Marc Johnson Profile picture
Sep 18, 2022 19 tweets 7 min read Read on X
SARS-CoV-2 lineages, Cryptic lineages, and a prediction of what the next dominant VOCs will be.
We sequence SARS-CoV-2 from wastewater using a different approach than most. We sequence smallish fragments of the genome so that we can tell if particular mutations are derived from the same virus. This way we are better able to determine if there is anything new circulating. Image
About a year and a half ago we detected something from a St. Louis sewershed that didn't make sense. SARS-CoV-2 lineages whose sequence did not match anything that had been seen from patients. We called these 'cryptic lineage'. Image
Wanting to know if this kind of thing was common, we started collaborating with @DrJDennehy to see if we could find anything similar in other places. NYC also had cryptic lineages. Not the same lineages, but lineages with similar characteristics.
nature.com/articles/s4146…
By the end of 2021, we had identified 9 sewersheds (out of about 180 that were being routinely surveyed) that contained cryptic lineages, including a lineage from California with @RoseKantor.
medrxiv.org/content/10.110…
My obsession with finding and characterizing these cryptic lineages accelerated in 2022. To date we have screened wastewater from around 700 sewersheds. In total we have found 24 putative lineages. I say putative because some of them we have only seen once.
We still didn't know where these lineages were coming from. I was convinced of an animal reservoir. What changed my mind is when we tracked a lineage in Wisconsin with @dho all the way to a single set of bathrooms. There is no animal contribution. It is from a person. Image
What we think is happening is that cryptic lineages are very long-term infections in people (often >1 year). Perhaps GI infections. The hosts are obviously mounting an immune response, but are not able to clear the infection.
Because there are no genetic bottlenecks from spreading from person-to-person, these viruses basically push the evolutionary fast-forward button.
What can these lineages tell us about circulating viruses? These are the sites in the Spike RBD that are most commonly changed in the cryptic lineages. We had seen lineages with these changes long before they were seen in Omicron. Image
When Omicron arrived (shown in red) it had mutations at many of the same sites. The main exceptions were L452 and N460, which were common in cryptic lineages, but were not in Omicron (BA.1). Image
About six months later we started seeing Omicron lineages with mutations at L452. Highlighted in red are the changes in BA.4/5 (which has L452R), but there were also lineages with L452Q, L452M, and others. These lineages took over, but there were still no changes at N460. Image
Finally, a few months ago N460K appeared in an Omicron lineage (BA.2.75). However, it was not combined with any of the L452 mutations. Nonetheless, BA.2.75 and its derivatives have continued to expand and slowly displace other lineages. Image
A few days ago, a new lineage appeared in a MO wastewater sample. Omicron with L452R+N460K (and K444M). This appears to match a new lineage that was just designated as BU.1 a few days ago. Currently there are only 13 sequences in GISAID with this combination of mutations. Image
However, I recently learned from @CorneliusRoemer that I was behind in my lineages. There is another completely independent lineage that arrived at almost exactly the same combination. This lineage is designated BQ.1.1. This group has L452R+K444T (rather than K444M).
In addition, BQ.1.1 has also picked up R346T (also in BA.4.6). We haven't focused as much on this region of spike, but most cryptic lineages that we have checked also have a mutation at this site. It seems to be pretty critical. BQ.1.1 is new, but it seems to be taking off.
There you have it. BQ and BU. I don't know if they will cause a spike in total cases, but barring something completely new appearing, I predict that they will be the dominant VOCs in the coming months.
Addendum. It seems a few other lineages have hit very similar 'jackpot' combinations very recently. In addition to BU and BQ:

BW.1 (BA.5.6 derivative)
BS.1 (BA.2.3 derivative)
BR.2 (BA.2.75 derivative)
other undesignated

They all have N460K, L452R + other changes.
Real pango experts, please correct me if I botch any of these, or have missed any. @CorneliusRoemer @PeacockFlu @siamosolocani @LongDesertTrain

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More from @SolidEvidence

Apr 20
We are recruiting sewersheds for an expanding project. Basically, we want to learn everything that can be learned from wastewater.
Read on if you are interested.
1/ Image
This is a collaboration with SecureBio that started about 18 months.

Basically, we isolate the viral fraction from wastewater and sequence the crap out of it (~1 billion reads/sample). This is unbiased sequencing; we don’t want to miss anything.
2/
securebio.org
There are three main levels to the analysis of the wastewater virome.
The first is SecureBio’s main focus, which is novel pathogen detection with a particular focus on engineered pathogens.
3/
naobservatory.org/blog/detecting…
Read 16 tweets
Apr 19
This battle between Harvard and the administration is so befuddling. The latest plot twist makes less sense than the last season of Lost.

Let me give a very quick summary for those not following along.
1/11
The last few weeks Harvard had been talking with the administration about concerns over antisemitism on campuses, but the talks lacked details, and Harvard was told that they would get a letter last Friday with more specifics.
2/
Then last Friday Harvard got an email from the acting general counsel of HHS with a scorched earth list of demands that would have effectively ended Harvard’s autonomy in hiring, admissions and curriculum.

Here’s the letter.
3/
nytimes.com/interactive/20…
Read 11 tweets
Apr 12
Last month there was an announcement that I thought was a major advancement in world health, but it got little attention.
I thought I would tell you all a little bit about it and why it is so important.
1/25
This breakthrough has to do with HIV, which was a zoonotic pathogen. The progenitor of HIV infects chimpanzees in Cameroon.

No one knows exactly when or how HIV crossed into humans, but the first undisputed HIV patient sample (discovered retrospectively) was from 1959 in what is now the Democratic Republic of Congo.Image
HIV smoldered for decades before becoming widespread in the early 80s.
At the time, being diagnosed with an HIV infection was a death sentence.
There was no real cure (still isn’t) and no treatment. By any measure, HIV was one of the worst diseases of the last century.
3/
nature.com/articles/d4158…Image
Read 25 tweets
Apr 6
I briefly thought the SA BA.3.2 was in the US, but it turns out the virus was just messing with me again.

This was kind of interesting though.
1/
We've been screening all of the new wastewater data a few times a week for signs of BA.3.2.

One of the many screens we have is looking for reads that have C21846T+T21864C together, which are in BA.3.2 but no current lineages (it works better to look for pairs of changes).

2/
This week we had a hit. This was the genotype of the read:

C21621A|(S:T20N) A21626G|(S:T22A) T21657C|(S:F32S) T21695C|(S:S45P) A21712T|(S:S50S) CATGCTAT21758-21765del C21767-21767del C21846T|(S:T95I) T21864C|(SI101T) TTA21890-21892del|

3/
Read 9 tweets
Mar 17
Here is this week's analysis. One mutation popped out as increasing in frequency in the last data set.

S:G842S

Wonder what that is from.

1/ Image
Not a very common mutation. Mostly associated with with XEC.11*
2/
cov-spectrum.org/explore/United…Image
If that's really from XEC.11*, then we should see other mutations from that lineage increasing.

So I looked up the mutations that differentiate XEC.11 from XEC:

Orf1a:V2090F
S:K182N
SV1264L
Orf3a:L85F

3/ Image
Read 8 tweets
Mar 17
I’m very pleased to announce the launch of our LungFish Data Explorer dashboard for tracking SARS-Cov-2 lineages from wastewater.

1/
inkfishmedical.github.io/wastewater-das…
Here’s the problem we hope this dashboard will help solve.  SARS-CoV-2 remains very prevalent in the US.

However, sequence surveillance from patients has plummeted. In addition to fewer samples, the average sequence takes >3 weeks to be reported (and it’s getting slower).

2/ Image
Fortunately, we have wastewater surveillance (primarily through CDC NWSS), which covers a large chunk of the population and has a fairly fast turnaround (<2 weeks).

3/ Image
Read 16 tweets

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