Full data from late-phase trials of AstraZeneca’s COVID-19 vaccine have pointed to the potential for AZD1222 to work after a single dose and prevent asymptomatic cases but left key questions about the efficacy of the candidate unanswered.
The results, which were posted in The Lancet, reiterate the headline findings shared by AstraZeneca and its partners at the University of Oxford. In a pooled analysis of 11,636 participants enrolled in two separate clinical trials in the U.K. and Brazil, the efficacy of two doses of the vaccine was 70%. The paper adds the detail that protection against symptomatic disease after at least one standard dose was 64%.
The two-dose efficacy figure masks divergent outcomes between subjects who began on a half dose and those that received two full doses. The efficacy on the 2,741-subject half-dose primer arm was 90%.
That discrepancy, which surprised the researchers running the trials, has been the subject of debate since AstraZeneca shared the top-line data. The Lancet paper provides background on how the U.K. trial came to give some subjects a half-dose primer and proffers potential explanations for the effect but leaves the core question of whether the regimen has 90% efficacy unanswered.
The authors of the paper accept “there is a possibility that chance might play a part in such divergent results” but also see reason to think the findings may reflect actual differences between the efficacy of the two regimens. Those reasons rest on data on the numbers of asymptomatic cases.
Participants in the U.K. phase 2/3 trial performed self-swabbing weekly to find asymptomatic cases. The process yielded positive results in the absence of reported symptoms in 69 subjects. The rate of asymptomatic infection in the half-dose cohort was 0.6%, versus 1% in the group that got two full doses. Divergences in the number of asymptomatic infections in the control arms contributed to the efficacy of the half-dose regimen coming in at 58.9%, versus 3.8% in the full-dose cohort.
The authors of the paper cited the divergent effects on asymptomatic infection as evidence the half dose may be more efficacious. If that regimen actually prevents asymptomatic cases, it could enable AstraZeneca and its partners to vaccinate more people and reduce viral transmission, thereby giving protection to people who lack immunity against the virus. Yet, the efficacy remains unproven.
“The wide [confidence intervals] around our estimates show that further data are needed to confirm these preliminary findings,” the authors wrote. The researchers plan to confirm the findings through future analyses of data from the ongoing clinical trials.
No participants aged over 55 years received the half-dose primer. The 18- to 55-year-olds in the U.K. trial who did receive the half-dose shot were originally intended to only receive one dose. Data from early immunogenicity cohorts persuaded the researchers to amend the protocol.
The rethink meant more than half of the low-dose group received their booster shot at least 12 weeks after the primer. Less than 1% received a second dose within eight weeks of the first shot. In the standard-dose cohort of the U.K. trial, less than 20% of participants got a second jab within six weeks of the first shot. In the Brazilian trial, more than 60% of people got two shots within six weeks of each other.
Those discrepancies could affect the results if the lag between the prime and boost shots matters. The data downplay those concerns, with the results from U.K. participants who went eight weeks or more between doses mirroring the wider data set and efficacy across the two trials being numerically better in subjects with at least a six-week interval.
Yet, the discrepancies provide ammunition for skeptics about the decision to pool results from two trials for the efficacy analysis and factor another two studies into the safety analysis. The authors of the Lancet paper defended the approach, stating that “despite minor differences across the studies, there is sufficient consistency to justify the proposal for pooled analysis of data, which will provide greater precision for both efficacy and safety outcomes than can be achieved in individual studies and provides a broader understanding of the use of the vaccine in different populations.” Analysts at SVB Leerink were downbeat about the data, though.
"The publication highlights a number of variances in the dosing regimens utilized in these trials that could make it difficult for the regulatory agencies to have confidence in the optimum dosing protocol for full approval without additional studies," the analysts wrote.
The safety section of the paper addresses the case of transverse myelitis that put development on hold. The authors state the independent neurological committee found “the most likely diagnosis to be of an idiopathic, short segment, spinal cord demyelination.” There were two other cases of the condition across the full safety population, one in the control arm and one in a participant who took AZD1222 and was later found to have “pre-existing, but previously unrecognised, multiple sclerosis.”