The news broke at the weekend that the Oxford AstraZeneca only demonstrated 10% efficacy against the South African B.1.351 variant. This variant possess a mutation called E484K which changes the shape of the Spike protein in a way that makes it far more challenging for the antibodies produced in response to the Oxford AZ vaccine to attach to it. Worryingly the UK/Kent B.1.1.7 variant of the virus has also recently acquired this E484K mutation in Bristol.
Data from the South African trial showed there was a 20 fold reduction in the ability of the antibodies to neutralise the South African variant, compared to the original virus variant. Other vaccines including Pfizer and Moderna (which produce a higher antibody response to begin with) showed a much smaller 6.5 and 8.6 fold respectively, reduction in neutralisation activity.
Why are individuals vaccinated with the Oxford AstraZeneca vaccine showing such a significant decline in their ability to neutralise an E484K variant?
All of the currently approved vaccines provide genetic information to the cells to enable them to produce the virus spike protein. The AstraZeneca Oxford virus provides the exact code seen in the original variant of the virus. Other Vaccine manufacturers including Pfizer, Moderna, Janssen and Novavax have modified the code used by their vaccines to produce what’s called a stabilised pre-fusion version of the original variant spike protein.
The naturally occurring spike protein seen in the Oxford AstraZeneca vaccine can spontaneously flip between two different forms (pre-fusion/post-fusion). Some of the most critical sites used by the virus to attach to our cells are only visible on the pre-fusion form of the spike protein. In order to stop the virus infecting our cells we need to make antibody that can bind to this pre-fusion form.
This is why most vaccine manufacturers have chosen to use a stabilised version of the Spike protein, put simply this locks the Spike protein in its pre-fusion form, with the aim of generating more of the most critical neutralising antibody. The Oxford AstraZeneca vaccine does not use a stabilised spike protein, which means the spike protein can spontaneously change to the post-fusion version .
The Gupta Laboratory in Cambridge who specialise in virus neutralisation studies acknowledge this could possibly be a problem as “the spike takes on the post-fusion confirmation if given the chance.” This has the potential to reduce the quantity of the important pre-fusion Spike protein a person vaccinated with the Oxford AstraZeneca is exposed to. This would likely result in reduced levels of the neutralising antibody most critical to stopping the virus from infecting our cells.
The most recently available figures for UK vaccinations (31st January) showed that 69% of those vaccinated had the Pfizer vaccine, 31% the Oxford AstraZeneca. Leaked figures from the UK government suggest that a single dose of the Pfizer vaccine reduces the symptomatic infection risk by 65 per cent in younger adults, and 64 per cent in over-80s. Figures are said to be roughly comparable in the Oxford AstraZeneca vaccine (against the existing variants seen in the UK).
There is no obvious medical risks associated with using an alternative vaccine for the second dose. Currently UK government policy is that a person will only receive an alternative vaccine for their second dose if there are supply issues or records of the first dose are lost.
Studies in animal models have already shown a combination of the Oxford AstraZeneca vaccine and an mRNA vaccine (from Imperial) can produce a superior immune response than two doses of the same vaccine.
One piece of good news is that the Oxford AstraZeneca vaccine produces effective T cell response after a single dose. There is little concern in regards to the effectiveness of T cells induced by the vaccine against B.1351 🇿🇦 as 87% of the T-cell binding sites (76 out of 87) are not impacted by the mutations seen in the South African 🇿🇦 B.1.351 variant. It is hoped that these T-cells will help prevent severe disease and deaths. This is supported by data from a similar Adenovirus vectored vaccine from J&J Janssen, which demonstrated 85% efficacy against severe disease caused by the B.1.351 🇿🇦 variant.
It must be noted that despite the J&J Janssen vaccine producing a similar overall level of neutralising antibody to the Oxford AZ vaccine it managed to demonstrate a 50% efficacy against symptomatic disease (Oxford AZ = 10%). It is thought this may be due to the J&J Janssen vaccine coding for a stabilised version of the Spike Protein ( This article explains why this is important >> https://coviddatareview.wordpress.com/2021/02/09/a-potential-reason-why-the-oxford-astrazeneca-vaccine-is-less-effective-at-providing-protection-against-the-south-african-b-1135-variant-than-some-of-the-other-vaccines/ )
The UK government last week announced a “first in the world” £7 million pound trial last week to determine the effects of using different vaccines for the first and second dose. These trials should be able to determine the impact this will make on the lmmune responses within a couple of months. This data should therefore be available ahead of mass rollout of the second dose of the vaccine (for those already vaccinated with the Oxford AstraZeneca vaccine) which will commence in April.
The UK government have proved when it comes to vaccines that they are more than capable of making bold and successful decisions. This decision would mean that many given a first dose of Pfizer would get a second dose of the Oxford AstraZeneca vaccine. There is no reason to think that this will be problematic, with a single dose of this vaccine already providing 65% protection against Symptomatic disease (for all age groups) and a booster of the Oxford vaccine almost guaranteed to boost this further. This is a decision that can plug a potentially large black hole by ensuring protection against E484K variants for millions of those most vulnerable to COVID infection. This is backed up by the news from AstraZeneca that it will be 6-9 months before a booster vaccination against E484K variants is ready for public use.
COVID Data Review 