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COVID vaccines from Pfizer, Moderna, J&J & Novavax code for a “Stabilised Spike”. Why did they stabilise the Spike and have Oxford AZ made a mistake by not stabilising the Spike?

The most effective vaccines generate neutralising antibody which prevents the virus from attaching to our cells. A virus can’t infect our cells if it can’t attach to (fuse with) our body cells. If the virus can not infect our cells it will not cause disease.   

The COVID causing virus has spike proteins on its surface which enable it to attach (fuse with) our body cells. These spike proteins can exist in one of two forms, each form has a different shape. One form is the pre-fusion shaped spike protein. The virus requires the spike protein to have this pre-fusion shape in order for it to attach to (fuse with) our body cells. Once the virus attaches to (fuses with) our body cell we see the the spike protein change to its post-fusion shape. 

Antibody is only effective at preventing the virus from infecting our cells if it can bind to the spike protein in its pre-fusion state. In order to be successful in preventing infections antibody must have a complementary shape to the the pre-fusion spike protein.  An effective vaccine must expose individuals to the pre-fusion shaped spike protein; this will result in the individual making large quantities of antibody that is capable of attaching to the spike protein in its prefusion shape. 

The majority of COVID vaccines provide genetic information to the cells enabling them to produce the virus spike protein. The AstraZeneca Oxford virus provides the code required to produce the exact same spike protein as is found on the original Wuhan variant virus. Other Vaccine manufacturers including Pfizer, Moderna, Johnson & Johnson and Novavax have modified the genetic code in their virus to produce a stabilised pre-fusion version of the Wuhan variant spike protein. 

Why have they done this?  

If you use the genetic code to make an exact copy of the spike protein on the Wuhan variant virus you run into a problem. The Spike proteins can sometimes spontaneously switch from its pre-fusion to post-fusion shape, before it actually attaches to (fuses with) our body cells. 

To prevent the virus infecting cells you need to generate antibody that can attach to the pre-fusion shaped spike protein. An antibody able to do this must have a complementary shape to the pre-fusion Spike protein. ExposIng your immune system to the pre-fusion shaped spike protein will cause this to happen. 

Exposing the body to the post-fusion shaped spike protein may fail to produce antibody that can bind to key sites on the pre-fusion shaped protein. We need antibody to bind to the pre-fusion shaped spike protein to prevent the virus attaching (fusing with) our body cells.

In a study looking at a different type of virus, the pre-fusion form of the Spike protein revealed two sites (colored red and orange) that the most potent neutralising antibodies bind to. These sites are not found on post-fusion shaped spike protein, which means that exposure to the post-fusion shaped spike protein will not generate antibody that can bind to these critical sites used by the virus for attachment. 

If a vaccine uses the exact same genetic code as seen in the original Wuhan variant virus you will produce Spike proteins that will often spontaneously switch to the post-fusion shape. As highlighted in the RSV example above, post-fusion shaped spike proteins will often fail to induce some of the most potent virus neutralising antibody. 

The solution of many vaccine companies to this problem is to introduce a couple of mutations to the genetic information coding for the Wuhan variant spike protein. In doing so the vaccine will produce a spike protein that locks a key joint in the protein. This fixes the spike protein in its neutralising antibody inducing pre-fusion shape.

This will theoretically mean that all of the spike proteins generated by the vaccine will be stabilised pre-fusion spike protein. This spike protein is fixed in the pre-fusion state, which will ensure high levels of neutralising antibody are generated against the regions of the pre-fusion shaped spike protein most critical to facilitating the binding of the virus to human cells. 

The Oxford AstraZeneca vaccine produces the spike protein in its naturally occurring form. This means that the spike proteins generated can spontaneously switch to the post-fusion shape. This will result in a reduction in the number of pre-fusion shaped spike proteins the vaccinated individual is exposed to. This will result in lower levels of neutralising antibody being produced, against the regions of the pre-fusion spike protein which are critical to facilitating the viruses attachment to human cells.

A single dose of the Oxford AZ vaccine therefore results in lower levels of neutralising antibody than a single dose of J&J vaccine that employs stabilisation. However by offering a 2nd dose of their vaccine Oxford AZ end up exposing the individual to as many pre-fusion Spike proteins as the single dose of J&J doses. This therefore results in both vaccines delivering identical levels of Neutralising antibody. This is based on a single dose of J& J versus two doses of Oxford AZ given 4 weeks apart. 

Extending the dosing interval for the Oxford AZ vaccine to 12 weeks, has the impact of doubling the levels of Neutralising Antibody. This is because there is a reduced immune response against the viral vector used to deliver the 2nd dose. This results in more Spike coding DNA reaching a persons cells, leading to the person being exposed to more pre-fusion Spike proteins. 

Oxford carried out a study to determine how effectively their vaccine was at exposing a persons Immune system to Pre-fusion spike. They observed that the majority of cells infected with Oxford AZ vaccine vector present pre-fusion Spike on the cell surface. You can read more about this intriguing study by following the link to my synopsis >>

Neutralising antibodies however are just one part of your Immune defence. If the virus manages to infect your cells by evading neutralising antibodies you require your T cells to destroy these infected cells. Infected cells display Viral Spike protein on their surface to induce this T cell response. In a natural infection this will come from a combination of pre and post-fusion Spike. It is therefore hypothesised that an advantage of not stabilising the Spike is that the vaccine infected cells present Spike as it would be seen in a natural infection.

This will lead to a robust T cell response, consisting of a wide range of different T cells which are potentially better able to recognise and destroy infected cells if the person is subsequently infected by the actual virus. This robust T cell response helps to significantly reduce the likelihood of Severe disease. This has been backed up in trials of the Oxford Vaccine in which there have been no severe cases amongst the vaccinated individuals. Whilst this 100% efficacy figure will of course be lower in real world use, it is still higher than the 85% figure seen for the J&J vaccine in a comparable US trial.

Oxford have found that 87% of the antigens that T cells (induced by the vaccine) bind to, are not impacted by mutations seen in South African B.1.351 variant. This suggests this robust T cell response (which protects against Severe disease) will be maintained against this variant.

Much is made of the South African trial in which Oxford failed to determine good efficacy against Symptomatic disease. In the small Oxford trial in South Africa (4 week dosing interval) there were only 10 cases of Moderate disease (6 in Placebo group and 4 amongst those vaccinated) and 0 cases of Severe disease. This made it impossible for Oxford AZ to determine Efficacy figures equivalent to those published by J&J, against Moderate/Severe and Severe disease. J&J carried out a much larger trial in South Africa which resulted in sufficient numbers of Moderate and Severe cases to determine this efficacy. They had 61 Moderate cases and 26 Severe cases in the trial (Severe cases 22 Placebo/4 Vaccinated)

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