
Variolation - Cactus2018
https://en.wikipedia.org/wiki/Variolation
======
ttfkam
Epidemiologists and virologists have literally dedicated their lives to
effectively containing and dealing with infectious agents. Other medical
doctors have focused at least a decade of intense study on the human body and
the processes by which human life perpetuates and ends.

But by all means, let's all presume that an economist like Robin Hanson—whose
primary interest it would seem to be opening up commerce during a pandemic—has
somehow come up with an idea that has escaped the notice of that entire
segment of the population dedicated to human health.

Let's ask Mike Pence about his thoughts on the use of bloom filters as
relational database indexes while we're at it. I'm sure he'll point out that
mauve seems to have the most RAM.

Sure, experts can have blind spots, but c'mon!

~~~
cameldrv
Sometimes you need an outsider. I don't think that the issue with this is
scientific -- basically we know that it might work, but we'd have to test it
to know. The problem is that medical ethics deviates from everyday ethics, and
also ethics in other government regulated fields.

This is mostly the legacy of Josef Mengele and to some extent the Tuskegee
experiment, but collectively we essentially said "we never want to do that
again, so let's make rules that keep us well away from that line."

The reason the idea isn't getting much attention is that anyone in the field
that is serious knows that the study would never get past an Institutional
Review Board, so it's pointless to even try.

It seems to me that we need to revisit our tenets of medical ethics in
borderline cases like this one, where the stakes are so high. To me, you
should be able to do riskier experiments in these cases if the subjects are
truly informed volunteers, and you keep the risk to them to an absolute
minimum consistent with doing the experiment. There's a very similar issue
with vaccine challenge trials.

~~~
vikramkr
The thing is, we already are doing way riskier experiments to deal with COVID.
We sent the Moderna vaccine into human trials with barely any mouse data at
all. What Hanson is proposing is giving his pet approach, inoculation with
live virus, special treatment. The reason we're not pouring time and money
into validating inoculation is because we have literally dozens of vaccine
platforms, some with decades of evidence backing them up, that promise far
higher theoretical safety and efficacy than inoculation's theoretical safety
and efficacy. We'd rather pour our focus into approaches like moderna's
vaccine, which could be highly scalable, and J&Js vaccine and AstraZeneca's
vaccine because those platforms are known to work in other diseases. We've got
companies like Codagenix using the tools of molecular biology to create
attenuated forms of the virus without tradition time consuming development
techniques. When we already have these candidates developed and have them
barreling forward, why would anyone want to spend time and effort developing
and testing a worse approach? The risk/reward doesn't make sense.

~~~
cameldrv
Yes, but it's uncertain when those vaccines will be available or whether they
will work. Even as a backup plan, it makes sense to me to evaluate
variolation. With millions of lives worldwide and the entire global economy on
the line, you do not want to put all your eggs into even ten baskets.

As for the time and effort, I'm assuming that the existing vaccine
developments are adequately staffed. There are many other medical researchers
that are working on other things that could work on this.

------
barrald
For anyone else watching The Great, Catherine's interest in variolation is
apparently a true story: [https://smarthistoryblog.com/2016/10/05/catherine-
the-great-...](https://smarthistoryblog.com/2016/10/05/catherine-the-great-
risked-her-life-for-science/)

~~~
40four
Fascinating. Since I never paid attention in history class, I'll admit The
Great did remind me of this practice. It's interesting people were
experimenting with techniques likes this so long ago, when their understanding
of medical science was so rudimentary compared to today.

------
kauffj
Robin Hanson has a been a strong proponent of this idea. If you're curious
about this subject, this post is a must read:

[http://www.overcomingbias.com/2020/03/variolation-may-cut-
co...](http://www.overcomingbias.com/2020/03/variolation-may-cut-
covid19-deaths-3-30x.html)

~~~
beepboopbeep
This man is claiming that staying at home increases deaths... He's also
claiming a vaccine could be years away.

I also see zero evidence as to why he should be considered a credible source
for effective covid treatments. The man is an economist at a university. Am I
looking at the wrong Robin Hanson?

~~~
skosch
You've got the right Robin Hanson.

The key argument is that there is lots of uncertainty, but variolation is
probably worth trying. And if volunteers can be found, why not? One shouldn't
need to be a virologist to credibly make that argument.

~~~
powersnail
I'm not a medicine professional, so I'm just curious here.

Since variolation has basically the same principle as vaccination, it's hardly
an alternative to vaccination. Is it really worth trying?

To me (with my very crude understanding), proposing variolation as an
alternative to vaccination is akin to proposing knife without a handle as an
alternative to a regular knife.

Is there any case where vaccination fails to work, while variolation succeed?

~~~
frank2
A vaccine is months or years away whereas variolation can be deployed right
now.

~~~
powersnail
To deploy it, wouldn't it need to be tested just like a vaccine? Or is it
suggested to just deploy virolation without testing?

~~~
frank2
>is it suggested to just deploy [variolation] without testing?

Yes: the blog post by economist Robin Hanson suggested deploying it without
waiting for the results of testing. (Of course, it would be good to test as
fast and as much as possible concurrent with the deployment.)

"deploying it": making available to the public a variolation service or
procedure designed by medical experts.

~~~
vikramkr
If we're lowering the standard, why only lower it for inoculation? We can just
start deploying the dozen+ vaccines we have in development too if we decide
testing isn't important.

~~~
ggreer
I'm pretty sure Robin Hanson would want challenge trials with experimental
vaccines as well. The issue is that authorities won't allow such trials, not
that there is a lack of willing medical experts or volunteers.

Though vaccine trials aren't quite as safe for the public as variolation. If a
vaccine doesn't work, the person can spread the disease. If variolation
doesn't work, then it has the same mortality as natural infection, but
afterwards the person is immune and can't spread the disease.

------
peterwwillis
Some things to note about variolation wrt Coronavirus:

\- About a 2% death rate when used with Smallpox (compared to 20-30% without
variolation), so we could expect mortalities from variolation with
Coronavirus.

\- You actually get infected with the virus, and are contagious, though the
effects are lowered and you gain an immunity to the stronger/regular virus. So
you'd still need to self-quarantine and people would need to still wear
masks/do social distancing and close places with lots of people.

~~~
zbjornson
There's no reason to expect any parallels between variolation with these two
unrelated viruses.

~~~
ggreer
If you read Robin Hanson's blog post on the topic[1], he found data on other
diseases:

> The most directly relevant data is on SARS[2] and measles[3], where natural
> differences in doses were associated with factors of 3 and 14 in death
> rates, and[4] in[5] smallpox, where in the 1700s low “variolation” doses
> given on purpose cut death rates by a factor of 10 to 30.

It looks like the initial dose size has a huge impact on mortality for a wide
range of diseases.

1\. [http://www.overcomingbias.com/2020/03/variolation-may-cut-
co...](http://www.overcomingbias.com/2020/03/variolation-may-cut-
covid19-deaths-3-30x.html)

2\.
[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367618/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367618/)

3\.
[https://pubmed.ncbi.nlm.nih.gov/3723239/](https://pubmed.ncbi.nlm.nih.gov/3723239/)

4\.
[https://www.nlm.nih.gov/exhibition/smallpox/sp_variolation.h...](https://www.nlm.nih.gov/exhibition/smallpox/sp_variolation.html)

5\.
[https://www.npr.org/sections/goatsandsoda/2018/02/01/5823701...](https://www.npr.org/sections/goatsandsoda/2018/02/01/582370199/whats-
the-real-story-about-the-milkmaid-and-the-smallpox-vaccine)

------
Cactus2018
The part that stood out to me is:

> Doctors sought to _monopolize the simple treatment_ by convincing the public
> that the procedure could only be done by a trained professional. The
> procedure was now preceded by a severe bloodletting, in which the patient
> was bled, often to faintness, in order to 'purify' the blood and prevent
> fever. Doctors also began to favour deep incisions [versus superficial
> scratches], which also discouraged amateurs.

------
kh_hk
[https://en.wikipedia.org/wiki/Balmis_Expedition](https://en.wikipedia.org/wiki/Balmis_Expedition)

------
OJFord
These aren't to me the clearest Wikipedia pages, but I think I now understand
that - in modern usage, ignoring origins - vaccination and inoculation are
both types of immunisation; the latter using a sample of the thing to immunise
against, while a vaccine is actually strictly speaking immunisation through
other means, some other substance to the thing that should be immunised
against?

I suppose I thought they were synonyms, but I certainly thought a vaccine was
'a bit of' the thing to immunised against, despite remembering Jenner and his
cow.

~~~
war1025
> certainly thought a vaccine was 'a bit of' the thing to immunised against

A lot of the original vaccines were made from deactivated viruses. I don't
know how that process works exactly, but your understanding isn't far off at
least for how they were originally produced.

~~~
Cactus2018
>> were made from deactivated viruses. I don't know how that process works
exactly

Check out the history of the Rabies vaccine, where the virus was weakened
through aging:

> derived from the spinal cord of an inoculated rabbit which had died of
> rabies 15 days earlier.

[https://en.wikipedia.org/wiki/Rabies_vaccine#History](https://en.wikipedia.org/wiki/Rabies_vaccine#History)

> A vaccine typically contains an agent that resembles a disease-causing
> microorganism and is often made from weakened or killed forms of the
> microbe, its toxins, or one of its surface proteins.

[https://en.wikipedia.org/wiki/Inactivated_vaccine](https://en.wikipedia.org/wiki/Inactivated_vaccine)

> The virus is killed using a method such as heat or formaldehyde.

> Whole virus vaccines use the entire virus particle, fully destroyed using
> heat, chemicals, or radiation.

> Split virus vaccines are produced by using a detergent to disrupt the virus.

> Subunit vaccines are produced by purifying out the antigens that best
> stimulate the immune system to mount a response to the virus, while removing
> other components necessary for the virus to replicate or survive or that can
> cause adverse reactions

------
vikramkr
Variolation refers specifically to smallpox. The terminology for a similar
approach against COVID is "inoculation" not "variolation." I understand the
proponent of it for COVID is an economist and not a medical professional, but
keeping the terminology clear is important to avoid confusion. Inoculation is
not guaranteed to be effective against covid. Just because there was a version
of it called variolation that worked against smallpox before being eliminated
because it was not as good as other approaches does not mean inoculation is
automatically safe and effective against a completely unrelated virus. Other
coronavirus are known to display antibody dependent enhancement, where a weak
immune response makes following infections worse, and we already don't see
consistent, strong responses from people who were sick.

What the economist Hanson is essentially suggesting is that we take a worse
method of immunization (just the normal live virus) and waive the regulatory
burden to show safety and efficacy because a similar approach worked with
smallpox. If we are getting into the business of ignoring the requirement for
an immunization approach to be clinically validated, then there are a few
dozen vaccines with far better theoretical safety and efficacy profiles that
we should be using instead. The reason a vaccine isn't coming immediately is
because we have to show they wont kill people and that they'll work, and then
we have to scale up production. You dont get to rebrand your worse vaccine
approach as "variolation" and then say it should be held to a different
standard so you can get the economy humming again.

~~~
pmayrgundter
Thanks for making the point about the name. I got in touch with Hanson after
his blog post[1] and co-authored a proposal with Hanson and three doctors on
low-dose inoculation of respiratory system, gut or skin[2]. We ended up not
using the name Variolation since it has too many connotations and it's
necessary to distinguish modes of inoculation for vaccination.

I think Hanson's blog post[1] about the general idea of variolation was useful
to get discussion going but agree that as stated it was not a good approach.

In contrast, the proposal we developed subsequently focused on making use of
human challenge trials[3] (where the control arm of the clinical trial is
actively exposed to the pathogen) to search for safer forms of inoculation,
hopefully benign.

I disagree with your point that live virus is necessarily a worse form of
immunization; I think it actually depends on the route of inoculation and on
finding a reasonable dose. I am working on the skin route separately[4] and
from this I've learned live-viruses are used in some (many?) of the most
successful vaccines (adeno, polio, measles, smallpox)[See appendix in 4.1]. In
polio and measles the virus was attenuated, but in the case of adenovirus,
it's used in its original wild-type form and inoculated into the gut via oral
dose to avoid the primary respiratory infection. Adenovirus is also notable
for comparison as it causes an ARDS-like condition and the gut infection
(benign diarrhea and fever) was considered secondary and acceptable enough
that the US Military doses all recruits this way since the 80s. And although
smallpox variolation had relatively high mortality rates, it's unclear how
specific the methods in use were. It's possible that the primary
(respiratory!) infection wasn't avoided e.g. by the methods of scab snuff
(ew!). Lastly, non-live virus vaccines may not provoke a sufficient immune
response, e.g. in the killed polio vaccine that was eventually retired. I
think this is generally a concern for potential synthetic CoV vaccines as
well.

So it seems like the idea from smallpox and adenovirus is to inoculate where
the body has a good chance of dealing with the infection (skin and gut,
respectively) when the primary infection (respiratory in both cases) is
dangerous and there aren't better alternatives. I'm working on the skin route
since it seems plausible (it appears skin can be infected by CoV2) and the
least risky (almost all reports of associated infections are benign; though
there are some reports of skin tissue necrosis). The gut route is also
interesting but in my opinion we're too early in the clinical understanding to
prioritize it since it is often associated with the primary infection.

I'm just starting to treat this as an open-source project[5]. Please feel free
to join!

[1] "Variolation (+ Isolation) May Cut Covid19 Deaths 3-30X"
[http://www.overcomingbias.com/2020/03/variolation-may-cut-
co...](http://www.overcomingbias.com/2020/03/variolation-may-cut-
covid19-deaths-3-30x.html)

[2] "Targeted Immunization of Low-Risk Individuals Using a Low-Dose
Inoculation (LDI)" \- [https://docs.google.com/document/d/1gSj-
mrjFwswU35RzBnkjTt9E...](https://docs.google.com/document/d/1gSj-
mrjFwswU35RzBnkjTt9Ep_OQNGIwcD9HyNlDSdg/edit)

[3]
[https://academic.oup.com/jid/article/221/11/1752/5814216](https://academic.oup.com/jid/article/221/11/1752/5814216)

[4] "SARS-CoV2 Live Virus Skin Vaccine" \-
[https://tinyurl.com/y8ujrcze](https://tinyurl.com/y8ujrcze)

[4.1] "Appendix: Live Virus Vaccines" \-
[https://tinyurl.com/y8ujrcze#heading=h.wpx27u7fe2kp](https://tinyurl.com/y8ujrcze#heading=h.wpx27u7fe2kp)

[5] [https://sites.google.com/view/open-
vax](https://sites.google.com/view/open-vax)

~~~
vikramkr
The use of human challenges get trials is a very different situation, and the
decision of whether or not to engage in one is definitely a question where
economists and ethicists have a lot to contribute, I'm glad you're engaged in
the conversation. Its a tough utility/risk-reward/ethics question, where we'd
be able to speed up development of immunization approaches by a LOT, but with
a virus we still don't fully understand and that keeps surprising us.
Definitely a decision that needs cross discipline input and discussion.

~~~
cameldrv
It's not a totally different situation. In fact, since with a human challenge
trial, you're probably going to be inoculating both arms of the trial with a
variable dose, you can use the data from the control arm of the challenge
trial as essentially a phase 1 of the variolation trial.

------
gerland
Additional trivia - Benjamin Franklin was a big proponent of inoculation. He
tried to spread the awarness and convince people that it's safe and effective.
Unfortunately his first son died of smallpox before he could be inoculated. He
was 4 and developed some other infection, so BJ decided to wait with
inoculation. Before he could perform it, he contracted the disease. It was
huge blow to the credibility of BJ claims about inoculation, but he continued
his mission nevertheless.

~~~
ptaipale
I think it is somewhat incorrect to call this vaccination, because the proper
term for what was available in Benjamin Franklin's time was variolation, or
inoculation.

~~~
elliekelly
An interesting tidbit about the origin of two terms from Wikipedia:

> Until the very early 1800s, inoculation referred only to the practice of
> variolation, the predecessor to the smallpox vaccine. Edward Jenner
> introduced the latter in 1798, when it was called cowpox inoculation, or
> vaccine inoculation (from Latin vacca = cow). Smallpox inoculation continued
> to be referred to as variolation (from variola = smallpox), whereas cowpox
> inoculation was referred to as vaccination (from Jenner's use of variolae
> vaccinae = smallpox of the cow).

The article goes on to explain how the meanings of the terms have since
expanded:
[https://en.m.wikipedia.org/wiki/Inoculation](https://en.m.wikipedia.org/wiki/Inoculation)

~~~
twic
I suppose the analogue of Jenner's cowpox innoculations would be infecting
people with coronaviruses other than SARS-CoV-2 and hoping that the cross-
immunity is helpful.

There is evidence for such cross-immunity, but not strong enough for this to
be a strategy you'd bet on.

------
alkonaut
Variolation is a form of vaccination like any other (a treatment given to
healthy individuals) so is subject to all the safety requirements of any other
vaccine. So its an idea for a vaccine but it's not a magical shortcut compared
to all the other vaccines under development (some of which are based on
attenuated virus).

------
marcosdumay
Isn't discovering a good dosage and application frequency for this just as
hard as testing a vaccine?

~~~
zozbot234
Right, and scaling it up to a large population is just as hard as making
vaccines. Not much reason for variolation nowadays.

~~~
davidw
The 'reason' for variolation is for people like the aforementioned Robin
Hanson to get attention by suggesting something controversial.

------
fab1an
Amusingly, this is one of the few cases where - extremely broadly - one
general idea of homeopathy works: you're basically just microdosing virus.
This is amusing because a lot of anti-vaxxers (at least in Germany) will also
be into homeopathy. There's possibly a good pro-vax-comms strategy in here:
reframe vaccines as homeopathic viral microdoses (instead of complicated
pharmaceutical compounds) and you might save a few kids.

~~~
PeterStuer
Not really.

Homeopathy assumes that which causes likewise symptoms to be a candidate for
cure, while here it is the idea of microdosing the disease, which hopefully
would not case symptoms like the full blown disease, and the second tenant of
homeopathy, the dilutions increase potency, would also hopefully be absent as
that would be like the viral load factor, but in reverse.

~~~
yetihehe
You are using facts. This is not very effective (against antivaxers and
homeopathy enthusiasts).

~~~
cmendel
Facts are very effective against homeopaths, you just have to dilute them 100x
first.

