Researchers from the United States and the United Kingdom have collaborated to produce a data collection pipeline that identifies potentially important mutations in the coronavirus in real-time as genome sequences are submitted to the Global Initiative for Sharing All Influenza Data (GISAID). The first tool they developed focuses on mutations in the spike protein, the protein on the virus's surface that it uses to infect cells. When the tool identifies mutations that could infect the ability of the virus to spread or the severity of disease, the team immediately initiates testing to identify the precise effects of the mutation.
Today they released a preprint* identifying the mutations in the spike protein that had accumulated through April 13.
The most important of these is D614G. The original form of the virus from Wuhan has the D allele, while the mutated form has the G allele.
Prior to March, the D allele was practically universal. In March, the G allele began spreading. It spread first in Europe. In every community it entered, it rose rapidly, often becoming the dominant form within a few weeks. By April, the G allele was dominant in Europe, Canada, and the United States.
The original D allele retained complete dominance over Asian countries through mid-March. In Asian countries outside of China, the G allele began spreading in mid-March. We don't know what happened in China, because China mostly stopped submitted genomic data to GISAID by March 1.
Some early Chinese samples did contain the G allele, but it appears to have begun its global spread in Germany.
That the G allele rapidly becomes dominant in most of the communities in which it is introduced suggests that it has an advantage in these environments and spreads more easily than the D allele. We do not currently know what makes it spread more easily, but there are several hypotheses that all have some support:
- In order to fuse to the cell membrane and gain entry, the spike protein needs to be cleaved in half after it initially binds to ACE2. The mutation is in a portion of the protein that causes the two halves to stick together. If the mutation makes them stick to each other less easily, it could enhance their separation and allow the virus to fuse with the membrane more easily.
- Although it is not present in the part of the protein that binds to ACE2 (known as the “receptor-binding domain” or RBD), it is present in an area that might effect whether the RBD faces in the right direction when the spike protein is attempting to bind to ACE2. That might indirectly make it better able to bind to ACE2.
- It is present in a part of the protein that is known to be targeted by antibodies in the context of the first SARS virus. In fact, it lies at the interface of one portion targeted by beneficial antibodies and another portion targeted by harmful antibodies. The beneficial antibodies are those we usually think of, the ones that neutralize the virus and protect against infection. The harmful ones participate in antibody-dependent enhancement. They actually bind to the spike protein and enhance its ability to gain entry into the cell. The mutation might help the virus evade the beneficial antibodies, or might help it take advantage of the harmful ones even better.
To see whether the mutation impacted the clinical outcome, they examined its prevalence in 453 cases in Sheffield, England. 165 of these were outpatients, 245 were hospitalized, and 23 entered the ICU. The G form was present in 75% of outpatients, 71% of inpatients, and 87% of ICU patients. These differences were not statistically significant. The mutation does not seem to impact severity of the clinical course, though, despite the lack of statistical significance, the data are consistent with a higher proportion in ICU. If it does impact severity, a much larger sample size would be needed to show it clearly.
The mutation was, however, associated with a slightly higher viral load.
Despite the plausible hypotheses for how the spike protein makes the virus so much more spreadable, the increased transmissibility could be a result of another mutation. In five out of seven cases, there are two other mutations that accompany the G allele: one is silent (meaning it doesn't make the viral proteins any different) and one impacts an enzyme involved in copying the virus's genetic information. Together, they make what the authors call the “G clade.” It is conceivable that the spike protein mutation is not the driving force behind the dominance of the G clade.
The paper identifies 12 other potentially important mutations in the spike protein, but none of them, as of yet, have clear implications for the ability of the virus to spread or cause disease.
I see two big implications of this research:
- If the virus develops mutations that have such a huge impact on its ability to spread this fast, this might make it a moving target for both natural antibodies needed for immunity, and antibodies provoked by vaccines. The more of a moving target the virus is, the greater risk that people could get reinfected after getting sick the first time, and the harder it would be to develop herd immunity or an effective vaccine.
- Given that some antibodies enhance disease, and that the virus's interaction with those antibodies may be a moving target as well, suggests that antibody testing should not be regarded as a means of testing who is immune until the effects of the antibodies are studied much more clearly. If done properly, they should be good markers of exposure, however.
We should not be pursuing exposure for the sake of herd immunity as some suggest, nor should we interpret positive antibody tests as signs of immunity, nor should we place our hopes in an eventual vaccine (which is just a coin toss at this point). I believe this supports my current stance that we should continue limiting exposure and supporting our defenses.
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* The term “preprint” is often used in these updates. Preprints are studies destined for peer-reviewed journals that have yet to be peer-reviewed. Because COVID-19 is such a rapidly evolving disease and peer-review takes so long, most of the information circulating about the disease comes from preprints.