Thread by @SGriffin_Lab

Much has been made of the following SAGE document, which has been reported in the media with a focus on some of the worst case scenarios within it. It has also been dismissed by some scientific commentators...notably not virologists.

Some thoughts...

assets.publishing.service.gov.uk/government/upl…

1. Clearly, this is not a press release! It is obviously a response to a broad-ranging brief designed to cover as many scenarios as possible. I'm genuinely surprised it has been released in this format.
2. Some suggest that this report is intended to stoke fear, I disagree.

As above, this has clearly been written to address a specific brief. There's nothing scientifically inaccurate in there whatsoever, each supposition is backed up by plausible rationale. However, whether something might happen, or will happen is usually a combination of humans and

luck...in this case, the bad variety. Oh, and viruses! The authors state numerous times that various eventualities are unlikely, BUT, there are precedents for many, and I'm not sure many people understand how lucky we've been so far with vaccines compared to some animal CoVs...

3. It's fair to say that the acquisition of another Spike protein, or part thereof, is unlikely, yet we've already seen reverse zoonotic events from e.g. mink. However, infection with more than one type of SARS2 is likely to be a relatively common event, and recombination has

been seen already, unless I'm mistaken (entirely possible!).
4. However, genetc drift in spike and other proteins is something we have all witnessed, with a striking degree of convergent evolution. So, even though the process of acquiring mutations in SARS2 is slow compared to eg

HCV, dengue etc, we've already experienced some formidable changes in the virus that present us with challenges...changes in spike can increase transmission or elude antibodies to an extent, sometimes both, but there are other changes in NS proteins that likely act vs innate

immunity and/or alter replication...this seems to constantly throw up new problems, to the extent that the denialists dismiss this as either a plot, or nothing to worry about...ignorance is bliss, I guess...
5. So why? How? CoVs are traditionally thought of slow mutators, not

least due to their proof reading element in the replicase and the density of essential regions of their genome. However, they also seem able to tolerate changes like deletions and truncations that would knacker other +RNA viruses...at least partly due to the structural plasticity

in proteins like spike...
6. However, the biggest driver of change is the sheer scale of the pandemic, combined with SARS2 still expanding to fill its shiny new human niche...and this has moulded, certainly more of late, by environment. By this, I mean the imposition of NPIs, and

OF COURSE our immune responses, elicited by vax and/or infection.
7. Now, I believe some comments on this doc, as well as following the @IndependentSage briefing last week are along the lines of vaccines causing variants, antivirals causing drug resistance, like it was a given.

Now, of course the virus is unlikely to evolve escape from one of these if it isn't there, but it's a question of deploying vax and/or drugs properly and quickly enough such that you stay ahead of any variants. For example, don't leave large swathes of your population unprotected

, don't give drugs as monotherapies, and don't provide an environment where R(t)>1 so any variant arising can expand...🤦‍♂️
8. This last point is just unbelievably frustrating because the VACCINES ARE REALLY VERY GOOD. Yet, for a reason I have still yet to accept is our reality, we

are allowing unmitigated spread amidst a population where just over half of us are fully vaxd. The vaccine has had a HUGE effect upon severe disease and also skewed the epidemic towards the younger groups...who says it's not good enough at preventing transmission?! Yes, room for

improvement, but cmon folks...
9. Cases may have dipped, they may well stay relatively low over summer, but if we fall short of vax targets by autumn, which is possible within certain age groups and non-white UK populations, there remains ample hosts for Delta to thrive. Yes,

ONS say 90% of adults have antibodies, but we know that both natural immunity and single vax is way less protective compared to the complete course. There's also the sizeable issue of 20-30% of our population not even being offered a vaccine, even though they can, for example,

work in public facing jobs amidst potentially high virus prevalence...alas SARS2 doesn't check ID...and I won't start on schools or #LongCovidKids as they require their own threads and I need to keep my BP reasonable...
10. So, from a virological perspective, the UK, despite our

brilliant vaccines, is starting to look like the training montage from one of the Rocky films, with Delta presumably wearing shorts with stars and stripes...too much?
11. I know what folks are going to say, we "need to learn" to live with (or near...or a short drive away) with

COVID...as we do with seasonal flu, RSV, HPIV etc...well, I understand that perspective, but I am troubled by this...
12. First, let me say that I in no way underestimate other resp viruses. My godson was hospitalised with RSV, a friend was in a coma with pH1N1...I also dabble in

the lab. BUT, it strikes me that we're not making the right comparison here, and if we want the possibilities discussed in the SAGE doc to remain just that, I worry that allowing SARS2 to keep crashing over us could spell trouble.
13. First, we have said COVID is not seasonal flu

and I hold to this in terms of pathogenesis, but also look at the change engine that will remain in play here for some years. We've already had half the Greek alphabet without really squeezing SARS2, in less than 18 months. Will it really play like flu and we'll be able to spot

variants in time to design (easy bit) make (much harder) and distribute (OK nationally, criminal globally), once a year? My view is that if we leave our population part vaxd and newer more difficult VOCs could arise more quickly, and with diverse geography...which of course will

be handled by our excellent quarantine system...🤪. A vax wall made of a hybrid vax/natural/no protection could also mean protecting vulnerable might not be enough - look at what happens when flu vax isn't quite right...
14. I also take issue with the idea of us "accepting" both

morbidity and mortality from flu etc. We don't, we invest in vaccines, we survey the planet, and all done on a shoestring due to cuts in public health, and yet the perception that flu is interchangeable with the common cold means that many simply don't take it seriously enough...

and that's seasonal flu...it's used as a benchmark by which we can supposedly afford to take a similar annual hit from COVID (in addition, of course)...my view is we should accept neither scenario.
15. So, back to the document. There will always be a risk of rare changes

happening, and they might well occur in low prevalence scenarios, possibly within immunocompromised patients etc. BUT, the one thing that makes any of the scenarios massively more likely is simply the huge number of infection events that may be allowed to take place amongst our

part-vaxed population.
16. This is something that we KNOW can be controlled using NPIs initially, and through vaccines in the longer term, supported by proper border policy and a functioning contact tracing body...unlike present call centres. I'm not talking about lockdown, I'm

talking about avoiding them, but we're not ready to open the flood gates just yet. We must, in my view, take full advantage of current vaccines and get ahead of this virus, this is the race we should be running now imo, rather than accepting a permanent cycle based on the flu

model...we have never dealt with a coronavirus pandemic, I think it's a mistake to presume it will merely adopt a flu like pattern whilst prevalence remains high.
17. We should also invest more in direct antivirals, not just repurposing stuff we dust off the shelves fro HCV, but

following Pfizer protease, molnupiravir, etc...it CAN be done, and we'll need more than one...
18. So, please don't think I'm forecasting disaster, I'm trying to make a point similar to the doc - there are many possibilities with this virus, we have an edge, we should use it now

19. To allow mass infection in the presence of a highly selective environment tips the balance back towards SARS2 in the longer term, unless we can achieve a meaningful population immunity - I'm worried that current strategy will result in a de facto GBD by vaccination, which

just won't work...
20. Last point, and a personal one. Yes, we're sick of restrictions, yes vax is the way forward, but to move forward in a way that endangers those most vulnerable in our country and also risks profound morbidity, when we have the means not to, frankly just

appalls me. We're in a ridiculous state due to a litany of failed policies that have had us yo-yo in and out of extreme restrictions with dire death and suffering. That does not give us permission to move forward, assuming "most folks" are fine. Underestimate SARS2 at our peril.