A Quick Update on the BA.2.86 Variant

This hyper-mutated variant has shown up in many places now, at a time when wastewater and genomic surveillance is greatly diminished around the world.

To date, the BA.2.86 variant has been detected in Israel, Denmark (3 individuals), the UK, the US (2 individuals, one coming back from Japan), and South Africa (2 individuals). It has also been detected in wastewater in 1 region in Switzerland (2% level), along with wastewater detection in Ohio and in Thailand. It’s safe say that BA.2.86’s presence is widespread across the world at this point.

The Immune Escape Issue

We know its new burden of mutations is considerable. The spike mutation map below compared BA.2.86, at the top graph below, (“Pirola,” and as yet without a WHO designated name) compared with EG.5.1,FL.1.5 (on the rise in the US) and XBB.1.5, the latter being the target of the “updated” new booster that is supposed to be available in a few weeks in the United States. Also shown is BA.5 which was the target of the bivalent booster released in September 2022 and is the only booster currently available. If you can expand the image, you can readily see the marked differences in mutations—more than 30—in the spike for BA.2.86 as compared with the XBB recombinant variants (XBB.1.5. EG.5.1, and FL.1.5.1).

The impact of these striking differences will be immune escape—that is more difficult for our immune response to recognize this variant even with prior vaccinations, boosters, and infections—because it is new and different. It’s still SARS-CoV-2 so we have built some immunity, especially via our cellular T-cell system that is less sensitive to variants (that is to say its response is largely preserved independent of variants). But the rapid ability to neutralize the virus depends on antibodies, and the levels of those neutralizing antibodies are bound to be much lower against BA.2.86 than versions of the virus we have previously been exposed to or immunized against. Also to note, the burden of new mutations for BA.2.86 is not confined to the spike and is seen broadly across other components of the virus.

The XBB.1.5 updated booster would have been quite useful because it matches up pretty well to EG.5 and FL.1.5.1 (gaining in the US) with only a few mutations that differ, but it isn’t likely to be as helpful against BA.2.86. If BA.2.86 takes off, it will be a real test of how good our T-cell response can rev up to meet the challenge.

How infectious is BA.2.86?

That’s what we don’t know yet and is the key to how this will play out. If we look at the early days of Omicron, it already declared its high transmissibility in Southern Africa.

Let’s look back at what was going on at the end of November 2021 when Omicron (then called B.1.1.529) first surfaced in Southern Africa. Quickly it was quite obvious that these 30+ new mutations in the spike had extremely high growth advantage (like 500%) and was hyper-transmissible.

We don’t see that now and that’s a bit reassuring. In Denmark, where genomic surveillance is solid, another week went by without new detection of BA.2.86, so that’s encouraging. But it is possible there is more transmission globally than what has been detected so far because our surveillance has dropped so profoundly.

But at least for now this is not the dreaded “Omicron event” when the only previously hyper-mutated new variant appeared and was quickly seen to spread throughout the world. But from a pure mutation standpoint, this is like “Omicron-squared” (30 mutations on top of 30 previous mutations). Take a look at the spike mutation map below: striking differences compared with BA.2, the ancestor of BA.2.86, and the original Omicron, BA.1 ,below. Both of these variants (BA.1 and BA.2.86) likely emanated from an immunocompromised individual who had accelerated and unchecked evolution of the virus in vivo and then transmitted it.

The optimist in me says we won’t see the Omicron-like spread, “catching fire” if you will, in the weeks ahead. The pessimist in me says we might, and that the likelihood of seeing that is because BA.2.86 is still evolving, picking up new mutations, just as BA.1 evolved (ultimately to BA.5 and XBBs). The BA.2.86 sequences we’ve seen are not all the same, as shown in this phylogenetic graph by Cornelis Roemer, from the first sequences. Time sequences indicate the common ancestor of BA.2.86 must have arisen in May-June 2023.

So either BA.2.86 has a lag time to get to critical mass to drive exponential growth or it may evolve further with more transmission power. Only time (and sequencing) will tell us if either of these scenarios will be actualized.

Chasing Variants Doesn’t Work Well

The strategy of picking a spike variant for the mRNA booster at one point in time and making that at scale, going through regulatory approval, and then for it to be given 3 or more months later is far from optimal, as the BA.2.86 story reinforces. By the time the XBB.1.5 monovalent booster shot is ready in mid-September we may already be facing BA.2.86’s rise. We desperately need to pursue a variant-proof vaccine and there are over 50 candidate templates from broad neutralizing antibodies that academic labs have published over the last couple of years. Only a couple of candidates (one from CalTech and the other Walter Reed) have gone onto early (Phase 1) trials. Project NextGen, a $5 billion initiative by the US Department of Health and Human Service (HHS), is supposed to be funding development and clinical trials of better vaccines, which includes nasal and variant-proof. Initial allocations for over $1 billion were just announced, but it isn’t clear when we will see any real progress and whether a pan-sarbecovirus vaccine is a priority. The “dream vaccine” has been written about for nearly 3 years. It isn’t a dream. We can do this; BA.2.86’s appearance tells us once again why it’s so important. You’d think we’ve forgotten how quickly the very potent Covid vaccines were made and validated in the first 10 months of 2020.

Sorry, The Pandemic Isn’t Over

Even if BA.2.86 doesn’t pose a real threat by virtue of low transmission, or its further evolution proves to be relatively benign, the fact that the inexorable evolution of the virus continues—to find new hosts and repeat hosts—cannot be ignored. If this isn’t “the one” it ought to signify that “the one” is still yet to come. If it never shows up, that’s great. But you sure don’t want to bet on that. All of us wish this was behind us, but it’s not. Facing that fact this virus, in one version or another, will be with us for many years to come, rather than denialism and complacency, is critical.

At the moment there’s no reason for alarm. The current wavelet in the US (which could certainly pick up steam) is not likely driven by the XBB descendants of EG.5.1 or FL.1.5.1.(More likely an outgrowth of waning immunity and behaviors). We know well the mitigating factors that work against all respiratory viruses. What we’ll see in the weeks ahead is whether BA.2.86 takes hold or not. If it does, that will pose a new challenge, and make the “updated” booster shots considerably less helpful than what was conceived when XBB.1.5 was selected as the target.

Someday, we might use our intelligence and resources to get ahead of this virus, but for soon what will be 4 years, and certainly right now, it’s out-running us.

I will update this post as soon as anything important about BA.2.86 shows up.

Update

31 August

The first lab assessment of BA.2.86, by Yunlong Cao and team, who have been extraordinary for getting rapid and accurate results on new variants, was posted on 31 August. It shows that the immune escape feature of this variant are extreme, but, fortunately, that cell infectivity is low, meaning that we can expect that infectiousness to not be high. Of course, as emphasized above, BA.2.86 can pick up more mutations to be more transmissible, so only over many weeks ahead will we be able to know if this is the next path for the virus’s evolution. In the meantime, the circulating variants here in the US, including EG.5.1 and FL.1.5.1, should prove to be a fairly close match to the XBB.1.5 booster due out in about 2 weeks.

As of 31 August, there are 28 BA.2.86 variants detected and sequenced, as summarized by graphic below from Josette Schoenmakers, with the place detected, date and mutation alignment of the spike. One added from South Africa is not found on this Table. Beyond the sequences, there have been many places where wastewater surveillance picked up BA.2.86 including Switzerland, New York City, Thailand and others since this newsletter was first posted.

Thanks again to the great scientists who so diligently track the SARS-CoV-2 variants, who include Ryan Hisner, Cornelius Roemer, Daniele Focosi, T. Ryan Gregory, Marc Johnson, JP Weiland, Raj Rajnarayanan, Federico Gueli, Tom Peacock, and many others.

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