Post #1200: Lethal dose testing and a takeaway from the Provincetown, MA outbreak.

Posted on August 3, 2021
“In general with respiratory viruses, the outcome of infection – whether you get severely ill or only get a mild cold – can sometimes be determined by how much virus actually got into your body and started the infection off. It’s all about the size of the armies on each side of the battle, a very large virus army is difficult for our immune systems army to fight off.

Source:  Professor Wendy Barclay, Imperial College, London, quoted in this article.

Sometimes I get the feeling that people really don’t quite understand how vaccines work.  Or how viral infections work.  Or what risk means.

That’s why I’m starting off with this quote.  If you can grasp that quote, then you will understand why a vaccine isn’t a free pass to engage in any behavior.  A vaccine gives our “immune systems army” a leg up.  If you manage to give the virus an even bigger leg up, by upping your exposure, you can more than offset the benefit of the vaccine.

To be clear, people seem to act as if vaccines are magic, and that if you are vaccinated, you have a low risk of infection independent of how you behave Or perhaps a better word would be “binary”.  They act as if, once you are vaccinated, you’re good to go. No matter what you do.

And I’m just here to say, that just ain’t so.  That is, in fact, wrong.

What COVID-19 vaccine does is speed up and generally improve your immune system’s response to the virus.  This reduces your risk that a given dose of virus will be able to replicate out-of-control for long enough to cause a noticeable infection.  In particular, it reduces your risk that a given dose of virus will replicate so much that it causes a serious infection.

If you change your circumstances enough, and up your exposure to the virus enough, you can more-than-offset that benefit of vaccination.  The upshot is that if you use vaccinated status as an excuse to spend hours in crowded, noisy bars, well, guess what.  You might actually be at higher risk of infection that if you’d remained unvaccinated and didn’t hang around in bars.

I went over this back in January, in response to the question “If I’m vaccinated, do I still have to wear a mask?”  (Post #959).  But since nobody is going to go back and read old blog posts, I think this is worth re-phrasing, particularly in light of the Provincetown MA outbreak.

But this time, I’m taking a different tack.

Let me start by discussing lethal dose testing of viruses.

Lethal dose testing.

What exactly happens when you get infected with a virus?

The best way to describe it is that when a virus invades your body, it sets off a race between viral replication on the one hand, and viral destruction by your antibodies and the rest of your immune system on the other hand. 

If you start with very few virus particles, and you already have antibodies to that virus circulating in your system, then you’ve skewed the race so that your immune system is likely to win.  And you get to keep on living.  At the extreme, the race is so one-sided that you have an asymptomatic infection.  Your immune system swats the virus down without even triggering normal symptoms of an infection.

And, to be clear, a typical estimate is that 40% of COVID-19 infections are completely asymptomatic.  (Versus, say, about 16 percent of common flu infections.)  In the extreme, extreme case, you might kill off the virus so quickly that no testing will ever show you were infected.  You might not even develop enough of the antibodies signalling past infection that blood test will reveal the presence of a past mild infection.

By contrast, if you start with a heavy dose of the virus and no antibodies circulating in your system, then the race is skewed in favor of the virus.  It has a big head start before your body can start fighting it.  And in that situation, you get sick and maybe you don’t get to keep on living.

Obviously, this abstracts from all the person-level variations that may matter.   Older people famously have a lower immune response when in comes to fighting infection.  Antibodies have some crossover, so (e.g.) exposure to related diseases might allow some of your existing antibodies to flag COVID-19 for destruction.  And, just, in general, people may vary.  I’m abstracting away from all of that.

Note that two things matter: 

One is the readiness of your system to recognize and take on that particular virus (your existing antibodies to that virus).  By exposing you to key proteins found on the surface of COVID-19, the mRNA vaccines we are currently using prime your immune system with antibodies that will attach to COVID-19 and flag it for destruction. And so, when the virus shows up, you’ve got a jump-start on fighting it.  (Your body also has the “memory” of those proteins and so can rapidly ramp up production of additional antibodies.)

The second is the amount of your exposure to the virus — the amount of virus you manage to inhale.  If you managed to get a very small dose, it’ll take a while before the virus can replicate to dangerous levels.  By contrast, if you inhaled a massive number of viral particles at a one go, then the virus starts the race with the upper hand.

(In fact, for various viral diseases, scientists estimate the “minimum infective dose”, which is the smallest number of  viral particles the typical person must inhale to trigger infection.  This can be as few as dozen or so particles for some diseases.  I’ve seen vague estimates of about 100 particles for COVID-19, but I have not tracked down any definitive study of that).

Now you’re ready for the concept of lethal dose testingAnd in particular, lethal dose testing of viruses that typically don’t cause death.  Because, the fact of the matter is, if you give an animal a large enough dose of some infectious virus, you can guarantee that the virus wins the race, and that the animal dies of the infection.  Even if that virus isn’t typically lethal at normal exposure levels.

And so, all ethical concerns aside, it’s a common laboratory practice to determine the the amount of virus it takes to kill (say) half of the exposed animals (“LD50”) or the minimum amount it takes to kill all of them (LD100).  (The LD here is, I think, lethal dose.)

I’m not going to go into that, except to say that the practice exists, is considered normal, and is protested by animal rights advocates.  In fact, it’s plausible that your flu vaccine was tested, in part, by lethal dose testing, as in this bit of research on mice.

None of that particularly matters here.  All that matters is that you understand that there is plausibly a dose-response relationship in viral infections.  So much so that if you challenge animals with a big enough dose of a virus that’s typically not lethal, you can kill them.  Even if they are otherwise healthy. And in some cases, even if they are vaccinated.  Just by giving that virus a big enough head start over the animal’s immune system.

The upshot is that if you change your behavior in such a way as to give yourself a bigger dose of COVID-19, the plausible response is that you’re more likely to get infected. 

That’s obviously true if you’re not vaccinated.  And that’s also true if you are vaccinated.  It’s just not obvious to most people.


When a clinical trial showed that the Pfizer vaccine was 91% effective, what did that mean, exactly?

In a nutshell, it meant that for two groups with equal levels of exposure to the virus, the vaccinated group only had 9% as many symptomatic infections as the unvaccinated group.

The key phrase there is in italics.  Much of the point of the entire randomized double-blind trial method was to ensure that that key phrase was true, to within some small random error.

Let me outline the COVID-19 vaccine clinical trial method from this scholarly publication , more-or-less the same as in this scholarly publication, putting key elements in boldface.

To test the vaccine, they randomly assigned volunteers to receive either the vaccine or a placebo.  Because half got the placebo, the participants carried on with their lives as they had been, including maintaining mask, social distancing, and other COVID hygiene.  None of them could count on becoming immune.

Then — and only then — did researchers count the number of people who showed up with symptoms and tested positive for COVID-19.  They found that there were just over 10 symptomatic, diagnosed COVID infections in the placebo group for every one in the vaccine group.  From that, they concluded that the vaccine reduced symptomatic COVID infections by 91%, relative to the placebo group, while both groups maintained existing COVID-19 hygiene and existing exposure levels.

And that’s what they mean by 91% effective. 

Please note how much this estimate of vaccine effectiveness depends on behavior.  Given equal behavior in both groups, researchers found only 9% as many COVID-19 infections in the vaccinated group than in the placebo group.

If you give the vaccine to a group that has a much higher exposure to the virus, you’re going to get more infections that you’d expect, based on the clinical trial results.  This is exactly what happened to the measured efficacy of the Chinese vaccine.  Under research conditions, in a randomized controlled trial, the vaccine was 75% effective.  In the real world, it was more like 50%.  That was attributed to giving the vaccine to a heavily-exposed population (health care workers).

And, guess what?  If you start to do things that greatly increase your exposure to COVID-19, you’re going to be the equivalent of those Chinese health care workers.

Note that the CDC initially told vaccinated individuals to keep their masks on and keep up other aspects of COVID-19 hygiene.  Why?  At that time, there was a lot of COVID-19 still circulating in the community.  If you got vaccinated, and dropped all hygiene, you (at least partially) offset the benefits of the vaccine, in terms of your overall risk of getting an infection.

CDC only told the vaccinated to drop their hygiene after levels of circulating virus had fallen to very low levels.

And now, with higher levels of virus circulating again, it’s completely unsurprising that the CDC has once again suggested that vaccinated individuals wear a mask in indoor public spaces.  At least where there’s a lot of virus about.

It’s not even hard to figure out the relative risk.  Crudely, at least.  If the vaccine is about 90% effective, your risk of infection, unvaccinated, when there are 2 new cases / 100K /day, is roughly the same as your risk of infection, vaccinated, and there are 20 new cases / 100K / day.

It’s really not rocket science, is it?

The upshot is that vaccination reduces your absolute chance of symptomatic COVID-19 infection by 91% if and only if you maintain your pre-vaccine level of COVID hygiene.  And if the amount of virus in circulation in the community remains constant.

In other words, your risk of getting infected drops by 91%, when you get vaccinated, if and only if your exposure remains the same as it was before you got vaccinated.  But if you couple that vaccination to an increase in risk-taking behavior, you could easily offset (some, most, or more-than-all of) that 91% reduction.  E.g., if you go from being a shut-in, pre-vaccine, to hanging around maskless in bars, post-vaccine, you may actually have upped your odds of getting infected.

My point is that the 91% reduction isn’t some absolute number.  It’s relative to your current odds.  If you do other things to change your odds of infection, that matters.  If your environment changes to change your odds of infection, that also matters.

I guess I’ve beaten this to death.  It’s all about the risk, the dose, and the odds.  Vaccination gives your immune system a leg up on the race between COVID-19 exposure and COVID-19 infection.  But that’s all it does.  It’s not a magic bullet in this case.  If it reduces your odds of infection an average of 91% against the Delta variant, for the first six months following vaccination.  If you engage in behavior that increases your exposure ten-fold, then all you  are doing is breaking even.

My guess is that the largely-vaccinated participants in those Provincetown July 4th parties probably didn’t grasp that at the time.  But I bet they do now.