What are the implications for current and future COVID-19 treatment?
Accra, March 14, GNA – Viral (coronavirus included) mutations are changes in the genetic code of a virus that naturally occur when an animal or person is infected.
What is also important to remember is that, every time a coronavirus (for the purposes of this article, SARS-CoV-2) passes from one person to the other, the likelihood of picking up mutations to its genetic code increases. While mutations in the genetic code are expected to occur over time, it’s essential to monitor those mutations which occur in important areas of the viral genome as it circulates in the population.
Even though several viral mutations may occur as a result of community spread, it is not all the mutations that affect the virus’s ability to spread or cause disease – because these mutations do not significantly alter the major viral proteins involved in infection. Eventually these non-essential (passenger mutations) variants are outcompeted by variants with mutations that are more critical for the virus’s survival and infection.
When coronavirus infectious disease (COVID) spread around the globe in 2019 (COVID-19) and most part of this year, many scientists wondered how the deadly virus behind the pandemic might be changing as it passed from person to person. Initial insights into how ‘chance mutations’ in HIV helped it to evade the immune system, led to the general belief that the same thing might happen with SARS-CoV-2 (the virus that causes COVID-19).
Even though there is currently an avalanche of genetic sequencing of SARS-CoV-2, scientists still have more questions than answers about these mutations. Whilst the current changes in the viral sequence have not raised alarming public-health concerns, studying the mutations in detail could undoubtedly be important for controlling the pandemic. It could help to pre-empt those mutations that could assist the virus to evade either the immune systems, vaccines or antibody therapies.
Generally, ribonucleic acid (RNA) viruses, such as influenza, HIV and SARS-CoV-2, tend to pick up mutations quickly as they are copied within their hosts, mainly because the enzymes responsible for copying RNA are inherently prone to making errors. For instance, after the severe acute respiratory syndrome (SARS) virus began circulating in humans, it developed a ‘deletion’ mutation that was believed to have helped in slowing down the spread of the virus. But current sequencing data on coronaviruses suggest that they change more slowly than other RNA viruses, probably because of the so-called ‘proofreading’ enzyme that inherently corrects potentially fatal copying errors. Even with this slow mutation, scientists have been able to catalogue more than 12,000 mutations in SARS-CoV-2 genomes.
Notwithstanding this slow rate of mutation, the rapid spread of SARS-CoV-2 variants has put the scientific world on alert and triggered several lockdowns in South Africa, Australia, Europe and the UK. One important question that needs to be asked is this: what are the defining characteristics of these variants, and why are they causing so much concern?
Firstly, as mentioned earlier, all viruses naturally mutate over time, and Sars-CoV-2 is no exception. Since the discovery of this virus about two years ago, thousands of mutations have emerged but majority of these mutations are “passenger mutations” – i.e. they do emerge and are carried along, but don’t significantly change the behaviour of the virus. But every once in a while, a virus may mutate in a way that helps with it’s survival and replication. In the right environment, such mutant viruses can then increase in frequency due to natural selection. This is what seems to be happening with the Sars-CoV-2 variant identified in the UK known as 202012/01, (a slightly different variant from 501.V2, that has recently been identified in South Africa).
There is currently no evidence that either of these mutations causes more severe disease, but the major worry for scientists is about their transmissibility, and the looming potential of the health system infrastructure to be overwhelmed by a rapid rise in cases. Although there is no direct correlation between the increased transmissibility and severity of infections, the impact of COVID-19 disease on hospitalisations and deaths is undoubtedly high for those in older age groups or with co-morbidities.
While these variants generally have distinct origins, it is now known that the variants share a common mutation in a gene that encodes the spike protein, which the virus uses to latch on to, and enter human cells. Reports indicate that the changes in the UK and South African variants of the spike protein gene are consistent with the possibility that they are more transmissible. Nevertheless, we should bear in mind that it is the nexus between the changing virus and what we’re also doing as far as the preventive protocols are concerned, that largely determines how fast the virus spreads.
As lockdowns (restrictions) are enforced, the situation with the new variant changes quickly, and there is less room for error in controlling the spread. Furthermore, since there is currently no evidence that the new variant can evade nose masks, social distancing, or regular washing of hands with soap, we just need to apply the protocols more strictly.
Compared with HIV, SARS-CoV-2 appears to be changing much more slowly as it spreads. But one mutation stands out. It is in the gene encoding the spike protein, which helps virus particles to penetrate cells. Scientists have observed that the mutation keeps appearing again and again in samples from people with COVID-19. At the 614th amino-acid position of the spike protein, the amino acid called aspartate (D – biochemical designation) was regularly being replaced by the amino acid called glycine (G) because of a copying error that altered a single nucleotide in the virus’s RNA code. Virologists call it the D614G mutation (the first letter indicates the amino acid that has been replaced, the number is its location on the protein, and the final letter is the new amino acid that has appeared at that site), and that, it is increasing in frequency at an alarming rate. Indeed, it has suddenly become the dominant SARS-CoV-2 mutant in Europe, United States, Canada and Australia, and represents a more transmissible form of SARS-CoV-2, which has emerged as a product of natural selection.
But when did this all-important mutation rear its ugly head? Many scientists believe that if such a mutation is helping the virus to spread faster, it probably occurred earlier, when it acquired the ability to spread efficiently from one person to another. This is because, since everyone is susceptible, and the spreading of the variant is occurring unabated, there is likely to be little selective or evolutionary pressure on the virus to ‘spread better’ in the population, and therefore, even non-harmful mutations might not flourish. As far as the virus for COVID-19 is concerned, every single person that it comes into contact with is a fertile ground – i.e. there’s no evolutionary pressure on the virus to be doing it any better.
The emergence of this new variant – estimated to be 70% more transmissible than the original SARS-CoV-2 virus of COVID-19 – along with others such as the Brazilian variants, has shed some clues on the characteristics of the mutation as the pandemic continues. In another sense, it has also raised concerns about how the virus might continue to change in the future as we roll out the vaccines. While these concerns are unfortunately valid, they nevertheless present a possible glimpse into the future where we are likely to contend in an arms race with this virus, just like we are with the flu virus. The flu vaccine has to be updated annually as the influenza virus mutates and adapts to evade immunity already present in the population. If SARS-CoV-2 adopts the same capabilities, it could mean we will have to adopt similar strategies to keep it in check, by regularly updating vaccines.
The above scenario begs a couple of questions regarding these transmissions: (1) Should the drug companies be updating their vaccines to target mutated versions of SARS-CoV-2 spike protein? and (2) Can the current patterns of mutations in SARS-CoV-2 protein around the world help in understanding how the virus will continue to evolve? These are difficult questions, but suffice it to say that suddenly, there seems to be several mutations appearing that could be associated with either immune escape or immune recognition. All of these different mutations might make it easier for the virus to evade the immune system. The implication is that, more patients could catch the disease twice, and perhaps also mean that the vaccines may need to be updated. In such a case, even a relatively small amount of immune escape could make it more difficult to achieve herd immunity.
When scientists discovered the rapid spread of D614G variant, it was initially interpreted as a classic example of natural selection. This was because the location of the mutations in the spike protein is a major target for ‘neutralizing’ antibodies that bind to the virus and render it non-infectious. D614G was first discovered in China and Germany in late January 2020. It’s now almost always accompanied by three mutations in other parts of the SARS-CoV-2 genome – a possible evidence of a common ancestry. The rapid rise of D614G variant in Europe was alarming. Before March 2020, when most European counties went into lockdown, both non-mutated ‘D’ viruses and mutated ‘G’ viruses were present, with ‘D’ viruses prevalent in most of Western Europe. In March, ‘G’ viruses rose in frequency, and by April they were the most dominant variant across the continent, with an educated guess, via natural selection.
A contrary opinion is that natural selection in favour of ‘G’ viruses cannot be the most likely explanation for this rise. It is possible that the European dominance of ‘G’ variants could simply be due to chance, where the mutation just happened to be more common in the viruses that arrived in Europe. Again, a small number of individuals seem to be responsible for the virus’s spread, and therefore a tilt in favour of ‘G’ viruses could explain their apparent dominance now. Such ‘foundation effects’ are generally common in viruses, especially when they spread unabated, as SARS-CoV-2 did in Europe until late March.
Researchers in Southern Illinois University (USA) have also identified another variant, called 20C-US, which has a number of mutations that could alter the virus’s ability to replicate once inside human cells. It also features a mutation near a site on the COVID-19 spike protein that facilitates the virus’s entry into human cells. This site, called the furin cleavage site, allows the virus to hijack a very important enzyme that cracks open the spike protein in order to reveal those hidden sequences that help it to bind more tightly to cells in the human respiratory tract. The other variant the researchers identified appeared in Australia and carries a serine to asparagine mutation at the 477th amino acid position (S477N mutation), which seems to have increased the virus’s ability to bind to human cells. Overall, these two new mutations may pose serious public health concerns in the future if they provide the virus with an advantage to spread in the population.
Whilst the development of COVID-19 vaccines from Pfizer/BioNtech, Moderna and Oxford/AstraZeneca is timely, we should note that in most viruses, the use of vaccines and other anti-viral treatments causes them to evolve ways to escape the immune system, so they can continue to spread. Those that develop resistance to treatments or can escape the immune system will have a survival advantage, and so spread their genetic material.
With the emergence of new vaccines, scientists and other health experts are racing to understand the repercussions for these vaccines, which are primarily based on the sequence of the spike protein.
There seems to be understandable concerns about the South Africa variant, which has several mutations in the spike (S) protein. Most scientists believe that the vaccines are likely to work to some extent to reduce infection/ transmission rates among the UK and South African variants – since the various mutations have not significantly altered the S protein shape that the current vaccine-induced antibodies will not recognize at all.
In the short-term, only the harshest of lockdowns will reduce case numbers. What lockdown does is reduce the number of people with the virus and reduce the amount of virus in the population and that’s a good thing. But in the long term, we are likely to face a scenario similar to flu, where new vaccines are developed and administered every year. The overarching challenge is this: as the virus variants multiply in the population, the greater the chance the variant will be able to escape part of the vaccine – and this may reduce its overall efficacy.
One other concern would be the emergence of other COVID-19 versions circulating in populations or demographics where the genetic sequencing capability needed to detect the variants is not readily available. One reason why the UK promptly picked up the B117 variant is because of its global lead in the genetic sequencing setup. The point is, if new variants emerge in a country without much genome sequencing, there could be a serious problem. But as the scientists watch the virus continue to evolve, they will also be acutely mindful of the many personal tragedies that have arisen from this pandemic, and hopefully, that will ginger more research to curtail the spread. Currently, more than two million people have lost their lives to COVID-19 to date.
Notable variants of SARS-CoV-2
Lineage B.1.1.7 / Variant 202012/01 – First detected in October 2020 in the UK – It is correlated with increase in COVID-19 infections in the United Kingdom, The variant has 30 – 70% increased transmissibility and lethality.
501.V2/20H/501Y.V2 Variant –This variant was first detected in December 2020 in South Africa with higher prevalence among young people with no underlying health conditions, resulting in serious illness. The variant is believed to be driving the second wave of the COVID-19 epidemic in the country due to its more rapid spread than earlier variants.
Lineage P.1 – This lineage was detected in Tokyo in January 2021, and has since been detected in Brazil. It has 17 unique amino acid changes, 10 of which are in its spike protein. The variant is associated with a rapid increase in infections in places where previous cases were very high.
Lineage B.1.429 / CAL.20C – This variant was first discovered at Cedars-Sinai Medical Center (USA) in July 2020. The variant contains mutation L452R, but has not yet been shown to be more infectious.
Cluster 5 – This variant, also referred to as ΔFVI-spike was discovered in early November 2020 in Denmark, and is believed to have been spread from minks to humans via mink farms. The World Health Organization (WHO) has classified cluster 5 as having a “moderately decreased sensitivity to neutralizing antibodies”. After introducing a lockdown, travel restrictions, and mass testing, the Danish health authorities announced on 19 November 2020 that cluster 5 in all probability had become extinct.
Nigerian Variant – Another variant has recently emerged in Nigeria but fortunately, it has shown no significant public health concern. According to the Nigerian Center for Disease Control (CDC), it’s a separate lineage from the UK and the South African lineages.
Importance of viral strain surveillance for public health
Since viruses generally mutate over time, giving rise to new variants, a strain surveillance is necessary to catalogue SARS-CoV-2 sequences in order to support public health response. It is also important to embark on routine analyses of the genetic sequence in order to identify variants for further characterization. The following are five potential consequences of emerging SARS-CoV-2 variants:
Ability to increase transmission
Ability to cause more severe disease
Ability to escape detection by specific diagnostic tests
Ability to decrease susceptibility to therapeutic agents
Ability to evade vaccine-induced immunity
How would the COVID-19 pandemic play out in 2021?
With most of the world still susceptible to SARS-CoV-2 infection, it is unlikely that acquired immunity is currently a major factor in the virus’s evolution. But as immunity rises in the general population, either through infection or vaccination, there is likely to be a gradual trickle of immune-escaping mutations that could help SARS-CoV-2 to establish itself permanently in the population, primarily causing mild symptoms when it infects individuals with some residual immunity from a previous infection or vaccination.
In this regard, there is the likelihood that the virus would eventually be maintained as a merely common, cold-causing coronavirus. It’s also likely that our collective immune responses to SARS-CoV-2, aren’t robust and long-lasting enough to generate a robust selection pressure that leads to significantly altered variants in the population.
Harmful mutations could also emerge if antibody therapies are not used wisely – for example, if COVID-19 patients receive one antibody, which could potentially be inactivated by a single viral mutation. In such a scenario, a cocktail of monoclonal antibodies, each of which can recognize several regions of the SARS-CoV-2 spike protein, might reduce the odds that favour such a mutation through natural selection. Vaccines arouse less concern on this basis because, they tend to elicit a range of antibodies just like the body’s natural immune response.
The author is a Professor in Molecular Virology and Pathology at Regent University College of Science and Technology, Accra
GNA