3 ms·

Variolation refers specifically to smallpox. The terminology for a similar approach against COVID is "inoculation" not "variolation." I understand the proponent

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 6y ago
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-covid19-deaths-3-30x.html http://www.overcomingbias.com/2020/03/variolation-may-cut-co... [2] "Targeted Immunization of Low-Risk Individuals Using a Low-Dose Inoculation (LDI)" - https://docs.google.com/document/d/1gSj-mrjFwswU35RzBnkjTt9Ep_OQNGIwcD9HyNlDSdg/edit https://docs.google.com/document/d/1gSj-mrjFwswU35RzBnkjTt9E... [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 6y ago
  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 6y ago
    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.

pmayrgundter 6y ago

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-covid19-deaths-3-30x.html http://www.overcomingbias.com/2020/03/variolation-may-cut-co... [2] "Targeted Immunization of Low-Risk Individuals Using a Low-Dose Inoculation (LDI)" - https://docs.google.com/document/d/1gSj-mrjFwswU35RzBnkjTt9Ep_OQNGIwcD9HyNlDSdg/edit https://docs.google.com/document/d/1gSj-mrjFwswU35RzBnkjTt9E... [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 6y ago
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 6y ago
  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.