on how well it works in the elderly, who are most susceptible to COVID-19.
“It needs further evaluation,” said Dean.
Unlike Pfizer and Moderna, Oxford University and AstraZeneca did not publish a full breakdown of their study protocols that other researchers were able to review at the start of their large-scale studies, making it difficult to understand the results presented in the previous press releases. Further transparency concerns arose in September when trials of the vaccine were suspended following suspected serious adverse effects in a UK participant. The hiatus was only made public after a private call with investors was posted on the biomedical news site Stat.
In a statement sent to BuzzFeed News last week, the Oxford group downplayed the importance of the dosing error, saying the plan to proceed with the analysis had been approved with UK regulators: “[W]When it was found that a lower dose was used, we discussed this with the regulator and agreed a plan to test both the lower dose / higher dose and the higher dose / higher dose so we can include both approaches. “
The new paper notes that the protocol was changed on June 5th, about a week after the trial began. And Pollard told reporters today at a press conference organized by the Science Media Center in London that this change was made prior to the process “database lock”, meaning it was part of the officially approved plan.
Still, the confusing results seem unlikely to the FDA. The US regulator is expected to wait for the results of another AstraZeneca study, currently underway in the US and carried out by AstraZeneca, not Oxford, before deciding whether to approve the emergency vaccine.
“All I can say is that there is a lot to explain,” Paul Offit, director of the Vaccine Education Center at Philadelphia Children’s Hospital and a member of the FDA’s Advisory Committee on Vaccines and Related Biological Products, told BuzzFeed News last week.
“It’s not obvious to come to a conclusion as to why there seem to have been significantly different efficacy results, 90% versus 62%,” Slaoui, senior scientist at Operation Warp Speed, told reporters during a December 2nd press conference which is a very clear one Explanation based on facts and data about what’s behind these two numbers. It is very likely that the package will not be enough for approval. “
Pascal Soriot, CEO of AstraZeneca, told the Science Media Center briefing that he expected the FDA to request results from the US study.
Another problem is that the results from UK and Brazilian studies were combined, which were originally designed as separate tests of the vaccine’s effectiveness and included slightly different treatment and placebo arms. The combination of data from the two studies became necessary after the Oxford group found that the UK’s success in reducing COVID-19 transmission by late spring meant that the UK study did not see enough cases to to get final results.
The Oxford team was initially optimistic about the chances of being the first to demonstrate an effective COVID-19 vaccine. “We’re probably in a location with one of the highest levels of COVID transmission in the world, certainly in Europe, so we can get a good result over the next three months,” Adrian Hill, director of The Jenner Institute in Oxford, told CNN in late April With.
But less than a month later, Hill told the Telegraph, “It’s a race against the virus’s disappearance and against time. Right now there’s a 50% chance we won’t get any result at all.”
Much is at stake with the high hopes that have been placed on the Oxford-AstraZeneca vaccine. This is particularly true in the UK, where Prime Minister Boris Johnson has praised the work of “our brilliant scientists” and urged a unit in his office to have Union Jack labeled vials with the vaccine, according to the Huffington Post.
The hurdles to emergency approval of the vaccine in the UK are expected to be lower than in the US. In fact, the country’s drug and health products regulator has already approved the Pfizer vaccine, which is still under review by the FDA. The U.S. Department of Health’s Advisory Board meets this Thursday to evaluate the results of the Pfizer vaccine, which is expected to be the first vaccine to receive emergency approval in the U.S.
UK approval of the Oxford-AstraZeneca vaccine could lead to a rush of orders given the cost and ease of delivery of the vaccine. It’s already in high demand, according to an analysis of data from the life sciences analytics firm Airfinity by the science journal Nature. Around 2.7 billion doses have already been pre-ordered, significantly more than any other single vaccine candidate.
Scientists are concerned about the questions revolving around the effectiveness of the vaccine as problems that emerge later could damage confidence in COVID-19 vaccines in general.
“Our greatest collective fear is that things will go wrong that will compromise public confidence,” said Moore. “We wanted a process that was as clean as possible.”
Stephanie M. Lee contributed to this story.