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Dynamic Expedition of Leading Mutations in SARS-CoV-2 Spike Glycoprotein

Spike Glycoprotein

The spike glycoprotein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a trimeric type I viral fusion protein that binds the virus to the angiotensin-converting enzyme 2 (ACE2) receptor of a host cell.^[1] It is composed of 2 subunits: the N-terminal subunit 1 (S1) and C-terminal subunit 2 (S2), within which multiple domains lie. The S1 region facilitates ACE2 binding and is made up of an N-terminal domain (NTD ~ 1 – 325), a receptor-binding domain (RBD ~ 326 – 525), and 2 C-terminal subdomains (CTD1 and CTD2 ~ 526 – 688), while the downstream S2 region is responsible for mediating virus-host cell membrane fusion.

Update (03/02/2023)

The recently confirmed leading mutations are listed as follows.

2023.01.31

Outlined Mutations	Confirmed in VOC/Emerging Variants
V445A	BQ.1.1

2023.01.17 - 2023.01.25

Outlined Mutations	Confirmed in VOC/Emerging Variants
H146-/K	BQ.1.1, XBB.1.5
E583D	BQ.1.1
Q613H	BQ.1.1
S939F	BQ.1.1

Summary

The dynamic epidemiology of coronavirus disease 2019 (COVID-19) since its outbreak has been a result of the continuous evolution of its etiological agent, SARS-CoV-2. Within the first 2 years of this pandemic, the World Health Organization (WHO) has already announced 4 variants of concern (VOC), namely alpha (B.1.1.7), beta (B.1.351), gamma (P.1), and delta (B.1.617.2), together with numerous variants of interest (VOI). The latest lineage to be designated a VOC would be omicron (B.1.1.529),^[2] from which a diverse variant soup is generated.^[3] From the BA.1 strain of November 2021, to the BQ.1 strain of October 2022,^[4] each omicron subvariant has successively proliferated and outcompeted its once dominant antecedent.^[5] The emergence of all these variants has assuredly brought along many novel mutations that continues to fine-tune the fitness of the virus,^[6] leading to its persistent global circulation.

Recent emerging variant (EV) data retrieved from GISAID, as of 17 January 2023, has revealed that the top 4 most rapidly spreading lineages are the BA.1.1.22, CH.1.1, XBB.1.5, and BQ.1.1 variants, among which XBB.1.5 has been found to be especially prevalent in the US, making up of more than 40% of its sequence coverage in early January 2023.^[7] The identified leading mutations are listed as follows:

References

↑ Jackson, C. B., Farzan, M., Chen, B. & Choe, H. Mechanisms of SARS-CoV-2 entry into cells. Nat Rev Mol Cell Biol 23, 3–20 (2021).
↑ Karim, S. S. A. & Karim, Q. A. Omicron SARS-CoV-2 variant: A new chapter in the COVID-19 pandemic. Lancet 398, 2126–2128 (2021).
↑ Callaway, E. COVID ‘variant soup’ is making winter surges hard to predict. Nature 611, 213–214 (2022).
↑ Wang, Q. et al. Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants. Cell 186, (2023).
↑ Del Rio, C. & Malani, P. N. COVID-19 in 2022 - The Beginning of the End or the End of the Beginning? JAMA 327, 2389–2390 (2022).
↑ Carabelli, A. M. et al. SARS-CoV-2 variant biology: Immune escape, transmission and fitness. Nat Rev Microbiol (2023).
↑ Highly immune evasive omicron XBB.1.5 variant is quickly becoming dominant in U.S. as it doubles weekly https://www.cnbc.com/2022/12/30/covid-news-omicron-xbbpoint1point5-is-highly-immune-evasive-and-binds-better-to-cells.html (2023).

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[Jackson2021-1] Jackson, C. B., Farzan, M., Chen, B. & Choe, H. Mechanisms of SARS-CoV-2 entry into cells. Nat Rev Mol Cell Biol 23, 3–20 (2021).

[Karim-2] Karim, S. S. A. & Karim, Q. A. Omicron SARS-CoV-2 variant: A new chapter in the COVID-19 pandemic. Lancet 398, 2126–2128 (2021).

[3] Callaway, E. COVID ‘variant soup’ is making winter surges hard to predict. Nature 611, 213–214 (2022).

[Wang-4] Wang, Q. et al. Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants. Cell 186, (2023).

[Del_Rio-5] Del Rio, C. & Malani, P. N. COVID-19 in 2022 - The Beginning of the End or the End of the Beginning? JAMA 327, 2389–2390 (2022).

[6] Carabelli, A. M. et al. SARS-CoV-2 variant biology: Immune escape, transmission and fitness. Nat Rev Microbiol (2023).

[CNBC_XBB.1.5-7] Highly immune evasive omicron XBB.1.5 variant is quickly becoming dominant in U.S. as it doubles weekly https://www.cnbc.com/2022/12/30/covid-news-omicron-xbbpoint1point5-is-highly-immune-evasive-and-binds-better-to-cells.html (2023).

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 ==Summary==
-The constantly shifting epidemiology of coronavirus disease 2019 (COVID-19) ever since its initial outbreak has been a result of the continuous evolution of its etiological agent, SARS-CoV-2, from which numerous variants have been generated. Even within the first 2 years of this pandemic, the World Health Organization (WHO) has already announced 4 variants of concern (VOC), which are the previously circulating alpha (B.1.1.7), beta (B.1.351), gamma (P.1), and delta (B.1.617.2) strains, and many other variants of interest (VOI). The successive emergence of new SARS-CoV-2 variants has brought along many novel mutations, most of which continually refine and improve the fitness of the virus. For instance, these functionally advantageous mutations include the N501Y of alpha and L452R and E484Q of the B.1.617 lineage, which are capable of enhancing the ACE2-binding affinity of the spike glycoprotein.<ref name="Aggarwal"/>
+The dynamic epidemiology of coronavirus disease 2019 (COVID-19) since its outbreak has been a result of the continuous evolution of its etiological agent, SARS-CoV-2. Within the first 2 years of this pandemic, the World Health Organization (WHO) has already announced 4 variants of concern (VOC), namely alpha (B.1.1.7), beta (B.1.351), gamma (P.1), and delta (B.1.617.2), together with numerous variants of interest (VOI). The latest lineage to be designated a VOC would be omicron (B.1.1.529),<ref name="Karim" /> from which a diverse variant soup is generated.<ref>Callaway, E. COVID ‘variant soup’ is making winter surges hard to predict. ''Nature'' '''611,''' 213–214 (2022).</ref> From the BA.1 strain of November 2021, to the BQ.1 strain of October 2022,<ref name="Wang" /> each omicron subvariant has successively proliferated and outcompeted its once dominant antecedent.<ref name="Del Rio" /> The emergence of all these variants has assuredly brought along many novel mutations that continues to fine-tune the fitness of the virus,<ref>Carabelli, A. M. ''et al.'' SARS-CoV-2 variant biology: Immune escape, transmission and fitness. ''Nat Rev Microbiol'' (2023).</ref> leading to its persistent global circulation.
-The latest SARS-CoV-2 lineage to be designated the status of VOC would be omicron (B.1.1.529) which first originated from South Africa.<ref name="Karim" /> This particular lineage alone has undergone substantial evolution over the course of its global dominance, spreading across the world like wildfire while simultaneously producing a diverse soup of dissimilar subvariants.<ref name="Tegally" /> The first of its kind would be the BA.1 strain first appeared in November 2022. The supremacy of BA.1, however, would not last long, forasmuch as the emergence of the more fit BA.2 strain in December 2022 would eventually outcompete its antecedent.<ref name="Yamasoba" /> Few months later, between March and July 2022, the successive emergences of BA.2.12.1, BA.4 and BA.5, and BA.2.75 would once again garnered the attention of the WHO and multiple countries. For one, the BA.2.12.1, BA.4, and BA.5 subvariants were found to possess enhanced antibody evasion capabilities and transmissibility when compared to the formerly active BA.2 strain,<ref name="Tegally" /><ref name="CaoY_Nature2022"/><ref name="WangQ_Nature2022"/> allowing them to become dominant in the US and the UK.<ref name="Callaway" /><ref name="Del Rio" />BA.2.75, on the other hand, was the dominant variant in India, which habors higher hACE2-binding affinity than the BA.4 and BA.5 subvariants.<ref name="CaoY_CellHM2022"/><ref name="Shaheen" /> The complex interactions between these omicron sublineages prompted the creations of even more novel strains, including the recombinant XBB subvariant derived from BA.2.10.1 and BA.2.75 in August 2022, and the BQ.1 subvariant derived from BA.5 in October 2022. Like their predecessors, XBB swiftly rose to prominence upon its emergence, which was then succeeded by BQ.1 up till the end of 2022.<ref name="Wang" /><ref name="European Centre" />
-In fact, BQ.1.1, a descendent of BQ.1, was found to be the culprit behind 36.3% of the total US reported COVID-19 cases in December 2022.<ref name="CNBC XBB.1.5" />
 Recent emerging variant (EV) data retrieved from GISAID, as of 17 January 2023, has revealed that the top 4 most rapidly spreading lineages are the BA.1.1.22, CH.1.1, XBB.1.5, and BQ.1.1 variants, among which XBB.1.5 has been found to be especially prevalent in the US, making up of more than 40% of its sequence coverage in early January 2023.<ref name="CNBC XBB.1.5" /> The identified leading mutations are listed as follows: