Omicron Variant Post #2

It’s now been three days since Post #1. The situation is evolving rapidly, so it’s time to check in. What have we learned since then? How should we update our beliefs and world models? There will inevitably be mistakes as we move quickly under uncertainty, but that’s no reason not to do the best we can.

Update Update

What should we look for here and in the coming days?

  1. No news is good news.Omicron is scary because many scary things are possible. The worse things are going to get, the sooner they will make themselves known. When we get news that something has happened, especially news that isn’t the result of a lab or statistical analysis, that will typically be bad news, but we expect a certain rate of such bad news. If we get less than expected, that’s good news.
  2. The pattern of where and how we find cases, and the details of those cases, will give us better insight into how widely and quickly, and in which directions, Omicron has spread. This will tell us how far along things are, and give a better estimate and narrower range of how infectious Omicron can realistically be.
  3. Information on how deadly Omicron is should update us quickly, and matters a ton for how to react, but beware of confounding factors, motivated statements and misunderstandings in both directions, and small sample sizes. Hospitalizations are not a natural category and at this stage deaths will be rare unless things are much worse than we expect. How mild the cases we find are will largely depend on how we are testing. Details matter.
  4. The reaction of various countries, the stock market and others will continue to tell us what they think is going on, what they expect to happen next, and how they respond when such things happen. The general vibe of elite and media messaging also reveals much information, with a focus on what kinds of actions they will try to engineer rather than the ‘facts on the ground.’
  5. Information on immune erosion will come from results from laboratory analysis and other looks at Omicron’s mutations, and other physical detail information, such as testing antibodies, and from statistics on who gets infected or sick once we have enough cases for that to mean something. It also comes from knowing how infectious Omicron is, since if we know how fast it’s spreading and we know how fast it spreads to the immunologically naive, we also then know how immune erosive it is because math. The vaccine reactions will also tell the story – we should expect manufacturers to react to the situation based on what they know, and to some extent governments as well.
  6. A lot of updating is having time to think, and integrate others who also have time to think. There doesn’t need to be new information for our estimates to improve.

It’s been announced that new versions of the vaccines are indeed coming, as they no longer expect the old ones to be fully effective, and are talking about a few months to get the new versions online.

Noah Smith gives his overview of the situation here. It provides a lot of the same links, some good new links, a set of views broadly similar to mine, and is generally reasonable. I do disagree with the conclusion, in that I think on the margin the most valuable focus is now testing and treatment, with further vaccinations vital but not primary. Ramping up vaccine production capacity is still a fantastic idea. I will also be checking out his list of Covid experts on Twitter. A lot of them are not people I am already following.

Here is Weekend Editor, author of many helpful comments and overviews, offering their best take, broadly compatible with mine, including an addendum right at press time. An especially worthwhile note there via Your Local Epidemiologist:

Boosters not only raise the number of antibodies, but also the diversity of antibodies to various spots on the spike protein. [11] So it’s important to get a booster once you’re eligible: you not only get short- to intermediate-term increased immunity from antibodies, you also get long-term increased immunity because your antibodies check more carefully for mutations in the spike protein, giving broader immunity to variants. That’s in addtion to antibody maturation, where your immune system refines the antibodies over time to get better and better; your memory B-cells are busy.

This set of slides is mostly a good summary with some exceptions, such as (in the mind of my instinct viewer) incorrectly associating the current winter wave of Delta with the emergence of Omicron, when they are two completely distinct things.

Immune Erosion and Transmissibility

Here is the WHO announcement on what we know, in which they reiterate all the things they would have said last week but deny that it’s possible to know things under uncertainty:

Image

An article on Stat News is a reasonable summary, and adds one key bit of information I hadn’t seen at the time:

The WHO said Saturday that early evidence indicated the variant was causing reinfections at higher rates than other variants in South Africa, suggesting some ability to get around the immune response.

As a reminder, when the majority of people in your country are not vaccinated, this kind of observation very much isn’t news:

Joe Phaahla, South Africa’s health minister, said Friday that breakthrough infections were occurring in the country, but the majority of hospital admissions remained among people who were not vaccinated, suggesting that vaccines were still maintaining some level of protection against Omicron. But, he acknowledged, “it’s still early days in terms of this particular variant.”

It’s possible that this is uncharitable and he was making a more meaningful observation, but he’s not claiming to have done so here.

Science offers a similar article, of the ‘this is scary but we don’t know anything for sure yet’ variety, emphasizing that the rate of growth combined with the mutations are the reason we are so concerned at this early stage, but that the growth rate could mostly be a coincidence.

Here’s a similar thread of a lot of ‘we don’t know’ strung together. It’s good to caution against overconfidence, but also important not to respond to uncertainty with only ‘we don’t know.’

Here is a thread from Christian Althaus asking what we can say about Omicron’s potential advantages.

This is 0.38 to 0.43 advantage per day. That’s a gigantic transmission advantage if anything like it holds up. Definitely well over 100% advantage the way it’s typically measured.

I am skeptical of ‘almost everyone.’ I can believe an IFR of 0.35% on its own, but some numbers: 89k confirmed deaths in South Africa out of 2.95mm confirmed cases, overall population 59.31mm. If almost everyone is infected then we’re talking about missing >90% of all cases, and about half of all deaths, and the IFR remaining 0.35%, excluding reinfections, at that level of care. Still, I am willing to buy that we’re missing a large majority of infections.

The WHO is saying that it looks like Omicron is ‘causing reinfections at higher rates’ but if almost everyone has already been infected in South Africa, then that’s not the observation it sounds like it is. It’s instead a statement that those previously diagnosed are getting infected more often than those who previously had milder cases that went undiagnosed, which is very different in its implications. It also seems like evidence that South Africa hasn’t mostly already been infected.

I like how this points out the relationships involved and how different numbers need to relate to each other. Those relations don’t change that much based on the share that had immunity, so long as that share was ‘large.’ It does emphasize that there’s too many free variables, and for now we can’t draw conclusions off an analysis like this, only constrain the set of possible worlds.

Several people pointed me to this Times of India report:

That would be the best case scenario. If Omicron only results in mild infections, we should welcome our new Omicron overlords as opposed to imposing new restrictions. However, it’s way too early for that, and the cohorts involved seem like they were younger and healthier. Here’s what I believe is another take on the same statement, from Haaratz:

According to the report, omicron patients tended to be younger, and the variant was not found as often among the older population. Those infected with the variant mainly experienced fatigue and body aches. Still, it is still unknown what effect infection has on the older adults with underlying medical conditions such as diabetes or heart disease.

Prof. Dror Mevorach, head of the coronavirus department at Hadassah University Hospital Ein Karem, said the preliminary reports on the clinical condition of people infected with the new variant are encouraging. “If it continues this way, this might be a relatively mild illness compared to the delta variant, and paradoxically, if it takes over, it will lead to lower infection rates,” and it will be easier to deal with globally.

Here’s another report, this time from the Telegraph. Once again, cohort young and healthy, but symptoms more mild than would have been expected given that.

Here’s a thread emphasizing that we can presume vaccines will continue to work against severe disease in Omicron.

Goldman Sacks endorses that the vaccines will keep working, does not recommend portfolio changes.

Travel Restrictions

Inevitably we are seeing a lot of this:

All-or-nothing arguments continue to be depressingly common. Either the vaccinations ‘prevent infection’ or they don’t, either something is safe or it isn’t, and so on.

As I noted last time, travel restrictions have zero chance of stopping Omicron, but they will be effective at slowing down Omicron so long as there is a large asymmetry in Omicron’s presence in different areas. I do think the time will come relatively soon when the restrictions stop accomplishing anything, but that time is not today.

This makes both ends of that even clearer, that it is both too late, and vital to slowing down spread if that is something you value:

I do think it is important to show our support for South Africa, its testing and its openness. They did a heroic job and right now it’s being effectively punished. What we don’t want to do is make that reward ‘lift the restrictions,’ we want to send them other forms of aid instead, both direct help and cash and hopefully better trade and other relations, which together leaves everyone better off.

So strongly agree with this:

Meanwhile, mainstream sources say things like this with straight faces.

Yeah, travel bans are one thing but it is really really not too soon to cancel your own trip.

Merlin recommends that travelers have a back up plan, suggesting trip stacking as a potential strategy. He said travelers should follow the news closely for updates on the omicron variant and resulting restrictions — not just for Africa but for parts of the world experiencing coronavirus surges, like Europe.

I am no travel expert but your backup plan right now should very much be ‘stay home for a while’ or at least something not international.

Vaccinations and Boosters

If you’re worried your booster shot is interfering with other people’s access to the vaccines, or with ‘vaccine equity,’ please stop. You’re not doing that, except to the extent you having less and someone else not getting more means more ‘equity.’ Link to article Alex links to. South Africa in particular has a surplus, the same as we do.

If there is a new Omicron vaccine, there will once again be scarcity, but right now the bottleneck is distribution and not supply. If you’re not taking up scarce distribution, go for it.

Lockdowns

Be very afraid of this attitude.

Americans need to be prepared to do “anything and everything” to fight the omicron Covid variant, U.S. infectious disease expert Dr. Anthony Fauci said Sunday.

Still, it’s “too early to say” whether lockdowns or new mandates will be appropriate, Fauci said on ABC’s “This Week.”

Anything and everything is an appropriate response to an existential threat. I still have some probability mass in Omicron being deadlier than Delta, but almost none that it is sufficiently deadly that ‘anything and everything’ would make any sense. That kind of rhetoric is laying the foundation for very poor trade-offs whose advocates are not doing any sort of cost-benefit analysis. It’s important to be ready to push back.

Similarly, notice rhetoric where lockdowns are punishments for non-compliant populations who have sinned against public health, rather than a tool to accomplish a goal. Here’s CNN, note the headline about ‘the virus is in control’ framing the situation as being about who is in charge and who is or isn’t following orders properly:

The new Omicron variant might prompt a return to stricter Covid-19 measures if not enough people get vaccinated or boosted, health experts say.

“It ought to redouble our efforts to use the tools that we have, which are vaccinations and boosters — and to be sure we’re getting those to the rest of the world, too,” Collins told CNN on Sunday.

“It also means we need to pay attention to those mitigation strategies that people are just really sick of, like wearing masks when you’re indoors with other people who might not be vaccinated, and keeping that social distance,” he said.

“I think we may, indeed, be in for a phase of many more masks, much more social distancing, and more restrictions and obligations for vaccination going forward,” Schaffner said.

That doesn’t mean there are no scenarios where a very short term lockdown would pass a cost-benefit test to ‘flatten the curve’ or buy time for treatment supplies, but the bar on that is high and the chance of an appropriately timed response is low. Locking down or taking other extreme measures too early is quite bad, as is maintaining lockdown for too long, and conditional on lockdown I expect both.

The scariest signs are coming here in New York, where I am worried I am going to start missing Andrew Cuomo and I do not even slightly miss Andrew Cuomo.

Kathy Hochul has no idea how exponential growth works. Clearing hospital capacity now and stopping elective surgery now is exactly the opposite of any reasonable procedure. Even in the worst case scenarios, Omicron won’t have much impact on case numbers for several weeks. After that, however long we have, we will need all the capacity we can get. The time to get other stuff out of the way is now.

The Timeline

Once again, I’ll use BNO’s important Omicron-related headlines in chronological order to tell the story. Here’s a link to BNO’s patreon, if you’d like to help them out.

Once again, a reminder that the majority of South Africans are unvaccinated.

That last one slightly out of order, happened after the next two updates. The positive test rate went down somewhat but held at 10%, much higher than the positive test rate in South Africa according to Our World In Data. Travelers presumably are exposed more than non travelers, but still, especially since in SA who gets tested in based largely on who has symptoms.

It seems clear that a substantial percentage of those who fly out of South Africa are infected with Omicron, and this was mostly true the day before they started checking.

This is the kind of half-measure that will slow things down a little but isn’t pretending to want to fully work.

I am curious about the details of this.

Boom. As I noted last time, this is the only policy with any chance of fully working.

I wonder what will happen when we check travelers that aren’t coming from Africa?

What’s weird is that it was listed as probable above?

Situation in South Africa continues to escalate super quickly, after we all started panicking so it’s out-of-sample data.

Well, ****. Presumably they found it first because they were looking.

Morocco is an unexpected twist. Maybe worth keeping an eye on them.

The positivity rate continues to rise, so fall in case count presumably is about lack of testing on weekends.

This is covered earlier. A lot of ‘no evidence’ talk, since it’s WHO, but at least not actively getting in the way.

The border closing order has a lot more to do with geography, trade and culture than suspending some flights. The contrast is interesting.

That last one is interesting. Going to hold off updating much on it yet, but if true then why didn’t background sequencing pick anything up?

Other New Information

There is some worry that Rapid Antigen Tests might not work on Omicron based on the sequence, but it looks like they will continue to work. Presumably ‘run actual tests and see what happens’ is the way to find out, looks like we found out.

Early sign of political reactions that were inevitable, but whose magnitude is not.

Some amount of this is inevitable and also necessary. There are those who really would have us in permanent midnight, and there’s a chance they will win, and they would happily use variants to make that happen regardless of whether it is appropriate.

Current Model

Chance that Omicron has a 100% or bigger transmission advantage in practice versus Delta: 30% → 35%.

Omicron is spreading at an alarming rate, but my confusion about what claims were being made is gone, and this is a huge transmission advantage. The counterargument is that we are seeing a lot of Omicron in a lot of places, in large numbers, very quickly, and that an advantage in Africa need not translate to a similar advantage elsewhere and we’re asking here about the advantage that will hold in the United States, but also there’s probably immune erosion which will matter more here than it does there. Given that this is ‘in practice’ which incorporates immune erosion, I’d say I’m slightly more concerned on net.

Chance that Omicron will displace Delta: 70% → 80%.

The spread and cases we are seeing clearly indicates that Omicron is spreading fast, but there have been previous variants that have taken over in some places and failed to take over other places, so that’s still on the table as well. The pattern of cases we are seeing implies that Omicron is already in a lot of places, but it will take a while to be confident. Still, given my estimate of how likely it is to be immune evasive, it seems like I should be moving up my chance it eventually displaces Delta if no other variant emerges first.

Note that this probability is conditional on no other variant emerging first, and that a bunch of this probability involves a slow rather than fast transition, depending on the size of the transmission advantage.

Chance that Omicron is importantly more virulent than Delta: 25% → 10%.

Chance that Omicron is importantly less virulent than Delta: ?% → 40%

We’re seeing early reports that Omicron might be less virulent than Delta rather than more. It didn’t come directly from Delta, and also we’re seeing cases show up that came from various different countries without it already having been detected, which is also evidence for it being potentially less virulent. Even more than that, it seems like evidence against it being more virulent.

Also Zeynep points out explicitly a point that’s easy to miss, which is that being immune erosive will lower average severity because breakthrough cases are less severe, so Omicron will probably look less virulent even if it isn’t.

I still think the baseline scenario is that this is similar to Delta until we hear more, but the signs are promising.

Chance that Omicron is importantly immune erosive, reducing effectiveness of vaccines and natural immunity: 50% → 80%.

This is looking likely, both in terms of what we’re learning and as I get a better understanding of what our information means. The monoclonal antibodies look like they will no longer work, new versions of the vaccines are likely coming. It’s still early and I don’t want to get too overconfident, but yeah, this is probably happening.

Chance that Omicron means the vaccinated and previously infected are no longer effectively protected against severe disease until they get an Omicron-targeted booster shot: 5% → 4%.

Immune erosion against infection makes me more worried, but as far as I can tell that is fully consistent with protection against severe disease holding up fine. Every biological analysis and expert sees no reason to doubt that protection against severe disease will hold up.

The focus on more vaccinations now is additional evidence in favor of them holding up against severe disease, to the extent that it would vary based on the physical situation. If there were more serious doubts, I would have expected to start seeing much more loud calls for considering rushing the new versions of the vaccines and of considering holding off on additional vaccinations. That could be me still being naïve, though, so I’m holding onto some model uncertainty.

Chance we will be getting boosters modified for Omicron within 6 months of our previous booster shot: 15% → 30%.

They look like they are going to make Omicron booster shots, so the question is whether those already boosted will still be told to get them. Note that I consider this ‘the authorities tell you to get a second booster this quickly’ rather than ‘I personally choose to get one this quickly.’

Chance that Omicron is less vulnerable to non-antibody treatments like Paxlovid or Fluvoxamine: 5% → 3%.

No one seems to be worried about this or have any biological basis for it, and no news is good news, so I’m going down further, but I have too much model uncertainty to go lower faster than this.

Chance we are broadly looking at a future crisis situation with widely overwhelmed American hospitals, new large American lockdowns and things like that: 20% → 15%.

There’s been explicit threats and even some current emergency measures, which raises the chance that there will be large lockdowns whether or not they make any sense. In the other direction, the chance that this will be a deadlier variant has gone down and the chance it is less deadly has gone up. If we do get that kind of scenario, it’s going to be much harder to justify extreme measures, and they would face more resistance. Also, the really really bad scenarios are generally less likely due to no news being good news, and I’ve had time to think, so I’m a little lower here.

Final Thoughts

The last few days have made it more likely that Omicron is real and is coming, although it is still too early to know for sure. They have made it more likely that immune erosion is largely responsible for Omicron’s spread, as opposed to spreading more among those who haven’t been infected or vaccinated. That’s the bad news.

The good news is that it’s more likely Omicron is milder, and less likely that Omicron is more severe. And we’ve reinforced that most of our treatments still work, and that vaccine protection against severe disease should hold. We’re not going back to square one.

As an individual, the situation has not changed much. Be prepared for what might happen, and get ready to be more prepared as we learn more. If possible, get boosted. If you have things to do, do them now, while you still can, rather than prematurely locking down and doing less too early. That would only backfire.

What are the most important things to do now more broadly?

More vaccinations and booster shots help, but I believe what matters most will be our ability to:

  1. Manufacture as much Paxlovid as possible as quickly as possible.
  2. Get testing that will allow those with symptoms to get tested and found reliably and quickly. We still haven’t fixed this. FIX IT!
  3. Get a distribution system ready that’s either better than or similar to the ones that exist in some states, to ensure that those who need Paxlovid and other treatments can get them quickly, without taking up too many system resources, while they will still work. If this is the kind of emergency it seems to be, once supply is adequate, you should be able to walk into a pharmacy with a Covid test you bought there, and walk out with Paxlovid, or do something damn near that. Again, FIX IT.

I will continue to monitor developments, and bring additional updates when it seems appropriate to do so.

Once again, I emphasize that I’m doing the best I can under uncertainty in a rapidly developing situation. I will make mistakes, including mistakes of thinking, and I definitely will miss important information.

I’m not looking to make any actual wagers, but I’d encourage those who have thought about things enough to have probability estimates to leave comments where you give your own current probability estimates, and explain ways in which your reasoning on them differs from mine.

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42 Responses to Omicron Variant Post #2

  1. AnonCo says:

    Thanks for moving to more frequent updates on this instead of waiting until Thursday!

    An administrative note for you: Since you are writing in the substack editor and copying over, all of the images are hosted on the substack CDN (see the URL of any image in this post).

    This is working fine, but is a big risk for your WP own-your-data backup strategy here.

    1. If they ever disallow hotlinking, all the images in these posts will be gone. (Given that hotlinking images costs them real money, this seems possible.)

    2. If you were to ever leave substack and close your account (or they banned you), all of the images in these posts will be gone.

    Just thought you would want to know

    • TheZvi says:

      Oh, wow, thank you for that note, I did not realize. I will need to think about what to do about that. Does anyone have any suggestions? I’d like to continue using the SS editor if I can.

      I don’t think they’d ever cut off hotlinking since I make them a non-zero amount of money.

  2. Craken says:

    Peru, with a median age of 29, had an excess mortality in the Covid period of 0.6% of the population. This leads me to question the suggested IFR of 0.35% for S Africa (median age 28). Another way: 8% of S Africans are >60, 9.2% of Peruvians are >60. Maybe early medical mismanagement or poor health in Peru explains it, but I have my doubts. I’d guess 60% previously infected in S Africa. Add another 15% who have pure vaccine immunity. America has a different mix of immune defenses.

    It looks like Indonesia has missed 85% of cases, Peru and India well over 90% of cases, America 65%. A 90% miss rate in S Africa shouldn’t surprise much.

    I had thought that if it’s immune erosive, it’s likely to be more virulent for those with natural/induced immune protection. But, now I see how it could be more infective only, without also being more virulent. Still, vaccines currently cut mortality about 90%. Would it really take much efficacy slippage to reduce that to 80%? And thereby double their mortality? Also, if there is a much higher infection rate and no change in the IFR, the number of hospitalized/dead will increase in proportion to the number of infections. The new meds ought to change the IFR drastically. If the transmission advantage over Delta is large, the number of cases could exceed previous highs.

    On Omicron’s transmissibility advantage over Delta: we have reasonably good numbers only from one part of S Africa, a poor urban area. Even those numbers are too small and short of duration to have much confidence in. If we take the numbers produced there at face value we get an R0 of ~20. Delta is about 6. Measles, the most infectious known human virus, runs at ~15. I do not believe (<5% chance) that the immune naive will face an R0 of 20 from Omicron. It's more credible (10% chance) that Omicron might triple infectivity among those who have some immune defense.

  3. sniffnoy says:

    I really have to wonder about this possibility that omicron is less severe. Like, it’s more transmissible; generally we should expect that also means it’s more severe, right? On the basis that inducing symptoms is typically a key part of how a virus spreads. But I guess we’ll see as more numbers come in…

    • lunashields says:

      Measles is not more severe than smallpox…

      • sniffnoy says:

        No, but measles and smallpox are not closely related, so they’re all going to be working by different mechanisms. For closely related diseases, there’s more reason to expect this.

      • lunashields says:

        Still, considering increased virulence due to change in spike protein, it’s almost like a different disease. Say increased affinity to nose lining and decreased for the rest of the body, will make a highly transmissible common cold out of it.

  4. A nitpick: Haaratz –> Haaretz.

    Re the Haaretz, Times of India, and Telegraph reports: I’ve been hearing that the “Omicron causes mild illness” theory might be a fluke, due to reports coming in of mostly younger patients, who have milder illness anyway. I’m not certain they’ve properly conditioned the severity of disease on the age cohort of patients (though I’d love it to be true that they did, and “our new Omicron overlords” turned out to be gentler!). Not to worry; somebody will check on this and we’ll know in a couple days.

    Re Althaus: I really liked Althaus’s fiddling about with Ω (fraction of population with immunity) to demonstrate you get radically different outputs depending on how you vary Ω. Most people don’t think to do a sensitivity analysis like that, and end up working on ill-posed problems. Good on him.

    Re “Well, ****. Presumably they found it first because they were looking”: Remember when Trump said the case rate in the US was too high because we tested too much? Trump is, of course, an idiot. But it seems the Israelis are very smart here. It just amuses me for some obscure reason that both cases are because of “a lot of testing”. Wish we did more testing, more easily, more cheaply, more quickly, and more routinely in the US.

    Re Japan border closure: My spouse is Japanese, so I have some small degree of personal experience there. Yes, there are — as you point out — some cultural issues with Japanese having a very distinct identity. But really, the border closure is because they’re scared. That’s pretty much a direct quote from members of the Japanese side of my family. If you look at their case rate per capita, it’s dramatically smaller than their neighbors and they’d really, really like to keep it that way. So the border closure – even though it keeps me away from an Oshōgatsu celebration – is understandable. (It still won’t work in the long run, but you can at least understand what they’re thinking.)

    Re monoclonal antibodies: While it’s possible monoclonal antibodies like Regeneron or the GSK/Vir infusions might have less efficacy vs Omicron, it’s important to remember that vaccine-induced antibodies your immune system makes are polyclonal. That is, they bind to various sites on the spike protein. It’s very hard for the spike protein to mutate so much that it can repel all the polyclonal antibodies, while still binding very tightly to the ACE2 receptor. So just because the artificial monoclonals work less well, there’s no reason to conclude that your endogenous antibodies will work less well (or at least not all of them).

    I won’t try to figure out my personal estimates of your probabilities, but 2 of them sort of spoke to me:

    Chance we will be getting boosters modified for Omicron within 6 months of our previous booster shot: I’d go with about 50% here. It’s doable, it will probably be awesomely effective, and prevention is always better than treatment. Also, it’s already in progress at both Pfizer and Moderna, so there’s not much inertia. And the FDA has said they’ll consider them with an accelerated process, about like annual flu vaccines. So the skids are kinda greased here.

    Chance that Omicron is less vulnerable to non-antibody treatments like Paxlovid or Fluvoxamine: I think I’m here with you at about 4-5%. I’d include molnupiravir, BTW. And as a former drug synergy guy, I’m eager to see somebody do a trial of combination therapy with these three drugs. Their mechanisms of action are completely disjoint from each other, and none seem to depend in any way on spike protein mutations. It really looks like an obvious good thing to do.

    Re molnupiravir and paxlovid: The FDA’s AMBAC committee meets tomorrow to decide whether to recommend molnupiravir be approved or EUA’d. Then the FDA has to act on that. Then the CDC has to get their committee to meet, then CDC has to act on that. Four steps in that pipeline to availability. Paxlovid will come up in early December, but the same 4-stage pipeline will have to be gone through.

    While I appreciate your enthusiasm to get lots of paxlovid manufactured, here’s where I’m going to go all grizzled old drug nerd on you. The way things might really work is:

    (1) All those committee meetings for molnupiravir and paxlovid have to happen now, as in: “Biden is waiting outside the room impatiently, and you can’t come out until you’ve reached a decision on both drugs”. No pressure on which way to decide, but extreme pressure to decide immediately.

    (2) The Feds should promise to buy N million doses, cash payment now, whether approved or not. That will goose the manufacturing process. I am given to understand this has already happened?

    (3) There needs to be a plan for distribution: shipping to warehouses all over the country, and indeed all over the world. More parochially, there needs to be CDC endorsement of prescription of molnupiravir, paxlovid, and fluvoxamine so that every drug store pharmacist can prescribe it upon seeing a positive test result. That would smooth the rocky path many people face in getting a doctor to pay attention to them, and allow your scenario: walk into a drug store, get a test, and walking out with paxlovid if it’s positive. Alas, I have little hope this will happen: too many veto points, and too many people either invested in the system as it is or afraid it will lead to abuse. It would be lovely to be wrong about this.

    (4) In the meantime, some highly visible federal official like maybe Biden himself needs to crack the whip over test availability, since the new anti-virals have to be given within 3-5 days of symptoms. Test kits should be widely available, cheap (or even free to the consumer), and fast reporting. I want to be able to walk to my corner drug store, get a test, show that to a pharmacist along with my insurance, and walk out with paxlovid. I will probably not get what I want.

    • TheZvi says:

      Great stuff. Might be good to split up into multiple comments in similar spots in future, to make it easier to discuss things.

      On milder case reports: Yep, have heard that, think I discussed it explicitly, along with ‘it’s milder because they’re reinfections/breakthroughs.’ As you say, we’ll know soon. I might have been a tad too high on the chance this is happening.

      Japan: As well they should be given their population, at least relative to others. I would have done the same thing, at least for a few days, if I felt I could lift it when I wanted to.

      Omicron booster: Not worried about original sin here? Or supply concerns? Also I notice a lot of people don’t believe the FDA will actually expedite reasonably, no matter what they’ve said.

      I’d probably include molnupiravir if they hadn’t made it so hard to spell, fair point that I shouldn’t let that actually stop me.

      Your scenarios on the drugs seem like they have better / more concrete detail, but are broadly what I imagined on all that. #2 has happened, but only for 10mm treatments, and if we want to survive Omicron’s scary scenario we could easily need 100+mm treatments for America alone, plus the rest of the world needs it too.

      The ‘afraid of abuse’ people – what are they afraid of exactly aside from wasting supply? If someone takes Paxlovid when they shouldn’t, I mean it’s not the safest thing but it’s not like it gets you high or something, not really a thing people will be taking a ton of without a good reason, I’d think.

      • Omicron booster: Not worried about original sin here? Or supply concerns? Also I notice a lot of people don’t believe the FDA will actually expedite reasonably, no matter what they’ve said.

        I’m laughing at ‘original sin’; thanks for the little joke.

        I assume you meant something like: since we screwed up the original vaccine rollout, why should we believe we won’t screw up the Omicron booster? Yes, that could of course happen. But on the other hand, the current round of boosters doesn’t seem terribly screwed up. Both of us just walked into a drug store, asked politely, showed our insurance and vax cards, and had a shot within minutes.

        We can learn, despite strenuous efforts to avoid doing so.

        If you meant something else, you’ll have to hammer it into my skull a bit harder.

        I’d probably include molnupiravir if they hadn’t made it so hard to spell, fair point that I shouldn’t let that actually stop me.

        Laughing again. That’s the way to do it: I knew I could get you to make fun of pharma-chosen drug names!

        The ‘afraid of abuse’ people – what are they afraid of exactly aside from wasting supply?

        Ok, fair point: I haven’t actually gone and interviewed any old colleagues who might be in a position to make that decision, I just guessed. But, fair enough: you called me on it.

        I think there would be 2 sorts of objections:

        (1) Fluvoxamine is well understood, so no objection there, or at least not much beyond some pro forma harrumphing mostly from psychiatrists. But the side-effects of molnupiravir and paxlovid haven’t been studied yet beyond the clinical trial, and not including people who might stupidly overdose themselves.

        So handing them out to the general public (without a PCP to supervise) is taking a risk that people will take the wrong dose (e.g., all 5 days at once; I’ve seen stupider things that I could tell stories about), or mix with something else, or… just imagine all the things that could go wrong.

        (2) Having established a precedent of making these drugs easily available via an end-run around the patient’s PCP, there will be inordinate pressure to do the same again later for other drugs, even in non-emergency situations. That’s a headache they’d probably want to avoid.

        Also, doing this might require regulatory approval. There’s a nonzero chance that there is somewhere a regulation that says you can’t do this, and it would have to be changed.

        Now personally, I think the benefits of fast, cheap, and wide availability of all 3 drugs outweighs both of those objections. “Just imagine all the things that could go wrong” is outweighed by imagining all the lives that could be saved. (Yeah I know: “whoever saves a single life is considered to have saved the whole world”. That’s sort of a big thing with me.)

        But I know plenty of people who would disagree enough to fight about it.

      • TheZvi says:

        All I hear are advantages to this route! Oh no, no one pressure anyone to make drugs that could help people more easily available to them, that would be terrible. But this does make it more clear – ‘afraid of things getting messed up’ is at least a real thing, as opposed to ‘abuse’ which is a huh?

        Sounds like objections that work in non-emergency situations and get overriden in true emergencies, but the question is what threshold is good enough.

        Original sin I meant original antigenic sin, as people are calling it, the idea that the booster might only retrigger the old reaction rather than generating a new one, so changing it wouldn’t help you? That’s a concern being expressed.

      • I see: I meant ‘abuse’ as in the system might get abused in various ways, not that molnupiravir or paxlovid would themselves be abused in the sense of street drugs. I should have chosen a better phrase, like “this will cause future drug application submittors to push us in ways we don’t want to be pushed”.

        And now that you mention original antigenic sin (abbreviated OAS): ok, fair point. No, I haven’t been particularly worried about that. But now that I think on it, I don’t have a good reason to ignore it. The relevant paper seems to be:

        EL Brown & HT Essigmann, “Original Antigenic Sin: the Downside of Immunological Memory and Implications for COVID-19”, mSphere 6:2, 2021-Mar-10. DOI: 10.1128/mSphere.00056-21.

        So that’s on my stack to think about. Thanks.

      • Triskele says:

        @WeekendEditor Yeah this is why one never listens to the one year old immunology expert (such as myself). But, Statnews discusses the issue shortly after the original OAS paper…

        https://www.statnews.com/2021/04/16/next-generation-covid-19-vaccines-are-supposed-to-be-better-some-experts-worry-they-could-be-worse/

        …with no definite conclusions. But, I had thought previously that “well, it’s not like it’s only vaccine related immunity that is on the table here”, and sure enough they talk about people with natural immunity as possibly subject to the same effect, maybe to a greater degree than vaccine-mediated immunity(!), but, nobody concluded for sure how this could shake out.

      • Brett Bellmore says:

        Triskele:

        Well, after all, it’s all natural immunity, until they can shoot you full of nanites that hunt the pathogen themselves. The vaccines are only different in the sense of presenting your immune system with a different combination of antigens.

    • Triskele says:

      “antigenic sin” is something I hadn’t heard about before a couple months ago (like much else immunological related). I haven’t seen anybody else besides Berenson et al talk about it, but is there someone with more than a year’s worth of knowledge of immunology who’s talked about this in the context of covid, who is more helpful? (or can jump in here?)

  5. Awsum says:

    Is Omicrom deadly? Has this been proven? I’m not sure it has, yet you describe it Omicron as deadly.

    • jp1 says:

      Yes, Omicron is deadly. We are looking for confidence in a probability, not proof. Look at the occurrences of the word in the post:

      “how deadly”
      “sufficiently deadly”
      “less deadly”

      We don’t yet know how deadly it is — its infection fatality rate, IFR. It kills in some fraction of infections. It has some chance of killing each infected person. Since it’s a harmful virus, that chance won’t be zero.
      more on this and related terms: https://ourworldindata.org/mortality-risk-covid#infection-fatality-rate-ifr

  6. Eye Beams are Cool says:

    I have no background in the sciences that are soft and squishy, but given those cladograms, how plausible or implausible is it that Omacron was intentionally engineered, given it’s lineage to not-delta and with it being so different? Sorry if it’s a stupid question, I have read a lot of comic books and watched a lot of X-files so I’m probably overturned to seeing supervillain plots.

  7. myst_05 says:

    “Chance we are broadly looking at a future crisis situation with widely overwhelmed American hospitals, new large American lockdowns and things like that: 20% → 15%”

    I would sell this to 5%. The logic is:

    1. Last year the peak of COVID was around January 15th, so 3 weeks after Christmas. We can expect a similar post-Christmas peak this year.
    2. We can assume that without Omicron no serious lockdowns would be in place and states with high vaccination rates would have sustainable hospital utilization. States with low vaccination rates might see a bad peak (like Florida) but they’re also the ones least likely to lockdown.
    3. Canada found 5 cases so far, we can presume the US would’ve found at least 5 as well if they cared to look carefully. I’d put a high estimate on total number of Omicron cases in the US at ~5000.
    4. Looking at the Delta wave in India, we can assume a doubling time of 10 days for a new widespreading variant in a situation with low vaccine availability. Looking at the latest wave in Germany the doubling time is around 14 days in a well vaccinated population. Lets assume 14 day doubling time for an Omicron wave in the US.
    5. Right now we have ~100k officially diagnosed cases per day in the US (ignoring the Thanksgiving dip) or ~300k cases overall assuming a 1/3 detection ratio. Assuming a person stays infected for 10 days, we have around 3m active cases right now, of which 5000 are Omicron.
    6. For Omicron to overtake Delta, it needs at least 1.5m cases. From a starting point of 5000 cases that’s 8 doubling periods or 8*14 = 112 days
    7. 112 days from now is right around the middle of March when Delta would be well on the downward slope, so for a while Omicron’s rise will be compensated by Delta’s fall.
    8. Middle of March is the beginning of spring. Places like NYC are rapidly warming up, places like Texas are still not hot enough to move everything indoors
    9. Biden’s vaxx mandates come into effect by early January, at least 50% of kids will be vaccinated by early February, at least 10% of the US will acquire natural immunity over the time period.
    10. Moderna/Pfizer are somewhat likely to have Omicron-specific doses ready for 70+ year olds within 112 days, assuming its bad enough to matter and the FDA is pushed by Biden to approve things more quickly. If its not that bad, then none of the above matters.
    11. We will have Paxlovid in sufficient quantities for the most vulnerable populations.

    My projection: assuming the SA data is valid, Omicron becomes dominant in the US between early March and early May. New hospitalization records are not broken during that period. No lockdowns are introduced anywhere in continental US.

    Possible problems with this calculation: underestimate of doubling time, underestimate of current Omicron cases, underestimate reactionary decisions in absence of spiking hospitalization data (see NY), overestimate vaccine efficacy against Omicron.

    • Yellowface Anon says:

      Lockdowns are more easily predicted by the absolute number of cases. If that’s high, even if 90+% of those are asymptomatic or mild, it will be done to “stop the spread”.

  8. Basil Marte says:

    “Kathy Hochul has no idea how exponential growth works. Clearing hospital capacity now […] is exactly the opposite of any reasonable procedure. […]”
    Exact Words? Her tweet says “boost hospital capacity AHEAD OF potential spikes”, which in genie-speak implies nothing about capacity during/following a spike.

    • TheZvi says:

      It gives hospitals instructions to maintain free capacity now and both instructions and authority to refuse treatments in order to maintain that. There is no other reason to actually declare the emergency now as opposed to later.

      • Basil Marte says:

        That’s what I meant. Public opinion summons an unfriendly genie and asks it to, quote, “boost hospital capacity ahead of” the coming wave. The genie tells hospitals to stop treating patients now, when capacity isn’t scarce, then when capacity does become scarce, it reverses course and actively tells the hospitals to work through the backlog of non-covid patients (especially if case counts start falling and thus the genie has plausible deniability). Oh, humans wanted to interpret “ahead of X” as emphasis that the duration needs to start before X because they were concerned that otherwise the genie would take its time and only deliver the goods too late, rather than as both the start and end of the duration falling before X?

        Also in the linked article:
        The governor recently launched a new vaccine incentive program, “Take Your Shot for an Outdoor Adventure,” for hunters, anglers and outdoor enthusiasts.

  9. Basil Marte says:

    European FDA-equivalent delenda est: https://www.reuters.com/business/healthcare-pharmaceuticals/eu-drug-watchdog-chief-could-approve-covid-19-shot-against-new-variant-3-4-2021-11-30/
    This latency is with the accelerated process, created 3/4 years ago specifically around the use case of vaccination against a new variant.

  10. Today the FDA’s AMBAC meeting voted to recommend molnupiravir get an emergency use authorization. But just barely: 13 yes, 10 no, 0 abstentions. And with a lot of caveats among the yes votes.

    Some issues:

    (a) The efficacy vs hospitalization was “wobbly”: the interim report had 48.3% (CL: 20.5% – 66.5%) efficacy, but when they added the rest of the data it was only 30.4% (CL: 1.0% – 51.1%). People thought this might mean there were responder/nonresponder populations, and nobody knew a biomarker to distinguish them.

    (b) While the mechanism and efficacy calculations from Merck were quite convincing, the FDA showed there were some issues with mutagenicity, particularly in the first trimester of pregnancy. (And I have to apologize: I got bored, and went grocery shopping at this point, stocking up in case the Omicronomicon gets loose. So I missed most of this, and am too tired to go back and listen. Maybe tomorrow.) Any woman will only get molnupiravir after a negative pregnancy test.

    (c) One point in favor was that people thought the efficacy of monoclonal abs will fade with Omicron, so they want an alternative. OTOH, they also said if there’s “another oral medication” with higher efficacy with less side effects (think plaxovid!), then the FDA should reconsider molnupiravir. So molnupiravir may get approved for like a month or so until paxlovid blows it away? They so carefully didn’t mention plaxovid that I wonder if there was some legal constraint.

    (d) Listening to the voting statements was almost painful: the AMDAC members were clearly conflicted.

    So the recommended EUA only for high-risk individuals, mostly the unvaccinated or those who had suboptimal response to vaccination.

    Pending FDA administrative action, molnupiravir is EUA’d… sort of.

    Seems like the most important action is to hurry along to the paxlovid hearings, no?

  11. Yellowface Anon says:

    Not sure if this has been posted here in the commenting section, but antivaxxers might have a point in one of the adverse side-effect of mRNA vaccination:

    https://www.ahajournals.org/doi/10.1161/circ.144.suppl_1.10712
    “Our group has been using the PLUS Cardiac Test (GD Biosciences, Inc, Irvine, CA) a clinically validated measurement of multiple protein biomarkers which generates a score predicting the 5 yr risk (percentage chance) of a new Acute Coronary Syndrome (ACS)… These changes resulted in an increase of the PULS score from 11% 5 yr ACS risk to 25% 5 yr ACS risk. At the time of this report, these changes persist for at least 2.5 months post second dose of vac.We conclude that the mRNA vacs dramatically increase inflammation on the endothelium and T cell infiltration of cardiac muscle and may account for the observations of increased thrombosis, cardiomyopathy, and other vascular events following vaccination.”

    I’ll let you crunch the numbers and see how this has to play in the risk-benefit calculation of COVID vaccination, esp. regular boosters. Wondering if this applies to non-mRNA vaccines as well.

  12. The AP reports just now that the first Omicron case in the US has been found in California, in a recent arrival from South Africa. All their contacts have tested negative. So at least it’s not in community spread mode, yet.

    Officials said those measures would only “buy time” for the country to learn more about the new variant and to take appropriate precautions, but that given its transmissibility its arrival in the U.S. was inevitable.

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