How will mutations in the SARS-CoV-2 virus affect the pandemic and our vaccine efforts?

Nature just published an informative review article discussing mutations and mutation rate in SARS-CoV-2, with special discussion of a particular mutant variant D614G that has become the most dominant strain in the pandemic, and its implications for our understanding of the virus and our vaccine efforts. I'll summarize a few key points here.


Brief primer on DNA and mutations

As a primer, all living organisms have a genetic code that determines their biological properties, and this genetic code is comprised of DNA residing in the nucleus of every cell. DNA stands for DeoxyriboNucleicAcid, which consists of a long sequence of letters A, C, G, and T, with each letter representing one of 4 chemicals, adenine (A), cytosine (C), guanine (G) and thymine (T). The human genome consists of a string of >3 billion letters spread across 23 pairs of chromosomes. SARS-CoV-2 virus consists of just under 30,000 letters all in a single sequence. It is remarkable that the specific sequence of these 4 letters in the DNA determines the identity of a biological organism (and individual), and serve as a blueprint for all of the biological processes governing that organism.


Mutations are changes in the DNA that occur when the cell replicates, or reproduces, often consisting of a change of a single letter, e.g. an "A" may change to a "G" in the sequence. These mutations happen all the time, including in our own cells, and a vast majority of the time they have no effect whatsoever on the organism. However, if they occur in specific locations of the genome that regulate particular biological processes, these mutations can affect the organism. Most often, these changes are deleteriously meaning that the mutation hurts the organism or makes it less likely to survive or reproduce. Sometimes, however, a mutation can be beneficial and allow biological improvements that make the organism more robust, able to live longer and avoid dangers, or give it an advantage for reproduction (and with a virus, ability to spread). The process of natural selection will tend to allow any such strain to gradually become more prevalent in the population.


So now to the key points of this article.

Slow mutation rate

The first key point is the relatively genetically stable and slow mutation rate of SARS-CoV-2.


First, the level of genetic diversity across individual SARS-CoV-2 viruses is not that great. Over 90,000 cases of the virus have been genetically sequenced (publicly available here) and they have found that two cases from anywhere in the world are nearly identical, varying by only an average of 10 letters out of 30,000.


Second, it is clear that SARS-CoV-2 mutates at a relatively slow rate. The article mentions that the virus accumulates only 2 single-letter mutation changes per month -- and that is during a time when it is spreading around the world and replicating like wild fire. This is considerably slower than influenza and HIV, for example.


This is mostly good news, as viruses that mutate at a fast rate are difficult to prevent via vaccine since the vaccine needs to bind at a particular location on the genome, and mutations in that region may prevent binding so that it doesn't work. That is why influenza vaccines need to be reformulated every year -- there is a high level of genetic diversity in the influenza strains out there, meaning there are lots of differences across their DNA, and it mutates quickly. Thus, the vaccine for a given year is designed to bind and neutralize the major genetic strains from the previous year, but with the fast mutation rates there are typically new strains for which the vaccine does not bind or is not as effective. And the strains not targeted by the previous year's vaccine have a survival advantage so by natural selection become more prevalent in future years. Thus, virologists are trying to hit a moving target and having to reformulate the vaccine every year.


The slower mutation rate of SARS-CoV-2 makes it less of a moving target and potentially easier to effectively treat with a vaccine, and also makes durable immunity more feasible. Given that there will always be some mutations, it is still important for the SARS-CoV-2 vaccines to be developed in a robust way, such that they focus on more essential locations on the genome that are likely to remain stable (e.g. such that a mutation in that region would kill the virus anyway), and are not dependent on one specific location on the genome that might get mutated, but instead can target multiple areas simultaneously. This is a major factor in the ongoing vaccine design efforts, so rest assured that it is being taken into account.


The D614G Strain

Biologists have studied the different genetic variants that have arisen, and have identified one very interesting strain that has appeared again and again. This strain contains what has become called the D614G mutation, a single letter change in the region of the genome coding the spike protein. This spike protein gives coronavirus its name (since it makes the virus resemble a "crown"), and is the key protein that allows SARS-CoV-2 to attack and penetrate host cells. Viral strains with this mutation are often called "G" viruses, and those without the mutation called "D" viruses.


Numerous laboratory studies have studied the molecular properties of the "G" viruses containing this mutation, and all have suggested that this mutation enables the spike protein to more efficiently enter host cells, making it potentially more infectious, and provide detailed molecular explanations as to why that is the case.


In the initial Wuhan outbreak, the "D" virus was dominant, but by the time the virus spread to Europe this mutation appeared, and the "G" virus quickly became dominant in Europe and the USA, and now is found in almost all SARS-CoV-2 samples worldwide. This fast dominance has led many scientists to believe that this "G" virus has become dominant through natural selection because of its greater ability to spread, although not all are convinced. There is something called a "founder effect" that makes it difficult to infer whether a dominant mutation has really arisen through natural selection, since it is possible that a dominant mutation not conferring a survival or reproduction advantage just happened to be there in the original viral strain that led to all subsequent spread in that location, i.e. the "founder." However, given the detailed biological knowledge of what this mutation does to the spike protein, the key tool used by the virus infects our cells, I personally think it is very likely that this strain has become dominant by natural selection, and is one reason why the virus has spread like wildfire around the world.


The spike protein is a key target for our immune system to attack the virus, and indeed is the focus of most vaccine efforts. Given that the key mutation in the "G" virus affected the spike protein, there as initial concern that this mutation might interfere with the ability of the immune system to recognize and neutralize the virus making it much harder to neutralize by vaccine. However, subsequent studies have found that the mutation does not interfere with the ability of the immune system to neutralize the virus, and on the contrary, preliminary vaccine studies have found some vaccines under development to be more effective in neutralizing the "G" virus than the "D" virus, so that is potential good news.


Fueled by lower-than-expected mortality rates in the summer, there has been speculation about whether COVID-19 has become a less severe disease as the "G" virus has become dominant.

However, there is no evidence whatsoever that this mutation has any effect on severity of disease, as no clinical differences are observed between individuals infected with the "D" and "G" virus. Thus, the assertion that the "G" virus may somehow leads to less severe disease is pure speculation at this point with no data whatsoever to support it.


Conclusion

This Nature article is very informative, and I recommend reading it.


In short, what we have learned is that the SARS-CoV-2 mutates more slowly than other viruses, making it a potentially easier target for vaccines, and that one specific mutation that appears to make the virus spread more easily has become dominant in the viral population but does not appear to affect severity of disease.


Since all viruses mutate, the infectious disease community will have to keep an eye on the viral population for any new mutations that become dominant, and ensure that treatment and vaccines under development will work on these variants, as well. But given the great attention and resources given to scientific and clinical study of the pandemic, I am confident any important changes will be quickly identified, studied, and taken into account in our clinical efforts.












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