Heavily Mutated Omicron Variant of COVID-19

New variants of COVID-19 have emerged following the first wave of the pandemic and created great panic among people throughout the world. Viruses constantly change through mutation. When a virus has one or more new modifications, it is referred to as a variant of original virus. The World Health Organization (WHO) has classified each emerging variant as either a Variant of Concern (VoC) such as Alpha, Beta, Gamma and Delta variants that made their appearance in UK, South Africa, Brazil and India respectively, and later spread to different countries, or Variant of Interest (VoI) such as the Eta, Iota, Epsilon, Zeta, Kappa and Lambda. They have been named by using Greek alphabets. There are also Variants of High Consequence, and none of them have been recognized. At the end of December 2020, variants of COVID-19 began to appear allowing the virus to be more contagious than before. Genetic variants have been emerging and circulating since then.

The changes in the variants occur when there is mutation of genes in the virus. The mutations of RNA viruses is a natural process which we have seen in flu viruses. Geographic separation has resulted in genetically distinct variants.

Many variants have emerged in COVID-19 and they are distinct from one another. In VoC, a SARS CoV2 variant exhibits greater transmissibility, increased fatality and a marked decrease in response to therapy or vaccines. The genetic capability of the variants affect the severity and transmissibility of the virus and exhibit immune escape and diagnostic escape. An increase in the number of variants has posed a greater risk to public health all over the world.¹ The causative virus of COVID-19 will continue to change over time and new variants will emerge following a change in their genes. Geographic separation facilitates emergence of genetically distinct variants. It must be noted that in the beginning of COVID-19 pandemic, most people were susceptible. Now the conditions have changed either due to natural infection and/or vaccination, and the pool of susceptible population has come down.

The Delta variant (B.1.617) was initially detected in India in December 2020. This is a highly contagious strain. It spreads more quickly than other variants. People who were vaccinated against the corona virus appeared to get complete protection against Delta. The emergence of this variant was linked to a more significant surge of infection in India in April 2021 as the second wave. This highly contagious variant spread worldwide and the infection was more prevalent among younger individuals. It was more transmissible than other COVID-19 variants. Then, emerged Delta plus variant and it was first recognized in Uttar Pradesh, India. Different variants of Delta were seen in Delhi, Punjab, West Bengal, Maharashtra and Karnataka.

Currently world is concerned about a highly infectious, fast-spreading corona virus delta variant B.1.1.529. Three cases from this strain were first detected in Botswana on 11th November 2021. Three days later six cases were reported in South Africa in the province of Gauteng, and one case in Hong Kong (in a traveler from South Africa) and another in Israel (from a person who returned from Malawi). Ten cases in three countries were confirmed by genome sequencing.

The variant had a spike mutation that enables it to be detected by genotyping test that gives the results much more rapidly than genome sequencing. The analysis of the samples (77) collected between 12th and 20th November 2021 from Gauteng by genotyping tests showed presence of B.1.1.529 variant. Researchers have begun testing the ability of the virus to evade infection-blocking antibodies and other immune responses. The variant is harboring a high number of mutations in the regions of spike proteins that antibodies recognize, potentially reducing their potency. Researchers are testing the ability of the virus to evade infectionblocking antibodies and other immune responses.² 

Nearly 100 sequences of this variant have been reported. South Africa alerted WHO about detection of a new delta variant on Nov 24, 2021. In Netherlands, a Delta variant had been found in samples of patients on 19th and 23rd November 2021. WHO stated that the global risk from the variants is high and it could be more contagious.

The World Health Organization on 26th November 2021 designated the new strain (B.1.1.529), as a VoC and named it Omicron on the advice of scientists who are part of WHO’s Technical Advisory Group on SARS-CoV-2 virus evolution.³ This is the 13th lineage that got a Greek letter nomenclature within a week of its detection. Thus, Omicron exhibiting a ‘very unusual constellation’ of mutations has joined Alpha, Beta, Gamma and Delta on the current WHO list of VoC. These variants have shown that they can spread more easily, cause more serious disease and make the vaccines less effective. Preliminary evidence has suggested that infection from Omicron is associated with resistance to neutralizing antibodies, causes mild disease and exhibits enhanced transmissibility. With every passing day, the cases of Omicron are increasing causing widespread concern.

Analyzing the early data, WHO has said that Omicron corona virus is more transmissible than the Delta strain, and reduces vaccine efficacy, but causes less severe symptoms.

Though the full significance of the new variant is being ascertained, it has shown high number of mutations in the regions of the spike, at least 32, which has raised concerns about its ability to evade the body defense with immuneescape mechanisms, and to spread quickly.⁴ The mutations in the spike protein have made it harder for immune cells to attack the pathogen. Most vaccines use the spike protein to prime the immune system against COVID-19. As the vaccine works by forming antibodies against the spike protein, presence of many mutations at the spike protein region is likely to lead to a decreased efficacy of COVID-19 vaccines. Mutations in the spike protein can affect not only the ability of the virus to infect cells and spread, but also make it difficult for immune responses triggered by vaccine to attack the pathogen. Thus, the variants have an increased ability to evade infectionblocking antibodies and other immune responses. They have sparked severe concerns as the mutations in the spike protein can affect the ability of virus to infect cells and spread. It has been speculated that the variant must have been evolved from a single immune-compromised patient during chronic infection.

World community was quick to take precautions to prevent the spread of the new strain of delta variant. Restrictions were imposed on travelers arriving from South Africa, Namibia, Botswana, Zimbabwe, Lesotho, Eswatini, and Mozambique. Their entry was banned in many countries. India has taken strict vigil on the travelers arriving from South Africa and neighboring countries. Individuals who are not fully vaccinated are to test negative before flying and undergo two PCR tests on arrival. Those who are fully vaccinated need to have a COVID test within 2 days of their arrival. The variant strain has serious public health implications in view of recently relaxed visa restrictions and opening of international travel.

Three types of behaviors are exhibited by virus, such as virulence (the seriousness of symptoms of the disease), transmissibility (rate at which it spreads from one individual to another) and immune evasion (the degree of protection received by a person from the vaccine or natural infection), and they determine the threat posed by a new variant. The genetics and evolutionary interactions make their behavior complex. Efforts are being made to find whether the variant can evade immune responses triggered by vaccines.

Since the key properties of the virus variant are unknown, it needs close monitoring and analysis of its infectiousness and immune escape. There is no data to say that Omicron causes more serious disease. The anecdotal reports from South Africa have suggested that the variant causes mild symptoms. However, it has created concern about its transmissibility and immune escape. The Omicron variant does probably spread more rapidly than other variants. The variant has been detected in 108 countries by 24th December 2021. It has been reported that 1,51,368 have been affected by Omicron with 26 deaths. Faster transmission has been noticed in South Africa where Delta is less prevalent, and in Britain where Delta is the dominant strain. Since Omicron is affecting those who had Delta infection, the strain is often referred as Delmicron.

Several states across India have reported Omicron cases. The number of cases identified on 24th December 2021 is 358. In an analysis of 183 cases, Indian Council of Medical Research (ICMR) found that nearly half of those infected were fully vaccinated. A little over a quarter had no international travel history, but had likely come in contact with the infected. The virus appears to spread faster than earlier strains. It appears to cause a mild disease and nearly 75% of the infected remain asymptomatic. The symptoms appear to be like common cold exhibiting features like a sore throat, weakness and body ache.

The worry about Omicron is that it could resist vaccinations and prolong the pandemic. The detection of Omicron has caused global alarm and there is imposition of new travel restrictions, and markets have been sold off fearing the variant could be resistant to vaccinations.

There are special tests to find the target genes related to parts of the SARS-CoV-2 such as S (spike protein), N (inner nucleocapsid protein), M (membrane protein) and E (envelope or outer shell protein). The primers used in RT-PCR help in identification of the characteristic genes that make these proteins. The TaqPath COVID-19 assays have been found useful to identify these gene targets from different regions. One of them is S region that codes for the spike protein that happens to be highly distinct region of the corona virus. The presence or absence of S-gene is utilized to confirm or rule out the presence of Corona infection.

Some characteristic amino acids are absent in S protein of alpha variant and the Omicron variant of corona virus.5 These variants that are negative for the S-gene are called the S-Gene Targeted Failure (SGTF) or S-gene drop out. Still, the case is positive for SARS-CoV-19 as it exhibits presence of genes on the ‘E’ and ‘N’. S-gene dropout test can be used as a marker to detect the presence of Omicron variant quickly pending confirmation by genome sequencing. This test is useful in a person with symptoms and is positive on a RT-PCR test.⁵

A sub-lineage-BA.2 of Omicron has been identified, and it exhibits a cluster of sequences that are found in the original Omicron, referred to as BA.1. However, it misses some mutations, but shows some additions. Thus BA-2 is genetically different from the sub-lineage BA-1.

Thus, it appears both BA-1 and BA-2 are equal sub-lineage of B.1.1.529. B.1.1.529 cluster has 86 mutations, of which 40 are found in the spike protein. Twelve mutations are found exclusively in the spike protein of BA-1, whereas BA-2 sub-lineage exhibits seven exclusive mutations in the spike protein. Thus 21 mutations found in the spike protein are common to both BA-1 and BA-2.6 BA-2 cannot be identified by the primers used in RTPCR test. BA-1 sub-lineage exhibits the characteristic S-gene dropout mutation. Such a mutation is not found in BA-2 sub-lineage. All the three target sequences in RTPCR primer will test positive in BA-2, whereas the test is positive for two genes but not for the S-gene in BA-1.⁶ The priority in India is to fully vaccinate all adults and administration of booster dose to enhance the number of antibodies is under serious discussion in the country. It is not recommended to any group of the population in the absence of evidence of its added value. The vaccines provide protection against severe illness and death. We do not have reliable evidence about protection against infection and transmission, and mild or asymptomatic disease.

The mutations in spike protein affects transmissibility, immune escape and sub-optimal response to the treatment. There is a high probability of re-infection.⁷ The impact of Omicron variant essentially depends upon the context and settings. A highly transmissible variant in a well vaccinated population is unlikely to bring about changes in the scenario. However, it might pose a real challenge to a population with low vaccination uptake. Hence, it has been suggested that the approach must be to accelerate the vaccination coverage among those who have remained unvaccinated or not yet fully vaccinated, and focus on improving adherence to COVID-19 appropriate behavior.⁷ The studies made in Oxford have found that two-dose COVID-19 vaccine regimens do not induce sufficient neutralizing antibodies against Omicron corona virus. There can be infection in those previously infected or vaccinated. However, there is no evidence yet that the lower level of the infection fighting antibodies against Omicron could lead to higher risk for severe disease, hospitalization or death in those who have got two doses of approved vaccines.⁸ Measurement of antibody levels to assess the degree of immunity is not recommended in clinical practice.⁹ The use of masks, physical distancing, hand hygiene and improvement of ventilation of indoor spaces, and limiting gatherings or congregations of people in close proximity with poor ventilation remains the key to reduce transmission of SARS-CoV-2 that includes Omicron. There is a need to augment the facility to conduct genetic sequencing studies to keep track of these variants. There is no convincing evidence that the variants have greater propensity to infect or cause disease in children. We have to be ever vigilant and monitor the situation carefully. We should continue our efforts to prevent virus transmission and to vaccinate more people.¹⁰ A higher level of adherence is necessary to control transmission with greater transmissibility of the variant. Contact tracing of COVID-19 cases in the affected areas must be carried out. Its impact on vulnerable population should not be underestimated. There is a lot of uncertainty in the magnitude of immune escape potential of Omicron. Still the current available vaccines do offer protection against hospitalization and death.

With the emergence of Omicron infection, the threat of third corona wave has been increasing. People should be ever vigilant and take steps to curb the spread of the infection. They must not panic, but be vigilant and follow COVID norms.