In 2025, GISAID cut off access to many critical SARS-CoV-2 resources, incl. our outbreak.info.
A month ago, GISAID leveled accusations against us, Cov-Spectrum, Nextstrain, and members of COG-UK, which are false and misrepresent known facts.
Our joint response:
blog.outbreak.info/joint-respon...
She was such a shining star and breathe of fresh air. Will be missed dearly. Sincerest condolence to her family and love ones.
There was a time when platforms enabled reporting of medical disinformation. This platform stills does. Another has enabled medical disinformation that paediatric measles is simply a stress rash and viruses simply don’t exist. For the record viruses are real and measles in kids isn’t trivial.
Precisely. And for us pragmatically determine the efficacy of particular clinical formulations on a small subset of variants that then weeks/months later become the dominant flavours within the communities where these formulations are used in a trial.
Important read on challenges of continued SARS-CoV-2 surveillance provided by tools like Nextstrain, using GISAID data. Just one comment as someone who is using Nextstrain for my research, for keeping up to date and for scientific talks:
nextstrain.org/blog/2025-11...
Agree. We have an ongoing collaboration with Ben Murrell, where this data is used to identify variants in a timely fashion to test in an ongoing clinical trial. See github.com/MurrellGroup...
Alex Kydd
Ocean, Nature & Travel Photographer
There are tools to help if there is will. In some instances that will has taken a step backwards. www.deseret.com/politics/202...
6- So the concept of “mild” outcomes will clearly be multifactorial. I’d also hesitate to call something “mild” until we understand the full consequences of what it does over longer periods of time. What happens in someone chronically infected for instance.
5- what does this tell us. Death rates took a dive. They fell off a cliff after the BA.1 wave. In our figure 4, this coincided with the peak of population immunity. It also coincides with the Omicron phenotype.
4-Here we have longitudinal datasets aligned with this figure. Population case loads with waste water. Death rates & vaccine doses (the US here as an example).
3- Figure 4. Is the one to look at. But let’s look at population immunity around this time with other datasets.
2- Around this time and throughout the pandemic we worked out a way to look at population immunity. A link to the work is here: pubmed.ncbi.nlm.nih.gov/39549677/
1- When Omicron arrived immunity was ramping across populations from vaccination. Delta at the time was well covered by early vaccines & subsequent appearance of severe disease/death was mitigated to some extent.
Potentially. Early ones were far more promiscuous in getting into cells and replicating. This was aided though by the fact we were immune naive & there was limited immune pressure. Population immunity now is very different & you could argue it shifted b/c of it.
27- On a final note, study of viruses following an "emergency phase" with them is important. It is hard to see current de-investment in efforts to do so. At a minimum, distilling down what we have learnt in our most recent pandemic is the best way to protect us from the next........
26- Yet viral transmission is the sum of parts. But what is clear is that the use of chaperone ACE2 in the current Omicron Spike conformation is one element that may contribute to this. Here we have found the third missing part.... the mechanistic role of a solute carrier in viral transmission.
25- Alternatively, to evade maturing immune responses of populations after large vaccine roll outs, the changes needed by the virus to navigate this immunity may have resulted in changes in the spike that came with the opportunity cost of using RAS-ACE2. Population immunity at this time was high.
24- Whilst maybe hard to prove, the emergence of omicron lineages may have been the consequence of a chronic infection in the gut. Here the virus would have adapted over time to a mix of immunity (presence of neutralising antibodies) and a large pool of Chaperone ACE2.
23- In humans it started as what we would refer to as promiscuous. With a immune naive population it could use RAS-ACE2 and Chaperone ACE2 freely to support latter TMPRSS2 use. Over time though it has dropped it use of RAS-ACE2+TMPRSS2 in favour of chaperone ACE2 and TMPRSS2.
22- So how did the virus get here and why? Early on I would hypothesise the virus was replicating in an animal and tissue that primarily may have had RAS-ACE2. Turns out the collectrin like domain where TMPRSS2 binds is highly conserved across many animals (e.g. Bats).
21- But is Chaperone ACE2 is only in the gut? Turns out another solute carrier SiT1 forms a similar complex with ACE2 in our respiratory tract. In addition SiT1 has been identified in large GWAS studies to increase susceptibility to SARS CoV-2 infections. www.nature.com/articles/s41...
20- What did this tell us? RAS-ACE2 negatively regulates TMPRSS2 cell surface activity. Expression of Chaperone ACE2 liberates TMPRSS2 from the ACE2-TMPRSS2 complex and in doing so rescues TMPRSS2 activity. Here Omicrons thrive as they depend on free TMPRRS2 activity for spread.
19- What was interesting though was that moving ACE2 away from TMPRSS2 was key here. Was ACE2 regulating TMPRSS2 activity? Here we took a TMPRSS2 substrate that can fluoresce when TMPRSS2 is active and placed it on RAS-ACE2 and Chaperone ACE2 + TMPRSS2 cells.
18- So what is going on here with TMPRSS2 and Omicrons? In brief, RAS-ACE2 can lock TMPRSS2 into a conformation that cannot be used by Omicron lineages. Here they cannot spread and are attenuated. In contrast this conformation can only sustain TMPRSS2 use by early pre-Omicron variants
17- With the use of the TMPRSS2 inhibitor Nafamostat we observed great TMPRSS2 use across all Omicrons when chaperone ACE2 was present and especially for more recent JN.1 lineages. Where RAS-ACE2 prevented TMPRSS2 use. Here we show this as a fold drop in titer with Nafamostat.
16- So this is what we saw overnight when mixing Chaperone ACE2 cells with nasopharyngeal swabs. The virus replicated rapidly and in a manner that was reminiscent of what we saw initially with Delta. What defined this for Delta was really good TMPRSS2 use.
15- Round after round of cell cloning, we eventually landed on cells clones with ACE2 and BoAt1 at the surface. Then we included TMPRSS2. So let's look at variants across the pandemic with what we call RAS-ACE2 and Chaperone ACE2 with TMPRSS2.
14- So is this the answer? How can we look at it? Turns out expressing a solute carriers like BoAT1 alongside ACE2 is a bit of a Goldilocks problem... Too much solute carrier and ACE2 never makes it to the cells surface. Too little and you basically have RAS-ACE2 with its neck exposed.
14- So is this the answer? How can we look at it? Turns out expressing a solute carriers like BoAT1 alongside ACE2 is a bit of a Goldilocks problem... Too much solute carrier and ACE2 never makes it to the cells surface. Too little and you basically have RAS-ACE2 with its neck exposed.
