Monthly Archives: April 2020

Peter Doherty on Variolation

Two noteworthy media mentions of variolation:

1. The New Yorker features Douglas Perednia talking about controlled infection and variolation, as its Exhibit A on on why conservative media shouldn’t presume to write on health/medicine, as they will only say stupid obviously terrible things:

After the Federalist tweeted it out, Twitter, which has been cracking down on coronavirus misinformation, temporarily locked the Federalist’s account. … He’d submitted it to a number of medical journals and blogs. “They all turned it down with no comment,” … tried the Federalist, almost at random. … The site accepted his article the next day, no questions asked. …

On the site … most commenters found Perednia’s idea absurd, dangerous, hilarious, or all three. … many angry e-mails and calls … Andrew Lover, an assistant professor of epidemiology at the University of Massachusetts-Amherst, told the Times that Perednia’s article was “exceedingly ill-advised and not evidence-based in any way shape or form.” …

Perednia [said] the way to adapt his idea to this reality was to make sure that the infecting was done with ‘the lowest possible dose’ … a concept known as variolation—which, he thought, would cut the death rate among those who chose to take part. (more)

2. A month ago, Adam Ford interviewed me on voluntary infection. Yesterday, Ford posted his interview with Nobel laureate Peter Doherty, author of Pandemics (2012), wherein Ford asked Doherty about variolation. Here are selected quotes from that discussion (fuller quotes below the fold):

47:10 Ford: “Controversially, in leu of actual vaccine that could come, hopefully in 9 months, but maybe even in 18 months if things go okay, if social isolation doesn’t work well enough too, would something like strategic or voluntary small dose low dose infection, like variolation, work in order to gain immunity, or nudge herd immunity? Is that something that we should be considering?

Doherty: (laughing) “Well let’s tell people what variolation was. … What they did was do this in young children, young children had a good immune response, generally survived smallpox, so what they were doing essentially is giving them smallpox, and they survived, whereas if they got it when they were older, they’d have a much worse disease. … So its not an unthinkable thing. …

52:40 With Covid19 I don’t know, but it would take a brave soul to be a test candidate, With younger people who are not severely affected, it’s possible. But you’d have to be enormously careful that they didn’t get any dose through their nose. But there would be ways of doing this. …

53:40 Ford: Is this something that could be achieved in the near term, if the vaccine timeline ends up looking like its going to be longer?

Doherty: If it was an absolutely catastrophic situation, if it was like the situation that is depicted in Contagion, where everyone who is within 100 feet of the virus gets it and dies, yes it could be reasonable. But I think for a virus where 80+% of people are definitely mildly infected at worse, or not sick enough to go into hospital, I don’t think you would take risk of that. The thing about a vaccine is that you have to give it to large numbers of normal people. You can’t take risks with vaccines.

You can take risks with end stage therapy. If someone is very very sick, and you’ve got something you think might work, you can try it pretty easily. People will approve that, … But you can’t take risks with vaccines. And the magnitude of the severity of this threat is not great enough to do that. You could say, … we’ll take a vaccine that looks a bit risky, maybe, and we’ll give it to the elderly. These are the people who are at risk, they can try it. … People like me, say would volunteer, I certainly would. I’d give it a go, and see if that works. But I wouldn’t want to be giving a vaccine that had any risk at all to younger people. You know, these are all theoretical arguments. But there is no way anything is ever given to anybody in this sense without going through extremely thorough review processes. … I think it is pretty unlikely.

So Doherty accepts “variolation” as a term that applies outside the context of smallpox. He thinks it could work, but oddly seems to see the main concept as infecting the young, rather than controlling dose, delivery vector, or strain. And he sees it only as justified in extreme circumstances, which Covid19 will never be, as it isn’t deadly enough. Even if the Great Suppression crashes the economy worse than the Great Depression, and even if millions will likely die from accidental infections, in his eyes and those of regulators that’s no excuse for letting healthy people voluntarily take substantial personal risks. Continue reading "Peter Doherty on Variolation" »

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Variolation Test Design

Okay, what the variolation concept needs most now is a trial/test/experiment ASAP. So to help get the ball rolling, let me sketch a tentative plan. I’m NOT saying this plan is now good enough. I’m saying let’s talk together about how to make it better. (Not so interested here in those ever popular “this can never work” comments.)

As with most projects, the obvious first top issue is staffing, especially leaders. This needs leaders who not only have the ability and expertise to execute it, but who can also inspire confidence in its other staff, subjects, patrons, sponsors, and audiences. (The most I’ve ever led is an assistant, so alas I don’t seem a good candidate.) The main point here is to inspire audiences to action, and that won’t happen if audiences don’t believe the project’s purported results, nor if they find its people too odious to associate with.

So the main purpose of this post is to try to attract participants, especially leaders, to pick up this ball and run with it. I’ll run with you, but I can’t run it by myself. When someone makes a good suggestion, such as in the comments, I’m likely to edit this post to include it. You are warned. Continue reading "Variolation Test Design" »

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Reply to Cowen On Variolation

In the last nine days I’ve done two online debates on variolation, with Zvi Mowshowitz and Gregory Cochran. In both cases my debate partners seemed to basically agree with me; disagreements were minor. Last night Tyler Cowen posted 1000+ words on “Why I do not favor variolation for Covid-19”. Yet oddly he also doesn’t seem to disagree with my main claims that (1) we are likely to need a Plan B for all-too-likely scenario where most of the world seems likely to get infected soon, and (2) variolation is simple, mechanically feasible, and could cut Covid19 Deaths by a factor of 3-30.

Tyler lists 8 points, but really makes 11. If he had one strong argument, he’d have focused on that, and then so could I in my response. Alas, this way I can’t respond except at a similar length; you are warned. Continue reading "Reply to Cowen On Variolation" »

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Beware R0 Variance

The big push now re Covid19 is to use “social distancing” to cut “R0”, the rate at which infection spreads. More precisely, R0 is the average number of other people that one infected person would infect, if they were not already infected. With no efforts to reduce it, estimates for natural R0 range from 2 to 15, with a best estimate perhaps around 4. The big goal is to get this number below 1, so that the pandemic is “suppressed” and goes away, and stays away, until a vaccine or other strong treatment, allowing most to escape infection. In contrast, if R0 stays above 1 we might “flatten the curve”, so that each infected person can get more medical resources when they are sick, but soon most everyone gets infected.

Apparently even with current “lockdown” efforts, all of 11 European nations studied now still have best estimate R0 over 2, with a median ~3.7. So they must do a lot more if they are to suppress. But how much more? My message in this post is that it is far from enough to push median R0 down below 1; one must also push down its variance.

Imagine a population composed of different relatively-isolated subpopulations, each with a different value of R0. Assume that few are infected, so that subpopulation pandemic growth rates are basically just R0. Assume also that these different R0 are distributed log-normally, i.e., the logarithm of R0 has a Gaussian distribution across subpopulations. This is (correctly) the usual distribution assumption for parameters bounded by zero below, as usually many small factors multiply together to set such parameters. The total effective R0 for the whole population is then found simply by integrating (via a lognormal) the effective growth over R0 subpopulations.

For example, assume that the R0 lognormal distribution has log mean (mu) -2 and sigma 1. Here the mode of the distribution, i.e., the most common R0 number, is 0.05, the median R0 is 0.14, only 5% of subpopulations have R0 above 0.70, and only 2% have R0 >1. Even so, if each of these subpopulations maintain their differing R0 over ten infection iterations, the mean growth factor R0 of the whole population is 20 per iteration!

As another example (for log mean -1, sigma 0.5), the R0 mode is 0.29, the median is 0.37, only 5% of subpopulations have an R0 over 0.85, only 2% have R0>1. Yet over ten infection iterations maintaining these same R0 factors per subpopulation, the mean growth factor R0 of the whole population is 1.28 per iteration. That is, the pandemic grows.

Of course these growth numbers eventually don’t apply to finite subpopulations, once most everyone in them gets infected. Because when most of a population is infected, then R0 no longer sets pandemic growth rates. And if these subpopulations were completely isolated from each other, then all of the subpopulations with R0<1 would succeed in suppressing. However, with even a modest amount of interaction among these populations, the highly infected ones will infect the rest.

The following graph tells a somewhat more general story. On the x-axis I vary the median value of R0 among the subpopulations, which sets the log-mean. For each such value, I searched for the log-sigma of the lognormal R0 distribution that makes the total average R0 for the whole population (over ten iterations) exactly equal to 1, so that the pandemic neither grows nor shrinks. Then on the graph I show the standard deviation, in R0 terms, that this requires, and the fraction of subpopulations that grow via R0>1.

As you can see, we consistently need an R0 standard deviation less than 0.21, and the lower the median R0, the lower a fraction of subpopulations with a positive R0 we can tolerate.

So, as long as there is substantial mixing in the world, or within a nation, it is far from enough to get the R0 for the median subpopulation below 1. You also need to greatly reduce the variation, especially the fraction of subpopulations in which the pandemic grows via R0>1. For example, when the median R0 is 0.5, you can tolerate less than 3% of subpopulations having an R0>1, just to hold the pandemic at a constant overall level. And to suppress in limited time, you need to go a lot further.

Different subpopulations with differing R0 seems plausible not just because our world has different nations, classes, cultures, professions, industries, etc., but because Covid19 policy has mostly been made at relatively local levels, varying greatly even within nations. In addition, most things that seem log-normally distributed actually have thicker than-lognormal tails, which makes this whole problem worse.

All of which is to say that suppressing a pandemic like this, with high R0 and many asymptomatic infected, after it has escaped its initial size and region, is very hard. Which is also to say, we probably won’t succeed. Which is to say: we need to set up a Plan B, such as variolation.

Spreadsheet for all this here.

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