COVID19 and Variants

COVID-19 and Variants
Mohathir Sheikh & Dr. Austin Martin

The World Health Organization (WHO) first announced the COVID-19 outbreak a Public Health Emergency back in January 2020 and then a pandemic March 2020. Since then, SARS-CoV-2, the RNA virus that causes COVID-19, has mutated into multiple variants that differ slightly from the original strain discovered in January 2020. 

What Are Strains and Variants?
There is a distinct difference between virus strains and variants and the terms are not interchangeable. The term strain is specific to the virus, but not the disease caused by it. In the context of the COVID-19 pandemic, the virus strain refers to SARS-CoV-2. A strain of a virus has distinct properties and a particular immune response. Virus strains can have many variants, which are caused by the accumulation of mutations resulting in a change in a minor portion of the genetic code. It is completely normal and expected for virus variants to occur due to the lack of proofreading function in their replicatory enzymes (Fleischmann, 1996). Variants will have different attributes compared to the original strain; however, not all variants are dangerous. Some variants will appear and disappear while others may persist and continue to spread and replace previous variants (Centers for Disease Control and Prevention [CDC], 2022). Variants that share distinctive mutations are grouped together in their virus family tree. Scientists can then track future mutations as they are passed down through a lineage, which is a branch of the family tree (Corum & Zimmer, 2021). 

Mutation D614G
The first significant SARS-CoV-2 mutation occurred early in the pandemic around March and April 2020 with the introduction of a mutation in the SARS-CoV-2 spike protein (Moore & Offit, 2021). The spike protein is how the coronavirus attaches to cells. Multiple studies showed the D614G mutation increased transmissibility and the replication efficiency of the virus (Korber et al., 2020; Moore & Offit, 2021). The SARS-CoV-2 variant with the D614G mutation quickly replaced the original strain worldwide and begun the B.1 lineage of the coronavirus (Moore & Offit, 2021). 

Variant B.1.1.7 (Alpha)
The variant B.1.1.7, later named Alpha, was discovered in August 2020, and had started to spread in the United Kingdom. This variant had several mutations in its spike protein leading to increased transmissibility (Corum & Zimmer, 2021; Moore & Offit, 2021). By December 2020, B.1.1.7 was labelled a Variant of Concern by WHO (Corum & Zimmer, 2021). The Alpha variant quickly spread through the UK and to many other countries including the United States. Eventually becoming the dominant variant in the United States.

Variant B.1.351 (Beta)
In December of 2020, variant Beta was identified in South Africa (Corum & Zimmer, 2021; Moore & Offit, 2021). This variant had concerning mutations near the tip of the spike protein. Clinical trials discovered reduced vaccine efficiency in neutralizing test viral samples, due to the generated antibodies not being able to bind effectively to the B.1.351 spike protein. Furthermore, the CDC had linked the Beta with a 50% increase in transmission (Mahase, 2021). Early studies indicate the Pfizer and Oxford-AstraZeneca vaccines have lowered effectiveness against the Beta variant at 72-75% and 82% respectively. 

Variant P.1 (Gamma)
The Gamma variant first appeared in Brazil and was declared a Variant of Concern in December 2020 (CDC, 2021). This was the dominant variant in several South American cities and is very similar to the Beta variant. Additionally, the Gamma variant was found to be 1.7 – 2.4 times more transmissible than wild-type SARS-CoV-2 and was able to overcome the immunity developed after infections by other SARS-CoV-2 variants, resulting in a surge of reinfections in South America (Mahase, 2021; Zimmer, 2021). 

Variant B.1.617.2 (Delta)
Delta is an aggressive variant that was first identified in India in late 2020 (CDC, 2021). This variant was initially called a double mutant due to the two prominent mutations: L452R and E484Q at the same location near the top of the spike protein (Corum & Zimmer, 2021). Delta quickly spread worldwide and became the dominant variant globally. One study estimates the Delta variant is almost 60% more transmissible than the Alpha variant (Mahase, 2021). Another study found Delta infected individuals had viral loads as much as 1260 times higher than wild-type SARS-CoV-2, resulting in individuals expelling more virus with every exhale. This variant can also cause symptoms two to three days sooner than the wild-type SARS-CoV-2, giving the immune system less time to defend against the viral infection. 

Variant B.1.1.529 (Omicron)
Omicron was first identified in South Africa in November 2021 (CDC, 2022; Corum & Zimmer, 2021). At the time of writing, Omicron has spread globally and is the dominant variant, overtaking Delta (World Health organization, 2022). This variant has around 50 mutations in combinations not seen before, including 30 mutations in the spike protein (Corum & Zimmer, 2021). Researchers found 13 extremely rare mutations grouped into three clusters, representing a significant jump in viral evolution. One of the clusters has four mutations that is believed to help Omicron to grab on to human cells more tightly than other variants. Another cluster has four other mutations that seem to help the variant evade some antibodies by binding tightly to human cells. The final cluster has five mutations allowing Omicron to fuse and infect human cells more easily. The significant number and location of the mutations has severely weakened the ability of COVID-19 vaccines to prevent infection by the variant (Ledford, 2022). Luckily, the vaccines are able to prevent severe disease outcomes, resulting in mild symptoms in most cases. Preliminary results from some studies, indicate that vaccinated individuals when infected with Omicron experience a large production in antibodies to eliminate the variant before serious illness occurs. However, they have also discovered that the antibodies created after being infected by Omicron was not as robust in blocking other variants (Ledford, 2022). The Omicron variant has a two sublineages called BA.1 and BA.2, both of which are currently classified as Omicron. At the global level, BA.2 is increasing over BA.1 and appears to have a growth advantage over BA.1. BA.2 differs slightly in genetic sequence but is more transmissible than BA.1 (World Health organization, 2022). However, the increase in transmissibility between the two sublineages is significantly less than what was observed between BA.1 and Delta. 

Future Variants
Based on the history of the SARS-CoV-2 pandemic and emergence of variants throughout the years, it is possible that we will continue to see more variants appear in the future. The CDC is constantly monitoring new variants as they appear and tracking their spread. As more studies are completed, researchers will have better tools available to tackle and prevent the spread of SARS-CoV-2 variants.

References
Centers for Disease Control and Prevention (2021). SARS-CoV-2 Variant Classifications and Definitions. Retrieved from https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-classifications.html
Centers for Disease Control and Prevention. (2022). About Variants. Retrieved from https://www.cdc.gov/coronavirus/2019-ncov/variants/about-variants.html
Corum, J., & Zimmer, C. (2021, February 9). Tracking Omicron and Other Coronavirus Variants. The New York Times. https://www.nytimes.com/interactive/2021/health/coronavirus-variant-tracker.html
Fleischmann, W. R. (1996). Viral Genetics. In S. Baron (Ed.), Medical Microbiology (4th ed.). University of Texas Medical Branch at Galveston. http://www.ncbi.nlm.nih.gov/books/NBK8439/
Korber, B., Fischer, W. M., Gnanakaran, S., Yoon, H., Theiler, J., Abfalterer, W., Hengartner, N., Giorgi, E. E., Bhattacharya, T., Foley, B., Hastie, K. M., Parker, M. D., Partridge, D. G., Evans, C. M., Freeman, T. M., Silva, T. I. de, Angyal, A., Brown, R. L., Carrilero, L., … Montefiori, D. C. (2020). Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus. Cell, 182(4), 812-827.e19. https://doi.org/10.1016/j.cell.2020.06.043 
Ledford, H. (2022). The next variant: Three key questions about what’s after Omicron. Nature, 603(7900), 212–213. https://doi.org/10.1038/d41586-022-00510-y
Mahase, E. (2021). Covid-19: How many variants are there, and what do we know about them? BMJ, 374, n1971. https://doi.org/10.1136/bmj.n1971
Moore, J. P., & Offit, P. A. (2021). SARS-CoV-2 Vaccines and the Growing Threat of Viral Variants. JAMA, 325(9), 821–822. https://doi.org/10.1001/jama.2021.1114
World Health Organization. (2022). Statement on Omicron sublineage BA.2. Retrieved from https://www.who.int/news/item/22-02-2022-statement-on-omicron-sublineage-ba.2
Zimmer, C. (2021, March 2). Virus Variant in Brazil Infected Many Who Had Already Recovered from Covid-19. The New York Times. https://www.nytimes.com/2021/03/01/health/covid-19-coronavirus-brazil-variant.html