COVID-19 vaccines are needed now more than ever. They arrive right on time as UK’s and South Africa’s problematic new strains emerge, B.1.1.7 and 501Y.V2, respectively. The strains have multiple mutations that appear to make the virus more transmissible. Both strains are different but share a mutation – called N501Y – which is in a crucial part of the virus that it uses to infect the body’s cells. The UK strain is now being discovered in many countries around the world.
Many people and also scientists ask themselves:
What happened? Why now?
Mutations
All viruses mutate, that is well-known. Some evolve quicker than others, such as the influenza virus. It is the reason why there is a new flu vaccine every year.
A September 2020 Nature article discusses SARS-CoV-2 mutations and selection pressures that could give the virus an evolutionary advantage:
Sequencing data suggest that coronaviruses change more slowly than most other RNA viruses, probably because of a ‘proofreading’ enzyme that corrects potentially fatal copying mistakes. A typical SARS-CoV-2 virus accumulates only two single-letter mutations per month in its genome — a rate of change about half that of influenza and one-quarter that of HIV, says Emma Hodcroft, a molecular epidemiologist at the University of Basel, Switzerland.
SARS-CoV-2 genome data from more than 100,000 isolates have been sequenced and made public by www.gisaid.org showing that there is an average of just 10 different RNA letters out of 29,903 when looking at any two SARS-CoV-2 viruses collected from anywhere in the world. Researchers have catalogued more than 12,000 mutations in SARS-CoV-2 genomes, but scientists can spot mutations faster than they can make sense of them. Many mutations will have no consequence for the virus’s ability to spread or cause disease, because they do not alter the shape of a protein, whereas those mutations that do change proteins are more likely to harm the virus than improve it.
If SARS-CoV-2 evolves slowly, then how did so many mutations arise in those 2 strains?
Selection Pressures
The theory of natural selection when applied to viruses that can spread easily, such as COVID-19 without a vaccine or human antibodies to stop it, states that these viruses are not “under pressure” to evolve into new strains. As of right now, with only few people getting the vaccine and not enough people with antibodies nearly everyone on the planet is susceptible, and there is likely to be little evolutionary pressure on the virus to spread better, so mutations that improve virus transmissibility might not become fixed in the virus population. From the September 2020 Nature article:
As far as the virus is concerned, every single person that it comes to is a good piece of meat,” says William Hanage, an epidemiologist at the Harvard T. H. Chan School of Public Health in Boston, Massachusetts. “There’s no selection to be doing it any better.”
The first mutation that received attention was D614G, with several teams using different pseudovirus systems to test it on various kinds of cell, with the experiments pointing to the same conclusion: viruses with the G mutation infected cells much more ably than did D viruses.
But if there are no selective pressures, why did these two strains emerge now?
Or are some of the treatments, such as remdesivir, causing selective pressures and escape mutants? What about Convalescent plasma which contains antibodies and was trialed in South Africa and perhaps might have been used at some hospitals? Could it be causing the emergence of these strains?
Resistance to Antibodies
The same September 2020 Nature article discusses evidence that other mutations could help the virus avoid some antibodies:
A team led by virologists Theodora Hatziioannou and Paul Bieniasz, at Rockefeller University in New York City, grew a modified virus with the SARS-CoV-2 spike protein in the presence of neutralizing antibodies. Their goal was to select for mutations that enabled the spike protein to evade antibody recognition. The experiment generated spike-protein mutants that were resistant to antibodies taken from the blood of people who had recovered from COVID-19, as well as to potent ‘monoclonal’ antibodies that are being developed into therapies.
The mutations were found at very low frequencies suggesting positive selection is not yet making the mutations more common.
With most of the world still susceptible to SARS-CoV-2, it’s unlikely that immunity is currently a major factor in the virus’s evolution. But as population-wide immunity rises, whether through infection or vaccination, a steady trickle of immune-evading mutations could help SARS-CoV-2 to establish itself permanently, says Sheahan, potentially causing mostly mild symptoms when it infects individuals who have some residual immunity from a previous infection or vaccination. “I wouldn’t be surprised if this virus is maintained as a more common, cold-causing coronavirus.” But it’s also possible that our immune responses to coronavirus infections, including to SARS-CoV-2, aren’t strong or long-lived enough to generate selection pressure that leads to significantly altered virus strains.
If immunity is currently not a major factor in the virus’s evolution then what explains those two strains?
In-vivo Serial passage
Applied evolution, in the form of serial passage in novel host cells, is a “classical” method to generate “live-attenuated viruses”. Serial passage refers to the process of growing bacteria or a virus in one environment, and passing some of it to a new environment. This process is repeated many times, and then the final product is studied, often in comparison with the original virus, hoping to select for a weaker virus. Although, it does not refer to passing the virus from human to human, which would be equivalent to an “in-vivo serial passage”, this process is used to evolve the virus and observe its evolution. Live attenuated viruses are often used as vaccines because, although they are weakened in the laboratory, they can stimulate a strong immune response. However, and this is discussed less often and as mentioned in this 2012 paper:
Many live-attenuated vaccines exhibit reversion to virulence through back-mutation of attenuating mutations, compensatory mutations elsewhere in the genome, recombination or reassortment, or changes in quasispecies diversity. Additionally, the combination of multiple live-attenuated strains may result in competition or facilitation between individual vaccine viruses, resulting in undesirable increases in virulence or decreases in immunogenicity.
Even less discussed is what happens during “Serial passage” between humans when people infect each other in a worldwide scale as it is happening now. As nobody, including the scientists, have ever experienced a pandemic such as COVID-19, there is little to say about this “In-vivo serial passage” between human hosts, except to rely on the theories of natural selection.
A team of UK researchers led by François Balloux reported in a November 2020 paper that they studied some 400 mutations in the SARS-CoV-2 genome and did not identify a single recurrent mutation in this set convincingly associated with increased viral transmission. The paper was published before the identification of the new strain.
n a December 14 tweet, François Balloux discussed mutations of the new UK strain, such as this one:
Some limited ‘official’ information on the ‘UK strain’. It carries N501Y, a priori not a concerning mutation. N501Y was very rare until recently (~0.2%) and was first observed in Brazil in April. The strain doesn’t seem ‘mink related’.
And in a December 24 tweet:
We previously inferred that none of the recurrent mutations observed in #SARSCoV2 is associated with higher transmission using the first ~47k genomes. Does N501Y, widely credited as the driver of the UK and SA lineages force us to revise this inference?
Could the “in-vivo Serial Passage” between humans at such a large global scale have resulted in some malignant chance mutations?
Virus evolution in a weakened immune system
In a December 23, 2020 article in Science, it was argued that patients with weak immune system who cannot rid themselves of the virus may allow the virus to acquire several mutations that could elude human antibodies.
So far, SARS-CoV-2 typically acquires only one to two mutations per month. And B.1.1.7 is back to this pace now, suggesting it doesn’t mutate faster normally than other lineages. That’s why scientists believe it may have gone through a lengthy bout of evolution in a chronically infected patient who then transmitted the virus late in their infection. “We know this is rare but it can happen,” says World Health Organization epidemiologist Maria Van Kerkhove. Stephen Goldstein, a virologist at the University of Utah, agrees. “It’s simply too many mutations to have accumulated under normal evolutionary circumstances. It suggests an extended period of within-host evolution,” he says.
The article discusses the observations by Dr. Ravindra Gupta, a virologist at the University of Cambridge, with an immunocompromised cancer patient in his preprint December 2020 paper, and the observations from a December 3 paper published in The New England Journal of Medicine that described an immunocompromised patient in Boston infected with SARS-CoV-2 for 154 days before he died. Again, the researchers found several mutations, including N501Y.
“It suggests that you can get relatively large numbers of mutations happening over a relatively short period of time within an individual patient,” says William Hanage of the Harvard T.H. Chan School of Public Health, one of the authors of the December 3 paper. (In patients who are infected for a few days and then clear the virus, there simply is not enough time for this, he says.) When such patients are given antibody treatments for COVID-19 late in their disease course, there may already be so many variants present that one of them is resistant, Goldstein says.
This seems the most plausible scenario. But how can these immunocompromised patients transmit the virus to others if they are treated in a hospital? It is possible that they transmitted it to healthcare workers. It is also possible that some of these patients are sent home to recover while still infected with an undetectable viral load. It is also possible some infected people remain infected without knowing it, without being treated, without quarantining, and without knowing they have a weak immune system. This conclusion would argue for providing vaccines to such immunocompromised patients first. It also follows, that the viral genome of such COVID-19 infected immunocompromised patients should be sequenced at intervals during the infection to monitor the evolution of the virus, and that overall, more viral sequencing will be necessary by hospitals and health agencies to monitor the emergence of new strains.