Tomas, love the analysis. I would also point out that some vaccines have already been shown to be less effective against variants. So, we may actually end up in a situation similar to influenza (where we have to vaccinate every year). The data out of Manaus, Brazil (that you cited), suggests that.
Yes indeed, it's a risk. I would say from what I've heard that it's a small risk. Here's my thinking, you tell me what you think:
1. It mutates much more slowly than the flu. Not as slowly as DNA, but still slower.
2. There are few known animal reservoirs. Minks AFAIK is the only domesticated animal that has been proven to be able to catch it and spread it widely. That makes it much easier to eradicate.
3. It took a LOT of cases for these variants to appear, and they're still impacted by some of the current vaccines.
4. RNA vaccines are a new tech that can dramatically reduce the time to market. I believe this will be a political decision we need to make.
1. It mutates much more slowly than the flu. Not as slowly as DNA, but still slower.
I don't know.
2. There are few known animal reservoirs. Minks AFAIK is the only domesticated animal that has been proven to be able to catch it and spread it widely. That makes it much easier to eradicate.
I'm not sure about that.
3. It took a LOT of cases for these variants to appear, and they're still impacted by some of the current vaccines.
True; it's early to tell.
4. RNA vaccines are a new tech that can dramatically reduce the time to market. I believe this will be a political decision we need to make.
As for the publication process, I have worried about one point. In your article, it seems like efficiency of vaccine is assessed too much. In the history of vaccine development, the balance in between human rights, safety, and efficiency is always a crucial issue. On such kinds of consideration, I have added the comment into translation related with how developer to care safety on the process of development of coronavirus vaccine (ref; https://bbc.com/news/health-55041371…) and possibility of emergence of resistant strains. If you are not happy about that treatment, please let me know.
Hi Soichi, it's an honor and a pleasure to work with you and with Mr. Kato. Yes, please translate and I will link it here.
For some reason, the BBC link doesn't work. I am not sure I grasped your point about vaccines, but knowing you and your team I trust your judgment. Please simply share with me a bit more detail so that I can update my thinking too if needed, or otherwise debate why not.
You can also DM me on Twitter so we can start a conversation there:
So my point on vaccines for the Oxford one, for example, is that (1) money could have flown in earlier on, (2) they already had some sense of what Phase I and II could do from previous tests, and more importantly (3) Phase III (the longest) could have been cut very short with challenge trials. I still think we could have gotten that one (and at least Moderna's) months earlier. What do you think?
Then, my focuses on current situation in vaccine are below two points. One is how much we can believe the final outcome of the vaccine from the start of vaccine development. The other is how is the ability/speed for future COVID-19 variant to escape the effect of vaccine.
In my understanding, all your point shown above is focused on how to shorten everything to develop new vaccine. From this point, now, basically I agree with you, but this is because I think it may be true the efficiency of this vaccine is high enough and its side-effect it relatively low to compare with the outcome from vaccines. Those are the things that we could not know at the start of development of new vaccines.
The latter one is about resistant strain (https://edition.cnn.com/2021/02/02/health/variant-mutation-e484k/index.html). As you pointed out your article, emergence of new variants is strongly related with selective pressure that virus feels. In such kinds of meanings, emergence of resistant strain is considerable future. In other word, in my opinion, if variants would "sleep" in some sense, vaccines would win, but we are not sure variants would sleep as hare does. So such kinds of meanings I have added some note on translation versions.
If Criterium 2 is your concern, for me the ROI is obvious.
The benefit of a challenge trial is hundreds of thousands of lives saved and tens of billions of dollars saved.
The risk is near 0 now given what we know of the vaccines, because a Phase III trial doesn't stop anyways until there's enough natural infections. So the only difference is that in one case we wait months for natural infections, and in the other we immediately do an artificial infection. That risk is SO small, and the benefit is so HUGE, that there is no way this is not worthwhile. From my shallow point of view.
Your math on the deadliness of the new variant may be correct but it could be flawed. It’s easy to see your point when you suppress asymptomatic cases as much as you do in the graph. But if the increased spread is heavily asymptomatic then the studies will miss an alternative consistent hypothesis. It may be less deadly because of a case “mix shift”. To illustrate
Suppose...The strain we have had for 1000 infections say for ease of math had 700 asymptomatic and 300 symptomatic cases. At 0.5% IFR overall that would be 5 deaths or 1.67% of those with symptoms.
Now suppose the new strain spreads asymptomatic more efficiently so to get 300 with symptoms we get 1200 without symptoms instead of 700. Let’s suppose now there are 6 deaths. That would mean the IFR has decreased from 0.5% to 0.4% overall but increased to 2% from 1.67% among those with symptoms. So if the “mix shifted” toward more asymptomatic infections it is both possible that the strain would appear more deadly (because we observe only those with symptoms) but actually be overall less deadly to the full population. This phenomenon will be exacerbated if we test less because the symptomatic patients we observe are likely to be sicker which is another form of a mix shift. I don’t know if this is right but before we panic we should see if this explanation is reasonable.
Anyway, I’m not saying this is right I’m just saying it’s an alternate explanation we should consider and investigate. And be careful that how you draw your graphs doesn’t mislead.
You're right this is possible. Thinking about it from first principles means this is unlikely: If the variant is worse because it replicates better, the more parsimonious explanation is the one I pointed at.
Well we will know soon enough in Florida where the British variant should soon be dominant. If you are right we will see a massive surge in deaths by the end of February—faster than case growth both symptomatic and not. Fwiw if infectiousness differential (50%) is higher than virulence differential (30%) at constant testing rates while only testing symptomatics the more parsimonious explanation is the mix shift
Tomas, the vaccine is not the only tool in our armoury. Surely similar focus and investment needs to continue also on treatments as these also continue to contain serious and fatal conditions. Both active and prophylactic treatments will help limit impacts too. We are seeing more of these coming to the fore. We have to live alongside not erradicate - our immune systems are there to adapt too.
Indeed! Yes treatments are messy. I always hear good options and then new results that are underwhelming. It looks like we're reduced the fatality rate by a reasonable %, but it also looks like the new variants will undermine that.
There's also no word about long covid.
For me the right alternative to vaccines is Zero Covid because until we're all safe, nobody will be safe. But if we find treatments that reduce long covid and fatality rates by 90%, that's very different!
Are you safe from crossing the road Tomas ? Or Cancer ? Hepatitis C ?, which kills as many people EVERY year as Covid caused this year (deaths from Covid as opposed to deaths WITH Covid). I only feel unsafe when i dwell on the fear and scare headlines of the media - when I sit calmly and look at the real numbers of deaths, serious illnesses etc I realise we are being manipulated to respond from fear. So safety is an attitude, and an attention to one's own well being and immunity and life. If you wait for zero Covid Tomas, you will likely die softly in your 90's from old age, wishing you had not spent your life - waiting ...
The list of "mistakes" should be a list of questions. We should be curious enough to want to get some real answers to those questions. If we don't fully understand the constraints, we don't know if they were mistakes.
Muchas gracias por el excelente estudio y la cantidad de datos aportada. Con estos parámetros y estudios, lo increíble es que sigan sin hacerles caso la mayoría de nuestros gobiernos. Enhorabuena por conseguir seguir buscando y demostrando lo qué se debe hacer y no caer en la desesperanza al ver que no se hizo caso de las advertencias y que eso ha llevado a tener millones de muertos, miles de patologías crónicas y la ruina económica de millones. Esperamos que la cordura y la humildad en algún momento consigan que se haga caso al conocimiento cintífico.
Muchas gracias por el excelente estudio y la cantidad de datos aportada. Con estos parámetros y estudios, lo increíble es que sigan sin hacerles caso la mayoría de nuestros gobiernos. Enhorabuena por conseguir seguir buscando y demostrando lo qué se debe hacer y no caer en la desesperanza al ver que no se hizo caso de las advertencias y que eso ha llevado a tener millones de muertos, miles de patologías crónicas y la ruina económica de millones. Esperamos que la cordura y la humildad en algún momento consigan que se haga caso al conocimiento cintífico.
Just to clarify, this may mean that polyclonal responses to infection by previous strain are insufficient to prevent re-infection and serious disease caused by P1. Unless current vaccines confer more effective immunity against P1 (how likely is that?) than an infection with whole bug, none of the current vaccines using the spike epitopes alone are likely to provide immunity against P1 disease.
I didn't, but I made a comment about it in a caption. Here it is:
The Russian vaccine also appears effective, but the data comes from Russian researchers from trials made in Moscow only. Given Russia’s track record of politically-motivated news, I can’t trust this data until it’s replicated by an independent source. The same happens with the Chinese vaccine.
Tomas, love the analysis. I would also point out that some vaccines have already been shown to be less effective against variants. So, we may actually end up in a situation similar to influenza (where we have to vaccinate every year). The data out of Manaus, Brazil (that you cited), suggests that.
Yes indeed, it's a risk. I would say from what I've heard that it's a small risk. Here's my thinking, you tell me what you think:
1. It mutates much more slowly than the flu. Not as slowly as DNA, but still slower.
2. There are few known animal reservoirs. Minks AFAIK is the only domesticated animal that has been proven to be able to catch it and spread it widely. That makes it much easier to eradicate.
3. It took a LOT of cases for these variants to appear, and they're still impacted by some of the current vaccines.
4. RNA vaccines are a new tech that can dramatically reduce the time to market. I believe this will be a political decision we need to make.
1. It mutates much more slowly than the flu. Not as slowly as DNA, but still slower.
I don't know.
2. There are few known animal reservoirs. Minks AFAIK is the only domesticated animal that has been proven to be able to catch it and spread it widely. That makes it much easier to eradicate.
I'm not sure about that.
3. It took a LOT of cases for these variants to appear, and they're still impacted by some of the current vaccines.
True; it's early to tell.
4. RNA vaccines are a new tech that can dramatically reduce the time to market. I believe this will be a political decision we need to make.
It will be a tough one.
Off-topic, but I thought you might find this music geography piece of interest. https://www.honest-broker.com/p/western-music-isnt-what-you-think?isFreemail=true&post_id=144003912&publication_id=296132&r=stzh&triedRedirect=true
Super cool thx for sharing
Dear Tomas,
our pro bono translation group, the COVID1001 finished to translate your article into Hungarian. You can see it on this link: https://www.covid1001.hu/variansok-kontra-vakcinak/
Regards:
Maria Vinkovits, translator and editor (COVID1001)
Ah perfect. Added, thanks!
Dear Tomas,
I am Soichi Tatsumi, who is a member of translation project of your article, Hammer and Dance, supervised by Tomohisa Kato (https://medium.com/tomas-pueyo/%E3%82%B3%E3%83%AD%E3%83%8A%E3%82%A6%E3%82%A4%E3%83%AB%E3%82%B9-%E4%BE%B5%E5%85%A5%E3%81%95%E3%81%9B%E3%81%AA%E3%81%84-%E8%94%93%E5%BB%B6%E3%81%95%E3%81%9B%E3%81%AA%E3%81%84-48e029801d0f…). Currently, in Japan, there is a lack of sense of crisis against variant like B117. In such kinds of meanings, we thought this article is also great worth to introduce Japanese society, then I and Kato have prepared Japanese version. If there is some problem on you, please let me know about that. If possible, I would like to publish article around next Monday.
As for the publication process, I have worried about one point. In your article, it seems like efficiency of vaccine is assessed too much. In the history of vaccine development, the balance in between human rights, safety, and efficiency is always a crucial issue. On such kinds of consideration, I have added the comment into translation related with how developer to care safety on the process of development of coronavirus vaccine (ref; https://bbc.com/news/health-55041371…) and possibility of emergence of resistant strains. If you are not happy about that treatment, please let me know.
All the best,
Soichi
Hi Soichi, it's an honor and a pleasure to work with you and with Mr. Kato. Yes, please translate and I will link it here.
For some reason, the BBC link doesn't work. I am not sure I grasped your point about vaccines, but knowing you and your team I trust your judgment. Please simply share with me a bit more detail so that I can update my thinking too if needed, or otherwise debate why not.
You can also DM me on Twitter so we can start a conversation there:
https://twitter.com/tomaspueyo
Best,
Tomas
Hi Tomas,
Sorry, two links are dead for some reason. I rewrite them as below.
Medium page of translated your article.
https://t.co/ROngqWeCUj?amp=1
BBC website to discuss development process for vaccines.
https://t.co/MWcXvG52Aq?amp=1
Thank you. Finally read it.
So my point on vaccines for the Oxford one, for example, is that (1) money could have flown in earlier on, (2) they already had some sense of what Phase I and II could do from previous tests, and more importantly (3) Phase III (the longest) could have been cut very short with challenge trials. I still think we could have gotten that one (and at least Moderna's) months earlier. What do you think?
Hi Tomas,
Thank you for your response. Now I have published translation in below URL. Please see and link it.
https://statsumi.medium.com/%E5%A4%89%E7%95%B0%E6%A0%AA%E3%81%A8%E3%83%AF%E3%82%AF%E3%83%81%E3%83%B3-%E3%81%A9%E3%81%A1%E3%82%89%E3%81%8C%E5%8B%9D%E3%81%A4%E3%81%8B-9ffcbf79729f
Then, my focuses on current situation in vaccine are below two points. One is how much we can believe the final outcome of the vaccine from the start of vaccine development. The other is how is the ability/speed for future COVID-19 variant to escape the effect of vaccine.
For the first point, my concern is mainly on challenge trial (https://en.wikipedia.org/wiki/Human_challenge_study). I think you have already known, then I found WHO document that cover my concern much enough(https://www.who.int/ethics/publications/key-criteria-ethical-acceptability-of-covid-19-human-challenge/en/). I do not have enough time to investigate whole this document, but my concern might be related with #2 (Assessment of risks and potential benefits) and #6 (Participant selection).
In my understanding, all your point shown above is focused on how to shorten everything to develop new vaccine. From this point, now, basically I agree with you, but this is because I think it may be true the efficiency of this vaccine is high enough and its side-effect it relatively low to compare with the outcome from vaccines. Those are the things that we could not know at the start of development of new vaccines.
I feel those kinds of controversy are not a problem to be solved by money. And that's why pharmaceutical companies do not take this way as a first choice (https://www.healthline.com/health-news/9-pharma-companies-join-to-release-open-letter-promising-covid-19-vaccine-safety). But now I begin to think challenge trials will be important based on current situation after reading this article (https://blogs.bmj.com/bmj/2021/01/08/human-challenge-trials-of-covid-19-vaccines-still-have-much-to-teach-us/).
The latter one is about resistant strain (https://edition.cnn.com/2021/02/02/health/variant-mutation-e484k/index.html). As you pointed out your article, emergence of new variants is strongly related with selective pressure that virus feels. In such kinds of meanings, emergence of resistant strain is considerable future. In other word, in my opinion, if variants would "sleep" in some sense, vaccines would win, but we are not sure variants would sleep as hare does. So such kinds of meanings I have added some note on translation versions.
That's all and thank you so much for your effort.
All the best,
Soichi
Thank you.
If Criterium 2 is your concern, for me the ROI is obvious.
The benefit of a challenge trial is hundreds of thousands of lives saved and tens of billions of dollars saved.
The risk is near 0 now given what we know of the vaccines, because a Phase III trial doesn't stop anyways until there's enough natural infections. So the only difference is that in one case we wait months for natural infections, and in the other we immediately do an artificial infection. That risk is SO small, and the benefit is so HUGE, that there is no way this is not worthwhile. From my shallow point of view.
Tomas, here you have the Spanish translation. Traduccion al castellano -> https://jlrbengoechea.substack.com/p/variantes-vs-vacunas
Updated!
Tomas, check out this Lancet publication: https://www.thelancet.com/journals/lancet/issue/vol397no10273/PIIS0140-6736(21)X0006-2
Looks like a list of links?
https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(21)00183-5.pdf
Tomas
Your math on the deadliness of the new variant may be correct but it could be flawed. It’s easy to see your point when you suppress asymptomatic cases as much as you do in the graph. But if the increased spread is heavily asymptomatic then the studies will miss an alternative consistent hypothesis. It may be less deadly because of a case “mix shift”. To illustrate
Suppose...The strain we have had for 1000 infections say for ease of math had 700 asymptomatic and 300 symptomatic cases. At 0.5% IFR overall that would be 5 deaths or 1.67% of those with symptoms.
Now suppose the new strain spreads asymptomatic more efficiently so to get 300 with symptoms we get 1200 without symptoms instead of 700. Let’s suppose now there are 6 deaths. That would mean the IFR has decreased from 0.5% to 0.4% overall but increased to 2% from 1.67% among those with symptoms. So if the “mix shifted” toward more asymptomatic infections it is both possible that the strain would appear more deadly (because we observe only those with symptoms) but actually be overall less deadly to the full population. This phenomenon will be exacerbated if we test less because the symptomatic patients we observe are likely to be sicker which is another form of a mix shift. I don’t know if this is right but before we panic we should see if this explanation is reasonable.
Anyway, I’m not saying this is right I’m just saying it’s an alternate explanation we should consider and investigate. And be careful that how you draw your graphs doesn’t mislead.
Phil
You're right this is possible. Thinking about it from first principles means this is unlikely: If the variant is worse because it replicates better, the more parsimonious explanation is the one I pointed at.
Well we will know soon enough in Florida where the British variant should soon be dominant. If you are right we will see a massive surge in deaths by the end of February—faster than case growth both symptomatic and not. Fwiw if infectiousness differential (50%) is higher than virulence differential (30%) at constant testing rates while only testing symptomatics the more parsimonious explanation is the mix shift
Tomas, the vaccine is not the only tool in our armoury. Surely similar focus and investment needs to continue also on treatments as these also continue to contain serious and fatal conditions. Both active and prophylactic treatments will help limit impacts too. We are seeing more of these coming to the fore. We have to live alongside not erradicate - our immune systems are there to adapt too.
Any thoughts on this for your analysis
Graeme
Indeed! Yes treatments are messy. I always hear good options and then new results that are underwhelming. It looks like we're reduced the fatality rate by a reasonable %, but it also looks like the new variants will undermine that.
There's also no word about long covid.
For me the right alternative to vaccines is Zero Covid because until we're all safe, nobody will be safe. But if we find treatments that reduce long covid and fatality rates by 90%, that's very different!
Are you safe from crossing the road Tomas ? Or Cancer ? Hepatitis C ?, which kills as many people EVERY year as Covid caused this year (deaths from Covid as opposed to deaths WITH Covid). I only feel unsafe when i dwell on the fear and scare headlines of the media - when I sit calmly and look at the real numbers of deaths, serious illnesses etc I realise we are being manipulated to respond from fear. So safety is an attitude, and an attention to one's own well being and immunity and life. If you wait for zero Covid Tomas, you will likely die softly in your 90's from old age, wishing you had not spent your life - waiting ...
The list of "mistakes" should be a list of questions. We should be curious enough to want to get some real answers to those questions. If we don't fully understand the constraints, we don't know if they were mistakes.
You're right
Analysis very much appreciated. Thank you.
https://www.sheffield.ac.uk/ihuman/covid-19-blog/what-does-covid-19-mean-expertise-case-tomas-pueyo
That's quite something. Thanks for unearthing!
Tomas, thanks for taking the time to put this brilliant piece togther! Perfectly referenced and very clear. You are an incredible teacher.
With deep respect
Vic
Muchas gracias por el excelente estudio y la cantidad de datos aportada. Con estos parámetros y estudios, lo increíble es que sigan sin hacerles caso la mayoría de nuestros gobiernos. Enhorabuena por conseguir seguir buscando y demostrando lo qué se debe hacer y no caer en la desesperanza al ver que no se hizo caso de las advertencias y que eso ha llevado a tener millones de muertos, miles de patologías crónicas y la ruina económica de millones. Esperamos que la cordura y la humildad en algún momento consigan que se haga caso al conocimiento cintífico.
Muchas gracias por el excelente estudio y la cantidad de datos aportada. Con estos parámetros y estudios, lo increíble es que sigan sin hacerles caso la mayoría de nuestros gobiernos. Enhorabuena por conseguir seguir buscando y demostrando lo qué se debe hacer y no caer en la desesperanza al ver que no se hizo caso de las advertencias y que eso ha llevado a tener millones de muertos, miles de patologías crónicas y la ruina económica de millones. Esperamos que la cordura y la humildad en algún momento consigan que se haga caso al conocimiento cintífico.
Just to clarify, this may mean that polyclonal responses to infection by previous strain are insufficient to prevent re-infection and serious disease caused by P1. Unless current vaccines confer more effective immunity against P1 (how likely is that?) than an infection with whole bug, none of the current vaccines using the spike epitopes alone are likely to provide immunity against P1 disease.
Tomas, it's always a treat to read and learn from your analysis. I just have a question y ve u not included Chinese vaccines in your analysis ?
I didn't, but I made a comment about it in a caption. Here it is:
The Russian vaccine also appears effective, but the data comes from Russian researchers from trials made in Moscow only. Given Russia’s track record of politically-motivated news, I can’t trust this data until it’s replicated by an independent source. The same happens with the Chinese vaccine.