New Covid Variant BA.2.86: How bad could it get ?

 

As predicted, SARS-CoV-2 hasn’t finished with us yet….

After a lull in the flow of ‘Variants if Concern’, we now have another Delta to Omicron-style evolutionary jump in the form of BA.2.86. The main concern with this particular variant is that it has lots of spike protein amino-acid mutations.

First, just how different is it to past and present variants ?

Relative to Omicron BA.2 (its putative ancestor) the BA.2.86 Spike Protein has 34 mutations: 29 substitutions, 4 deletions, 1 insertion.

Relative to Omicron XBB.1.5 (more recent strain recommended for vaccine development) it has 36 mutations: 32 substitutions, 3 deletions, 1 insertion.

Relative to the early Wuhan-Hu-1, it has a whopping 58 mutations: 52 substitutions, 5 deletions, 1 insertion.

The key point here is that the number of spike amino acid mutations in the BA.2.86 variant relative to BA.2 and XBB.1.5 is comparable to the number of mutations in first Omicron strains relative to Wuhan-Hu-1.

Although it’s early days, and there’s no direct evidence yet of major antibody resistance, the sheer number of spike mutational changes this variant is displaying is worrying in itself. More to the point, deep mutational scanning experiments have indicated that no less than 16 of these mutations are flagged up as having the potential for inducing antibody escape.

Why is this important ?

Our approved vaccines are all based on immunising exclusively against the complete viral spike protein. The latest mRNA booster vaccines are bivalent, i.e. they encode for the S-Protein from the original Wuhan strain and one of the earlier Omicron BA.n variants. This approach was designed to 'catch up' with the many mutational changes the virus had undergone since it first appeared. The problem is that vaccine development, and in particular the subsequent testing and approval, all takes time, and will always lag behind the rate at which the virus can evolve.

A new variant with a spike protein that ‘looks’ different enough to the antibodies and T Cells we currently have circulating as a result of vaccination and /or having had the disease could render our existing immunity ineffective.  Although in this situation we would expect to retain some residual immunity to Covid, since our immune responses produce populations of polyclonal antibodies with a wide range of specificities, this might be insufficient, particularly in immune compromised patients, to prevent the virus getting out of control during an infection and triggering a fatal immune ‘meltdown’.

To avoid undue concern at this stage, I should stress that we don’t have enough information to assess the degree of antibody escape this variant is actually capable of.  

To date, its population penetration against the predominant circulating Omicron variants is low (USA ca 1% as of 30.8.23), but cases have been identified in a wide range of territories, which indicate BA.2.86 has retained the highly infectious properties of its Omicron predecessors and is already spreading rapidly.  This in turn suggests that it may have a competitive advantage over earlier BA.n variants. 

The fact that UK NHS have brought forward their Flu and Covid vaccination programmes by a month this autumn, and have also attached a financial premium to vaccinators for early completion in care homes, indicates that the authorities are concerned they could have a new epidemic on their hands by Christmas.

The other issue we face going into the N hemisphere winter is 'Covid fatigue' - by this I mean the feeling amongst the general population that the pandemic is a thing of the past, and we no longer need to worry about Covid. 

The problem with this view of life is that Covid is still very much capable of causing harm. 

None of our vaccines prevent infection 100%, although they do raise the exposure threshold required for infection; few people are now taking any practical precautions against infection. Thus we should expect infection rates to remain high. 

Since testing is now 'out of fashion' and lateral flow testing kits are no longer free, epidemiological data is sparse, and we have a limited 'handle' on how things are progressing. Of those that do get infected, a significant proportion will still suffer harm, whatever their vaccination status. Abnormal clotting in particular is a frequent complication, as is so-called 'Long Covid'. A recent study in Australia found that in a very highly-vaccinated population infected with Omicron that one in five people described long Covid symptoms as a residual effect post-recovery. 

How likely is it that one or more Covid variants will emerge with properties which increase the number of hospitalisations and deaths ?

What will ultimately determine this is whether there is sufficient selection pressure on the virus such that a more harmful variant is able to displace existing ones. At present there is little pressure in this direction - in fact the reverse is probably true. Generally, the most successful viruses are those which cause the least harm to their hosts while remaining highly infectious. Covid actually does achieve this in most cases, being rapidly transmitted and often completely asymptomatic. Its 'achilles heel' is in fact the inability in some cases of our own immune system to control viral load adequately, which can still lead to hyper-immune response, organ failure and death. 

We would expect the evolutionary process to remove this tendency over time, but the current variants still have a way to go, and will need to moderate their replication apparatus to reduce their virulence. The virus may still continue to throw up more antibody resistant variants - as mentioned above, this trend could accelerate as more of our population develop acquired immune defence against current variants. This could in turn temporarily increase the hospitalisation and death rates, but it's unlikely that there will be another large 'wave ' of deaths, provided we keep on top of vaccination boosting, which is the key to maintaining population immunity. It's also important that we maintain adequate population surveillance in the absence of free community self-testing.

Where should we go with our vaccines ?

Our current situation with vaccines also highlights once again a flaw in our vaccine development strategy. So far there has been little attempt to broaden the range of viral targets in our vaccines.  As a hedge against the emergence and spread of a really effective escape S-Protein variant, we should be trageting at least one other viral component in the mix. Playing ‘catch up’ as we are currently doing with S-only vaccines against the latest variant’s S-protein mutations will always be inefficient for a fast-evolving RNA virus such as this, given the time taken to obtain regulatory approval, even for a minimally 'tweaked' mRNA vaccine. 

As a 'worst case scenario', it could also spell disaster, given the propensity of any new and highly infectious SARS-CoV-2 variant to spread round the globe in a matter of days. 

So far, mercifully, there is no indication that susceptibility to serious disease and hospitalisation is any greater for this variant than its predecessors.

How then could we 'beef up' our vaccines using new viral targets ? The obvious choice for a new structural protein target, given its much lower susceptibility to mutation and its known high immunogenicity during infections is the viral nucleocapsid protein. 

Although as yet there is no published information on its nucleocapsid structure, BA.2.86 is likely to follow the pattern of other recent omicron variants with few, if any, nucleoprotein changes. Thus a vaccine with a nucleoprotein sequence component would be a much longer-lasting prospect than the current S-protein only vaccines.

Let’s hope the vaccine development industry sees the light soon….

Further updates to follow.

Update 9.9.23: We now have some limited data from the US on the likely immune escape capabilities of BA.2.86 as compared with ‘prior art’.

So far things are looking reasonably promising. The best estimate of immune escape potential is approx. a 2-fold increase in the ability to withstand antibody neutralisation as compared with XBB.1.5. This gives it only a moderate advantage over the competition. Although BA.2.86 is spreading worldwide (UK 36 cases reported so far), this seems to be a slower process than anticipated, and may indicate that the virus does not have the necessary competitive edge to take over from the predominant circulating forms.

There is no indication to date that BA.2.86 causes more severe disease in susceptible individuals, but we should be cautious about writing this variant off so early in its development, and more epidemiological work needs to be done to evaluate the threat (or lack of it) fully.

One slightly worrying recent observation is that another ‘evolutionary jump’ variant (FL.1.5.1) with a new ‘constellation’ of mutations has appeared alongside BA.2.86, and this one is currently causing 15% of all new infections in the US. FL.1.5.1 has proved the most immune-evasive variant seen so far in recent testing, so may actually prove more problematical than BA.2.86 over the course of this autumn and winter.

Booster vaccination is definitely advisable for susceptible groups, and there is talk of widening the UK eligibility for free vaccines beyond the current over 65s + susceptible groups remit.

Update 11.11.23: Two new variants have surfaced since the last update - HV.1 and JN.1 . HV.1 was identified in September and has now become predominant in the US but has not really taken hold in UK & Europe so far. JN.1 is a newer variant still currently under investigation. At first sight, although they do appear to marginally more transmissible, neither JN.1 nor HV.1 appear to be any more effective at evading our antibodies. Watch this space for further updates.

First published 31.8.23