🦠 Omicron - on a scale from 1-10, how bad is this going to be? This one's a weirdo, so I'm a 3, a 10, or anything in-between.
A thread below with my take on some of the key questions.
outbreak.info/situation-reports/omicron
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The key questions I'll address in descending order of confidence in currently available evidence:
1. Mutation profile
2. Emergence
3. Immune escape properties
4. Transmission fitness
5. Virulence
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1⃣ Gut feeling:
Timing: recent, deep roots (high confidence)
Emergence: animals (very low confidence)
Immune escape: significant (medium-high confidence)
Transmission: increased (low confidence)
Virulence: similar (low confidence)
Details 🧵👇
Before we start, please heed this advice from @EvolveDotZoo because it really is important to understand - there are so many different scenarios that can explain what we're observing.
So we can discuss "possible" scenarios, but not assign meaningful likelihoods yet.
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... and read this great article from @kakape on some of the early observations.
science.org/content/article/patience-crucial-why-we-won-t-know-weeks-how-dangerous-omicron
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2⃣ Mutation profile
Omicron has a lot of mutations - more so than previous VOCs. In the spike it has ~40 differences to the original Hu-1 virus (33 AA substitutions, 3 deletions, and 1 insertion).
You can compare Omicron to other VOCs here:
outbreak.info/compare-lineages
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The recently identified BANAL-52 virus only has ~20 differences to Hu-1 (16 AA substitutions + no furin cleavage site).
In nucleotide space, however, that switches - 61 for Omicron vs 206 for BANAL-52. Why the difference?
Selection:
twitter.com/sergeilkp/status/1465134289603858435?s=20
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Many of the mutations have been seen before in other VOCs, but others have not - and some are 'private' to Omicron (not seen in the larger SARSr-CoV phylogeny).
Interestingly, many of the mutations are basic R or K with a lot of N>K (pos: 440, 478, 547, 679, 764, 856, 969):
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So what are these mutations doing? We don't know - and remember, what really matters here is the combination of mutations and not any single mutation on its own.
Good article here:
nytimes.com/2021/11/29/health/omicron-covid-mutation-epistasis.html
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What is clear though, is that many of these mutations are on the surface of the spike, where, for example, they may be involved in:
- Optimization to human ACE2?
- Optimization to non-human ACE2?
- Alternative/additional receptor?
- Immune evasion?
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Compare the mutations seen in Omicron vs those in Delta - it's a big difference:
twitter.com/COGUK_ME/status/1465455990204252160?s=20
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Omicron also has two indels around position 631 that look to be the result of copy-choice recombination, potentially with host, not virus, origin. Recently described in this excellent study:
virological.org/t/putative-host-origins-of-rna-insertions-in-sars-cov-2-genomes/761
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3⃣ Emergence and reservoir
So where did Omicron come from? And when? We don't know... But let's take a look at some of the data and hypotheses. When it comes to age, we can answer two primary questions:
1. When did the lineage brach off?
2. How old is Omicron itself?
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It's clear that the lineage leading to Omicron is old - possibly mid-2020, but there's a huge amount of uncertainty in exactly when and where. We also don't know from what basal lineage this branched off and convergent evolution makes this tricky.
nextstrain.org/groups/neherlab/ncov/21K.Omicron
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For how long has Omicron been circulating in humans? We can estimate that based on the diversity in sampled genomes and most estimates land ~mid October (with wide uncertainty), so we believe it's relatively young.
Good thread from @trvrb here: twitter.com/trvrb/status/1464353224417325066?s=20
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We believe (a) the lineage leading to Omicron branched off a long time ago, (b) Omicron is young, but (c) is already widespread in parts of Africa. So what led to Omicron?
Three main hypotheses:
1. Undetected circulation
2. Immunocompromised patient(s)
3. Animal reservoir
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I don't believe #1 is likely, leaving evolution in immunocompromised patient(s) or a reverse zoonosis, followed by a new zoonosis (human>animal>human) as the two hypotheses I find most plausible - although I have no confidence in either.
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I slightly favor reverse zoonosis for a few reasons:
1. The lineage is old and undetected circulation in immunocompromised patient(s) for this long seems unlikely
2. SARS-CoV-2 is a generalist virus and we have seen human>animal>human transmission happen in e.g., mink
..
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3. Several of the mutations in Omicron have been observed in animals, including rodents:
virological.org/t/mutations-arising-in-sars-cov-2-spike-on-sustained-human-to-human-transmission-and-human-to-animal-passage/578/11
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Many articles have already concluded that Omicron came from an immunocompromised person ("HIV" is often mentioned), but I disagree with that conclusion. While that's certainly possible, we don't have any data showing that's the case.
Let's keep all hypotheses open.
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4⃣ How did Omicron become widespread so quickly?
We believe Omicron has increased rapidly in frequency for a few reasons:
1. It appears to be displacing Delta in South Africa
..
youtube.com/watch?v=Vh4XMueP1zQ&t=5s
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2. It's been observed in travel associated cases originating from multiple locations, including a single flight with ~10% of passengers being positive for COVID-19 (caveat - not yet clear if they were all Omicron):
washingtonpost.com/world/2021/11/27/amsterdam-omicron-covid-variant-lockdown/
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3. Cases are rising rapidly in places where Omicron seems to be dominating
twitter.com/Tuliodna/status/1463911554538160130?s=20
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Combine the rapid rise of Omicron with the observation from genetic data that it appears to be relatively young, what best explains that?
1. Increased immune evasion
2. Increased transmission
3. Combination of both
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Here's where it gets sketchy - because we really don't have any good data to make any firm conclusions on what/which factor(s) we think contribute the most.
Remember Oli's advice:
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The reason why we can't yet distinguish the two, is because a scenario in which Omicron has no immune escape, but is more transmissible can explain what we're observing. The same for a very 'escapy' VOC with the same (or lower) transmission.
twitter.com/trvrb/status/1465364300936085506?s=20
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This is the difference between estimating R0 (the basic reproductive number) vs Rt (the effective reproductive number, which is Rt = R0*x, where x = fraction of susceptible).
healthknowledge.org.uk/public-health-textbook/research-methods/1a-epidemiology/epidemic-theory
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Immunity will lower the fraction of susceptibles (x), leading to lower Rt. A more transmissible variant will increase R0, increasing Rt. But, Rt will also increase if a variant is capable of eroding immunity in the population - R0 stays the same, but x is now higher.
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Here lies the problem, because while we can reasonably estimate Rt, we don't know whether an increase is due to R0 being higher (e.g., increased transmission) or x being higher (e.g., increased immune evasion).
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... all of this is also ignoring other factors that influence Rt, including contact patterns, duration of infectiousness, NPI usage, etc.
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This means that a more transmissible variant with no difference in immune escape properties *or* a variant with no difference in transmissibility, but with more immune escape properties could explain available evidence.
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Good (technical) discussion from @C_Althaus on why it's so hard to distinguish the two: twitter.com/C_Althaus/status/1464922681585897478.
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Based on the mutations and early epi data, I expect Omicron will likely be more 'escapy' than previous VOCs, however, I don't know by how much and whether it may be combined with increased transmission. Maybe - and mutations in e.g., the FCS (K679, H681) may suggest as much.
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More on immune properties of Omicron from @jbloom_lab here: twitter.com/jbloom_lab/status/1464005676842184705?s=20.
Recent virological post with overview here: virological.org/t/report-on-omicron-spike-mutations-on-epitopes-and-immunological-epidemiological-kinetics-effects-from-literature/770
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To conclude this part, it's important to remember that variants may have a localized ability to compete, but much less so outside a certain environment - we saw this with Beta, which was competitive in South Africa, but couldn't compete with Alpha in most of the world.
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Keep a close eye on what happens to cases (and hospitalizations) over the next few weeks in places like South Africa, US (medium vax), UK (high vax), and Israel (high vax+boost):
ourworldindata.org/explorers/coronavirus-data-explorer?zoomToSelection=true&time=40..latest&facet=none&pickerSort=asc&pickerMetric=location&Metric=Confirmed+cases&Interval=7-day+rolling+average&Relative+to+Population=true&Align+outbreaks=true&country=USA~GBR~ISR~ZAF
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5⃣ Impact on virulence/severity
Now to the million dollar question - is disease severity any different with Omicron?
That's been speculated to be the case based on anecdotal reports, but we have no good data.
twitter.com/rjlessells/status/1464723163481354242?s=20
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It is *possible* that infection with Omicron may lead to a different clinical spectrum than previous variants, although for other VOCs we have observed that increased transmission typically also leads to increased virulence:
gov.uk/government/publications/investigation-of-sars-cov-2-variants-routine-variant-data-update#history
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However, even if it's true that previous VOCs had increased virulence, that correlation does not necessarily have to also hold up for Omicron.
There's no selection for virulence (decreased or increased - despite what many may want you to believe)...
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But there are plausible mechanisms in which increased transmission could lead to decreased virulence - e.g., a virus that becomes primarily an upper respiratory virus, as opposed to what we have observed so far with SARS-CoV-2 being both upper and lower.
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SARS1, SARS2, and NL63 (an aCoV) all use ACE2 as their receptor, yet SARS1 primarily leads to lower respiratory infections (severe disease, but limited transmission) while NL63 is primarily upper respiratory (limited disease, relatively high transmission).
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So is it possible Omicron could have evolved to primarily lead to upper respiratory infections with higher transmission and less disease?
Sure, it's possible - the increased transmission would quickly be selected for and the lower virulence would be a nice side effect.
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BUT, here's the kicker - I'm not convinced by those arguments and we don't have any current evidence that would suggest it being the case. However, it *is* possible IMO, I'm just not sure how plausible.
I feel seen... 🤪
twitter.com/TheMenacheryLab/status/1465143753820315651?s=20
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So for disease severity, we really have no good data at all.
For now, let's assume there's no difference and plan accordingly.
twitter.com/jburnmurdoch/status/1465659957546782725?s=20
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6⃣ Our repeated failures...
Now, let me reflect on a final point - why do we keep sucking so badly at our COVID-19 response? Bloody hell, we haven't learned a thing. And we're still making the same mistakes - exhibit #1:
twitter.com/Tuliodna/status/1465389873611915275?s=20
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Omicron has been detected in many countries and is likely widespread - travel bans, while they may delay things slightly, they're not going to help - quite the opposite.
twitter.com/arambaut/status/1465259225739935749?s=20
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Plus, if we're still resorting to travel bans to "delay things" by a few days, what the hell have we been doing over the past two years? Seriously.
Let's try again and maybe do it right this time - because, frankly, we're running out of time.
theguardian.com/commentisfree/2021/ov/28/scientists-sharing-omicron-date-were-heroic-lets-ensure-they-dont-regret-it
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Starting with fixing this problem - because what the hell are we doing exactly?
twitter.com/OurWorldInData/status/1463856209623142401
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Vaccine equity is *the* most pressing issue we're facing and we keep flunking it. Bad. Over and over and over again.
It's pathetic.
Omicron is a reminder to get this fixed - now. As in, months ago.
Mosoka wrote about it here:
nature.com/articles/d41586-021-01964-2
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Finally, a HUGE thank of gratitude to amazing scientists in South Africa, Botswana, and elsewhere for alerting us to the presence of Omicron, as they did Beta. Without their work we'd be in a much worse spot - so let's make sure this type of work is rewarded, not penalized.
fin/