The full interim review of the safety and efficacy of the Oxford Covid-19 vaccine, developed in collaboration with AstraZeneca, has been published in The lancet. This document represents the most complete set of results from any of the phase 3 trials of Covid-19 vaccines to date.
These are still only interim results, which means they only show how the ongoing phase 3 trial has progressed so far. Final results may differ. But what this analysis reveals is how the Oxford team calculated the efficacy of their vaccine, which they announced in late November.
This interim analysis included 11,636 people, of whom 7,548 were in the UK and 4,088 in Brazil. All participants received two injections, but as has been widely reported, one of the UK groups received a half dose rather than a full dose for the initial injection. This has made analyzing the effects of this vaccine more complicated than it likely will be for others in the later stages of testing.
Importantly, the evidence that the vaccine is safe is compelling. 175 serious adverse events were reported in the trials, and they were actually more common in the control group (receiving saline or a meningococcal vaccine) than those receiving the Covid-19 vaccine.
Three of these events were considered to be possibly related to the experimental or control vaccine. They included a case of transverse myelitis, a rare but serious spinal inflammatory disorder, in someone from the vaccine group, a case of hemolytic anemia in someone from the control group, and another person who developed a fever over 40 degrees Celsius. So far we do not know if this person received the Covid-19 vaccine or a control.
In the entire study, ten patients got sick enough with Covid-19 to require hospitalization, but all were in the control arm.
Calculating the effectiveness
The leading figure given for the overall efficacy of this vaccine is 70.4%. This is less than the equivalent efficacy reported by Pfizer (94%) and Moderna (94.1%) for their vaccines.
Both Pfizer and Moderna have based their estimates on trials much larger than the Oxford vaccine, so their estimates are likely to be more accurate. But we still need to be able to see their results published in full in peer-reviewed journals before we can make valid comparisons between the efficacy and safety of the three vaccines. But lower efficacy runs the risk of leaving a greater proportion of the vaccinated population unprotected.
But the most difficult problem with the Oxford / AstraZeneca study is that it has pooled the analysis of vaccine efficacy from three separate trials. The UK-based arm of the trial was indeed two studies. One study used two standard dose injections and the other half dose followed by a standard dose. A third study in Brazil used two standard doses.
These different dosing strategies produced very different efficacy readings. The average efficacy among all those involved in the three studies combined produces the figure of 70.4%, but this does not really reflect the efficacy of the vaccine in any of the dosing scenarios.
Both arms of the standard dose study gave similar estimated efficacy: 60.3% in the UK and 64.2% in Brazil. Combined, the efficacy of these two standard dose trials was 62.1%. In contrast, the low-dose regimen indicated 90% efficacy. This finding would place the Oxford vaccine close to the reported efficacy of the Pfizer and Moderna vaccines.
But how reliable is this estimate of what is, in effect, a subgroup within the study? Disaggregating the analysis in this way to look at the results in specific groups may be appropriate in randomized controlled trials, but it increases the risk that what appear to be positive results is simply due to chance.
This type of practice is “particularly unreliable” and “can produce false results,” experts have noted. I would add that you have to be even more cautious when subgroup analyzes produce unexpected results, which is exactly what has happened here, as the low-dose regimen originated from an accident. Further evidence of the low-dose regimen is needed.
Another problem is that the study group that produced the estimate of 90% was only carried out with people under 55 years of age and almost exclusively with people of white ethnicity. By contrast, the burden of serious illness and death from Covid-19 tends to fall on older people and people from black and Asian ethnic groups, and priority populations for immunization in the UK are largely over 55 years.
Given their greater vulnerability, it is important to know if older people respond well to this vaccine. Problematically, we know that older people often do not respond as well as younger people to vaccination. On the other hand, in another recent Lancet In an Oxford Vaccine Group article, groups of participants aged 18 to 55, 56 to 69 and over 70 were found to have similar antibody levels after receiving the standard dose regimen, suggesting that it will be just as effective in all ages.
But we do not yet know what the effect of the apparently most effective low-dose regimen is in those over 55. So in addition to needing more trials of the low-dose regimen, they should also include older people and people of black and Asian races. Only then can we be sure that it is effective in different groups.
We also don’t yet know for sure how effective any of the Covid-19 vaccines will be in preventing asymptomatic infection or transmission of the virus. But the results from phase 3 of the Oxford vaccine suggest that immunization with the vaccine will put some downward pressure on transmission.
Achieving the development and testing of the Oxford vaccine so far is an incredible achievement, and the vaccine will undoubtedly become an important tool in our ability to combat the current pandemic. The vaccine is safe and effective, although it may not be as effective as the other two main candidates from Pfizer and Moderna. The low-dose regimen may be closer to efficacy than these other vaccines, but we need more data to be sure.
Paul Hunter is Professor of Medicine at the University of East Anglia.
This article first appeared on The Conversation.