A transmission electron micrograph of a SARS-CoV-2 virus particle, with the spike proteins in green. Photo: NIAID/Flickr, CC BY 2.0
- The extant and circulating omicron sub-lineages, including BA.2.12.1 and BA.2.38, are unlikely to pose a severe threat in India.
- The BA.4 and the BA.5 sub-lineages have little chance of triggering a large wave, as India has experienced a large BA.2 wave already.
- In India, the threat of a large fourth wave lies either with a new variant or new recombinants with components of the delta variant.
- Fortunately, even if a new variant has delta-like severity, the observed or apparent severity could still be lower due to several layers of protection.
- This said, there are still a few factors that could disrupt our current predictions.
- Most worrying – A brand-new variant followed
- A ‘wrong’ recombinant (involving the delta variant, e.g.)
- New members of the omicron family
- Existing recombinants (like XD or new), and
- Least worrying – existing omicron variant sub-lineages
The second COVID-19 wave, driven by the spread of the delta variant of the novel coronavirus, wreaked widespread devastation in India and triggered panic in the social and health services. The third wave, driven by the omicron variant, was relatively milder even though it caused a great many number of infections.
Its presumed mildness, owed no doubt to its intrinsically less virulent nature, was also aided by the then-widespread vaccine-acquired, natural and hybrid immunity. Both natural and vaccine-acquired exposure offer some protection against severe disease and death, but to different extents.
However, Hong Kong, China, South Korea, Vietnam, Taiwan and other countries found that the omicron variant was probably not as mild as many believed it to be. Recent reports from Hong Kong said that the BA.2 sub-variant invokes a risk of death similar to previous strains of the virus.
This is contrary to perceptions in other parts of the world, that the omicron variant is less severe. There are also indications that the omicron variant is as dangerous in terms of long-term complications in children as the delta variant – especially in the US.
Nonetheless, the omicron variant’s presumed mildness has encouraged many countries and their people to become complacent. Governments lifted restrictions, discontinued mask mandates and allowed large gatherings. In Denmark, the government halted COVID-19 vaccination.
What all these states forgot is that the pandemic is not over and that the virus hasn’t stopped evolving. Every new infection provides the virus with an opportunity to mutate and to evolve. The lack of virulence of the omicron variant was supposedly a strategic move by the virus – a bargain to gain immune evasion.
There is as a result still some speculation among experts about the future trajectory of the COVID-19 epidemic in India. Will there be another wave? If yes, will it be as mild as the one caused by the omicron variant? Could there be a new variant of concern (VOC) among the sub-lineages of the omicron variant or could the delta variant stage a comeback?
Let us analyse these probabilities one by one.
The virus evolves
The SARS-CoV-2 virus is evolving at an unprecedented pace – at least 2.5-times faster than the influenza subtype H3N2, which is considered to be the fastest evolving virus, with a lot of drifts.
When a virus evolves into a new variant, the variant’s fitness depends on its intrinsic transmissibility and escape from the existing population immunity. The first set of variants (including the alpha to the delta variants) largely spread because they were more transmissible – but the omicron variant spread primarily because of its ability to evade immunity.
Further, the evolution of the SARS-CoV-2 virus is quite unlike that of the influenza virus, which evolves in a step-ladder-like fashion, where mutations appear on top of previous mutations – meaning each variant emerges from the previous one. The omicron variant on the other hand typified a long jump: a wildly divergent variant that was descended not from the previous variant of concern but all the way from the ‘original’ strain.
Survival of the fittest
Let us first briefly consider the different sub-lineages of the omicron variant. This variant of concern is a family of sublineages: BA.1, BA.2, BA.3, BA.1.1, etc. Thus far, researchers have detected more than 100 sub-lineages of the original omicron variant, BA.1, with almost one new sub-lineage with distinct additions being designated every day.
Among them, BA.2’s advantage over BA.1 appears to be due to intrinsically higher transmissibility. In BA.2’s genome, the S1 region, corresponding to the spike, appears to be highly similar to that of the BA.1 sub-lineage. Studies have also observed that both sub-lineages have similar vaccine effectiveness.
As BA.2 dominates worldwide, the virus appears to be evolving on this line. The Pango Network has thus far classified 21 sub-lineages of the BA.2 sub-lineage itself; most of them are inconsequential in terms of their impact on the virus’s epidemiology, however.
Instead, the three key sub-lineages to watch are BA.2.12.1, BA.4 and BA.5. BA.2.12.1 is circulating mostly in the northeast US. BA.4 and BA.5 are primarily circulating in South Africa and in some European countries.
All three are still considered by the WHO to be the omicron variant by name. This may not be entirely wise. This is because all three have the L452R/Q mutation. We know that the L452R was a nasty mutation in the delta variant, and other omicron variant sub-lineages haven’t had it thus far.
The B.2.12.1 sub-lineage has the mutations L452Q and S704L on the spike protein, in addition to the BA.2’s other mutations. In the past few weeks, three separate sub-lineages of BA.2 have emerged – each with a different AA mutation at the site 452.
Scientists have previously identified the L452Q mutation in several variants of concern, including the delta, the delta plus, the lambda and the epsilon. Initially, they reported that the L452R mutation facilitated fusion (of the virus with the host cell) and infectivity. They also noticed that the omicron variant with the L452R mutation bolstered the infectivity by enhancing the cleavage of the spike protein.
Whereas the omicron variant of concern mostly infects nasal tissue, its sub-lineages with the L452 mutation infect both nasal and lung tissues, which could lead to more severe disease.
The second mutation, S704L, is more mysterious. Its name indicates that at position 704, serine has been switched with leucine. But unlike L452Q, S704L is relatively rare in the major variants and its exact impact on the virus is not well-studied. But based on its position in the S2 region of the spike protein, we can speculate that the mutation may affect either viral fusion or cleavage efficiency.
The BA.4 and the BA.5 sub-lineages share the spike mutations L452R, F486V and reversion of Q493R. The substitution F486V might confer some additional immune escape relative to BA.2. (We already know that individual substitutions or mutations aren’t very significant. Instead, the company they keep decides their properties.) The sub-lineages with the 452R/Q mutations may continue to expand in future. As they do, they may acquire additional mutations, with the ‘winning’ sub-lineage accumulating the ‘best’ constellation of mutations.
That said, some other mutational constellations could arise and overtake these new 452R/Q lineages. Such an accumulation of mutations may drive further host adaptation and antigenic drift in the coming months. So it is critical that we remain vigilant in our surveillance of these sub-variants.
Taken together, it would appear there is a contest of sub-lineages underway. For example, in the US, first the BA.1 sub-variant variant vanquished the delta variant, only for BA.2 to knock off BA.1 and for BA.2.12.1 to be en route to knocking off BA.2.
We know that the BA.1 sub-variant – the ‘first’ omicron variant – was the fastest variant of concern at that point, with a three-fold greater effective reproduction number compared to the delta variant. BA.2, which replaced BA.1 the world over, was 30% more transmissible than the latter, and BA.2.12.1 is 25% more transmissible.
Apart from these sub-lineages, scientists have also tracked the circulation of some recombinant variants, like BA.1 x BA.2 and delta x BA.1. The current list of BA.1 x BA.2 recombinants includes XE, XG, XH, XJ, XK, XL, XN, XP, XQ and XR. Among them, XP is interesting because its spike protein resembles that of the BA.1.1 variant. The delta X BA.1 recombinants include XD in France and XF in the UK.
Recombinant variants that contain the spike and structural proteins from a single virus (like XE or XF) are likely to act similarly to their parental virus. The XD is for this reason a little more concerning: it contains the structural proteins from the delta variant. Should one of these recombinant variants act much differently from its respective parent, it is likely to be the XD.
However, XD does not seem to be able to outcompete BA.2, which is the current dominant variant. In fact, none of the currently circulating recombinants has the potential to ‘grab’ a new Greek letter.
Omicron sub-lineages and new waves
In the US, the BA.2.12.1 sublineage is behind the new surge – of infections as well as of hospitalisations. For example, in New York city, it accounted for up to 14% of all cases, up from zero, within three weeks. But due to the wealth of BA.2 cases in the last few months, the BA.2.12.1 virus may be impeded by antibodies we developed by getting infected during that wave.
This could explain why the number of cases due to BA.2.12.1 remains relatively low relative to the ‘original’ omicron wave.
There are also clear signs of a fifth wave in South Africa. The positivity ratio is currently as high as it was in the previous four waves. Researchers have tracked immunity against the omicron BA.4 and BA.5 sub-variants in people infected with the BA.1 variant. Their findings are consistent with the possibility that BA.4 and BA.5 could be responsible for the next wave of infections.
This is why we should not be fooled into thinking that without a whole new variant in the picture, we can let our collective guard down. The BA.4 and the BA.5 sub-variants are as antigenically distinct from the BA.1 sub-variant as other variants were from each other – and they were responsible for new waves of their own.
This said, the BA.4’s and the BA.5’s ability to evade immunity – while not as dramatic as that of the original omicron variant’s ability to evade immunity due to vaccines or by an infection of the delta variant – is sufficient to lead to a new wave. On the flip side, BA.4 and BA.5 are not likely to cause more severe disease than in the previous omicron-wave.
Could delta come back?
A recent study out of Israel, based on wastewater surveillance, has warned that the delta variant hasn’t disappeared completely and that the possibility of it making a comeback remains open.
The researchers reported finding that the delta variant remained in circulation even when the omicron variant was at its highest level in the wastewater. This cryptic persistence of the delta variant has surprised many experts. Thus far, whenever a new, dominant variant has appeared, it has overpowered its predecessor after a short period of coexistence. But this does not seem to have happened with the delta variant, which seems to possess a certain ability to survive.
The authors of the study have also claimed that the omicron variants’ levels in the population will decrease until they are eliminated – while the delta variant will continue to circulate. If this really comes to pass, the delta variant may reemerge in a new wave or, possibly, generate a new threatening descendant variant.
The significance of this finding extends far beyond Israel, and indicates that internationally the delta variant may still pose a threat.
However, some virologists do not think that we should be worried about either possibility. According to Tom Peacock at the Imperial College of Infectious Diseases, London, if we carry on vaccinating with the ancestral strain (the immunity it confers is fairly protective against the delta variant, but not so much against the omicron variant), the chances of a delta comeback become negligible.
But there remains a non-trivial chance that a future variant could evolve from the delta branch.
The Indian scenario
Recently, Delhi, Uttar Pradesh and Haryana, among other states and Union territories, reported an uptick in SARS-CoV-2 infections – but the upsurge remained transitory. We know India had a big outbreak between December 2021 and February 2022, fuelled mainly by the BA.2 sub-lineage. So most Indians possess a good population or hybrid immunity – a combination of natural infections and vaccination – against this variant.
Most current sub-lineages circulating in different parts of the world are descended from the BA.2 sub-lineage. By this measure, we need not worry for now about the BA.4 and the BA.5 sub-lineages. According to the latest data available, the BA.2 sub-lineage remains dominant, accounting for 63.5% of all genetic sequences until May 9, 2022, followed by BA.2.10 (14%) and BA.2.38 (8-9%).
Indeed, we should keep a close watch on BA.2.38, which is BA.2 plus the K417T mutation, because it has a spike mutation of concern (K417T) and has demonstrated a 54% growth advantage in India. The K417T mutation is known to be associated with increased binding to human cells, which may make it easier for the virus to spread. Uttar Pradesh, Delhi, Gujarat, Telangana, Haryana and Rajasthan have reported most cases of this sub-lineage.
Futures / Probabilities
Currently, three sub-lineages – BA.4, BA.5 and BA.2.12.1 – of the omicron variant are circulating worldwide. It could be that we will have more second-generation BA.2 lineages in future. The BA.4 and the BA.5 may also replace the ‘plain’ BA.2 lineages. But this will be more like BA.2 replacing BA.1 (thus prolonging the omicron waves) – and not as drastic as when the omicron variant first appeared and sent case numbers skyrocketing.
BA.2.12.1 may be more immune-evading and more transmissible than the BA.4 or the BA.5. It may also well be that a very different variant will arise in the next few months with higher intrinsic severity. A question arises here: which new lineage or recombinant variant will be the most damaging?
As for India, I do not think the extant and circulating sub-lineages, including BA.2.12.1 and BA.2.38, should pose a severe threat. As discussed above, BA.4 and BA.5 have little chance of triggering a large wave. India is different from South Africa because South Africans have not experienced BA.2 waves before. In India, the threat of a large fourth wave lies either with a new variant or new recombinants with components of the delta variant.
Fortunately, even if a new variant has delta-like severity, the observed or apparent severity could still be lower due to several layers of protection – that is, we have multiple natural infections and high vaccine coverage.
This said, there are still a few factors that could disrupt our discourse thus far. First, we know a prior COVID-19 infection does not confer long-lasting protection. The risk of getting reinfected is pretty high after four months. In this regard, the Indian government’s decision to offer a booster dose nine months after the second dose is quite unscientific and may leave a significant chunk of the population[footnote]Mainly the elderly, people with comorbidities and people with compromised immune systems[/footnote] without requisite protection.
Further, the protection afforded by our vaccines – mainly the viral vector and inactivated-virus vaccines – may wane even faster than that afforded by the mRNA vaccines. Recent studies, such as this one, have indicated suboptimal T-cell immunity, particularly CD8 cells, against severe disease and deaths. We know the adenovirus vector-based vaccines provide robust CD8-cell protection.
Next, India is currently not performing rapid-sequencing of SARS-CoV-2 isolates – the results of which can provide real-time information on the emergence of a new variant. I think the Indian government must turn its focus now to booster doses.
We have an excellent immunogen in the form of Covavax, the Novavax shot manufactured by Serum Institute: its design has the potential to provide not only extra protection against the omicron variant and its sub-lineages but can also help keep future variants of concern from emerging.
Dr Vipin Vashishtha, MD, FIAP, is a consultant paediatrician at the Mangla Hospital and Research Centre, Bijnor.