Variants Of Concern- a nightmare coming true?

Viruses mutate when they make more copies in host cells- there is nothing unusual about it. Mutations are changes in genetic material (DNA or RNA) that may cause changes in the coded proteins. These processes are not something bizarre happening to SARS CoV2 virus, such coping errors happen when genetic materials (DNA or RNA) are replicated. Mutations are keys to evolution, which happens in all species, from viruses to human cells. A mutated version of the virus is called a ‘variant’. If such mutations in genetic material result in changes in the protein it codes, which subsequently can transform the virus functionally (that may alter the features of the disease)- then it is termed as a ‘strain’ (there are different strains of flu virus). Mutations accumulate in viral genetic material during propagations that eventually may result is a new strain with significant genetic drift from an ancestor virus (see the diagram above) and occasionally becomes the dominant version. We are experiencing viral evolution in front of us! In a pandemic they can easily capture millions of hosts and produces numerous copies harboring several random mutations. If the mutations are suitable for viral propagation-that variant will flourish, if the mutations are detrimental for virus-that variant will perish.

RNA dependent RNA polymerase, the enzyme that makes copies of RNA does not have very efficient error correcting mechanism like our cell’s DNA coping system. Flu virus, which is a fragmented RNA virus, notorious for frequent mutations, escapes our immune surveillance system and that is the reason for different flu variants and why every year we need different flu vaccine. Compared to flu virus the ´copier machine´ for SARS CoV2 is less error prone. RNA being the genetic material of SARS CoV2, while making copies they also will make several errors. This virus accumulates variations during the process of transmission from one infected individual to another. Transmissions across the population may accumulate mutations in viral genome, generally these random mutations won’t drastically alter the coded protein and hence won’t change the virus much. However, some of those random mutations can make the virus more efficient in terms of transmission, that may be the case we are observing in UK, South Africa, Denmark etc.

The UK variant

The recently reported UK variant is termed as VUI 202012/01 which means Variant Under Investigation year 2020, month 12, variant 01 also known as B.1.1.7, is spreading to multiple countries. UK identified this variant because the genomic sequencing analyses on COVID19 cases in UK is very efficient than other countries. Preliminary data suggests that this variant shows an increase in R-value (which indicates the disease spread), decrease in Ct value (indicates the higher viral copies in the sample), increase in viral load (quantity of virus in the sample). UK scientific advisory body reported that they had ´moderate confidence´ that VUI-202012/01 was substantially more transmissible than other variants of SARS CoV2. Underlying mechanisms of increased transmissibility is still unknown. Even though there are indications that this variant might have altered features from the original SARS CoV2, to declare this ‘alleged-variant’ guilty needs more thorough biological experimental evidence, which warrants time (biological experimental data for higher transmissibility, virulence etc.).

The UK variant shows a dozen of changes in the spike protein of SARS CoV2 (several in receptor binding region). Current origin hypothesis is- a patient with weakened immune system might have harbored the virus longer, thereby transformed into a breeding ground for such a variant with several mutations. The spike proteins on the surface of this virus help the bug to latch specifically to the host cell receptors. More importantly, the spikes studded on the corona are very vital for our defense system. Because, neutralizing antibodies created by vaccines bind to those spikes preventing from receptor binding.

Interestingly, another gene in the virus called ORF-8 (a gene supposed to help in replication of this virus) was also affected by a mutation. This was earlier reported from Singapore and thought to attenuate the viral disease. These copying errors made by the virus are useful for genetic ´detectives´ researchers, since they can easily trace the track the viral propagation. It is very important during an epidemic episode to understand more about the route-map of pathogen. The UK variant is suggested to have rapid transmission, but this feature of the variant could be due to several other factors rather than just mutations according to some experts. Such as disregarding social vaccination protocols (public health measures like masking, social distancing etc.), which may result in rapid spread of a variant. This is technically referred as chance or founder effect.

South African variant

Genomic analyses of surging cases in South Africa revealed a variant named 501Y.V2. Though the UK and SA variant emerged independently and contains multiple mutations, they have some common changes in spike proteins. UK variant has 8 changes while SA mutant has 9 changes in the spike protein. Some of these mutations can make the virus flourish in the host´s respiratory system, may be a reason for higher transmissibility.

Other variants

D614G mutation in the spike protein was reported in early March 2020 and its spread to global dominance by a month, suggesting viral evolution and natural selection of D614G. Genomic investigation in Netherlands and Denmark demonstrated human to mink, mink to mink, and mink to human transmission. Sequences from those outbreaks had a Y453F mutation in the receptor binding region of spike in addition to other mutations, affecting its binding to receptor. To avoid such potential recurrent spillovers large scale cullings were implemented in mink farms.

Studies on the effectiveness of the administered vaccines on these reported variants are ongoing and some initial data are coming out. A non-peer reviewed data suggests that the antibodies produced in Pfizer/BioNTech vaccine work against a mutation (N501Y) shared by both UK and SA variants. Information on vaccine efficiency on other worrisome mutations (like E484K) are expected soon.

Fighting a variant

Even if this variant is proven more transmissive or virulent, what could do to treat this disease is the question. Whatever mitigation measures currently we take that includes social distancing, masks, hand hygiene, avoiding indoor gatherings etc. should be continued for longer time, in fact more strictly! Important to note that original SARS CoV2 virus is quite successful in propagation compared to other viruses, that’s why SARS CoV2 managed to spread around the globe in a short time. A variant with ´more transmissibility´ is in a way more detrimental than one that causes ´more severe disease´. ‘’A 50% more transmissible SARS CoV2 variant would be a much bigger problem than a variant that’s 50% more deadly’’ says Prof. Adam Kucharski, at London School of Hygiene and Tropical Medicine, UK. If a variant becomes more contagious, it exponentially transmits to many including the vulnerable, thereby more quickly can choke the health system in the absence of various mitigation strategies. Considering that, the hasty decisions on travel bans seems appropriate. We may have to think again about flattening the curve, protecting the vulnerable and may have to introduce lockdown at outbreak epicenters, but remember that there are significant differences this time- we know more about the disease, more equipped with diagnostics and moreover we have several vaccines in our arsenal. This gives huge relevance to the faster rolling out of the vaccines that were developed at lightning-speed, to as many as possible.

Making of an escaping virus?

Whether the new variant can evade the trained immune system of the naturally SARS CoV2-infected or vaccinated is a big worry. The initial data suggests that this variant cannot escape the immunity from the lead running vaccines that are already rolling out and further, this variant is not making the disease worse. A dilemma here is, most of the vaccines are targeting the vital spike protein of the virus (though a vaccine will elicit multiple kinds of antibodies and cell-mediated immune responses) but this may be the first time a virus is subjected to such a tremendous selection pressure from vaccine in the population. Under a selection pressure, the virus may mutate into a strain with variations in spike protein, thereby can evade the immune system of the immunized individual-which is a nightmare (a situation of ‘vaccine escape mutants’ is unlikely but does not mean that it can’t happen). Data from vaccine trials suggest that the vaccinated are certainly protected from serious illness and hospitalizations, but they are prone to asymptomatic infections and thereby can spread around the virus. Having inactivated virus vaccines (e.g., Covaxin (India), Sinopharm (China) that may prepare immune system to create defense weapons against different viral proteins (not only the spike), in our stock thus becomes more relevant. We should be vigilant and only rigorous scientific studies will reveal the true colors of this variant or any yet unidentified ones! This variant should be taken ´very seriously´ while travel bans are premature according to Dr. Antony Fauci.

Some countries are planning to vaccinate as many with just the first shot and delay the booster dose shot. One cannot rule out the possibility of emergence of some variants evading such incompletely trained immune system. ‘’We can generate difficult escape mutants if we subject a virus to low antibody pressure and then slowly move up’’ according to Prof. Florian Krammer, Mount Sinai, USA. Under a selection pressure from inadequate vaccine regimen (especially, in the context that vaccinated can undergo asymptomatic infections), the virus can mutate into a strain that can evade the immune system in an immunized individual-which may become a real concern!

There are variants out there circulating and current data suggests that they could be more transmissible than the preexisting forms, which is a serious situation according to experts. Constant surveillance of the cases with genomic and epidemiological investigations are very vital. We need more biological evidence about the features of these variants, before ruling them as ‘nastier’ than the original…right now, gear up with vaccinations and follow the instructions from the health authorities.

Video of the blog

Mutations lead to evolution- watch the awesome experiment done on bacterial antibiotic resistance. Bacteria undergo random mutations while they divide and some of them at the antibiotic boundary attains antibiotic resistance, which then creates a resistant colony. Then it easily propagates through the antibiotic medium until it reaches the next higher-level antibiotic boundary. Again, it evolves to survive in the highest antibiotic concentration. Thus, random mutations help bacteria to grow eventually at the highest concentration in a short-time period!