Tracking and identifying the rapidly emerging variants of SARS-CoV-2 is one of the key strategies to check the spread of the COVID-19 pandemic. For this, the virus samples are obtained from infected people and a proactive genome sequencing is done in laboratories. Tracking also enables to detect the origin and spread of a specific variant.
In India, more than 50,000 genome sequences have been made so far, which provide crucial information regarding virus mutations, its evolution and spread, and its variants. Worldwide, over 2.5 million genome sequences are available publicly.
Gene Sequencing
Sequencing the genome of a virus means determining the sequence of the letters of RNA of that virus, in which genetic instructions are coded in a particular sequence. These instructions are used by the virus to generate its own copies. In case of the SARS-CoV-2 virus, these instructions are coded in a sequence of 29,903 letters of RNA (ribonucleic acid bases–A, U, G, and C) which constitute its ‘genome’.
Genome sequencing is a way to look closely at the mutations that take place in the virus during replication inside the human body after infection. Such mutations can help find out if a new variant of SARS-CoV-2 has come into existence in a region.
Nomenclature of Variants
Researchers stress on the need for adopting a uniform naming system for different variants. The Pango (a library for layout and rendering of text, with an emphasis on internationalisation) nomenclature is a system to give names to different lineage of SARS-CoV-2 genomes. it was developed by virologists at the University of Edinburgh, the University of Sydney, and the University of Oxford. The system is designed to assign lineages in a dynamic manner in such a way that a group of genomes will be assigned a new lineage name if they have specific set of attributes like common ancestors and common mutations, etc.
There are some general norms that are followed while naming a variant.
- Pango lineage names consist of an alphabetical prefix and a numerical suffix. The alphabetical prefix contains Latin characters only which are case insensitive.
- The letters I, O, and X are not used in the prefix of the names of standard lineages.
- Each dot in the numerical suffix means “descendent of” and is applied when one ancestor can be clearly identified. So, lineage B.1.1.7 is the seventh named descendent of lineage B.1.1 and C.1 is the first named descendent of lineage C.
- The suffix can contain a maximum of three hierarchical levels, referred to as the primary, secondary, and tertiary suffixes.
- In order to avoid four or more suffix levels, a new lineage suffix is introduced, which acts as an alias. For instance, C is an alias of B.1.1.1, hence, the descendent of B.1.1.1 is called C.1 (rather than B.1.1.1.1). Consequently, the name C, by itself, is never directly applied to a sequence.
- In some instances, it is not possible to unambiguously identify an ancestral lineage within the Pango nomenclature for a given lineage of interest. This is the case for lineages A and B, because of their position near the root of the phylogeny. For these “special case ancestors”, the alphabetical part alone can be applied directly to sequences. In all other cases the suffix is mandatory.
For recombinant lineage naming, the rules are as follows:
- Every new recombinant lineage is given a new top-level lineage prefix.
- The minimum number of genomes required to designate a new recombinant lineage is the same as the number required to designate a non-recombinant lineage.
- All top-level lineages that are recombinants have a prefix that begins with X.
- In order of discovery, recombinant lineages prefixes are XA, XB, XC…, XAA, XAB, … XBA, etc.
- Recombinant lineage names do not contain information about their putative parental lineages. Any such information (which might be uncertain or incomplete) can be provided in the Pango lineage summary table.
- Recombinant lineages are “special case ancestors” because they do not have a single unambiguous ancestral lineage within the Pango nomenclature. Therefore, sequences can be directly allocated to the prefix without a numerical suffix. In this way, recombinant lineages behave like lineages A and B.
- Non-recombinant descendent lineages follow the usual suffixing rules, XA.1.1, XA.1.2, etc.
- When the maximum number of suffix levels is reached, the usual aliasing rules apply. So, if AJ is the next available top-level prefix, then XA.1.1.1.1 becomes AJ.1. (AJ is an alias of XA.1.1.1 but is not used without a suffix because it is not a special case ancestor.)
- Any recombinant of recombinants is given the next available top-level name that starts with an X. Information about ancestry is added to the lineage summary table.
Classification of Variants
Broadly, variants are classified into three:
- Variant of Interest (VoI) is a SARS-CoV-2 variant, with genetic changes that are predicted or known to affect virus characteristics like transmissibility, disease severity, immune escape, diagnostic or therapeutic escape. It is known to cause significant community transmission or multiple COVID-19 clusters, in many countries with increasing relative prevalence as well as increasing number of cases over time, or other apparent epidemiological impacts which indicate an emerging risk to the global public health.
Though most changes have little to no impact on the properties of the virus, some changes may, however, affect virus properties in terms of its spreads, the associated disease severity, or the performance of vaccines, therapeutic medicines, diagnostic tools, or other public health and social measures, etc.
Actions Taken by WHO and Member-States If a new potential VoI is identified, a member-state informs WHO about VoI-associated cases like person, place, time, clinical, and other relevant characteristics through International Health Regulation (IHR) mechanism. The member-state is also required to submit complete genome sequences and associated metadata to a publicly available database like GISAID (a global science initiative and primary source set up in 2008 that provides open-access to genomic data of influenza viruses, etc.). Besides, the country performs field investigations to improve understanding of the potential impacts of the VoI on COVID-19 epidemiology, severity, effectiveness of public health and social measures, or other relevant characteristics. The member-state performs laboratory assessments as per capacity or contacts WHO for support to conduct laboratory assessments on the impact of the VoI on relevant topics.
On the other hand, WHO conducts comparative assessment of variant characteristics and public health risks, and coordinates laboratory investigations with member-states and partners, if necessary.
- Variant of Concern (VoC) through a comparative assessment, has been demonstrated to be associated with one or more of the following changes at a degree of global public health significance: increase in transmissibility or detrimental change in COVID-19 epidemiology; or increase in virulence or change in clinical disease presentation; or decrease in effectiveness of public health and social measures or available diagnostics, vaccines, and therapeutics.
Actions Taken by WHO and Member-States If a VoC is identified, a member-state submits complete genome sequences and associated metadata to a publicly available database like GISAID, and reports initial cases/clusters associated with VOC infection to WHO through the IHR mechanism.
They may also perform field investigations and laboratory assessments in coordination with the international community to improve understanding of the potential impacts of the VoC on COVID-19 epidemiology, severity, effectiveness of public health, and social measures, besides diagnostic methods, immune responses, antibody neutralisation, or other relevant characteristics.
WHO conducts comparative assessment of the characteristics of the variant and public health risks in consultation with its Technical Advisory Group on Viral Evolution. WHO also coordinates additional laboratory investigations with member-states and partners if necessary, and communicates new designations and findings with member-states and public through proper channels.
Reclassifying VoIs and VoCs
A previously designated Variant of Interest (VoI) or Variant of Concern (VoC) can be reclassified if they conclusively do not pose a major added risk to global public health compared to other circulating SARS-CoV-2 variants. The reclassification is undertaken through a critical expert assessment taking into account several criteria like the observed incidence/relative prevalence of variant detections among sequenced samples over time and between geographical locations, the presence/absence of other risk factors, and any ongoing impact on control measures.
- Variant of High Consequence (VOHC) is a variant that clearly shows that prevention measures or medical countermeasures (MCMs), to contain it, have significantly reduced effectiveness relative to previously circulating variants. Its effect on medical countermeasures (MCM) include—demonstrated failure of diagnostic test targets, a significant reduction in vaccine effectiveness, a disproportionately high number of vaccine breakthrough cases, or very low vaccine-induced protection against severe disease, and significantly reduced susceptibility to multiple emergency use authorisation (EUA) or approved therapeutics, and more severe clinical disease and increase hospitalisations.
A variant of high consequence would require notification to WHO, reporting to the Centers for Disease Control and Prevention (CDC), an announcement of strategies to prevent or contain transmission, and recommendations to update treatments and vaccines.
So far, no SARS-CoV-2 variant of high consequence has been identified.
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