Presenting itself in different forms since it arrived a little over two years ago, COVID-19 continues to sweep across the world, and the end does not seem to be in sight, definitely not any time soon. Figure 1a shows the recent global surge in COVID cases. India is no exception nor unique, and unsurprisingly, the third wave of the COVID-19 epidemic is now upon us, the peak of which is yet to come even as there is a recent visible decline in the number of cases in Africa, Europe and North America (Fig. 1b).
As of January 20, the daily caseload in India had climbed to a figure of 3,17,532, up by about 28 per cent as compared to the previous week. Given this steep rise since the beginning of the year, it would hardly be surprising if the number very soon surpassed the peak figure of 4,14,188 that was seen on May 7, 2021, during the second wave, which lasted from March to July 2021 (Figs. 2a & b). The uptick in the number of cases in the current wave was visible towards the end of December 2021 and came after a two-month-long plateau of around 10,000 plus cases.
While the second wave that swept the world was due to a mutant form, or a variant, of SARS-CoV-2, the causative virus of the disease COVID-19, called Delta (first detected in India in October 2020), the current resurgence of infection is due to a highly transmissible variant called Omicron.
As a result of natural selection, viruses constantly change through mutation, and sometimes these mutations result in a new variant. Some variants disappear soon after emerging, while others persist, gaining a survival advantage over the extant and circulating strains. Will Omicron out-compete Delta and completely replace it to emerge as the dominant strain across the world? Trends seem to suggest that this may happen, but the situation is still evolving and it may be too early to predict. According to the World Health Organisation (WHO), current global data do seem to indicate that Omicron has a significant growth advantage over Delta. Because of its high transmissibility, the Omicron variant is spreading significantly faster than the Delta variant in countries with documented community transmission.
So what fraction of the new cases in India is due to the Omicron variant? This is not a question easy to answer. Only genomic sequencing of virus isolates from cases, a time-consuming process, can unambiguously determine the variant causing the infection. Although, admittedly, it is not possible to send all isolates for sequencing, the pace of SARS-CoV-2 genome sequencing in the country has been tardy right through the pandemic.
As of January 20, only 9,287 of the total of over three lakh cases had been confirmed by genome sequencing to be due to Omicron. But according to the data put out by the Indian SARS-CoV-2 genome-sequencing consortium INSACOG on December 27, 2021, the Delta variant accounted for 32 per cent of the genomes sequenced in December 2021, while the Omicron variant accounted for 14 per cent.
Of course, there would be a significant time lag between the collection of isolates and their sequencing. Also, in January (whose data are not public yet), the situation is likely to have changed significantly. However, given Omicron’s high transmissibility and judging from variant-specific data from elsewhere, it can be presumed that the bulk of the current cases in India is likely to be due to Omicron. In the United Kingdom, on December 30, 2021, the prevalence of Omicron was estimated at >95 per cent; in Denmark, Omicron accounted for 90 per cent of the cases as of December 28; and in the United States, Omicron accounted for 95 per cent of the cases as of January 1. Nevertheless, since Delta and other variants are still in circulation in the country, it is important to bear in mind—particularly for a proper epidemiological perspective and for the health care system to respond appropriately—that all new cases need not be due to Omicron.
Omicron was first detected in a sample picked up from a COVID case in South Africa on November 9, 2021, and following a clinical diagnosis on November 18, the discovery was reported to the WHO on November 24. On the basis of the genetic make-up of the mutant and the evident epidemiological situation of a sharp increase in the number of cases in South Africa, the world body classified it as a variant of concern (VOC) on November 26. (In the established system of virological nomenclature based on virus lineage, the Delta variant is called B.1.617.2 and Omicron B.1.1.529. Also, Omicron has three sub-lineages: BA.1, BA.2 and BA.3.)
“This variant has a large number of mutations, some of which are concerning. Preliminary evidence suggests an increased risk of reinfection with this variant, as compared to other VOCs,” the WHO had noted. Reinfection means a person who was infected and had recovered getting infected again by the same virus. Although recovering from COVID-19 does provide some protection from repeat infections, the emergence of a new variant can increase the risk of reinfection. Subsequent epidemiological evidence from South Africa and other parts of the world where infection due to Omicron spread rapidly, chiefly through travel, has indeed borne out this preliminary observation.
Not just reinfection, there is evidence of Omicron causing “vaccine breakthrough infections” as well, that is, a fully vaccinated person getting the infection. While COVID-19 vaccines are effective at preventing infection, serious illness and death, some individuals who are fully vaccinated can still catch the infection because vaccines are not 100 per cent effective at preventing infection.
Two men returning to Karnataka from South Africa were the first cases of infection due to Omicron to be detected in India, on December 2. According to the WHO, as of January 6, cases due to Omicron have been reported from 149 countries (Fig. 3).
According to a non–peer reviewed study in South Africa, Omicron is 36.5 per cent more transmissible than Delta. Delta was 40-60 per cent more transmissible than the earlier Alpha variant and nearly twice as transmissible as the original Wuhan strain of SARS-CoV-2. Early reports from South Africa suggested that Omicron, though highly transmissible, was not highly virulent, causing mostly only mild symptoms compared with the earlier VOCs, the Delta variant in particular. Delta was not only highly transmissible (which is what enabled it to emerge as the dominant strain) but also caused severe COVID-19 and death in large numbers (Fig. 4a). Recall the immense distress and misery that the Delta variant brought upon the people of the country and the consequent near-breakdown of the Indian health care system during the second wave.
Like elsewhere, evidence from the ongoing Omicron wave in India too suggests that the infections that the variant causes are mostly mild, not generally requiring hospitalisation or oxygen support. Of course, vaccination coverage (with two doses) of the eligible population (above 18 years of age) in the country during the Delta wave (April 2021) was only 2 per cent as against 72 per cent now, which, Omicron’s immune evasion potential notwithstanding, does endow sections of the population a fair degree of immunity against serious disease.
Reason for faster spread
Symptoms are mostly related to the upper airway, including low grade fever, cough, runny nose and body ache, and the virus does not seem to infiltrate down to the lower respiratory tract and infect the lung tissues to cause severe disease. A study from Hong Kong University found that Omicron infects bronchus tissues faster and better than Delta and has a 70 per cent higher replication rate in the human bronchi than Delta. This is perhaps the reason for the high viral load in saliva, which enables higher sensitivity of the RT-PCR (reverse transcriptase polymerase chain reaction) tests even with saliva samples. Therefore, compared with people infected with other variants, those infected with the Omicron variant will eject many more viral particles into the air even when they are not coughing, resulting in a far greater spread of Omicron. The mild symptoms are seen to disappear in five to seven days, implying that a seven-day self-quarantine should suffice to rid oneself of the infection. The South African experience suggests that this should apply to all age groups and not be limited to young people.
According to Dr Angelique Coetzee, chairperson of the South African Medical Association, cases requiring hospitalisation were a fraction of what was seen during the Delta wave, and the duration of stay in hospital for such cases was also much shorter. The peak of the South African wave due to Omicron was reached quickly—within six weeks, half the time it took during the Delta wave—and the number of cases rapidly declined thereafter.
Omicron cases requiring hospitalisation have been mostly among those who were either unvaccinated or not fully vaccinated (with two doses) and among the elderly and other immune-compromised groups. Thus, for subsequent protection from reinfection, full vaccination (if one is not already vaccinated) and strict adherence to wearing masks, hygiene and physical distancing are a must.
Also read: Omicron cases fuelling the surge in India’s third COVID-19 wave
According to Dr Shabir Madhi, a professor of vaccinology at the University of the Witwatersrand, Omicron accounted for only about 5 per cent of all the COVID-19 deaths in South Africa, while Delta contributed to 50 per cent and Beta and Alpha to 20 per cent each. “There has been a complete decoupling of infections and deaths,” Madhi said. Also, significantly, 40-50 per cent of Omicron infections in South Africa were asymptomatic. This was revealed through routine testing for COVID-19 infection in patients presenting themselves in hospitals for other reasons, childbirth for instance, Madhi said in an interview with The Wire . There is no reason for the situation in India to be any different, given that (according to the fourth national sero-survey) a fairly high 67.6 per cent of the population carried antibodies against COVID-19 (either because of prior infection or vaccination).
As has been seen elsewhere, the effective reproduction number (Rt) for Omicron in India too is about 3 as compared to 1-2 during the second wave (Fig. 4b). Correspondingly, the case doubling time is shorter: two to three days compared with four to five days during the Delta wave. But these figures would be gross underestimates of the true infection load due to Omicron because a large number of infections appear to be asymptomatic.
Given the extent of asymptomatic infection due to Omicron, as Madhi pointed out and perhaps rightly so, restrictions on mobility, curfews and lockdowns, extensive testing, contact tracing, and looking at the infection load and positivity rate will not achieve much and will be a waste of resources, particularly in a highly populated and resource-constrained country like India. What is important and significant from an epidemiological and health care perspective would be to focus on hospitalisation rates and cases of severe disease due to Omicron so that the system is adequately prepared.
With increasing levels of incidence of infection, in a populous country like India, even a low fraction requiring hospitalisation would be a large number. Over time, this could lead to significant pressure on health services. As will be seen later, from an individuals’ point of view, full vaccination is key to protection against future infection. This, coupled with COVID-appropriate social behaviour, is the only way to ride out the current wave.
However, the WHO flagged this important caveat in its technical brief of January 7. “Current evidence about severity and hospitalisation,” it said, “comes largely from countries with high levels of population immunity [either through vaccination or prior COVID infection], and there remains uncertainty about the severity of Omicron in populations with different vaccination coverage and prior exposure to other variants.” In fact, WHO Director-General Tedros Adhanom Ghebreyesus recently cautioned against overemphasising that the current COVID-19 wave was mild. From an epidemiological perspective, this warning becomes particularly relevant, especially when there other variants, particularly Delta, are co-circulating, as is indeed the case in India. Also, the current vaccination coverage of the eligible population in the country is only 72 per cent.
Unusual genetic characteristics
While the emergence of yet another variant is not unexpected, Omicron is unusual because it is the most heavily mutated variant of SARS-CoV-2 so far. So how did Omicron emerge with such unusual genetic characteristics? Writing in Conversation , the virologist Suresh V. Kuchipudi of Pennsylvania State University said that a possible explanation for the emergence of a variant with multiple mutations is through prolonged infection in an immune-compromised patient, which can lead to rapid viral evolution. According to him, another possibility for the source of unusual variants is through animal hosts. SARS-CoV-2 can infect many animal species, including minks, tigers, lions, cats and dogs, and a recent study led by Kuchipudi found widespread infection by SARS-CoV-2 among white-tailed deer in the U.S. “We cannot, therefore, rule out the possibility that the Omicron variant emerged in an animal host through rapid evolution,” Kuchipudi wrote.
It is the replication rate—how fast the virus make copies of itself in the host—that determines the survival and growth advantage of a particular strain over other circulating variants. A study not yet peer reviewed estimates that the Delta variant produced 1,000 more viral particles than the variants preceding it. Its more efficient binding to the ACE2 receptor on the cells enabled Delta to reproduce at a faster rate. Scientists are yet to establish the replication rate of the Omicron variant.
The mutations on the Delta variant also enabled it to evade neutralising antibodies. It was the combination of high transmissibility, immune evasion and the fact that the mutations made the vaccines less effective that caused Delta to emerge as the dominant strain. Studies by scientists, including from India, who looked at isolates from Maharashtra during the second wave, had shown that one particular mutation on the spike (S) protein of the Delta variant, P681R, was the key reason for Delta’s ability to enter cells efficiently and cause severe disease. Similar studies on the Omicron variant are on to get a full understanding of its behaviour.
An atomic resolution analysis of Omicron’s viral structure by scientists of the University of British Columbia (UBC), Canada, using cryo-electron microscope imaging has shown that Omicron has over 50 mutations, many novel ones and some that overlap with the earlier variants. On the S-protein alone, there are 37 mutations relative to the original Wuhan strain, which was the basis for the development of most of the vaccines. This is three to five times more mutations than seen in any of the previous variants, the UBC paper notes. The work was published in the online preprint repository bioRXiv on December 21, 2021.
The S-protein forms the protrusions on the surface of the virus that facilitate its entry into the human cell, and antibodies attach to the S-protein to neutralise the virus. It is also the protein that most vaccines for COVID-19 use to induce antibodies against the SARS-COV-2 virus. The large number of mutations on the S-protein thus assumes significance for how the virus is transmitted, how the immune system fights it off and the efficacy of vaccines and other treatments.
The UBC work also found that, of the 37 mutations on the S-protein of the Omicron variant, 15 are in the receptor-binding domain (RBD), the region that mediates the attachment of the virus to human cells and is also the target of the neutralising antibodies of the human immune system. In comparison, the Delta variant, has only 7 mutations on the S-protein relative to the Wuhan strain of which only 2 are common with the Omicron variant. “Analysis of the sequence of the Omicron suggests that it is not derived from any of the currently circulating variants,” the UBC authors observed. Among the three mutations that the UBC scientists found to be in common with the earlier variants, two (N501Y and K417N) are known to play a role in the binding affinity of the virus to the ACE2 receptor: while the first increases the affinity, the latter decreases it significantly. However, an experimental comparison with the original Wuhan strain and the Delta variant in the UBC work showed that while Omicron exhibited an increased affinity with respect to the Wuhan strain, the affinities of both Delta and Omicron were similar. This means that the 12 novel mutations on the RBD, whose roles have not been studied in depth yet, had a compensating effect of restoring Omicron’s binding efficiency to Delta’s level despite the presence of the mutation K417N.
However, what is surprising is that despite both Delta and Omicron having a similar binding efficiency to ACE2, Omicron’s entry into cells and its fusion with them seem to be inefficient and impaired compared with Delta, resulting in infections due to Omicron not causing severe disease.
SARS-CoV-2 enters cells via two mechanisms. The major and the important one is through fusion of the virus envelope with the cell membrane. The minor process is by fusion with the endosomes (certain organelles within the cytoplasm of cells). Virus replication is much more efficient with the major mechanism than the minor. Also, in the first mechanism, all adjacent cells also fuse with the infected cell and form what is known as a “syncytium”, which is essentially a giant cell with multiple nuclei. Syncytia are often found in lung pathology following severe respiratory disease.
However, this process crucially requires cleavage of the S-protein and the ACE2 receptor, allowing the viral genetic material to enter the cell. The virus then hijacks the cell machinery to replicate itself and spread. Recently, using pseudoviruses (viruses created artificially in the laboratory to carry envelope proteins from a different virus and which do not replicate) carrying mutations of Omicron and Delta, researchers at Cambridge University showed that, despite having three mutations that were predicted to favour the S-protein cleavage, the Omicron variant had lower cleavage efficiency than Delta and thus impaired entry into cells.
Also read: Omicron concerns rise in India as virus rages in other parts of the world
The group also showed that once Omicron had entered the cells, it was less able than Delta to cause cell-cell fusion to form syncytia, thus impairing the cell-to-cell spread of the virus. Indeed, when the team used a live Omicron variant and compared it with Delta in spreading infection in lung cells, Omicron was found to be significantly poorer in replication, thus demonstrating in the laboratory what has been seen clinically with the Omicron variant. “The fact that Omicron is not good at entering lung cells, and that it causes fewer fused cells with lower infection levels in the lab suggests that this new variant may cause less severe lung-associated disease,” Ravindra Gupta, a professor of clinical microbiology at the Cambridge Institute of Therapeutic Immunology and Infectious Diseases, was quoted as saying in a Cambridge University press release.
Irrespective of its ability to cause severe COVID-19, as in the case of Delta, immune evasion after past infection or vaccination has a significant role in the rapid growth in Omicron cases. Preliminary data from multiple non–peer reviewed studies suggest that there is a reduction in neutralising antibody titres against Omicron in individuals who have been vaccinated (with two doses) or in those who have had prior SARS-CoV-2 infection. In addition, increased risk (five- to sixfold) of reinfection has been reported in South Africa, the U.K., Denmark and Israel, which all go to suggest significant immune evasion in the case of Omicron.
Vaccine’s effectiveness
Multiple studies on cellular immunity have concluded that 70-80 per cent of T-cell responses were maintained in people who had prior infection and/or had been previously vaccinated when they became infected with Omicron. Well-preserved cellular immunity to Omicron, as indicated by studies, will protect against severe disease and death, and this, according to the WHO’s Technical Brief of January 7, may indeed be the reason for the observed lower risk of hospitalisation in cases of infection with Omicron.
Studies on the effectiveness of the mRNA, Ad26.COV2.S (Johnson & Johnson) and AstraZeneca vaccines suggested that their effectiveness was significantly lower against the Omicron infection and symptomatic disease compared with Delta and was found to increase with booster doses, both with the primary vaccine (homologous) or a different (heterologous) vaccine. According to two studies, vaccines were more effective in preventing hospitalisations due to the Omicron infection than they were in preventing symptomatic disease but were, nonetheless, less effective than they were against Delta.
An analysis by researchers from Imperial College London compared the hazard ratio of symptomatic infection with Omicron with that of Delta for different vaccine schedules. It was found that after two and three doses of vaccine, there was a higher risk of infection with Omicron than with Delta. This data translated into an estimated vaccine effectiveness of 0-19 per cent against symptomatic infection from Omicron with two doses, which increased dramatically to 54-77 per cent after a booster dose. This work also underlines the importance of booster doses for especially vulnerable sections of the population, such as elderly (60 years and above) and those with comorbidities. Another U.K. study showed that vaccine effectiveness against disease caused by Omicron requiring hospitalisation was 72 per cent 2 to 24 weeks after the second dose, which dropped to 52 per cent after 25 weeks and more. However, this increased to 88 per cent following a booster dose. The U.K. studies and commentaries by medical experts seem to have had an impact on the Indian government’s policy on booster (or precautionary) doses in the country. In early December 2021, it was categorically said that the decision with regard to booster doses would be taken only after vaccination coverage of the entire population was completed. However, later the policy was changed to allow booster doses for the elderly and other vulnerable sections of the population. Jacob John, the virologist and a former professor at the Christian Medical College (CMC), Vellore, observed: “Had India gone on a massive public education [campaign] on the importance of two doses of vaccine to mitigate the Omicron wave, and also on the value of booster doses to increase protection, we could have had a relatively normal life during January-February.”
As regards effectiveness of therapeutics and treatments against Omicron, studies indicate that some of the monoclonal antibodies developed against SARS-CoV-2 may have a decreased neutralisation effect against Omicron. However, therapeutics against the disease caused by Omicron, such as Interleukin-6 receptor blockers and corticosteroids, are expected to remain effective in the management of severe and critical disease since they mitigate the host inflammatory response to the virus, the WHO has stated.
Is Omicron’s reduced virulence a sign that the COVID-19 pandemic is moving towards endemicity like flu, and requiring annual vaccine jabs? One cannot say. Ravindra Gupta believes that Omicron was an evolutionary mistake and a more virulent variant is likely to emerge. Jacob John and M.S. Seshadri, a retired professor and head of the Department of Endocrinology, Diabetes and Metabolism at the CMC, speculated in The Hindu that both Delta and Omicron would co-circulate and we might need vaccines against all variants of SARS-CoV-2, including Omicron and any future variants.
