Update on omicron variant: What we know so far.

The new omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged in South Africa in November 2021 has been declared as a Variant of Concern by the World Health Organization. This variant has been found to carry multifold mutations that have not been observed in any of the variants detected so far. The majority of these mutations are present in spike protein, contributing to its ability to escape the currently available neutralizing antibodies and vaccines, as well as increasing the chances of reinfection. This brief communication provides an insight into mutations detected in the omicron variant and their impact on currently available interventions against SARS-CoV-2 and the need for a booster dose. We also discuss the severity status of infection due to this variant. Additionally, we highlight the hypothesis supporting the association of high HIV prevalence and the appearance of the omicron variant of SARS-CoV-2 in immune-compromised individuals.

Introduction

Omicron (or B.1.1.529 variant) was first reported in Botswana, South Africa, in early November 2021 and eventually designated to be a variant of concern (VOC) by the World Health Organization on November 26, 2021.[1] The name B.1.1.529 is named as per the Pango system to denote that its lineage goes back to its ancestor.[2] A steep rise in SARS-CoV-2 cases was also observed in those regions of South Africa where the omicron variant emerged.[3] The identification of this most mutated nCoV-2 variant is triggering alarm in all worldwide.[4]

Even WHO has warned all the countries against the new omicron variant, owing to its higher rate of transmission and re-infection rate compared to the delta variant.[5] Omicron is fifth VOC, after alpha, beta, gamma, and delta variant.[4] After being first detected in South Africa, omicron variant has also been reported in countries such as Germany, The Netherlands, Hong Kong, Australia, Italy, Botswana, Israel, Belgium, and Britain.[67]

As stated by few research groups, working on exploring the genome of different SARS-CoV-2 variants, the novel variant omicron has been found to exhibit a “very unusual constellation of mutations,” which raises many concerns as this might enable its spike protein to evade antibodies produced during either a vaccination or a previous coronavirus infection.[4] Notably, these mutations in new variant might also be associated with higher transmission, stronger affinity for binding to host cells, and antibody escape.[8]

The various mutations observed in the structure of spike protein suggest that presently available drugs targeting the attachment of SARS-CoV-2 virus to the host cell may not turn out to be the treatment of choice against infection due to omicron variant.[8]

In this brief communication, we aim at providing the description of mutations observed in omicron variant of SARS-CoV-2 and their impact on currently available therapeutic strategies. Furthermore, we briefly describe the clinical features that have been observed in case of COVID-19 infection due to omicron. We also highlight the hypothesis that has been proposed for the emergence of this new variant of SARS-CoV-2.

Mutations in omicron

Several mutations have been detected in SARS-CoV-2 variants worldwide.[29] In case of omicron (Gene Bank Ref Seq: NC_045512.2), genomic sequencing revealed nearly 51 mutations, comprising insertions, deletions, missense mutations, substitutions, and other mutations [Table 1].[21011] Omicron variant has substitution mutations for 44 amino acids, deletion for 6 amino acids, and insertion mutation at one amino acid position. Most of the mutations were found in spike protein (S), i.e., 1 insertion, 3 deletions, and 29 substitutions (namely, A76V, T95I, 142-144del, Q498R, E484A, G339D, G446S, G339D, N440K, S477N, Q493R, T478K, G496S, Y505H, T547K, H655Y, N501Y, D614G, N679K, S371 L, N764K, P681H, D796Y, N856K, N969K, Q954H, L981F, S373P, L212I, S375F, N969K, K417N, and ins214EPE).[11] Some new mutations were also seen in spike protein along with the previously known mutations.[212] For instance, the insertion mutation in spike protein (ins214EPE) is a new mutation that was not found in any of the previous SARS-CoV-2 variant. The receptor-binding domain (RBD) region of spike protein contains a total of 15 mutations. According to Chen et al., delta variant had 5 mutations in spike region that contributed to its high infection rate and spread worldwide. However, omicron variant has mutations even more than the previous delta variant, raising a concern regarding its transmissibility.[13] Different proteins of omicron variant such as E protein (mutated at T9I), M protein (mutated at Q19E, A63T, and D3G), nucleocapsid protein (mutated at R203K, G204R, and P13L) and Non-Structural Proteins (NSPs) (mutated at P323L and T492I) have also been examined for the presence of mutations[1314] [Table 1]. Some of these mutations are known to be associated with altered receptor interaction, transmissibility, and immune escape.[15]

Table 1

Mutations found in the omicron variant

Protein involved	Number of mutations	Mutation
Spike protein	33	A76V, T95I, 142-144del, Q498R, E484A, G339D, G446S, G339D, N440K, S477N, Q493R, T478K, G496S, Y505H, T547K, H655Y, D614G, N679K, N764K, P681H, D796Y, N856K, N501Y, N969K, Q954H, L981F, S371L, S373P, L212I, S375F, K417N, and ins214EPE
ORF1a	6	K856R, L2084I, A2710T, T3255I, P3395H, 3758V
ORF1b	2	P314L, I1566V
ORF9b	1	P10S
NSPS	1	T492I
NSP12	1	P323L
E protein	1	T9I
M protein	3	D3G, Q19E, A63T
N protein	3	P13L, R203K, and G204R
Total mutations	51

NSPS=Non-Structural Proteins, ORF=Open Reading Frame

The spike protein (s1) aids in binding of the virus to the angiotensin-converting enzyme-2 (ACE2) receptor of the host cell and has a major role in viral infectivity.[131617] Receptor recognition is critical for the viral genome to be released into the cytoplasm of the host cells, followed by viral replication, ultimately leading to infection.[181920] Upon investigation, it was revealed that the binding free energy between spike RBD and host ACE2 receptor is directly proportional to virus infectivity. Based on this observation, aim to decrease the viral infection rate via monoclonal antibodies targeting the RBD of spike protein was the most exploited approach to deal with COVID-19 infection in case of previously known variants. However, mutations in RBD region of spike protein would ultimately affect the affinity and efficacy of currently available antibodies and vaccines as well as increase the chances of reinfection.[13] According to in silico study, the RBD region of omicron makes stronger interaction (electrostatic interaction and hydrogen bonding) with ACE2 host cell receptor.[21] Figure 1 depicts the structure of omicron variant along with the associated mutations.

Figure 1

The key mutation in omicron variant. Note that the mutations have been marked in red

In early 2020, TopNetmAb model model predicted that the mutational residues 452 and 501 were located in the spike protein region. These two residues have a higher mutation rate in more infectious strains of SARS-CoV-2 virus, as confirmed in variants such as alpha (α), beta (β), gamma (γ), delta (ծ), theta (ø), lambda (λ), mu (μ), and presently omicron which have mutation at position L452R/Q and N501Y.

Table 2 depicts the total number of mutations found in different SARS-CoV-2 variants.

Table 2

Total mutations in 5 variants of SARS-CoV-2

Variant	Lineage	Total mutation
α	B.11.7	21 mutation
β	B.1.351	16 mutation
γ	P. 1	22 mutation
ծ	B.1.617.2	20 mutation
Omicron	B.1.1.529	51 mutation

SARS-CoV-2=Severe acute respiratory syndrome coronavirus 2

The TopNetmAb model study found that omicron is ten times more infectious compared to other strains of SARS-CoV-2. The spike RBD region of omicron has mutations at N440K, T478K, and N501Y residues, making omicron twofold more infectious compared to delta variant. Other mutations on spike RBD region of omicron such as K417N, E484A, and Y505H are able to prevent the binding of most antibodies (approximately 132) against RBD region of omicron.[13] The interactivity between RBD domain of omicron S protein and ACE2 host cell receptor has increased remarkably due to mutation at the site of K417N, Q493R, N501Y, and Y505H residues[22] [Figure 1]. Mutations in other proteins of such as in nucleocapsid protein at positions R203K and G204R further increase the viral RNA expression and viral load.[12] One of the monoclonal antibody cocktail developed by Eli Lilly has reduced efficacy against omicron due to mutations at K417N, E484A, and Q493R residue positions in RBD region of virus.[13] Other examples like Rockefeller University monoclonal antibody whose binding capacity has also been reduced due to mutation at position E484A in the RBD region.[1323] Furthermore, BNT162b2 antibody was found to neutralize two omicron variant isolates, namely HKU691 and HKU344-R346K, with an efficacy of 20% and 24%, respectively.[24] Therefore, a more efficacious vaccine would be required against it.[13]

Clinical features and severity of omicron infection

As per the CDC genomic surveillance, there are some new mutations of the COVID-19 being tracked to help public health officials to make better decisions. New variant of COVID-19, B.1.1.529 was first reported to the WHO. Following this WHO named this variant as Omicron and classified it as Variant of Concern (VOC).[25] Subvariants like BA.1 and BA.2 are documented as per the current evidence and research. Clinical features for these subvariants are not yet established fully. Clinical features of omicron are categorized in the Table 3.[26]

Table 3

Clinical features of omicron

General	Pulmonary	Extra-pulmonary
• Severe fatigue	• Cough,	• Abdominal pain
• Mild body ache	• Shortness of breath	• Diarrhea
• Fever	• Sore throat	• Nausea and vomiting
• Generalized myalgia
• Malaise
• Muscle ache

Pharmacotherapy

As per the recent WHO guidelines for COVID-19 updated on 24th Feb 2022, COVID-19 should be treated according to the disease severity. For patients does not require supplemental oxygen therapy, the panel is strongly against the use of corticosteroids like dexamethasone but if the patient already on dexamethasone for underlying condition can continue. As per the panel recommendations for the hospitalized patients who require supplemental oxygen, any one of the following can be used includes remdesivir, dexamethasone plus remdesivir, add on second immunomodulatory drug like tocilizumab or baricitinib can be used for rapidly increasing oxygen demand and severe systemic inflammation. Regarding the alternatives, IV sarilumab can be used instead of IV tocilizumab and tofacitinib can be used instead of baricitinib. Anticoagulant therapy can be considered according to the severity of the disease. [Table 4] As per WHO Living guidelines of COVID-19 (January 2022), there is conditional recommendation for the use of new monoclonal antibody sotrovimab in patients with non-severe COVID-19 disease at higher risk of hospitalization.[2728] Interleukin-6 (IL-6) inhibitor: Tocilizumab is considered on a case to case based prefer within 24 to 48 hours of progress of severe disease. It is considered in cases where no improvement is observed in the levels of significantly raised inflammatory markers.[29] The current treatment guidelines would be suitable against the omicron variant specifically drugs for symptomatic relief and steroids and IL6 antagonist.[30] Recently FDA sanctioned Emergency use authorization (EUA) to a combination of ritonavir and nirmatrelvir tablets (Paxlovid) for the treatment of COVID-19.[31]

Table 4

Anticoagulation therapy can be considered according to the severity

Disease severity	Anticoagulation recommendation
Hospitalized but does not require supplemental oxygen	Prophylactic dose of heparin unless it is contraindicated
Hospitalized require supplemental oxygen	Therapeutic dose of heparin can be considered if the patient D-dimer level if elevated Prophylactic dose of heparin unless it is contraindicated
Hospitalized require supplemental oxygen through high flow or NIV	Prophylactic dose of heparin unless it is contraindicated
Hospitalized require oxygen via mechanical ventilation or ECMO	Prophylactic dose of heparin unless it is contraindicated

Management of Omicron variant

Symptomatic management is the only effective measures available for this variant. There is no approved drug available for this variant to up to date. According to preliminary results, Omicron has a 13fold higher viral infectivity and is 2.8 times more infectious than the already existing Delta variant.[32] After previously approved MAbs showed decreased efficacy against the Omicron variant, their emergency use authorizations were removed. Sotrovimab, the only authorized MAb is effective against this variant. Another new monoclonal antibody Bebtelovimab recently got an emergency use authorization for the treatment of COVID-19 have evidenced that the same drug also works against omicron variant.[33] Finding drug target and molecule for these emerging variants is a big challenge for the research community.

Omicron and HIV

The mechanism underlying the new SARS-CoV-2 variants is hypothesized to be based on intra-host evolution in immune-compromised individuals. When compared to the global population, HIV prevalence in South Africa is 20 times higher among the general population. The infection rate for SARS-CoV-2 is also 5%, compared to 3.5% globally. Therefore, it can be assumed that a larger chunk of the population in South Africa must have been co-infected with HIV and SARS-CoV-2 virus. Weak and less responsive immune system in HIV patients aids in prolongation of other severe infections including COVID-19, allowing the co-infecting pathogens to acquire certain mutations that would enable it to escape the neutralizing factors in the body. This could be a plausible way for the emergence of more infectious variants, as is also observed in case of omicron.[3435]

Conclusion

Omicron variant can trigger global epidemic situation as no existing vaccines show significant protective role against it due to the highly mutated RBD region of spike protein. Therefore, there is a need to develop newer generation vaccines and drugs against this variant as well as highly virulent variants that may emerge in future. The drugs effective against omicron are only for symptomatic management. There is no approved drug available for this variant to up to date. The drugs effective against omicron are only for symptomatic management. There is no approved drug available for this variant to up to date. Furthermore, since omicron variant has been found to be less susceptible towards neutralizing antibodies induced by vaccine shots, and the fact that cases of re-infection are increasing at an explosive rate, it is of utmost importance that, the mutational profile of omicronbe well-characterized, in order to understand the factors that might be responsible for its resistivity or sensitivity towards available vaccines.[12] Booster dose of BNT162b2 demonstrated the ability to augment the response of neutralizing antibodies against Omicron variant, as found in the preliminary study by Pfizer.[36] Therefore, the proposal to recommend booster doses of vaccines can be considered as a protective measure till the next generation vaccines are available for use.

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Conflicts of interest

There are no conflicts of interest.