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Could the New BA.2.75 Sub-Variant Lead to Another COVID-19 Wave in India?

Could the New BA.2.75 Sub-Variant Lead to Another COVID-19 Wave in India?

Colourised scanning electron micrograph of a cell (teal) infected with SARS-CoV-2 virus particles (orange), isolated from a patient sample. Image: NIAID/Flickr, CC BY 2.0

  • Just as the BA.5 sub-variant was poised to take over all the other omicron sub-variants, BA.2.75 popped up to complicate the Indian SARS-CoV-2 dashboard.
  • In India, BA.2.75 appears to have a very high growth advantage of 16% per day over all other BA.2 sub-lineages. As you read this, BA.2.75 may already have surpassed BA.5.
  • The BA.2.75 sub-variant has a sudden and large collection of 16 new mutations. Eight of them are in the spike region, including four on the receptor-binding domain.
  • BA.2 and its sub-lineages are prevalent in India at present; BA.4 and BA.5 have not caught up significantly. So BA.2.75 is competing with other BA.2 sub-lineages now.
  • Against this background, could BA.2.75 lead to a large, new COVID-19 wave in India? It is too early to be sure, but another omicron-like wave seems likely.

For several months, the number of new COVID-19 cases in India stayed below  3,000 – but in the last month or so, they have started to rise again. In the last 10 days, in fact, the number has been hovering in the 15,000-19,000 range. This is still quite low considering the size of India’s population (19,000 means fewer than one case per 100,000 people).

The current daily test positive rate is around 4%, down from around 16-17% in January 2022, at the peak of the first omicron wave.

However, the current testing rate is also quite low, with an average of 3-4 lakh tests per day, whereas the corresponding rate was around 16-18 lakh tests a day in January.

Against this background, there are many uncertainties with important consequences for all of us. The chief among them can be captured in two questions: Will a new wave emerge? If so, how bad will it be?

Which sub-variant?

Let us first do a quick situation analysis. The first prerequisite to ignite a large, widespread wave is to have a variant of the novel coronavirus that has extremely high transmissibility and the ability to evade existing population immunity.

The last large wave in India was caused by the omicron variant, particularly its BA.2 sub-variant. According to computational biologist Raj Rajnarayanan, of Arkansas State University, the most prevalent sub-variant in India as of June 24 was BA.2.38, which accounted for 36% of all sequenced isolates). It was closely followed by BA.2 (34%), BA.5 – the most worrisome of the omicrons sub-variants (10%) and BA.4 (1-2%).

So the BA.2.38 and the BA.2 sub-variants are behind the minor surge currently underway in India.

The BA.5 sub-variant has already been detected in – and started dominating in – at least 63 countries. In India, the BA.5 sub-variant is currently circulating in Tamil Nādu, Karnataka, West Bengal, Maharashtra, Telangana, Delhi, Haryana and Gujarat. A few cases have been reported from Ladakh as well.

Is BA.5 serious?

Of all the SARS-CoV-2 viral variants circulating today, BA.4 and BA.5 are clearly the most competitive: their frequencies have been consistently increasing in multiple countries. The BA.5 sub-variant has the most transmissibility and immune escape potential of any variant since the COVID-19 pandemic began.

Both BA.4 and BA.5 have their own unique mutations, including changes in the receptor-binding domain of the spike protein. These changes – designated L452R and F486V – could tweak their ability to latch onto host cells and skirt some immune responses.

Although BA.5’s spike sequence is nearly the same as that of BA.4, there are several mutations in other parts of the sub-variant that could account for its increased fitness. Some researchers have estimated that BA.5 is around 36% more infectious than BA.2 – the ‘original’ omicron variant – and is thus expected to become the new dominant variant by natural selection.

The effective reproduction numbers of these sub-variants are greater than that of BA.2 as well. Neutralisation experiments revealed that the immunity induced by BA.1 and BA.2 infections is less effective against BA.4 and BA.5. Cell culture experiments revealed that BA.4 and BA.5 replicate more efficiently in human alveolar epithelial cells than BA.2, and that BA.5 fuses better with host cells than does BA.2.

Further, infection experiments using hamsters have indicated that BA.5 is more pathogenic than BA.2. Other studies on the viral characteristics of BA.5 have also demonstrated the higher pathogenicity of BA.5.

CCL-81 cells heavily infected with SARS-CoV-2 virus particles (small spherical structures in the centre). Photo: NIAID/Flickr, CC BY 2.0

Indeed, taken together, the BA.5 sub-variant is expected to be able to cause more severe illness than prior sub-variants of omicron (especially BA.1 and BA.2) – but may have significantly lower pathogenicity than the delta variant and its ancestral WT-D614G variant, if we are to go by the fusogenic potential of these sub-variants.

The BA.5 sub-variant is surging worldwide because it can spread faster than other circulating variants and sub-variants – but mostly BA.2. Hospital admissions are also rising for COVID-19 patients in Australia, Belgium, Denmark, France, Germany, Israel, Japan, the UK and the US, among others, paralleling the sub-variant’s surge.

The sub-variant is thus expected to have a similar effect in other countries where it is starting to become more common. However, the omicron sub-variants in general have also been causing fewer deaths and hospitalisations than their older cousins – a sign that growing population immunity could temper the immediate consequences of news waves.

The advent of BA.2.75

“A week is a long time in politics,” the idiom goes, and it is just as true for novel coronavirus variants. When I sat down to write this article last week, the BA.5 sub-variant was poised to take over all the other omicron sub-variants. But on June 30, a new sub-variant, designated BA.2.75 – the second generation of BA.2 variants – popped up to complicate the Indian SARS-CoV-2 dashboard.

This subvariant is showing extremely rapid growth, and at the time of writing accounted for 18% of recent samples. Most of the data from 80-odd Indian samples have been uploaded from Maharashtra and Karnataka. In India, BA.2.75 appears to have a very high growth advantage of 16% per day over all other BA.2 sub-lineages. As you read this, BA.5 may already have been surpassed by BA.2.75.

The BA.2.75 sub-variant has some alarming mutations in the key spike protein. It has a saltation[footnote]A sudden and large collection of new mutations[/footnote] of 16 mutations. Eight of them are in the spike region: four in the N-terminal domain and four in the receptor-binding domain (see graphic below).

Mutation profiles of the BA.1, BA.5 and BA.2.75 sub-variants. Image: Raj Rajnarayanan

The lineage-defining signature mutations are spike K147E, W152R, G446S and R493Q. The last two – G446S and R493Q – are more cause for concern. The G446S mutation can influence both immune escape and ACE2 binding. Given the data at hand, it is very likely that while this mutation could decrease the sub-variant’s binding efficiency, it could contribute to significant immune escape. This in turn implies reinfections and breakthrough infections could drive the spread of BA.2.75.

But according to Vinod Scaria, a scientist at the Institute of Genomics and Integrative Biology, New Delhi, there is no need to panic. While India has sequenced only a few samples with BA.2.75 (at least according to information in the public domain), its rapid rise in recent weeks suggests it might have a growth advantage compared to BA.2 and its other sub-lineages.

The point to note here is that BA.2 and its sub-lineages are the ones prevalent in India at present; BA.4 and BA.5 have not caught up significantly, especially in Maharashtra, where most of India’s BA.2.75 sequences have come from. So essentially, BA.2.75 is competing with other BA.2 sub-lineages now.

Thus far, in India, nine states have reported samples with BA.2.75. Positive samples for this sub-variant have also been found in eight different countries.

New wave?

Against this background, could BA.2.75 lead to a large, new COVID-19 wave in India and elsewhere? According to Tom Peacock, a virologist at Imperial College, London, it will likely lead to another omicron-like wave if it does take off – akin to the wave we experienced from around November – instead of seeing something more intense, like the delta wave in early 2021.

As for disease severity: an infection of the BA.2.75 sub-variant is most likely to be as severe as an infection of BA.2 – but it is too early to tell. But there is a chance that BA.2.75 could induce milder disease than previous omicron-variant lineages.

The last large omicron wave in India was mainly the handiwork of the BA.2 sub-variant, while BA.1 had a brief sojourn.

Notably, there is still no massive uptick in the number of daily cases in India despite the presence of BA.5. Does this mean BA.2.75 could overrun BA.5 – just like BA.2 overran BA.1 earlier? It is difficult to answer this question right now. The BA.2.75 sub-variant could be optimised to escape prior BA.2-induced immunity in a similar way that BA.5 appears to be optimised for escaping prior BA.1-induced immunity.

Further, India also had a huge delta-variant wave, and which could affect the spread of BA.5. According to one recent study, serum samples from patients who had been infected by the delta variant could neutralise both new incursions of the delta variant as well as of the BA.5 sub-variant. Recall that both strains have the L452R mutation. So immunity gained against L452R in the delta variant wave could offer some protection against BA.5 as well.

This phenomenon could be indicated by the BA.5 sub-variant being more or less dormant in India.

Having said that, we must remember that the overall assessment of population immunity is a bit complicated. One individual’s immune response to COVID-19 could have a different shape from another individual’s response, because it depends on both prior infections, vaccination and their timelines.

While the dreaded delta variant also first appeared in Maharashtra before raging through India and other countries, there is no need to be frightened just yet. We still don’t know whether the BA.2.75 sub-variant is associated with severe disease or higher mortality.

Instead, it is more the sudden appearance of multiple mutations at once that makes it a wildcard, relative to ‘normal’ sub-lineages. The point to keep in mind is that the novel coronavirus is continuously evolving and accumulating more mutations, and that it is too early to jump to conclusions.

Our vaccines

Illustration of the Novavax vaccine, in vials. Photo: Reuters/Dado Ruvic/Illustration

Neither laboratory neutralisation nor real-world data for immune evasion are yet available for BA.2.75. But considering its mutation profile, the sub-variant may have significant immune evasion and the current crop of vaccines are likely to struggle against it.

BA.5 and its emerging sub-lineages – i.e. BA.5.1, BA.5.2, etc. – have been able to evade both natural and vaccine-induced immunity. Similarly, most of our monoclonal/polyclonal antibodies may fail to work. So we may see ourselves revert to a situation worse than when the ‘original’ novel coronavirus first emerged.

In a recent study in Israel, researchers showed compared to the response against the ancestral 2020 isolate, the neutralising antibody (NAb) titre was lower by a factor of 6.4 against BA.1, by a factor of 7 against BA.2, and by a factor of 21 against BA.4 and BA.5. Additionally, compared to the median NAb titre against BA.1, the median titre was lower by a factor of 3.3 against the BA.4 and the BA.5 sub-variants.

The researchers observed similarly large reductions in NAb titres following natural infections as well. Even people with hybrid immunity – i.e. who had had a prior infection and had been fully vaccinated – against the BA.1 sub-variant produced antibodies that struggle to incapacitate BA.4 and BA.5.

Research teams have attributed this feature to the sub-variants’ L452R and F486V mutations. This means the immunity gained through past infections by BA.1, BA.2, and BA.2.12.1 or vaccination may not protect against BA.4 and BA.5.

There is a silver lining, however. The protein subunit vaccine Novavax, which Serum India’s Institute is  producing under the brand name ‘Covavax’, has been shown to protect to a good degree even against the BA.5 sub-variant. Its booster dose form was also found to accord a substantial level of protection against all variants.

So it would seem that this vaccine is our best bet now against new sub-variants like BA.5, owing to its specific design: where some conserved epitopes are targeted to provoke an immune response. [footnote]Epitopes are those parts of the virus that trigger an immune response; conserved epitopes are those that aren’t affected by mutations.[/footnote] The Government of India must focus on this facet of the Covavax vaccine and prioritise its use in the national booster vaccination drive in all age groups.

As things stand, in most places, both members of the general population and of the government are becoming complacent against COVID-19. They think the pandemic is over. This is wrong. We must not forget that the virus has not stopped evolving –  as indicated by the rise of new sub-variants.

As Danny Altmann, a professor of immunology at Imperial College London observed, “Living with the virus is proving much harder than the early vaccine success suggested: this fight is far from over.”

Dr Vipin Vashishtha, MD, FIAP, is a consultant paediatrician at the Mangla Hospital and Research Centre, Bijnor.

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