The Ignored Potential of Variolation

Alas - It was way too cheap!

Most of us learned in school that in the year 1796, Dr. Edward Jenner discovered that a small injection of cowpox, the bovine form of smallpox, could create a lasting immunity against the scourge of smallpox.

What isn’t generally known, is that the death rate from smallpox in the British Isles had been falling for several decades before smallpox vaccines became available.

In the Middle East, someone long ago had figured out that if you found a child with a mild case of smallpox, collected the pus oozing from one smallpox pox, and rubbed a tiny amount of it on the arm of a child without immunity, that child would either show no symptoms, or develop a very mild case of smallpox. In either case, the child wouldn't die, or be disfigured, and they would have a life-long immunity to smallpox. Lady Mary Wortly Montagu observed this practice in Constantinople in 1717 and brought the knowledge to London.

They called called it ‘variolation.’ (Variola was the Latin name for smallpox.) It was not without risks, primarily because back then they did not have any way to precisely measure the smallpox dose given.

If a child got too small a dose, they wouldn't develop immunity: they could still catch smallpox at a later date, and die.

If a child got too big a dose, they would get sick with smallpox, usually a mild case. The main risk here was that every time a variolation failed and a child got sick, the people around that child could become infected, perhaps fatally.

There was even a famous variolator: Johnnie Notions was a self-taught physician who did about 3,000 variolations in the Shetland Islands and reputedly never lost a patient.

Because there was some risk of causing an outbreak of smallpox by giving variolations, they weren't usually done when smallpox was far away. But if a smallpox outbreak was anywhere near, it was well worth the risk. Variolations saved hundreds lives when they succeeded for each life that was lost when they failed.

The reason that variolation worked is that the severity of smallpox, like most viruses, was dose dependent. If you got infected with a large dose, the body’s immune system was quickly overwhelmed. If you got infected with a very small dose, the immune system learned how to fight off the virus before the virus could replicate enough to become life-threatening.

The technical term for creating immunity to a viral disease by giving very low doses of the virus is protective-dose inoculation. Protective dose inoculation has been used to provide immunity against a number of viral diseases - particularly those where no vaccine exists. Because variolation against smallpox was the most widely known example of protective-dose inoculation, the term ‘variolation’ is now often used more generally to mean to mean any protective-dose inoculation.

COVID is also dose dependent. That’s why we saw such a huge range of outcomes. Those infected with a very low dose of COVID typically showed no symptoms. (Unless tested, such people often didn’t even know they’d had COVID.) At a somewhat higher dose of the COVID virus, people got mild flu-like symptoms. Those unlucky enough to receive a high initial dose of the COVID virus were at risk of serious illness, even death.

At what dose the COVID virus became dangerous went down the older you were - but even 90-year-olds often survived COVID if they were fortunate enough to receive a very low initial dose.

Could we have used variolation as a defacto form of vaccination until such time as the COVID vaccines became available? I believe so, but we’ll never know, because no-one bothered to explore that possibility.

Variolation against COVID would have entailed a far lower risk than variolation against smallpox, given that it is now possible to measure the dose of the virus given with a high degree of precision.

Variolation would have had three important advantages over the mRNA vaccines:

First, variolation would create antibody protections against the entire COVID genome, not simply against the spike protein. Given that the spike protein is more prone to mutation than many parts of the COVID genome, vaccines based only on the spike protein are at much higher risk of immune-escape variants - as, in fact has happened, particularly with Omicron.

Second, if the variolation dose was delivered nasally, the body would develop strong immune responses in both the nose and throat. These tissues are normally the body’s first-line defenses against a respiratory infection, and are arguably the body’s best immune defense against such viruses. Because the mRNA vaccines were injected, they activated second-level immune responses via the bloodstream. Though these secondary defenses were generally sufficient to prevent viral spread, the immune response in the nose and throat - where you would most want it - was somewhat muted.

Finally, variolation could have been available as a treatment option far earlier than any vaccine. We had cases of COVID in both Canada and the US as early as February of 2020. If we had taken virus samples from these first patients and started clinical trials of variolation at that point, it is likely we could have developed a treatment protocol as early as May of 2020: six months before vaccines became available.

Testing the concept of variolation would have required volunteers willing to act as guinea pigs. (There are lots off people willing to volunteer for such trials - that’s the raison d’etre for the British non-profit One Day Sooner.)

You’d start by giving young, healthy volunteers a dose of COVID that you suspect is too low to create an immune response. Give them COVID PCR tests after a few days to see if they test positive. Wait two weeks and see if they test positive for COVID antibodies. (Isolate the trial volunteers so they can’t infect anyone else.)

If those in this first trial have negative PCR and antibody tests, conduct a second trial with new volunteers and a somewhat higher dose. Repeat this process until you get positive COVID test results. (The object is to find the lowest possible dose of COVID which will create an immune response in all trial subjects.)

If you can find a test dose where everyone develops an immune response to COVID, and no-one develops symptomatic COVID, you’re ready for what’s called a challenge test.

After your volunteers have tested positive for COVID antibodies, you expose them to someone with an active case of COVID. If they do not become infected, this confirms that a positive antibody test is evidence of a robust natural immunity to COVID.

Once you’ve determined the minimum dose which will consistently create a robust immune response, run a new trial where a second set of (not variolated) volunteers stays with the test subjects during the two weeks after they are variolated. In the best case scenario, none of these companion volunteers tests positive for COVID. In that case, you will have an extremely valuable de facto vaccination process you can use easily without the need to isolate those who were variolated.

If some of the companion volunteers test positive for COVID, you do further testing to determine the exact range of days after variolation during which the variolated person might infect other people. It is still possible to variolate under such circumstances - albeit with the caveat that each variolated person would need to self-isolate during their window of possible infectiousness.

Once you have determined the effectiveness of variolation with young, healthy adult volunteers, trials could be done with different age cohorts.

I suspect variolation will have limited applicability with the oldest age groups. Our immune systems typically weaken the older we become. This means an oldster will need a higher variolation dose to create a strong enough immune response to protect them from future COVID. At the same time, as a person gets older, the variolation dose needed to make them sick will get progressively lower. At some point, there is no interval between the dose needed to protect a person and the dose that will make them sick.

I make the above prediction based on what we have seen with the vaccines. The older a vaccinated person is, the greater the likelihood they will have a ‘breakthrough’ COVID infection. And the older someone is, the more vaccination itself becomes a significant stressor - enough so that some jurisdictions will not vaccinate anyone over a certain age.

This does not mean that variolation would be without value in protecting seniors. If all the staff who worked at seniors’ facilities were variolated, it would greatly reduce the risk of COVID outbreaks at such facilities.

Similarly, anyone who has an older relative living in their home, could greatly reduce their risk of infecting that person by getting variolated themselves.

I know of quite a number of people who found it extremely painful to not be able to visit their aging relatives at a senior’s home. Again, getting variolated would have made it safe to visit granny.

Front-line doctors and nurses would be obvious candidates for variolation. Something like 20,000 medical personnel around the world died of COVID before vaccines became available. How many of those deaths could have been avoided?

Ditto for all essential workers and anyone in a job with a high level of human contact. Variolation would have not only have protected the workers themselves, it would have reduced the number of times such workers spread COVID to other people.

In is well within the realm of possibility that COVID variation could have had a level of effectiveness in preventing COVID deaths as good or better than that of the existing vaccines.

Even if variolation was only used until such time as vaccines became widely available, variolation could still have saved hundreds of thousands of lives.

Variolation would have been incredibly cheap, enough so that even the world’s poorest countries could afford widespread use of variolation.

Unfortunately, that same rock-bottom low cost was almost certainly the kiss of death for variolation. We have a profit-based system to develop new medications and medical treatments. No pharmaceutical company would invest in a solution which would be unprotected by patents, and dirt cheap.

If variolation had proven to be cheap, effective and quickly available, it would have seriously undermined the global market for vaccines. I’m sure Big Pharma did its level best to discourage academic, non-profit and government research facilities from exploring the potential of variolation, in exactly the same way Big Pharma worked tirelessly to prevent ivermectin and HCQ from being recognized as effective early treatments for COVID.

We have an ideology in North America that unfettered capitalism will create the best of all possible worlds.

I suspect, if we do get a full and thorough evaluation of everything that happened during the COVID pandemic, it will become clear that our profit-based pharmaceutcal industry killed millions of people - both in the very lucrative avenues it pursued, and it the inexpensive options it prevented from being researched and put into practice.

Nowhere is this more obvious than in the complete and utter failure to investigate whether COVID variolation could have functioned as a de facto form of vaccination.

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PS: Once it became clear that existing vaccines were next to useless against the Omicron variant, there was a second window where we could/should have explored the potential of variolation. The low virulence of Omicron could have been made even safer if we pursued variolation using low doses of Omicron.

PPS: As an interesting aside, some researchers have suggested that part of the relative ineffectiveness of lock-downs in preventing COVID deaths is tied to the severity of COVID being dose-dependent.

If you caught COVID out in public, in a brief contact with a bus driver, a supermarket clerk, or a waiter in a restaurant, most often you’d get low dose of the virus, and hence a very mild case of COVID. Through that, you’d gain natural immunity against future infection.

On the other hand, if lock-downs had you cooped up with your family members for days on end, and someone in your family caught COVID, it was quite likely you’d receive a very large dose of the virus due to close and extended contact. Which would greatly increase your probability of serious - even fatal - COVID. Oops!