LONDON – The Oxford University team behind the development of Astrazeneca plc’s COVID-19 vaccine have become the first to publish full and complete interim phase III data in a peer-reviewed journal.

The paper, appearing in The Lancet on Dec. 8, confirms AZD-1222 is safe and effective, with no severe disease or hospitalizations in the COVID-19 group, up to the data cutoff on Nov. 4.

The results are based on a prespecified, pooled analysis of 11,636 people who were vaccinated in phase III studies in the U.K. and Brazil, along with safety data from participants in four trials in the U.K., Brazil and South Africa.

Headline results were announced on Nov. 23, showing 70% efficacy across two dosing schedules, of either two full doses or a half dose followed by a full dose. The efficacy claim attracted controversy when it subsequently emerged the half dose was a result of a mistake in the concentration in some of the vaccine.

Participants in the two full-dose group received two 5x1010 viral particles per dose. A subset of 1,367 people in the U.K. received a half dose, followed by a full second dose, as a result of differences in quantification methods between batches of the vaccine.

While two full doses showed 62% efficacy, the half-dose/full-dose regimen was 90% effective. However, the latter group did not include adults over the age of 55 because the half dose was given in an early stage of the trial before recruitment of older adults had commenced. That led to suggestions the 90% result was only obtained because younger people mount better immune responses, making it inappropriate to quote a median 70% efficacy.

The researchers admitted when announcing the headline interim results last month that they did not know why the half dose/full dose showed greater effect. However, commentators have suggested it was a result of people developing immunity to the chimpanzee adenoviral vector, making two full doses less effective.

Discussing the data published in The Lancet, Andrew Pollard, director of the Oxford vaccine group and chief investigator of the trial, said the error in the concentration of some vaccine was uncovered in advance of administration and was reported to the U.K. Medicines and Healthcare products Agency, which gave approval to go ahead with the half-dose/full-dose regimen, and for the pooled analysis.

Both regimens stand up on their own and the vaccine was safe and effective in both the U.K. and Brazil individually. “Use of the low dose was unplanned, but it was discussed with regulators in advance,” Pollard said. “We think the half dose primes the immune system, but it needs looking into.”

The regulators have got the full data pack and it will be up to them to decide what the label says about dosing, the researchers said. Even at the 62% efficacy seen with two full doses, AZD-1222 would have a significant impact on health care systems and public health, said Sarah Gilbert, professor of vaccinology at Oxford University and co-author of the paper. “It is very safe, highly effective and can be manufactured in very large quantities, at low cost,” she said.

The half-dose debate led to accusations information was being held back and that the uncertainty engendered would fuel anti-vaccine sentiment. “There has been a lot of comment around the need for transparency,” said Mene Pangalos, executive vice president of biopharmaceuticals R&D at Astrazeneca. “The best way [to address this] is to publish in a high-quality peer-reviewed journal. We’re the first group to do that,” he said. Others can now scrutinize the data for themselves.

“For me, the results are compelling. There were no severe infections or hospitalizations and the vaccine was safe and well-tolerated,” Pangalos said.

The safety data cover a median of 3.4 months monitoring all 23,745 volunteers in the U.K., Brazil and South Africa. Out of those, 168 people experienced a total of 175 severe adverse events over the period, but 172 events were unrelated to the COVID-19 vaccine or to the control. One case of hemolytic anemia was in the control group, while one case of transverse myelitis, considered possibly related to the vaccine, occurred in the COVID-19 vaccine group.

A case of severe fever was reported in South Africa in a participant who remains masked to group allocation and who recovered rapidly and was not hospitalized. All three participants have recovered or are recovering, and continue to be part of the trial, the researchers said.

The controversy over half dose/whole dose obviously resulted in some to and fro between the Oxford researchers and The Lancet peer reviewers, with requests for subgroup analyses to look at the difference in efficacy against symptomatic disease between the two regimens, to help understand whether the difference was related to the dosing, or other factors such as the age of participants and time between vaccine doses.

The researcher found that, irrespective of age or time between doses, these analyses suggest higher efficacy in the half-dose/full-dose group.

Overall, there were 131 cases of symptomatic COVID-19 infection more than 14 days after the second vaccine dose in the 11,636 people in the interim analysis. That included 30 cases in 5,807 volunteers (0.5%) in the vaccine group, and 101 in 5,829 volunteers (1.7%) cases in the control group. Those are the figures on which efficacy of 70% is claimed.

The study also is assessing protection against asymptomatic disease as a secondary endpoint, with 6,638 U.K. participants taking weekly COVID tests to check if they had contracted COVID-19 without feeling unwell.

There were 69 cases of asymptomatic COVID-19 disease identified in weekly COVID-19 testing. That included 29 cases in 3,288 people (0.9%) in the vaccine group, and 40 of 3,350 (1.2%) cases in the control group. That translates to vaccine efficacy against asymptomatic transmission of 27%.