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Etiology

Coronaviruses (CoVs) are positive-stranded RNA(+ssRNA) viruses with a crown-like appearance under an electron microscope (coronam is the Latin term for crown) due to the presence of spike glycoproteins on the envelope. The subfamily Orthocoronavirinae of the Coronaviridae family (order Nidovirales) classifies into four genera of CoVs:

• Alphacoronavirus (alphaCoV)
• Betacoronavirus (betaCoV)
• Deltacoronavirus (deltaCoV)
• Gammacoronavirus (gammaCoV)

BetaCoV genus is further divided into five sub-genera or lineages.[1] Genomic characterization has shown that bats and rodents are the probable gene sources of alphaCoVs and betaCoVs. On the contrary, avian species seem to represent the gene sources of deltaCoVs and gammaCoVs. CoVs have become the major pathogens of emerging respiratory disease outbreaks. Members of this large family of viruses can cause respiratory, enteric, hepatic, and neurological diseases in different animal species, including camels, cattle, cats, and bats. For reasons yet to be explained, these viruses can cross species barriers and can cause, in humans, illness ranging from the common cold to more severe diseases such as MERS and SARS. To date, seven human CoVs (HCoVs) capable of infecting humans have been identified. Some of the HCoVs were identified in the mid-1960s, while others were only detected in the new millennium. In general, estimates suggest that 2% of the population are healthy carriers of a CoVs and that these viruses are responsible for about 5% to 10% of acute respiratory infections.[2]

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• Common human CoVs: HCoV-OC43, and HCoV-HKU1 (betaCoVs of the A lineage); HCoV-229E, and HCoV-NL63 (alphaCoVs). These viruses can cause common colds and self-limiting upper respiratory tract infections in immunocompetent individuals. However, in immunocompromised subjects and the elderly, lower respiratory tract infections can occur due to these viruses.

• Other human CoVs: SARS-CoV and MERS-CoV (betaCoVs of the B and C lineage, respectively). These viruses are considered to be more virulent and capable of causing epidemics manifesting with respiratory and extra-respiratory manifestations of variable clinical severity.

SARS-CoV-2 is a novel betaCoV belonging to the same subgenus as the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV), which have been previously implicated in SARS-CoV and MERS-CoV epidemics with mortality rates up to 10% and 35%, respectively.[3] It has a round or elliptic and often pleomorphic form and a diameter of approximately 60-140 nm. Like other CoVs, it is sensitive to ultraviolet rays and heat. In this regard, although high temperature decreases the replication of any species of virus. Currently, the inactivation temperature of SARS-CoV-2 is being researched. A stainless steel surface held at an air temperature of 54.5°C (130 °F) results in the inactivation of 90% of SARS-CoV-2 in approximately 36 minutes. At 54.5°C, the time for a 90% decrease in infectivity was 35.4 ± 9.0 min and the virus half-life was 10.8 ± 3.0 min.[4] Conversely, it may resist lower temperatures even below 0°C. Also, these viruses can be effectively inactivated by lipid solvents, including ether (75%), ethanol, chlorine-containing disinfectant, peroxyacetic acid, and chloroform except for chlorhexidine.

Genomic characterization of the new HCoV, isolated from a cluster-patient with atypical pneumonia after visiting Wuhan, had 89% nucleotide identity with bat SARS-like-CoVZXC21 and 82% with that of human SARS-CoV. Hence, it was termed SARS-CoV-2 by experts of the International Committee on Taxonomy of Viruses. The single-stranded RNA genome of SARS-CoV-2 contains 29891 nucleotides, encoding for 9860 amino acids.

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Although the origin of SARS-CoV-2 is currently unknown, it is widely postulated to have originated from an animal implicating zoonotic transmission. Genomic analyses suggest that SARS-CoV-2 probably evolved from a strain found in bats. The genomic comparison between the human SARS-CoV-2 sequence and known animal coronaviruses indeed revealed high homology (96%) between the SARS-CoV-2 and the betaCoV RaTG13 of bats (Rhinolophus affinis)[5]Similar to SARS and MERS, it has been hypothesized that SARS-CoV-2 advanced from bats to intermediate hosts such as pangolins and minks, and then to humans.[6][7] A recently released report by the WHO describing the possible origins of SARS-CoV-2 was inconclusive as it did not clearly specify the origin of the virus; however, it did report that the circulation of SARS-CoV-2 occurred as early as December 2019. This report explored several possible hypotheses of the origin of the virus that included the origin of the virus in an animal, the transmission of the virus to an intermediate host, and subsequent passage into humans.

SARS-CoV-2 Variants

As mentioned earlier, SARS-CoV-2 is prone to genetic evolution resulting in multiple variants that may have different characteristics compared to its ancestral strains. Periodic genomic sequencing of viral samples is of fundamental importance, especially in a global pandemic setting, as it helps detect any new genetic variants of SARS-CoV-2. Notably, the genetic evolution was minimal initially with the emergence of the globally dominant D614G variant, which was associated with increased transmissibility but without the ability to cause severe illness.[8] Another variant was identified in humans, attributed to transmission from infected farmed mink in Denmark, which was not associated with increased transmissibility[7]. Since then, multiple variants of SARS-CoV-2 have been described, of which a few are considered variants of concern (VOCs) due to their potential to cause enhanced transmissibility or virulence, reduction in neutralization by antibodies obtained through natural infection or vaccination, the ability to evade detection, or a decrease in therapeutics or vaccination effectiveness. With the continued emergence of multiple variants, the CDC and the WHO have independently established a classification system for distinguishing the emerging variants of SARS-CoV-2 into variants of concern(VOCs) and variants of interest(VOIs).

SARS-CoV-2 Variants of Concern (VOCs)

• Alpha (B.1.1.7 lineage)
• • In late December 2020, a new SARS-CoV-2 variant of concern, B.1.1.7 lineage, also referred to as Alpha variant or GRY(formerly GR/501Y.V1), was reported in the UK based on whole-genome sequencing of samples from patients who tested positive for SARS-CoV-2.[9][10]
  • In addition to being detected by genomic sequencing, the B.1.1.7 variant was identified in a frequently used commercial assay characterized by the absence of the S gene (S-gene target failure, SGTF) PCR samples. The B.1.1.7 variant includes 17 mutations in the viral genome. Of these, eight mutations (Δ69-70 deletion, Δ144 deletion, N501Y, A570D, P681H, T716I, S982A, D1118H) are in the spike (S) protein. N501Y shows an increased affinity of the spike protein to ACE 2 receptors, enhancing the viral attachment and subsequent entry into host cells.[11][12][13]
  • This variant of concern was circulating in the UK as early as September 2020 and was based on various model projections. It was reported to be 43% to 82% more transmissible, surpassing preexisting variants of SARS-CoV-2 to emerge as the dominant SARS-CoV-2 variant in the UK.[12] The B.1.1.7 variant was reported in the United States (US) at the end of December 2020.
  • An initial matched case-control study reported no significant difference in the risk of hospitalization or associated mortality with the B.1.1.7 lineage variant compared to other existing variants. However, subsequent studies have since reported that people infected with B.1.1.7 lineage variant had increased severity of disease compared to people infected with other circulating forms of virus variants.[14][10]
  • A large matched cohort study performed in the UK reported that the mortality hazard ratio of patients infected with B.1.1.7 lineage variant was 1.64 (95% confidence interval 1.32 to 2.04, P<0.0001) patients with previously circulating strains.[15]Another study reported that the B 1.1.7 variant was associated with increased mortality compared to other SARS-CoV-2 variants (HR= 1.61, 95% CI 1.42-1.82).[16] The risk of death was reportedly greater (adjusted hazard ratio 1.67, 95% CI 1.34-2.09) among individuals with confirmed B.1.1.7 variant of concern compared with individuals with non-1.1.7 SARS-CoV-2.[17]
  • The B.1.1.7 variant emerged as one of the most dominant SARS-CoV-2 strains circulating in the US.

• Beta (B.1.351 lineage)
• • Another variant of SARS-CoV-2, B.1.351 also referred to as Beta variant or GH501Y.V2 with multiple spike mutations, resulted in the second wave of COVID-19 infections, was first detected in South Africa in October 2020.[18]
  • The B.1.351 variant includes nine mutations (L18F, D80A, D215G, R246I, K417N, E484K, N501Y, D614G, and A701V) in the spike protein, of which three mutations (K417N, E484K, and N501Y) are located in the RBD and increase the binding affinity for the ACE receptors.[19][19][11][20] SARS-CoV-2 501Y.V2(B.1.351 lineage) was reported in the US at the end of January 2021.
  • This variant is reported to have an increased risk of transmission and reduced neutralization by monoclonal antibody therapy, convalescent sera, and post-vaccination sera.[21]

• Gamma(P.1 lineage)
• • The third variant of concern, the P.1 variant also known as Gamma variant or GR/501Y.V3, was identified in December 2020 in Brazil and was first detected in the US in January 2021.[22]
  • The B.1.1.28 variant harbors ten mutations in the spike protein (L18F, T20N, P26S, D138Y, R190S, H655Y, T1027I V1176, K417T, E484K, and N501Y). Three mutations (L18F, K417N, E484K) are located in the RBD, similar to the B.1.351 variant.[22]
  • Notably, this variant may have reduced neutralization by monoclonal antibody therapies, convalescent sera, and post-vaccination sera.[21]

• Delta (B.1.617.2 lineage)
  • The fourth variant of concern, B.1.617.2 also referred to as the Delta variant was initially identified in December 2020 in India and was responsible for the deadly second wave of COVID-19 infections in April 2021 in India. In the United States, this variant was first detected in March 2021
  • The Delta variant was initially considered a variant of interest. However, this variant rapidly spread around the world prompting the WHO to classify it as a VOC in May 2021
  • The B.1.617.2 variant harbors ten mutations ( T19R, (G142D*), 156del, 157del, R158G, L452R, T478K, D614G, P681R, D950N) in the spike protein
  • Researchers have predicted the B.1.617.2 variant to be the most dominant SARS-CoV-2 strain in the US in the coming weeks

• Omicron (B.1.1.529 lineage)
  • The fifth variant of concern B.1.1.529, also designated as the Omicron variant by the WHO was first identified in South Africa on 23 November 2021 after an uptick in the number of cases of COVID-19.[23]
  • Omicron was quickly recognized as a VOC due to more than 30 changes to the spike protein of the virus along with the sharp rise in thenumber of cases observed in South Africa.[24] The reported mutations include T91 in the envelope, P13L, E31del, R32del, S33del, R203K, G204R in the nucleocapsid protein, D3G, Q19E, A63T in the matrix, N211del/L212I, Y145del, Y144del, Y143del, G142D, T95I, V70del, H69del, A67V in the N-terminal domain of the spike, Y505H, N501Y, Q498R, G496S, Q493R, E484A, T478K, S477N, G446S, N440K, K417N, S375F, S373P, S371L, G339D in the receptor-binding domain of the spike, D796Y in the fusion peptide of the spike, L981F, N969K, Q954H in the heptad repeat 1 of the spike as well as multiple other mutations in the non-structural proteins and spike protein.[25]
  • Initial modeling suggests that Omicron shows a 13-fold increase in viral infectivity, and is 2.8 times more infectious than the Delta variant.[26] Early reports also suggest that monoclonal antibodies including Bamlanivimab and the Rockefeller University antibody C144 are likely to have reduced efficacy against the Omicron variant, however, REGN-COV2 (Casirivimab and Imdevimab), as well as the Rockefeller University antibody C135 are predicted to still be effective against Omicron based on early modeling studies.[26]
  • The Spike mutation K417N (also seen in the Beta variant) along with E484A is predicted to have an overwhelmingly disruptive effect, making Omicron more likely to have vaccine breakthroughs

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SARS-CoV-2 Variants of Interest (VOIs)

VOIs are defined as variants with specific genetic markers that have been associated with changes that may cause enhanced transmissibility or virulence, reduction in neutralization by antibodies obtained through natural infection or vaccination, the ability to evade detection, or a decrease in the effectiveness of therapeutics or daypg.com far since the beginning of the pandemic, WHO has described eight variants of interest (VOIs), namely Epsilon (B.1.427 and B.1.429); Zeta (P.2); Eta ( B.1.525); Theta (P.3); Iota (B.1.526); Kappa(B.1.617.1); Lambda(C.37) and Mu (B.1.621)

• Epsilon (B.1.427 and B.1.429) variants, also called CAL.20C/L452R, emerged in the US around June 2020 and increased from 0% to >50% of sequenced cases from September 1, 2020, to January 29, 2021, exhibiting an 18.6-24% increase in transmissibility relative to wild-type circulating strains. These variants harbor specific mutations (B.1.427: L452R, D614G; B.1.429: S13I, W152C, L452R, D614G). Due to its increased transmissibility, the CDC classified this strain as a variant of concern in the US.[27]

• Zeta (P.2) has key spike mutations (L18F; T20N; P26S; F157L; E484K; D614G; S929I; and V1176F) and was first detected in Brazil in April 2020. This variant is classified as a VOI by the WHO and the CDC due to its potential reduction in neutralization by antibody treatments and vaccine sera.
• Eta (B.1.525) and Iota (B.1.526) variants harbor key spike mutations (B.1.525: A67V, Δ69/70, Δ144, E484K, D614G, Q677H, F888L; B.1.526: (L5F*), T95I, D253G, (S477N*), (E484K*), D614G, (A701V*)) and were first detected in New York in November 2020 and classified as a variant of interest by CDC and the WHO due to their potential reduction in neutralization by antibody treatments and vaccine sera.

• Theta (P.3) variant, also called GR/1092K.V1 carry key spike mutations (141-143 deletion E484K; N501Y; and P681H) and was first detected in the Philippines and Japan in February 2021 and is classified as a variant of interest by the WHO.

• Kappa(B.1.617.1) variant harbor key mutations ((T95I), G142D, E154K, L452R, E484Q, D614G, P681R, and Q1071H) and was first detected in India in December 2021 and is classified as a variant of interest by the WHO and the CDC.

• Lambda(C.37) variant was first detected in Peru and has been designated as a VOI by the WHO in June 2021 due to a heightened presence of this variant in the South American region.

• Mu(B.1.621) variant was identified in Columbia and was designated as a VOI by the WHO in August 2021.

The CDC has designated the Epsilon (B.1.427 and B.1.429) variants as a VOC and Eta(B.1.525); Iota (B.1.526); Kappa(B.1.617.1); Zeta (P.2); Mu(B.1.621,B.1.621.1) and B.1.617.3 as VOIs.

Transmission of SARS-CoV-2

• The primary mode of transmission of SARS-CoV-2 is via exposure to respiratory droplets carrying the infectious virus from close contact or droplet transmission from presymptomatic, asymptomatic, or symptomatic individuals harboring the virus.
• Airborne transmission with aerosol-generating procedures has also been implicated in the spread of COVID-19. However, data implicating airborne transmission of SARS-CoV-2 in the absence of aerosol-generating procedures are emerging and being evaluated. However, this mode of transmission has not been universally acknowledged.
• Fomite transmission from contamination of inanimate surfaces with SARS-CoV-2 has been well characterized based on many studies reporting the viability of SARS-CoV-2 on various porous and nonporous surfaces.
• Under experimental conditions, SARS-CoV-2 was noted to be stable on stainless steel and plastic surfaces compared to copper and cardboard surfaces, with the viable virus being detected up to 72 hours after inoculating the surfaces with the virus.[28]
• Viable virus was isolated for up to 28 days at 20 degrees C from nonporous surfaces such as glass, stainless steel. Conversely, recovery of SARS-CoV-2 on porous materials was reduced compared with nonporous surfaces.[29]
• A study evaluating the duration of the viability of the virus on objects and surfaces showed that SARS-CoV-2 can be found on plastic and stainless steel for up to 2-3 days, cardboard for up to 1 day, copper for up to 4 hours. Moreover, it seems that contamination was higher in intensive care units (ICUs) than in general wards, and SARS-CoV-2 can be found on floors, computer mice, trash cans, and sickbed handrails as well as in the air up to 4 meters from patients implicating nosocomial transmission as well in addition to fomite transmission.[30]
• The Centers for Disease Control and Prevention(CDC) recently released an update stating that individuals can be infected with SARS-CoV-2 via contact with surfaces contaminated by the virus, but the risk is low and is not the main route of transmission of this virus.
• Epidemiologic data from several case studies have reported that patients with SARS-CoV-2 infection have the live virus present in feces implying possible fecal-oral transmission.[31]
• A meta-analysis that included 936 neonates from mothers with COVID-19 showed vertical transmission is possible but occurs in a minority of cases.[32]