The SARS-CoV-2 Variants Of Concern.

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The graphic above is from Eric Topol of the Scripps Research Institute in San Diego. He is a clinician researcher whose group published important work on asymptomatic spread of the SARS-CoV-2 virus and he has been following COVID-19 developments closely, including the latest on vaccines and variants of concern, including the three shown in the table. All of this is just by way of explaining Topol's bonafides to you. 

Below are some take aways/explanations, focusing on the receptor binding domain or 'RBD' of the 'spike' protein. Much of what I'm going to type can be gleaned from a very recently peer-reviewed and published paper from a group at Oxford in the top-ranked journal 'Cell' titled 'Antibody evasion by the P.1 strain of SARS-CoV-2':

How the variants arise: SARS-CoV-2, like all viruses that have RNA as their genetic material, has an error prone RNA polymerase. The latter is the enzyme that is required to make new genetic material/RNA. The errors lead to mutations in viral genes, including the gene for the spike (S) protein. This produces a viral variant and those mutations can change the 'code' for amino acids in numbered positions in the viral proteins. The mutation in the spike protein that is common to all three 'variants of concern' shown above, all of which are currently present in British Columbia, is the N501Y mutation. This means that 'asparagine' amino acid (code name 'N')  at position 501 in the spike protein has been changed to a 'tyrosine' (code name 'Y') which slightly changes the shape and electrostatic characteristics of the bit of the spike that binds to our cells (that 'receptor binding domain'/RBD again).

How the variants emerge/spread: The spike protein is critical for binding to our cells and getting the virus inside them via the RBD. Thus, when we make our own antibodies against the virus after we've been infected with it, or because we've seen the spike protein before due to vaccination, the ones we make against the RBD portion of the spike protein are the ones that can 'neutralize' the virus and prevent it from infecting our cells. Any mutation/amino acid change in the RBD that increases its ability bind our cells (i.e. could increase transmissibility) or decreases the ability of our antibodies to bind to the RBD (i.e. could cause immune evasion) will give the variant a selective advantage and so lead to its emergence and spread in a given locality/human population where community spread is occurring. When the variants 'take over' due to this advantage it can be a significant problem for public health-based control and vaccine efficacy as noted below.

The spike protein that all the (current) vaccines code for: They all code for the 'classic' spike protein coded for by the original Wuhan viral strain. Most of the vaccine-coded spike proteins have two changes (via 2 proline amino acid mutations/substitutions) that were engineered into them to 'lock' the protein into the configuration/shape that is normally found on the surface of the virus before it binds to cells. The two vaccines that do not have this 'lock' are the Oxford and Sputnik ones, and some researchers are now starting to think that this is why these vaccines aren't as good at producing neutralizing antibodies against some variant spike proteins.  Another thing worth knowing is that the mRNA vaccine makers are already at work making vaccine boosters based on the new varian forms of the spike proteins. Being able to do this quickly and efficiently is one of the advantages of the mRNA vaccine technology.

The B.117/UK variant: This one was first identified in the United Kingdom and, due to it's increased transmissibility, it very quickly spread and became the dominant form of the virus in the fall and early winter of 2020. It has a bunch of spike protein mutations but, as noted above, it also has that N501Y mutation that is common to the other two variants of concern and it is thought that this mutation increases transmissibility. This variant is also appears to be more lethal despite what it says in Topol's table above (about 1.6X). Luckily, it looks like all the current vaccines work reasonably well against this variant. This includes the AstraZeneca vaccine which has been the one that has been rolled out widely to good effect in the UK (for a comment on the rare, serious clotting disorder associated with taking this vaccine, see....here). According to the numbers we have so far, this is currently the most prevalent variant in British Columbia (scroll down). 

The P.1/Brazilian variant: In addition to the N501Y mutation seen in the UK variant, the P.1/Brazilian variant also has E484K (which is sometimes referred to as the 'eeek' mutant) and K417T mutations in the RBD that affect binding to cells and may also contribute to immune evasion. This is the variant that has been spreading rapidly in British Columbia recently, including at Whistler. P.1/Brazilian is also the variant where we have the least hard data. Topol's table states that the effect on transmissibility is not clear, but there is one non-peer reviewed report of an increase of greater than two fold which I assume is the one that local folks are basing their comments on in media reports. The lethality is also not clear, but there have been anecdotal reports that it is problematic in younger patients. 

    So, do the vaccines work against this variant? In a true clinical setting that is not clear as the data are not yet available, but in terms of making neutralizing antibodies it looks like there is reduced activity, but it is still there - the caveat here is that the mRNA vaccines look to be better than the AstraZeneca one (see Figure 7C/D). 

The B.1351/South African variant: It has very similar changes to the RBD as does the P.1 variant. The transmissibility and lethality changes are not clear. However, both the mRNA and Astra Zeneca vaccines least proficient at generating neutralizing antibodies against it (see the same Figure 7C/D). There are clinical data for this variant though. The mRNA vaccines work, but not as well against the 'classic' virus and a small scale, phase II clinical trial concluded that the AstraZeneca vaccine doesn't have much, if any, efficacy. This has caused a lot of concern but it is important to realize that they were only looking at mild-to-moderate disease as an endpoint (as opposed to severe disease, or worse) and the sample size was so small that the 95% confidence intervals were very wide (i.e. the statistical power was low). 

    Here in British Columbia, where we are now rolling out the AZ vaccine to folks 55-65 in a lot of locations (my appointment is on Thursday), one ray of hope on this front is that this variant is still at quite low numbers and it appears, assuming we are on top of things, to be increasing slowly compared to the other two variants.

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My usual disclaimer here is that, while I am a life scientist and a cell biologist, I am not a virus or vaccine expert...Thus, please understand, that I'm only trying to explain things that have been raised in media reports more fully based on what I can glean from the available scientific literature and the comments of true experts like Eric Topol mentioned above.

We here in B.C. have been lagging a bit with variant tracking but, as Andrea Woo reported in the Globe on the weekend, a group at St. Paul's led by Marc Romney has figured out how to speed that up - their actual paper is here....Here's hoping our PHO and the BCCDC adopt their methods so that we can get closer to real time variant tracking - it looks like it could really help keep us ahead of things, both from public health and vaccine implementation points of view.

Thanks again to all the readers who have sent helpful links to material to have a look at and consider.

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