Classification, Genetics and Clinical Importance

SARS-CoV-2 Virus Variants:

Classification, Genetics and Clinical Importance

By Terry Clark, MD, FCAP

In the beginning of 2020 the world learned there was a “Novel Corona Virus” in China, which over 8 weeks became pandemic and the media added additional labels. Some of these were: Covid-19 virus, China Virus, Wuhan Virus, KungFu Virus. Eventually the scientific community settled on SARS-CoV-2. Early on the U.S. was infected with 2 strains, only slightly genetically different; one in New York City (directly from Europe) and the other on the West Coast (directly from China). By fall 2020 global viral proliferation had given rise to large clusters of mutated virus that had higher contagion ability and slightly higher morbidity/ mortality. The earliest of these became known as the UK and South African variants. They were labelled B.1.1.7. and B.1.351 in the most popular system used by the scientific community. The media and even the CDC and WHO largely used the UK and South African monikers. Soon a Brazilian variant also joined the discussion. Having multiple systems for naming the virus has been confusing for everyone—the public, media, government agencies, and even the scientists studying the viruses. Some history of the nomenclature follows.

In traditional viral taxonomy, SARS-CoV-2 is a member of the Coronavirus subfamily, a single stranded RNA virus subfamily that primarily infects mammals and birds. Genus and “species” of virus are designated mostly by the species they infect or the disease they cause. Corona virus genomes are 26-32,000 nucleotide bases in length, with 9-12 genes. Mutations are very common during replication. Hundreds of mutant virus occur and are secreted in the mucus and breath from every patient infected, whether they are symptomatic or not. The vast majority of these are defective. Rarely, they can be more virulent.

As the Covid-19 outbreak progressed, numerous mutant clones rapidly evolved; only a few clinically important. A new system was needed to label the important ones. The popular method of labeling them by the country in which they first blossom into public notice is not necessarily accurate as to origin and has nothing do with their pathogenic properties. The most populated countries have multiple variants arising.

The Global Initiative on Sharing Avian Influenza Data (GISAID) monitors the mutant influenza strains that emerge globally every year. They help the manufacturers to modify flu vaccines to be effective. When the Covid-19 pandemic hit they undertook to create a database of all of the laboratories doing genomic sequencing of the SARS-CoV-2 isolates. Several different systems of identifying the variants have been used, but most prevalent in the literature is the alphabet-numeric system is called “Pango” (ie; B.1.1.7). There is a computer program (Pangolin, there are already 3 generations) used by participants in the GISAID data base. This identification algorithm, proposed around April 2020, attempts to trace the virus mutants along their evolutionary lines since the early spread. The first letter A is assigned to those mutants arising directly from the original China strain, B to those from the first Italian isolates. Subsequent extensions (ie: B.1.1) indicate the succeeding mutant variant from the immediate ancestor B.1 line. The UK virus designation B.1.1.7 indicates the 7th variant that was identified arising from the B.1.1 mutation lineage and the S. African strain B.1.351 is the 351st variant arising from the B.1 ancestor.

There is so much mutational activity that even this system has problems.

Within a year of expanded genome sequencing surveillance

VARIANTS continued from Page 27 of this system had become too cumbersome for public discussion. In consensus, around Feb 2021; WHO, CDC and other research groups implemented a more useful labeling of current significant SARS-CoV-2 strains. Letters of the Greek alphabet have been assigned to the most significant variants. The Alpha variant was originally “UK”, the Beta was “South Africa”, Gamma was “Brazil”, Delta had no previous country of origin name but arose in Peru in Aug 2020 and is now the predominant virus in the world. There are currently at least 3 mutational spin-offs from the Delta SARSCoV-2 stain (B.1.672.1) designated as subgroups AY, AY2,AY3. They have no mutations that make them more or less dangerous than the original Delta strain. Mu is the latest added variant which was first noticed in Colombia and Ecuador in Jan 2021, but has minimally spread out of S. America and is decreasing as Delta is replacing it. Epsilon, Kappa, and Iota variants are also named but are of very little interest. Of note — there is no C, F, J, ,Q or V in the Greek alphabet. Non-English “fraternity” favorites you might recognize are Psi, Phi,Theta, Chi and Omega; which will probably be used in the not to distant future.

To help prioritize the importance of the variants the U.S. SARS-CoV-2 InterAgency Group (SIG) assigns each to one of 3 categories based on their genetic and clinical risk profiles. » Variants of Interest (VOI): These variants carry some mutations that are thought to enable enhanced contagion or mortality; or ability to avoid immune response to infection, or avoid recognition in PCR testing or may be resistant to current vaccines, monoclonal antibodies, or chemotherapeutic agents.

However, they are currently a minor percentage of cases in most countries (especially the U.S.). They have not shown “significant” increases in severe disease or mortality in vaccinated patients.

SIG designated VOI are Eta, Iota, and Kappa and all seem unlikely to be a danger. WHO keeps its own list and has recently listed two additional as VOI: Lambda and Mu. U.S. SIG has not included them, since U.S. cases are <1%. » Variants of Concern (VOC): These variants meet criteria of

VOI, and have shown rapid spread within many populations and usually there is some but not extensive evidence of increased severe infection/mortality in unvaccinated individuals. Some evidence for resistance to vaccines is present at least in elderly or immunocompromised individuals. Delta, Alpha, Beta, Gamma are in this category. » Variants of High Consequence (VOHC): These variants would be genetically, as VOI and VOC, worrisome; and would have shown definite ability to evade current vaccine protection against severe disease or mortality, or not be detected by PCR testing, or resistant to multiple chemotherapeutic agents or resistant to most monoclonal antibody preparations. There are no variants currently placed in this category. *See cdc.gov/science/surveilence for exact wording of all category criteria

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Below are profiles of the variants with WHO or SIG assigned categories as of Sept 3.

» Eta: (B.1.525) First seen UK and Nigeria, Dec 2020.

Genotype suggests potential monoclonal antibody resistance, convalescent plasma antibodies resistance, and vaccination induced antibody resistance. Variant spread is limited and genetic potential does not seem realized. » Iota: (B.1.526) First seen US, NewYork, Nov 2020. Manifests monoclonal antibody resistance (bamblanivimab/esesevimab combination products only ). This is not the more widely used brand REGN-COV2 from the Regeneron Corp. Convalescent plasma antibodies, and vaccination induced antibodies show reduced neutralization in lab tests. Clinical vaccine resistance is unproven. Variant is limited in prevalence globally. » Kappa (B.1.617.1) First seen India, Dec 2020. Genetics suggest potential for reduced neutralization by monoclonal antibody and convalescent plasma antibodies, but evidence for clinical resistance is unproven. Variant is limited in prevalence globally and decreasing. » VOI without WHO designation: (pango B.1.617.3) First seen India Oct 2020. Shows 7 mutations felt to increase resistance to vaccines but no definite evidence in clinical studies. Genetics also suggest there may be resistance to monoclonal antibody drugs. Very low prevalence globally. » Lambda: (B.1.1.1.37) First seen Peru, Aug 2020. Was dominant virus in South America. Only 0.1% US (about 2,000 cases) and falling everywhere as Delta spreads. Genetically 7 mutations are present, particularly 3 in the S receptor gene with one being an unusual large deletion mutation.

Vaccination induced antibodies show moderate reduced neutralization in lab tests. Clinical vaccine resistance is unproven but suggested since it arose in a highly vaccinated city (Chinese Sinovac product).1 No clinical evidence of resistance in mRNA based vaccines. It does have a mutation that some PCR testing platforms may miss, but not the vast majority of platforms. » Mu: (B.1.621 and B.1.621.1) First seen in Colombia, Jan 2021. As with all mutants followed under the SIG criteria, this shows many mutations worrisome for more contagion or resistance to vaccines. Mu has reached maximum prevalence in Colombia at 39% of cases. There is still low prevalence globally, US 0.2%. Only one lab study seems to have been reported; out of Italy, with convalescent plasma from Pfizer

vaccinated patients which showed only mildly decreased neutralization of the Mu variant compared to the early Italian lineage B.1 virus in cell culture.2 » Alpha: (B1.1.7 and sublineages “Q”) First seen in United

Kingdom, mid 2020. 13 spike protein mutations. Definite increased contagion compared to B.1 lineage, about 1.5 times more. Cases in UK first surge were felt to show increased severity of disease as well. No monoclonal antibody resistance has been seen. Minimal to no impact on vaccination efficacy has been seen. » Beta (B1.351 and sublineages B.1.351.2 and 351.3) First seen S. Africa, mid 2020. 10 spike protein mutations are present. Definite increased contagion is present, similar to

Alpha. No impact of vaccination efficacy. Significant resistance to monoclonal bamlanivimab/etesevimab combination preparation has been reported. » Delta: (B.1.1617.2, and sublineages AY1-3) First seen

India, late 2020. The variant shows 15 different S protein mutations. The most of any variant. It was responsible for the largest surge in India cases and deaths. Transmissibility is estimated at 2-5 times that of the Alpha (UK) strain. No evidence for resistance to monoclonal antibody therapy has been seen. Some lab studies have shown moderate decreased neutralization of the virus compared to the Alpha virus by convalescent plasma from patients of Pfizer, Moderna, and J&J vaccinations. Some labs have seen only mild or no decrease. Recent clinical studies have found some evidence of more breakthrough cases and moderate disease but rare deaths in frontline healthcare workers and in patients at long term care facilities3,4. At issue is whether the increased breakthrough infections in the vaccinated are really due to the Delta virus’ intrinsic pathogenicity or due to waning vaccine induced antibody levels over time. Delta only exploded globally in July. The studied populations (ie. Long term care patients, healthcare workers, Israelis) were the first groups to receive vaccines in Dec 2020 and Jan 2021.

Studies of vaccine induced antibody levels show definite declines at 6-8 months, most dramatic in the elderly. This is an argument for a third inoculation, at least for high risk individuals in the coming months. » Gamma (B.1.1.28.1, alias P.1) First seen in Brazil and Japan,

Oct 2020. The virus has many sublineages as well. It has 11

S protein mutations. In lab, there is moderate resistance to convalescent and vaccine induced antibody neutralization.

There has been no evidence of reduced vaccine efficacy clinically. Significant resistance to monoclonal bamlanivimab/ etesevimab combination preparation has been reported.

Variants with WHO or SIG assigned categories as of Sept 3.

Iota

Nov. 2020

New York

Eta

Dec. 2020

UK

Alpha

Mid-2020

UK

Mu

Jan. 2021

Colombia

Lambda

Aug. 2020

Peru

Gamma

Oct. 2020

Brazil

Beta

Mid-2020

S. Africa

Kappa

Dec. 2020

India

Delta

Late-2020

India

Gamma

Oct. 2020

Japan

In conclusion, more variants will arise every month around the world. One hopeful observation from the genetic studies of the variants is that increased mutations in transmissibility capabilities seems to diminish the number of mutations in genes that promote severe disease. The more deadly variants are at a competitive disadvantage with the highly contagious variants like Delta during viral surges. It seems that variants are unlikely to be both highly transmissible and highly lethal.

References • Kimura I, et al. “SARS-CoV-2 Lambda Variant Exhibits

Higher Infectivity and Immune Resistance”. bioRxiv

Preprint Server for Biology. 28 July 2021 https: //doi. org/10.1101/2021.06.28.2159673 • Messali K, “ A cluster of the new SARS-CoV-2 B.1.621lineage in Italy and sensitivity of the viral isolate to the Pfizer

vaccine”. Journal of Medical Virology 9/8/2021 doi:10.1002/ jmv/2021.09.08.27247 • Fowlkes A, et al. “Effectiveness of COVID-19 Vaccines in

Preventing SARS-CoV-2 Infection Among Frontline Workers

Before and During B.1.617.2 (Delta) Variant Predominance —

Eight U.S. Locations”, December 2020–August 2021. MMWR

Morb Mortal Wkly Rep 2021;70:1167-1169. DOI: http::// dx.doi.org/10.15585/mmwr.mm703e4. • Nanduri S, et al. “Effectiveness of Pfizer-BioNTech and Moderna

Vaccines in Preventing SARS-CoV-2 Infection Among Nursing

Home Residents Before and During Widespread Circulation of the SARS-CoV-2 B.1.617.2 (Delta) Variant — National

Healthcare Safety Network, March 1–August 1, 2021”. MMWR

Morb Mortal Wkly Rep 2021;70:1163-1166. DOI: http::// dx.doi.org/10.15585/mmwr.mm703e3

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