The first full peer-reviewed results of phase 3 trials of the COVID-19 vaccine developed by AstraZeneca and Oxford University show that it is safe and up to 90% effective in preventing infection, supporting regulatory submissions for emergency use.
The interim analysis, published today in The Lancet, identified no severe coronavirus disease or hospitalizations in pooled results from the 11,636 adults vaccinated in the United Kingdom and Brazil. Of the 11,636 adults, 131 (1.1%) had symptomatic COVID-19 more than 14 days after the second vaccine dose, including 30 of 5,807 (0.5%) in the COVID-19 vaccine group and 101 of 5,829 (1.7%) in the control group, indicating a vaccine efficacy of 70%.
The trial revealed 62% effectiveness in participants given two full doses of COVID-19 vaccine and 90% in the 1,367-participant subset in the United Kingdom given a half dose followed by a full one. Half of the study participants were given two doses of the COVID-19 vaccine, and the other half received either a meningococcal conjugate vaccine or saline.
Oxford University scientists had presented the unpublished data on Nov 23.
Data on safety, asymptomatic COVID-19
Safety data in today's study showed that over a median of 3.4 months, only 3 of 23,745 adult participants in four trials in the United Kingdom, Brazil, and South Africa had serious adverse effects that could have been related to the COVID-19 or control vaccines, with one such event in the vaccine trial arm (transverse myelitis), one in the control group (hemolytic anemia), and one in a participant blinded to group allocation (high fever). All three have recovered and remain in the trial.
The other 172 serious adverse events, including 10 hospitalizations and 1 death, were deemed unrelated to the COVID-19 vaccine.
Sixty-nine participants in the UK weekly 6,638-person COVID-19 testing group were infected with asymptomatic COVID-19, including 29 of 3,288 (0.9%) in the vaccine group and 40 of 3,350 (1.2%) in the control group, translating to a 27% vaccine effectiveness against asymptomatic spread.
Of the group receiving an initial half-dose of COVID-19 vaccine, 7 of 1,120 (0.6%) participants in the vaccine group and 17 of 1,127 participants (1.5%) in the control group had asymptomatic infections, equating to a vaccine effectiveness against asymptomatic spread of 59%. In those who received two standard doses, 22 of 2,168 participants (1%) in the vaccine group and 23 of 2,223 in the control group (1%) had asymptomatic infection, indicating a 4% vaccine effectiveness against asymptomatic spread.
Unexpected dosing deviation
AstraZeneca attributed the surprise deviation in trial dosing (ie, the half-dose/standard dose regimen) in the 1,367-participant subset to a manufacturing error in the quantification methods used between batches, resulting in some vials having 50% less vaccine than the others.
Why this regimen would be much more effective than the intended dose has not been explained, although the researchers have theorized that the lower first dose more closely mimicked that of an infection, while other experts saying that it could have been the result of the different size and type of participants in the subgroup.
The subset receiving the lower first dose didn't include participants older than 55 years—who tend to mount a weaker immune response than their younger counterparts—because the different dosage was given early in the trial, before older adults were recruited.
While the original trial design included only a single dose of COVID-19 vaccine, a second dose was added after phase 1/2 trial results showed improved immune responses to another dose.
Important remaining questions to be explored
The Oxford and AstraZeneca vaccine uses a chimpanzee adenovirus viral vector to trigger expression of the characteristic spike protein of SARS-CoV-2, the virus that causes COVID-19, in humans. The human cells then produce the protein and train the immune system to marshal antibodies and T-cells against it without causing disease.
Adenoviruses are common causes of fever, cough, sore throat, diarrhea, and pink eye—especially in children.
The vast majority of trial participants (82%) were 18 to 55 years old. Of the 11,636 participants in the efficacy part of the trial, only 12% were older adults, and 83% were white.
Future analyses of the data will include investigation of differences in key subgroups such as older people and those of different races. They will also explore dosages, timing of booster vaccines, which immune responses signify protection from infection, and the duration of that immunity.
For example, this analysis included only five cases of symptomatic COVID-19 in participants older than 55 years—too few to assess vaccine effectiveness in this group, coauthor Merryn Voysey, DPhil, of the University of Oxford, said in a Lancet press release.
"Since recruitment of older adults started later than in younger adults there has been less follow up time for these cohorts and less time to accrue COVID-19 cases," she said. "This means we have to wait longer to have sufficient data to provide good vaccine efficacy estimates in smaller subgroups.”
Coauthor Sarah Gilbert, PhD, of the University of Oxford, said in the release that the possibility of approval of more than one safe and effective COVID-19 vaccine is promising. "Here we have shown for the first time that an adenoviral vectored vaccine—a type of vaccine technology which has been in use since 2009—is efficacious and could contribute to disease control in the COVID-19 pandemic.”
An 11,000-participant trial of the vaccine in the United States is ongoing.
Lower cost, stability in standard refrigeration
In a commentary in the same journal, Maria Deloria Knoll, PhD, and Chizoba Wonodi, MBBS, DrPH, MPH, both of Johns Hopkins University, noted that the Oxford/AstraZeneca vaccine has advantages over the mRNA vaccines developed by Moderna and Pfizer/BioNTech in terms of lower cost and 6-month stability in standard refrigeration.
They said that the two different doses required with the Oxford/AstraZeneca vaccine will add complexity for healthcare workers but can be managed with packaging alterations and change-management processes. And further exploration of the reasons behind the higher efficacy of the initial low-dose regimen can help assuage concerns about the trial results, they added.
When deciding which vaccine is best for their setting, national vaccine advisors will have to factor in the issues of delivery, community trust, longevity of immunity, reduction of infection and transmission as well as illness, effectiveness in high-risk groups, and safety, Knoll and Wonodi said.
"With a range of manufacturers, a very large global investment in production, and cooperation in procurement and distribution, it seems likely that 2021 will see COVID-19 vaccines made available to all countries in the world—at least for their priority groups," they wrote. "Perhaps by this time next year, we can celebrate the global control of SARS-CoV-2, in person."