The University of Oxford and pharmaceutical company AstraZeneca have published a peer-reviewed analysis of Phase III trials of the COVID-19 vaccine ChAdOx1 nCoV-19 in the Lancet.1 The publication confirms that ChAdOx1 has an efficacy of 70.4% across two dose regimens, as previously announced.
In a press conference, Sarah Gilbert, professor of vaccinology at the University of Oxford, said that today is probably "the best day that we've had in 2020," and confirmed that the data has been submitted to the Medicines and Healthcare products Regulatory Agency (MHRA). The data represents the first peer-reviewed Phase 3 results of a COVID-19 vaccine.
Where has the data come from?
The data has been pooled from an interim analysis of Phase III trials of ChAdOx1 including 11,636 volunteers in the United Kingdom, Brazil and South Africa. The study participants are aged 18 years and above and have been assigned (randomly) to receive either the ChAdOx1 vaccine or a control.
An interim analysis involves reporting on data that is available in a clinical trial or scientific study before the full data collection is complete. Such studies, particularly when large in size, require substantial amounts of resources and funding. An interim analysis helps to provide insight as to whether the study is worth this investment, in a manner that is free from conflict of interest.
Due to a dosing error in the UK Phase III trial, data on two different dosing regimens of ChAdOx1 is available:
- Two separate doses of 5×10¹⁰ viral particles (n=8,895) – the standard dose.
- One initial dose of 2.5 x1010 viral particles followed by the standard dose two weeks later (n=2,741).
The peer-reviewed publication shows that vaccine efficacy when participants receive two standard doses is 62.1%, whereas a lower dose followed by a standard dose produces an efficacy of 90%. Hence, the overall efficacy of ChAdOx1 is calculated at 70.4%. The matter of why a lower dose achieves a higher efficacy remains unclear, although the authors of the study propose that higher levels of neutralising antibody or lower levels of immunity against the vector carrying the viral particles may be a factor.
The issue of age
The Oxford team acknowledge that the majority of the volunteers included in this initial analysis are in the age bracket of 18-55 years (90% in Brazil and 87% in the UK). Participants aged 56 years or older represent only 12% of the cohort, and as there were only five reported cases of COVID-19 in this analysis in this age bracket, the efficacy of ChAdOx1 in an older population requires further assessment. This is pertinent considering that elderly populations are most vulnerable to the virus.
When asked about the matter of age in the interim analysis, Oxford Vaccine Group director Professor Andrew Pollard said, "20% of the people in the trials are older adults, both in the UK and in Brazil…but they were recruited later than the younger adults. So, they've had less time for cases to accrue in those age groups, and for us to be able to measure an efficacy signal. Remember, this is an interim analysis, where the data that we have at the moment are largely from younger adults."
Preventing asymptomatic disease
A unique factor of the ChAdOx1 trials is that the research team have explored how effective the vaccine might be in preventing asymptomatic disease. This data was collected by the use of weekly testing of trial volunteers based in the UK. No such data has been released by other vaccine trials.
The results suggest that the lower dose may provide protection against asymptomatic infection, but it is not clear. Maria Deloria Knoll, from Johns Hopkins Bloomberg School of Public Health, wrote: "Although efficacy was lower (58·9% [1·0 to 82·9]) against asymptomatic infection in the LD/SD cohort (and unfortunately only 3·8% [−72·4 to 46·3] in the SD/SD group), the results nonetheless provide some hope that COVID-19 vaccines might be able to interrupt some asymptomatic transmission, although fewer data (69 cases among 6638 participants) were available with this outcome and more data are needed to confirm.
"The idea is that a vaccine can have two purposes: prevent infection and prevent disease. It would be great if there was a vaccine that would reduce transmission because the numbers keep going between 40-50% of cases are caused by people that are truly asymptomatic or pre-symptomatic, so I think it’s important if we had a vaccine that could reduce transmission. That is a little difficult to ascertain from studies because you have to follow people and their contacts. I think that’s something that we’ll probably get a truer sense of once the vaccine has been released," Eric Yager, associate professor in microbiology at Albany College of Pharmacy and Health Sciences, told Technology Networks.
It's not a competition between developers
A COVID-19 vaccine is required by the US Food and Drug Administration to demonstrate at least 50% efficacy to be considered for approval. Even the lower efficacy rate of 62.1% exceeds this benchmark, however the World Health Organization has set 70% as a "preferable" rate.
There are other vaccines in development and undergoing authorization that have demonstrated a higher efficacy through interim analysis; however this is the first peer-reviewed pooling of data that has been made available. It has been emphasized that we are likely to need several different COVID-19 vaccines globally. "This can't be a competition between developers, it has to be a competition against the virus," Pollard said.
How will the different data for different efficacy rates impact the potential approval of ChAdOx1? Will the lower dose followed by a higher dose regimen be approved first? Will the vaccine be approved for individuals aged 55 and below only? These are questions that will be left to the MHRA, Pollard clarified in the press conference.
As we wait to hear news regarding authorization status, AstraZeneca are continuing to manufacture doses in large quantities. The UK has ordered 100 million doses.
“Today’s peer-reviewed publication enables a full disclosure of the Oxford program interim analysis. The results show that the vaccine is effective against COVID-19, with in particular no severe infections and no hospitalisations in the vaccine group, as well as safe and well tolerated. We have begun submitting data to regulatory authorities around the world for early approval and our global supply chains are up and running, ready to quickly begin delivering hundreds of millions of doses on a global scale at no profit,” concluded Pascal Soriot, chief executive officer at AstraZeneca.
1. Voysey M, Clemens SAC, Madhi SA, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. The Lancet. doi:10.1016/S0140-6736(20)32661-.