AstraZeneca has published a press release announcing that the Oxford-AstraZeneca COVID-19 vaccine US Phase 3 trial met primary efficacy endpoint in preventing COVID-19 at interim analysis.
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This is clearly stated as an AstraZeneca-led trial, and it more closely follows the large phase III vaccine trials reported by other sponsors. In this respect it is a solid 30,000 plus participant study with a placebo control, and a simple 4 week dosing interval, such that interpretation is more straightforward than previous Oxford/AZ vaccine trials. It has a good age mix with more than 6,000 participants aged >65 years and also wide ethnic representation. Interim efficacy is clearly stated as being 79% against symptomatic COVID-19 and 100% effective against severe disease. Detailed numbers are not provided at this time and the lower confidence limit is not stated. Importantly the trial provides further support for efficacy in the elderly (80%) where previous clinical trial data, other than immunological data, had been lacking. The study randomized two subjects to receive vaccine for every subject that received placebo providing a large safety database of 20,000 plus participants who received active vaccine. As described, this has been used to investigate the potential association of the vaccine with thrombotic events and specifically cerebral venous sinus thrombosis, of which there were no cases detected. Overall it was reported that there was no increased risk of thrombosis. These data are therefore timely in further addressing any safety concerns that could undermine vaccine uptake.
The trial is directed at generating data to support emergency use in the US but also provides valuable data to other countries – both confirming efficacy using a 4-week dosing interval and re-enforcing vaccine safety.
These results are not surprising given what we know now. The US regulatory authorities are reluctant, even in a pandemic, to rely totally on data obtained outside the US, so this trial was done to provide convincing evidence of efficacy and safety in a sufficiently large number of US patients. The benefits of these results will mainly be for the rest of the world where confidence in the AZ vaccine has been eroded, largely by political and media comment. Once that happens, reporting of adverse effects becomes very biased and confidence can spiral downwards. The rest of the world that will rely on this low-cost vaccine may be able to procced with vaccinating their populations.
Vaccine development and rollout should be an international collaboration rather than nationalistic fervour whether in favour of, or against, a particular vaccine. Assessment should be based on science alone.
It is important also to realise that the “headline” efficacy numbers are valid for comparison between the groups in a trial, but great care is needed in comparisons between trials. The way that events are assessed and counted as well as the context of a trial means that exact values for any between trial comparison are uncertain, not only because of statistical uncertainty, but also because of these other factors.
It is clear this vaccine has very good efficacy (remember that 60% was, prior to any trials being started, regarded as a good target), and that this efficacy does not show a notable decline at older ages. This was expected and the speculation that it was ineffective (or “quasi-ineffective”) at older ages was totally unjustified.
This is good news for the global community and one hopes that any political statements around this good news are avoided.
This press release provides more good news about vaccines in general and the Oxford/AstraZeneca vaccine in particular.1 It is consistent with previous studies of the vaccine.
Part of the importance of the study it describes is that it will support the emergency use authorisation which is reportedly soon to be (if not already) being applied for in the United States.
The press release describes a large phase III trial conducted in the US, Peru and Chile, with 32,449 participants of all ages and of different ethnicities, two-thirds of whom were given the active vaccine, and the other third a placebo vaccine (no doubt the full peer-reviewed papers will tell us what the placebo contained). It gives us information from an interim analysis of data from these trials.
The press release tells us that there were 141 cases of symptomatic disease in participants, and that the vaccine showed the following characteristics:
79% vaccine efficacy at preventing symptomatic COVID-19
100% efficacy against severe or critical disease and hospitalisation
Comparable efficacy result across ethnicity and age, with 80% efficacy in participants aged 65 years and over”
This is a large study, so these results can be expected to be robust. They could be expected to be even more so if there were more cases to compare between the groups; but 141 is still a substantial number of cases.
The press release also tells us that:
Amongst participants in the interim analysis, approximately 79% were white/Caucasian, 8% black/African American, 4% native American and 4% Asian, and 22% of participants were Hispanic.
Approximately 20% of participants were 65 years and over, and approximately 60% had co-morbidities associated with an increased risk for progression of severe COVID-19, such as diabetes, severe obesity or cardiac disease.”
The full, peer-reviewed paper will no-doubt provide more detailed information on the efficacy in these subgroups; but with only 141 cases, the numbers in different subcategories may be too small to detect small efficacy differences between subgroups, if they exist. Nevertheless, it is reassuring to read that there was no obvious difference between them.
Note that the vaccine showed “100% efficacy against severe or critical disease and hospitalisation”. In other words, NO vaccine recipients had severe or critical disease, or was hospitalised (at least, not with Covid-19), so there is no way to distinguish between efficacy at preventing different subcategories of more severe disease, and we don’t know if the study distinguished between levels of severity greater than mild-to-moderate disease.
This also means that there were no cases of the more severe forms of disease in people aged 65 years and over – in this age group, the vaccine had 100% efficacy at preventing such disease; 80% efficacy against any symptomatic disease in this age group. (The same concept applies to other subgroups.)
The report also shows that there were no safety concerns. It looked particularly at clotting (“thrombotic”) events and found no excess of cases in vaccine recipients. It was unable to shed further light on the specific clotting event that has raised concerns recently, cerebral venous sinus thrombosis (CVST), other than to confirm that such events are very rare. No CVST events were detected in either arm of the study, we are told, so it was unable to confirm or refute the suggestion that this particular condition may be more common following vaccination.
The fact that there were no such events, however, does emphasise the rarity of this condition, and that even if there were to be an increase in the relative risk following vaccination, the absolute risk remains very low.
(I have yet to see any explanation as to why this particular clotting event (CVST) might be more common post-vaccination when other clotting events are not. If you look for enough rare events, one of them will, by chance, be more common in people who were vaccinated in the study population you used, without this being a causal relationship but just chance. My strong suspicion is that this will prove to be the case for CVST.)
The press release does refer to the prime-boost interval, stating:
This AstraZeneca-led US Phase III trial included two doses administered at a four week interval. Previous trials have shown that an extended interval of up to 12 weeks demonstrated greater efficacy, which was also supported by immunogenicity data. This evidence suggests administration of the second dose with an interval longer than four weeks could further increase efficacy and accelerates the number of people who can receive their first dose.”
Decades of vaccine research tell us that a longer prime-boost interval is likely to increase vaccine efficacy, and, as they say this is supported by immunogenicity data; but it should be noted that the study the press release is describing used a four-week prime-boost interval. There is nothing in the press release to suggest that the study examined vaccine efficacy with different prime-boost intervals.
One thing that is not clear in this press release is whether the study provided any information on the real-world efficacy of the vaccine against different variants of the virus. There is no information on whether genomic typing of the cases was undertaken, the prevalence of different variants in the study population, or the dates during which the data were collected (which would allow some inferences to be drawn on variant prevalence and thus vaccine efficacy against the variants). We know from other work that the vaccine seems to be highly effective against many variants, in particular the more transmissible B.1.1.7 variant; but we do not know if the study will add to our knowledge on this.