Pandemic and emergence of variants

By Prof Kirthi Tennakone

The behaviour of the coronavirus bears resemblance to a high-speed magnified video of Darwinian evolution. The virus changes in front of our eyes and variants emerge as the fittest that survive. Genome surveillance has succeeded in reading the genetic changes accurately and sees how the genotype expresses as phenotype. Genotype being the chemical-genetic constitution and phenotype, characters as manifested in the environmental background.

Humans have sinisterly arrested the natural evolution of animals and plants; but despite scientific advancements, find it difficult to deal with a fast-evolving virus, science alone cannot resolve a social calamity. Containment of the pandemic would be difficult if our actions lag in relation to the pace of virus evolution.

Mutations: cause of biological evolution

According to Charles Darwin’s theory of evolution, life on earth continues by descent, inheriting parental characters subject to infrequent variations or mutations. After the discovery of DNA, the mechanism of inheritance and mutations was understood.

The genetic material DNA, present in all living cells, is a double-stranded structure composed of bead-like moieties pairs, known as nucleotide bases, denoted by symbols A, T, G and C. The sequence of these entities in a strand encodes genetic information analogous to a four-letter alphabet. Some viruses contain one strand referred to as RNA and encode information in the same way. When the cell or the virus replicate, most of the time, the sequence of nucleotides is copied exactly giving birth to a genetically identical cell or a virus. Rarely, copying errors creep in during replication. For example, the sequence AAGCT may be miscopied as AAGCG. This is a minor change in comparison to the entire genome, nevertheless a genetic change or a mutation. Most mutations will not lead to overriding alterations in the character of an organism. Mutations are often deleterious. Very infrequently, a change in character, owing to a mutation, turns out to be beneficial for the species to survive and procreate.

Mutants fitting the environment survive and proliferate. Paleontological findings provide ample evidence of the evolutionary process, when noticeable changes in living species manifest during, more or less, millennia. In most cellular organisms a mutation, fit to get established, takes place once in a million generations. For that reason, we do not see sporadic changes in the progenies of animals and plants. In the past there had not been significant alterations in genetically transferred characters of wild animals. The leopards we see today are not different from ones that lived during the Anuradhapura period, their hunting capabilities are similar.

The situation is different if a virus invades a population devoid of immunity. Their intrinsically fast mutation and replication rates and sheer numbers, invariably bring forth more adaptable strains in very short periods. Certainly, the same phenomenon occurred during previous epidemics and pandemics. Today it is happening at an escalated level because of high human population density, mobility and unrestrained interference in the environment.

Viruses live on cellular life, constantly interacting and following their evolution, while they themselves evolve.

Unicellular and multicellular and viruses

The first living cells or unicellular microbes seemed to have originated 3.5 billion years ago. A giant step in the advancement of life on earth has been the appearance of multicellular organisms, living systems made of assemblies of cells. A mutation in a unicellular agent around 1.5 billion years ago is believed to have cleared the way for the development of multicellular life. These individual cells, sharing similar DNA, formed colonies. Later colonies subdivided, each expressing genetic instructions differently to create complex animals, with organs performing varying functions. The above developmental pathways, leading to advanced forms of life existing today, took more than one billion years.

Viruses are distinct from cellular forms of life. The latter possesses the capacity to grow and reproduce, deriving energy and essence of structural materials from non-living substances; whereas the former needs to enter a living cell to reproduce. All cellular creatures and viruses replicate, mutate and interact with each other and the external environment and evolve.

The pandemic is just one episode of this universal phenomenon, progressing fast and tracked by humans, the concern now is the threat posed by variants.

Variants of Coronavirus (SARS-CoV-2)

A variant means a mutated version of an organism, distinct from the original in a noticeable deviation of an observable trait. For example, king coconut is a variant of coconut, the distinguishing attribute being the colour of the nut. Apart from the shade of the nut, this particular mutation had turned the tree into a dwarf, very disadvantageous for harvesting sunlight. Unable to compete with other trees, the king coconut would not survive in the wild. Attracted by the colour, humans (in Sri Lanka) have taken care of the variety and propagated it.

In the case of the Coronavirus, the important qualities distinguishing variants are higher infectivity, degree of virulence and resistance to vaccines.

The Coronavirus and other RNA viruses mutate faster than DNA based organisms. Here the probability of a viable mutation per generation (replication) exceeds 10,000 times that of a cellular life form. Furthermore, the generation time of the Coronavirus is a few hours compared to years and months in the case of animals and the total population of viruses in bodies of infected persons, during the time of the pandemics, is many billions times larger than an animal population. Consequently, Coronavirus variants popped up in durations as short as a few months, after the aggravation of the pandemic in late 2020. The longer the pandemic lasts and the greater the intensity, the more variants we encounter.

Since the emergence of COVID-19 in Wuhan, China in December 2019 and its global spread, many variants have appeared in geographically distinct regions and crossed borders. The original version of the virus which triggered the epidemic in Wuhan underwent the mutation D614G altering the spike proteins, making it more contagious. Soon the strain D614G surfaced almost everywhere initiating the pandemic. It is the common ancestor of almost all variants seen today. The World Health Organization and Center for Disease Control, United States, have classified Coronavirus variants into three categories.

Variants of Concern

: They have increased transmissibility, detrimental alteration in epidemiology, enhanced virulence, decrease effectiveness in public health measures or available vaccines and diagnostics. The Alpha variant detected in the United Kingdom, September 2020; Beta in South Africa, May 2020; Gamma in Brazil November 2020; Delta in India October 2020 falls into this category.

Variants of Interest

: These are strains of the Coronavirus genetically distinguished by sequencing with potentialities of higher transmissibility, disease severity, and immunity resistance. They could pose threats in the future and need to be watched. Variants; Eta, Iota, Kappa, Lambda and Mu recently detected in Colombia are classified as variants of interest.

Variants of high consequence

: These are variants that would largely escape known control measures. Fortunately, at the moment, no candidates come under this category.

How Coronavirus variants originate

A variant begins as a mutation of one single virus in an infected person somewhere. It is very unlikely it would enter someone else and cause the disease. The variant requires to breed sufficiently in the individual in whom it was created. Again, in order to procreate and proliferate, it will have to compete with the parent strain, initially dominant in the patient. The variant will succeed in competing if it replicates faster and more effectively invades cells. As expected, all variants of concern possess the above qualities. Similarly, if the mutant had acquired the trait of evading host immunity, it could overshoot the parent strain.

Variants possibly originate and breed in immunosuppressed persons chronically infected with COVID-19. They carry large viral loads for prolonged durations, a pathology conducive to the birth and growth of variants. A wide range of mutants have been detected in such patients.

Characteristics of variants

Variants of concern spread faster in contrast to the parent strain. A pertinent question is, what changes in the virus provide this facility? For the virus to invade the human system, it must attach to a cell in the respiratory tract and transfer genetic material to the interior of the cell. The virus does this with a special protein in the spikes, binding selectively to a receptor in human cells named ACE2. In variants, the chemistry and architecture of the spikes are redesigned to enhance attachment. Thereafter, the migration of the replicating viruses to adjacent cells is also facilitated by the same process. The host antibodies drive the immune response by attacking spikes to suppress their bondage to the receptors. Mutagenic alterations in the spikes also help the variants to escape host immunity.

Most contagious Delta variant

The delta variant first identified in India, October 2020, resulted in an aggressive epidemic there and rapidly diffused. Several mutations in the spike proteins facilitated its fast spread. While retaining the common ancestral mutation D614G, the Delta carries three other mutations named P681R, L452R and D950N. The mutation D614G increases the number of spikes on the viral envelope. Production of higher viral loads in Delta-infected patients is believed to be a character manifested by the P681R mutation. Their respiratory tracts carry 1000 times more virus particles. The L452R mutation seems to protect spikes from antibodies helping immunity evasion. An ability of the Delta variant to attack a wider group of cells probably originates from a trait induced by D950N mutation. Mainly because of the changes in the spike proteins, the Delta variant reproduces faster by cell-to-cell invasion. Consequently, once this brand of Coronavirus enters a susceptible person, the symptoms appear in a shorter period of four to five days, compared to about a week for the alpha variant.

The Delta variant is 60 percent more transmissible than the alpha which stands 50 percent higher than the ancestral strain. A parameter defining the transmissibility of an infectious disease is the average number of cases reproduced by one carrier of the pathogen, the basic reproduction number (R0). An infection reaches epidemic proportions if R0 exceeds unity. When the pandemic originated in China, the value of R0 was about 2.5. The estimated value of R0 for the delta variant is somewhere between six and nine, an enormous increase in transmissibility relative to the previous strains.

Virus variants compete, whenever the Delta entered new territory, it out-competed other strains.

Vaccinations and Delta Variant

Except for a partial immunity evasion of the Delta variant, vaccines are effective against both variants. Vaccines lower the probability of catching the infection, more importantly greatly reduce serious complications and death. Some statistical assessments conclude that breakthrough infections (re-infections) are higher for the Delta variant compared to Alpha.

The discrepancies reported could also be indications of the fact that the Delta variant is far more contagious than previous strains. Here, the statistically meaningful epidemiological parameters are the number of different categories of infected persons (vaccinated, the severity of infection as determined by hospitalizations and mortality) as a percentage of the total number of infected individuals, recorded temporally. It is extremely difficult to keep track of these quantities when the disease spreads fast. Even the total number of people infected cannot be ascertained reliably. Under such circumstances, the anomalies reported as lesser effectiveness of vaccines in the case of the Delta variant, could also entail errors in data interpretation, arising from the fact that the Delta variant spreads fast.

There are also reports to the effect that more unvaccinated younger adults and children are hospitalized after the arrival of the Delta variant, reflecting the severity of symptoms. Theories have been put forward to explain the apparent anomaly. However, because of faster transmission of the Delta variant, proportionately younger patients may seek hospitalization.

As the dominant strain infecting a large proportion of people; the Delta variant will continue to mutate and evolve. Few mutational changes have already been noticed and named Delta pluses, but there is no evidence to conclude they are more dangerous.

Doomsday variant

News spreads like viruses. Just as mutations, inadvertent or deliberate distortions and exaggerations happen in reproducing news. Versions with more sensational twists disseminate faster.

In May 2021 a new variant carrying mutations suggestive of fast transmission and immunity resistance was identified in South Africa. Months later a reputed epidemiologist tweeted that the variant could be an imminent danger, prompting media to name it a doomsday variant. The ensuing panic was the result of premature unconfirmed assertion. The World Health Organization announced that this variant is not propagating as fast as the Delta.

Stories of pathogens spreading exceedingly fast, evading immunity, are common in science fiction. There is no evidence for such, even at times when preventive measures were completely unknown. Attributes encoded in different mutations do not add arithmetically. If one virus has a trait that allows it to spread fast and another to evade immunity, these two qualities will not necessarily be pronounced, to the same extent, in a third virus endowed with both mutations. Fear-mongering concerning doomsday viruses is most unlikely to persist.

Herd immunity and Delta variant

When the percentage of subjects acquiring immunity (either by vaccination or contracting the illness) exceeds a threshold, epidemics wane and disappear. The point at which this transpires depends on the value of the basic reproduction number R0; determined on the assumption there were no immune individuals, at the time the pathogen initiated the epidemic. As the immunity of the community increases, the reproduction number decreases proportionate to the fraction of people remaining susceptible and the rate of transmission is determined by an effective reproduction number RE. If N is the total population and M the number among them immune, the fraction susceptible is 1- M/N. Therefore the reproduction number reduces to the effective value RE = R0 (1 – M/N). Once RE reaches a value less than unity, the epidemic ceases to continue and the threshold corresponding to RE = 1, occurs when M/N = 1 -1/R0. At the beginning of the pandemic, the value of R0 was approximately 2.5 and the above formula yields M/N = 0.6, so that herd immunity threshold is 60 percent. For the highly transmissible Delta variant, a mean value of R0 is 7.5 and the same formula gives a herd immunity threshold of 87 percent. As vaccinated persons sometimes get re-infected, the actual threshold may exceed the above number, suggesting herd immunity is virtually beyond reach. Fortunately, R0 can be reduced by preventive measures such as social distancing, wearing masks and hand sanitization, thereby lowering the threshold.

Are we sufficiently disciplined to follow preventive measures stringently? The virus will continue to evolve via random mutations and their selection may be influenced by our behaviour. Will it turn more deadly or less deadly? These questions are too complex and unpredictable.

Fortunately, vaccines answer satisfactorily and redesigning and improvements are within reach. Preventive measures dampen transmission significantly. Every individual needs to follow these two strategies confidently, without resorting to unproven practices and myth.