PDF Download 
Chitra Pattabiraman, “Tracking SARS-COV-2 Variants of Concern,” ORF Special Report No. 144, June 2021, Observer Research Foundation.
Viruses mutate and sometimes pick up biologically advantageous traits such as the ability to transmit faster or escape the host immune response; they could also become resistant to certain therapeutic drugs used to treat the infection. This is, for instance, why flu vaccines are revised every year – to keep up with the changes in the virus, and why a combination of drugs rather than a single drug is used to treat HIV.
The early evolution of SARS-CoV-2[a]—understood by experts based on viral genomes sequenced from Wuhan, and later, from other parts of Europe and Australia—suggested that the virus was undergoing a mutation every few weeks.[1] This in itself was not alarming, as the mutation rate was roughly half that of the influenza virus and one-fourth that of HIV.[2] In the early part of the pandemic, there was a low number of mutations seen in the virus; the presence of these mutations allowed researchers to track the movement and spread of the virus to many different parts of the world. However, as changes accumulated in the spike protein of the virus, they became a cause for concern due to the key role played by this protein in how the virus recognises host cells and how in turn it is recognised by the body’s immune system.[3],[4] Additionally, multiple vaccines are based on the spike protein sequence and it was unclear if changes or mutations in the spike protein would make them less effective.
What variants of SARS-CoV-2 have been identified so far, one and a half years since the World Health Organization (WHO) declared a pandemic of COVID-19?
Any change in the ancestral virus for SARS-CoV-2 that was known to be circulating in Wuhan in December 2019 would result in a variant. This in itself is consistent with the evolution of the virus in a susceptible host. Looking at where mutations occur over the entire length of the genome of the virus, it is clear that some parts of the virus genome mutate more often than others. (See Figure 1)
Figure 1. Diversity across the SARS-CoV-2 genomes
These changes may give rise to variants with increased fitness – those that are more infectious and transmit faster; escape immunity or the vaccine, resulting in reinfection; or cause more severe disease. These variants could spread through a population to become dominant, depending on various epidemiological factors that determine the availability of susceptible hosts. Variants that are more virulent, have increased viral loads and transmit more quickly, or can re-infect, may even cause surges in cases in a conducive environment.
Variants with such biological properties are broadly classified as “variants of concern”. The term captures those variants whose proportion increases significantly in a population in a short span of time.[7] Genomic surveillance efforts in many parts of the world[b] are now involved in tracking the emergence, spread, and evolution of SARS-CoV-2 variants with these properties. A historic and astronomical 1.5 million sequences of SARS-CoV-2 have been sequenced as of early May 2021.[8]
Until April 2020, there was little evidence for the selection and dominance of a single variant. All SARS-CoV-2 variants after many hundred thousand infected in Asia and Europe could be summarised in about ten mutations.[9] The first variant with a “fitness advantage” was detected in late January 2020 during the outbreak of SARS-CoV-2 in Europe.[10] It had a single change in the spike protein which resulted in an amino acid Glycine instead of D Aspartic Acid at position 614 – so called the “D614G change”. It is now clear both from studies in cell culture and from epidemiological data across the world that viruses that have the 614G version are more infectious than the ones that carry a 614D on the spike protein.[11] The lineage of the virus carrying this mutation, named B.1, now dominates across the world and majority of the circulating viruses are offspring of the lineage B.1—including all four variants of concern—i.e., B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta),[c] and P.1 (Gamma).[12] Since the first variants of SARS-CoV-2 were identified, many have become extinct.
Figure 2. Frequency of global SARS-CoV-2 sequences over time[13]
Given the large number of available genomes, the tracking of SARS-CoV-2 is done by monitoring the relationship between sequences (phylogenetic analysis) in a known cluster of cases, and each sequence is classified as an offspring or a sibling sequence. Sequences that are closer to each other are likely to have shared an ancestor more recently than those that are not as similar.
In order to understand the progression of the COVID-19 pandemic, it was useful to look at a small number of mutations, defining related sequences, and classifying those sequences into a lineage. The most popular nomenclature is the Phylogenetic Assignment of Named Global Outbreak Lineages (PANGOLIN)—in this system, a lineage is a set of sequences that are close to each other, which have a known epidemiological context such as an outbreak in a region or in a mink farm. It captures the leading edge of the pandemic.[d] At the time of writing this report, researchers have identified well over 800 SARS-CoV-2 lineages from different parts of the globe. Of these, over 100 have been detected in sequences from India.
Figure 3. The evolution of selected lineages of SARS-CoV-2
Laboratory studies using cultured cells and the SARS-CoV-2 virus have catalogued the list of mutations that the virus acquires in order to thrive in the presence of antibodies.[14],[15] The highlight of these studies was that the spike protein is able to tolerate a large number of mutations. The mutations also cluster into particular positions, mainly in the receptor binding domain, or that part of the spike protein that binds the human/host cells and helps the virus enter the cell. Mutations that occur naturally in circulating viruses are compared to this catalogue and a match can provide indirect evidence for potential immune escape.[e] These must then be confirmed by further studies to test if the new circulating variant can be seen and checked by antibodies from either previously infected or vaccinated individuals.
One: B.1.1.7 (Alpha) / Described in December 2020 from the United Kingdom (UK).[16] This variant has a transmission advantage. It spread quickly within the UK, was associated with increased hospital admissions, and a surge in cases.[17] Even with increased checks in place, this variant spread to multiple countries in the world. India reported first cases from international travellers in the last week of December.[18] B.1.1.7 is now a dominant lineage in many parts of the world.
Two: P.1/P.2 (Gamma) / Described from Brazil in early January. Features include reinfection – previously infected people were only partially protected, leading to a huge surge in cases in Manaus, Brazil.[19],[20] This variant has been seen in many parts of the world since its first report, and has been sequenced from 49 counties.
Three: B.1.351 (Beta) / Described from sequencing efforts in South Africa in late December. Grew rapidly to become a dominant variant in South Africa. Features include antibody escape – decrease in neutralisation by antibodies from vaccinated individuals.[21],[22]
Four: B.1.617.2 (Delta) / Described from sequencing efforts in India. Earliest sequences are from late 2020, but sequences only became available in early 2021. This highlights the need for continued surveillance of SARS-CoV-2 variants.[23]
Without combining epidemiological data on who got infected, how, and when—with genomic data on which variant it was, it is difficult to determine if this variant caused a surge in India. What is known, however, is that an increase in the proportion of this variant ran parallel to the surge in certain states.[24] Early data from the introduction of this variant by travellers from India to the UK suggests that it is at least as transmissible, if not more, than B.1.1.7.[25] The rapid increase in the frequency of B.1.617.2 is consistent with data available from the sequencing efforts in India across multiple states, including Maharashtra, West Bengal, and Karnataka.[26]
What is known and not known about VOCs, and why is it important to track them?
Early data based on outbreaks in vaccinated populations in Israel, Qatar, and the UK suggests that vaccines are effective against known VOCs so far.[27],[28],[29],[30] Although early laboratory studies raised some concerns about decreased antibody recognition and neutralisation, particularly for P.1 and B.1.351.[31] Early data suggests that vaccines are likely to protect against B.1.617.[32],[33] Predictive modelling based on laboratory experiments suggests that vaccines protect from severe disease, even against VOCs.[34]
It is still the early days of global efforts to identify and study the SARS-CoV-2 variants of concern. There is little yet known about the factors that help these variants emerge. Long transmission chains, persistent infections, and availability of susceptible and immunocompromised hosts, may all be contributing to the emergence of variants. It follows that variants will continue to emerge as the pandemic continues. Once variants of concern emerge, they spread across the world even with reduced travel, and restrictions on movement are in place.[35]
This becomes a particular challenge in areas that do not have access to healthcare and adequate vaccine coverage. A variant of concern that emerges or spreads to rural India, for example, would easily overwhelm the healthcare system.[36] While the epicentres of outbreaks of SARS-CoV-2 in India have so far been cities, migration data suggests that people could carry the virus with them to other areas. Given the lack of molecular testing in rural set-ups, one way to check the spread would be to encourage travellers from urban to rural areas to take rapid antigen tests—cleared for home use by the Indian Council of Medical Research (ICMR).[37] These travellers should also observe pandemic-appropriate behaviour. While these measures may not check the emergence of variants, cutting down the transmission chain would ensure that a variant that emerges does not spread, at least not quickly.
Surveillance and tracking can aid preparedness and serve as an early warning system. Tracking how the virus is changing gives the opportunity to fine-tune diagnostics and revise vaccines. This requires monitoring SARS-CoV-2 variants across the world. In India, a consortium of laboratories and nodal agencies has been set up for genomic surveillance of SARS-CoV-2 INSACOG (Indian SARS-CoV-2 Genome Sequencing Consortia).[38] In order to pick up the emergence of a variant of concern, it is necessary to conduct continuous tracking both across space and time.
Among India’s states, Kerala is the first to implement a comprehensive genomic surveillance programme—a partnership between the Department of Health & Family Welfare, Government of Kerala, National Health Mission Kerala, and CSIR Institute of Genomics & Integrative Biology.[39] The programme releases public reports every two weeks, giving detailed trends of the pandemic and providing district-wise breakdowns of known VOCs and variants of interest in a graphical format that emphasises the emerging trends. This model will be critical for leveraging genomic insights towards their policy implications. Current evidence strongly suggests that methods of prevention work against VOCs and limiting transmission might be the best strategy for checking them.
Chitra Pattabiraman is an India Alliance (DBT-Wellcome Trust) Early Career Fellow at NIMHANS, Bengaluru.
(Author’s note: The views expressed here are those of the author and not those of the institution or the funders. The integrated genomic analyses performed by Outbreak.info and Nextstrain.org used as the basis for this article are only possible due to all of the sequencing efforts across the world and open and timely data sharing by researchers who deposit sequences to GISAID.org.)
[a] SARS-CoV-2—or severe acute respiratory syndrome coronavirus 2—is the virus that causes COVID-19.
[b] These include COVID-19 Genomics UK Consortium (COG-UK); NGS-SA: Network for Genomic Surveillance in South Africa; CADDE – Brazil-UK Centre for Arbovirus Discovery, Diagnosis, Genomic and Epidemiology; Indian SARS-CoV-2 Genome Sequencing Consortia (INSACOG); and other laboratories submitting SARS-CoV-2 data to GISAID.
[c] This lineage was first described from India and earliest sequences date to November 2020.
[d] Meaning, the mutations that are shaping the pandemic at a certain juncture.
[e] ‘Immune escape’ refers to the potential threat that variants could do a run-around of the human immune response. Such “immune escapes” could mean more people who have had COVID-19 remain susceptible to reinfection, and that proven vaccines may, at some point, need an update.
[1] Ewen Callaway, “The coronavirus is mutating – does it matter?” Nature, 08 September, 2020.
[2] Callaway, “The coronavirus is mutating”.
[3] Lakshmanane Premkumar et al,. “The receptor binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients,” Science immunology vol. 5, 48 (2020): eabc8413. doi:10.1126/sciimmunol.abc8413.
[4] Qihui Wang et al., “Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2,” Cell , vol. 181, 4 (2020): 894-904.e9. doi:10.1016/j.cell.2020.03.045.
James Hadfield et al., “Nextstrain: real-time tracking of pathogen evolution,” Bioinformatics (Oxford, England) vol. 34,23 (2018): 4121-4123. doi:10.1093/bioinformatics/bty407.
[7] WHO. 2021. Weekly epidemiological update – 25 February 2021. https://www.who.int/publications/m/item/covid-19-weekly-epidemiological-update
[9] Callaway, “The coronavirus is mutating” Andrew Rambaut et al., “A dynamic nomenclature proposal for SARS-CoV-2 lineages to assist genomic epidemiology,” Nature microbiology, vol. 5,11 (2020): 1403-1407, doi:10.1038/s41564-020-0770-5.
Jessica A Plante et al., “Spike mutation D614G alters SARS-CoV-2 fitness,” Nature, vol. 592,7852 (2021): 116-121. doi:10.1038/s41586-020-2895-3.
[12] WHO, “update” .
[13] nextstrain.org. (Accessed May, 2021), Allison J Greaney et al., “Complete Mapping of Mutations to the SARS-CoV-2 Spike Receptor-Binding Domain that Escape Antibody Recognition,” Cell host & microbe, vol. 29,1 (2021): 44-57.e9. doi:10.1016/j.chom.2020.11.007.
Tyler N Starr et al., “Prospective mapping of viral mutations that escape antibodies used to treat COVID-19,” Science (New York, N.Y.), vol. 371,6531 (2021): 850-854. doi:10.1126/science.abf9302.
[16] Andrew Rambaut et al., “Preliminary genomic characterisation of an emergent SARS-CoV-2 lineage in the UK defined by a novel set of spike mutations,” Dec 2020, VirologicalOrg (Accessed June 08, 2021)
Erik Volz et al., “Assessing transmissibility of SARS-CoV-2 lineage B.1.1.7 in England,” Nature, vol. 593,7858 (2021): 266-269. doi:10.1038/s41586-021-03470-x.
Áine O’Toole et al., “Tracking the international spread of SARS-CoV-2 lineages B.1.1.7 and B.1.351/501Y-V2,” Wellcome open research, vol. 6 121. 19 May. 2021, doi:10.12688/wellcomeopenres.16661.1.
M Nuno R Faria et al., “Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil,” Science (New York, N.Y.), vol. 372,6544 (2021): 815-821. doi:10.1126/science.abh2644.
Ester C Sabino et al. “Resurgence of COVID-19 in Manaus, Brazil, despite high seroprevalence,” Lancet (London, England), vol. 397,10273 (2021): 452-455. doi:10.1016/S0140-6736(21)00183-5.
MYiska Weisblum et al., “Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants,” eLife, vol. 9 e61312. 28 Oct. 2020, doi:10.7554/eLife.61312.
Houriiyah Tegally, “Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa,” medRxiv, 2020.12.21.20248640;
Meredith Wadman, “Blind spots thwart global coronavirus tracking,” Science (New York, N.Y.) , vol. 372,6544 (2021): 773-774. doi:10.1126/science.372.6544.773.
[24] INSACOG. “Note on INSACOG Data and Mutants 21-04-2021.pdf”. (Accessed June 08, 2021)
[25] Public Health England,2021 “SARS-CoV-2 variants of concern and variants under investigation in England”.
[26] INSACOG, “Note”.
[27] Eric Topol comment on variants of concern. (Accessed on June 08, 2021).
Eric J Haas, et al. “Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data,” Lancet (London, England), vol. 397,10287 (2021): 1819-1829. doi:10.1016/S0140-6736(21)00947-8
Laith J Abu-Raddad, et al. “Effectiveness of the BNT162b2 Covid-19 Vaccine against the B.1.1.7 and B.1.351 Variants,” The New England journal of medicine, NEJMc2104974. 5 May. 2021, doi:10.1056/NEJMc2104974
Pengfei Wang et al. “Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7,” Nature, vol. 593,7857 (2021): 130-135. doi:10.1038/s41586-021-03398-2
Markus Hoffmann et al.,“SARS-CoV-2 variants B.1.351 and P.1 escape from neutralizing antibodies,” Cell, vol. 184,9 (2021): 2384-2393.e12. doi:10.1016/j.cell.2021.03.036
B Sarah Cherian et al., “Convergent evolution of SARS-CoV-2 spike mutations, L452R, E484Q and P681R, in the second wave of COVID-19 in Maharashtra, India,” bioRxiv, 2021.04.22.440932;
David S Khoury et al., “Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection,” Nature medicine, 10.1038/s41591-021-01377-8, 17 May 2021, doi:10.1038/s41591-021-01377-8
[34] Khoury et al.,“Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection”
[35] O’Toole et al., “Tracking the international spread of SARS-CoV-2 lineages B.1.1.7 and B.1.351/501Y-V2”
[36] Wadman, “Blind spots“ ICMR, Advisory for Home testing. (Accessed June 08, 2021)
[38] INSACOG, (Accessed June 08, 2021)
[39] GENESCoV2 Kerala. (Accessed June 08, 2021)
The views expressed above belong to the author(s). ORF research and analyses now available on Telegram! Click here to access our curated content — blogs, longforms and interviews.
Chitra is the Founder and Chief Scientific Officer of Infectious Disease Research Foundation a not for profit for carrying out locally relevant infectious disease research ...
Read More +
.png)
PREV
.png)
.png)