A Brief History of SARS-Cov-2 Evolution

SARS-CoV-2 is a beta coronavirus that emerged in Wuhan, China, in December 2019. The virus has since spread globally, causing the COVID-19 pandemic. Over time, several variants of the virus have emerged, with different genetic characteristics and phenotypic traits. The emergence of these variants has raised concerns about their effects on viral transmissibility, disease severity, reinfection rates, and vaccine effectiveness. This article will provide an overview of SARS-CoV-2 Evolution, focusing on the alpha, beta, delta, gamma, and omicron variants.

SARS-CoV-2 Evolution

SARS-CoV-2 has a ~30 kb nonsegmental positive-sense single-stranded RNA genome. It has an envelope and four major structural proteins. Mutations can occur at any point in the genome, but those in the spike protein, the primary entry protein and antigen of SARS-CoV-2, have played a significant role. The spike protein binds to the human ACE2 receptor, allowing the virus to enter human cells. If mutations occur in the ORFs (Open Reading Frame which are accessory proteins) such as deletions in the ORF8, the virus can escape from the host immune defence during infection and replicate. However, the clinical disease appears to be milder than spike protein mutation. Similarly, mutations in ORF6 inhibit the host’s immune activation.

The variants arising from spike mutations are in shown below inchronological order,

Alpha Variant (D614G)

The first significant change in SARS-CoV-2 was noted after about eleven months of covid-19 virus detection when a single spike substitution (D614G) emerged. This substitution gave the virus around 20% growth advantage over the preceding SARS-CoV-2 and quickly became dominant in Europe by June 2020. The D614G substitution increases infectivity and transmissibility in humans but does not cause more severe clinical disease. It does not affect the existing laboratory diagnostic methods, clinical management, and public health infection control.

Alpha Variant (B.1.1.7)

B.1.1.7 alpha variant was first identified in the United Kingdom in September 2020 and quickly became the dominant strain in the country. It was also called SARS-CoV-2 VOC 202012/01 – Variant of Concern, the year 2020, month 12, variant 1. The variant contains several mutations in the spike protein, including N501Y, which has been linked to increased transmission but is not associated with disease severity. The N501Y mutation is in the spike protein’s receptor-binding domain (RBD), responsible for binding to the human ACE2 receptor. This mutation increases the affinity of the spike protein for the ACE2 receptor, potentially increasing the virus’s ability to infect human cells. N501Y mutation was believed to emerge from the immunosuppressed host at that time. It does not affect the lateral flow device (LFD) diagnostic ability, as it contains several primers of SARS-CoV2 genes.

The two doses of AstraZeneca vaccine protect against the Alpha variant to 66%, and the Pfizer two doses safeguard up to 93%. AstraZeneca is not available in the UK anymore, although it was popular during the primary vaccination at the start of the pandemic.

According to the WHO, CDC and ECDC, alpha variants, including both D614G and N501Y, are moved into the de-escalated variants for the following reasons: low level of circulation and not much impact on the vaccine-induced immunity.

Beta Variant (B.1.351)

The Beta variant of COVID-19, also known as VOC-202012/02 or Lineage B.1.351, is one of the highly transmissible and more concerning variants of SARS-CoV-2. It was first detected in South Africa in October 2020 and sequenced in the UK in December 2020. Since then, it has spread to many countries around the world.

Several mutations characterise the Beta variant in its spike protein, part of the virus that enables it to enter and infect human cells. Some critical mutations include K417N, E484K, and N501Y but are also found in the Alpha and Gamma variants.

The K417N mutation is in the spike protein’s receptor-binding domain (RBD) and has been associated with increased resistance to neutralising antibodies. The E484K mutation is also located in the RBD and has been associated with reduced susceptibility to some monoclonal antibodies and convalescent plasma. The N501Y mutation is found outside the RBD and has been shown to increase the binding affinity of the spike protein to the human ACE2 receptor, which is the receptor the virus uses to enter human cells.

In addition to these mutations, the Beta variant also has the D614G mutation, found in almost all SARS-CoV-2 variants and is associated with increased viral infectivity. It also has the A701V mutation, located outside the spike protein and is believed to have a role in viral replication and transmission.

The Beta variant is no longer on the WHO’s list of variants of concern.

Delta Variant (B.1.617.2)

The Delta variant, also known as B.1.617.2/AY sublineages, was first identified in India in December 2020 and quickly became the dominant strain in many countries. The variant contains some mutations in the spike protein, including L452R, which has been linked to increased transmissibility and potentially increased pathogenicity. The L452R mutation is found in the RBD of the spike protein, which may encourage the virus to bind to the ACE2 receptor, facilitating viral entry into human cells. The Delta variant has been associated with potentially increased disease severity, leading to many cases and hospitalisations in many countries. It is around 60% more transmissible than the already highly infectious Alpha variant. The Delta variants have intrinsic viral properties such as optimisation of spike furin cleavage, making them fitter than Alpha and Beta variants.

Delta is found to be resistant to vaccines compared to the preceding variants, particularly in people who received only one dose. The repeat second dose of the AstraZeneca vaccine gives protective immunity against the Delta variant to 60%. Meanwhile, two doses of Pfizer’s jab were more effective (88%).

They are detected at low levels, and hence, they are categorised into de-escalated variants. They are no longer on the list of WHO’s variants of concern.

Omicron variant

In November 2021, the Omicron variant, B.1.1.529/BA sublineages, was first identified in South Africa. The scientists recognised the massive impact of significant spike protein mutation changes in more than 30 mutations in the RBD alone. Consequently, the Omicron variant can evade the immune system, and the neutralising antibodies are produced less in response to the original virus or vaccines. Chronic infections, like a reservoir in immunocompromised patients, were believed to be the driving factor for antigenic shift mutations.

So far, there are five distinct Omicron sublineages – BA.1, BA.2, BA.3, BA.4, and BA.5. The Omicron variant has been associated with increased transmissibility, potentially faster viral replication but causes less severe disease compared to the preceding variants. These variants have the properties to infect people with previous immunity against covid-19 virus, either due to vaccination or past infection, found to be more resistant to antiviral agents. However, boosted vaccination remains the primary preventive measure against the development of severe covid-19 disease. Although the number of Omicron cases was found to be increased four months after a booster dose, they decreased quickly. Booster doses of mRNA vaccines, such as Moderna bivalent vaccines, are effective against the Omicron variants, including BA.4 and BA.5, in addition to the original strains. Overall, the Evolution of SARS-CoV-2 underscores the need for ongoing efforts to control the spread of the virus, including vaccination and continuing surveillance and monitoring of viral Evolution. By understanding the molecular mechanisms underlying viral Evolution and the emergence of new variants, we can better prepare for future pandemics and work towards developing more effective strategies for controlling infectious disease outbreaks.

References:

1. Carabelli, A.M., Peacock, T.P., Thorne, L.G. et al. SARS-CoV-2 variant biology: immune escape, transmission and fitness. Nat Rev Microbiol 21, 162–177 (2023). https://doi.org/10.1038/s41579-022-00841-7
2. Gupta, R. K., Thomson, E. C., Harrison, E. M., Ludden, C., Reeve, R., Rambaut, A., COVID-19 Genomics UK (COG-UK) Consortium, Peacock, S. J., & Robertson, D. L. (2021). SARS-CoV-2 variants, spike mutations and immune escape. Nature reviews. Microbiology, 19(7), 409–424. https://doi.org/10.1038/s41579-021-00573-0
3. Knight Lab. COVID-19 Timeline. Retrieved from https://cdn.knightlab.com/libs/timeline3/latest/embed/index.html?source=1R5-OtMKMZwKxdC1tIwIkwEYlja4o3loCISxZoQrZDho&font=Default&lang=en&initial_zoom=2&height=650
4. European Centre for Disease Prevention and Control. Variants of concern. Retrieved from https://www.ecdc.europa.eu/en/covid-19/variants-concern
5. UK Government. SARS-CoV-2 variants of public health interest. Retrieved from https://www.gov.uk/government/publications/sars-cov-2-variants-of-public-health-interest/sars-cov-2-variants-of-public-health-interest-10-march-2023
6. Rambaut, A., Holmes, E.C., O’Toole, Á., Hill, V., McCrone, J.T., Ruis, C., du Plessis, L. &Pybus, O.G. (2020). A dynamic nomenclature proposal for SARS-CoV-2 lineages to assist genomic epidemiology. Nature Microbiology. DOI:10.1038/s41564-020-0770-5
7. O’Toole, Á., Hill, V., Pybus, O.G. et al. (2021). Tracking the international spread of SARS-CoV-2 lineages B.1.1.7 and B.1.351/501Y-V2. Wellcome Open Research. DOI:10.12688/wellcomeopenres.16661.1
8. World Health Organization (2020) Covid-19-Global. World Health Organization. Available at: https://www.who.int/emergencies/disease-outbreak-news/item/2020-DON305 (Accessed: March 28, 2023).
9. World health organisation (2022) Tracking SARS-CoV-2 variants. World Health Organization. Available at: https://www.who.int/activities/tracking-SARS-CoV-2-variants/ (Accessed: March 28, 2023).
10. Peacock, T.P., Penrice-Randal, R., Hiscox, J.A. & Barclay, W.S. (2021). SARS-CoV-2 one year on: evidence for ongoing viral adaptation. The Journal of General Virology, 102(4), 001584. https://doi.org/10.1099/jgv.0.001584
11. Zeng, B., Gao, L., Zhou, Q., Yu, K., & Sun, F. (2022). Effectiveness of COVID-19 vaccines against SARS-CoV-2 variants of concern: a systematic review and meta-analysis. BMC medicine, 20(1), 200. https://doi.org/10.1186/s12916-022-02397-y
12. Institute for Health Metrics and Evaluation. (n.d.). COVID-19 vaccine efficacy summary. Retrieved from https://www.healthdata.org/covid/covid-19-vaccine-efficacy-summary
13. Institute for Health Metrics and Evaluation. (n.d.). Global COVID-19 deaths. Retrieved from https://covid19.healthdata.org/global?view=cumulative-deaths&tab=trend
14. Olivero, N.B., Gonzalez-Reiche, A.S., Re, V.E. et al. Phylogenetic analysis and comparative genomics of SARS-CoV-2 from survivor and non-survivor COVID-19 patients in Cordoba, Argentina. BMC Genomics 23, 510 (2022). https://doi.org/10.1186/s12864-022-08756-6
15. Lundberg, A., Lorenzo-Redondo, R., Ozer, E., Hawkins, C., Hultquist, J., Welch, S., Prasad, P., Oehmke, J., Achenbach, C., Murphy, R., White, J., Havey, R., & Post, L. (2022). Has Omicron changed the Evolution of the pandemic? JMIR Public Health Surveill, 8(1), e35763. https://doi.org/10.2196/35763(Placeholder1)
16. “COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU).” Johns Hopkins University, 18 Mar. 2022, https://coronavirus.jhu.edu/map.html.
17. “COVID-19 situation update worldwide, as of 18 March 2022.” European Centre for Disease Prevention and Control, 18 Mar. 2022, https://www.ecdc.europa.eu/en/geographical-distribution-2019-ncov-cases

References:

Aye Thar Aye
MBBS, MSc, MRCP, FRCPath
Higher Speciality Trainee (Medical Microbiology)
Gateshead Health NHS Foundation Trust