It’s three for three as far as positive outcomes from Covid vaccine trials are concerned. But the announcement from AstraZeneca and Oxford University, at a first glance, may not seem to be as exciting as those from Pfizer-BioNTech and Moderna. The figures are a bit of a head-scratcher, so let’s look at them in more detail.

Monday’s results from AstraZeneca and Oxford University state that the combined Phase 3 interim analysis from their COV002 and COV003 studies (based in the UK and Brazil respectively) included 131 Covid-19 cases and that the vaccine was found to be 70.4 per cent effective overall — but that vaccine efficacy in two dosing subgroups was 90 per cent in one and 62 per cent in the other. Unfortunately, the complex design of this trial, in comparison to the Pfizer-BioNTech and Moderna studies, means that its difficult to examine these numbers in more detail and estimate how many Covid-19 cases could have been in each group. According to the trial protocol for the UK study (COV002), participants were recruited in different age groups: 18 to 55, 56 to 69, and aged 70 and older. Those in the 18 to 55 age group were randomised 1:1 to either ChAdOx1 nCOV19 vaccine for Covid or the MenACWY for meningitis and septicaemia as the control. But for those in the 56 to 69 age group, randomisation was 3:1 candidate versus control, and for those aged over 70, randomisation was 5:1.

The deviation from 1:1 randomisation is interesting and hasn’t been seen with the other studies published to date. But allocating more participants to the candidate vaccine may have advantages in the collection of safety data, for example. A larger sample size for those taking the ChAdOx1 nCOV19 vaccine gives more power to detect adverse events.

What is interesting from AstraZeneca’s announcement are the results surrounding the different dosing regimens. We are told that one dosing regimen (with a sample size of 2,741 participants) showed efficacy of 90 per cent when the ChAdOx1 nCOV19 vaccine was given as a half dose, followed by a full dose at least one month apart, and another dosing regimen (with a sample size of 8,895) showed 62 per cent efficacy when given as two full doses at least one month apart. The estimated efficacy for the half dose gave a higher result than that estimated for the full dose. This seems counterintuitive and unexpected. But the sample size for the half dose was smaller than for the full dose and so the point estimate of 90 per cent efficacy for the half dose will be subject to more uncertainty than for the full dose.

Furthermore, we are told that the half dose was actually an accident. Mene Pangalos, head of AstraZeneca’s non-oncology research and development told Reuters that the plan was for trial participants to receive two full doses, but that researchers were puzzled when they noticed fewer side effects than expected. Pangalos said they ‘went back and checked… and we found out that they had underpredicted the dose of the vaccine by half’. It will be interesting to see the full results of this accident when they are published, but questions that immediately come to my mind are:

1. This accident only happened in the UK, and quite possibly only at one site. It may even have only happened within one age grouping. We must then ask ourselves how generalisable are the results to the worldwide population? It is likely that further investigation into the efficacy of this dosing regimen will be needed on a wider scale.
2. It is perfectly acceptable to make changes to the protocol prior to database lock, so the protocol could have been updated to include this additional analysis (the point of closing a database is to ensure a trial can remain blind, meaning researchers can’t carry out ad-hoc analysis or potentially selectively report results before proper analysis takes place). However, according to version 14 of the protocol, dated 9 November 2020, the primary analysis was set to be the efficacy of two doses of vaccine (across both half and full dose), with secondary analyses being the efficacy of at least one full dose and efficacy of two full doses of vaccine. Efficacy of half dose with a full dose booster was not considered as a secondary analysis in the protocol and so could be an ad-hoc analysis post database lock.

There have been numerous comparisons made between the AstraZeneca announcement and the previous announcements from Pfizer-BioNTech and Moderna, but there are several reasons why that isn’t a sensible thing to do. Direct comparisons of results from different trials should generally be done with caution due to differences in study population, endpoints, and regions. If one wishes to carry out a comparison of the vaccine efficacy of multiple candidates, this should be done in a head-to-head clinical trial. Otherwise, you are not comparing apples with apples. For example, in the Moderna study, to be considered a case of Covid-19 for the evaluation of the primary efficacy endpoint, the following criteria needed to be met:

• The participant must have experienced at least two of the following systemic symptoms: Fever (over 38ºC), chills, muscle pain, headache, sore throat, new olfactory and taste disorders, or
• The participant must have experienced at least one of the following respiratory signs or symptoms: cough, shortness of breath or difficulty breathing, or
• Clinical or radiographical evidence of pneumonia; and
• The participant must have at least one nasopharyngeal swab, nasal swab, or saliva sample (or respiratory sample, if hospitalised) positive for SARS-CoV-2 by RT-PCR.

For Monday’s AstraZeneca and Oxford University results, a Covid-19 case was defined as meeting the following criteria:

• A participant with a positive PCR swab, and
• At least one of the following symptoms: cough, fever (over 37.8ºC), shortness of breath, loss of smell, or loss of taste.

So the way that Covid-19 cases were defined was different in each of the studies. Furthermore, both the Pfizer and Moderna studies were placebo-controlled, whereas the AstraZeneca study used the meningitis vaccine MenACWY as the study comparator. Finally, we also know that the different results correspond to different populations. Monday’s results from Oxford-AstraZeneca are based only on participants based in the UK and Brazil, with clinical trials being conducted in the US, Japan, Russia, South Africa, Kenya and Latin America, and planned trials in other European and Asian countries. The Pfizer-BioNTech results, for example, are global results, meaning that the two estimated efficacies are not directly comparable.

These certainly won’t be the final results that we’ll get from AstraZeneca. There will be more numbers coming through from the other studies taking place worldwide. Furthermore, we have not yet been given information about the estimated efficacy across age groups and ethnicities. We are told that there were no severe Covid-19 cases or hospitalisations in the vaccine group, be we aren’t told how many there were in the control group (if any). This study also carried out monitoring for asymptomatic infection and we are yet to see these results although we are told that early indications suggest the vaccine ‘could reduce virus transmission from an observed reduction in asymptomatic infections’. Crucially, this vaccine has a huge advantage over others in the way that it is stored. The Oxford-AstraZeneca vaccine will be easily administered in existing healthcare systems, stored at fridge temperature and distributed using existing logistics. Vaccine efficacy is just one part of the puzzle. Here we have a vaccine that could demonstrate vaccine effectiveness for around 90 per cent of people and be easy to store and distribute. That is definitely something to celebrate.