5 ms·

It's fascinating to see how knowledge evolves over time. So far most of the emphasis has been on the spike protein and its cleavage mechanisms. Now we start to

by zmmmmm 5y ago

It's fascinating to see how knowledge evolves over time. So far most of the emphasis has been on the spike protein and its cleavage mechanisms. Now we start to see that may even be a relatively minor factor compared to the nucleocapsid. It is quite important to understand all these things if we are seeing new variants arise and need to assess how dangerous they are likely to be. Most especially since vaccines are based on the spike protein on the premise that it is essential to the infectiousness. But what if a variant can arise with a highly compromised spike protein yet compensate enough to still be highly infectious due to other factors? The most interesting thing is to think about where the other empty spaces in our knowledge are that are yet to be filled in - what will we know this time next year that will have us saying "previously we thought ...."

mdp2021 5y ago
Forthcoming vaccine Valneva will be based on inactivated virus. Nucleocapsid preserved.
- angelzen 5y ago
  Novavax has also applied for approval in Canada, UK, Australia and NZ, and possibly already received EUA in Indonesia. https://news.ycombinator.com/item?id=29111197 https://news.ycombinator.com/item?id=29111197 https://ir.novavax.com/press-releases?category=2 https://ir.novavax.com/press-releases?category=2 https://www.forbes.com/sites/joshuacohen/2021/11/03/if-approved-the-novavax-covid-19-vaccine-could-help-reduce-vaccine-hesitancy-in-the-us/ https://www.forbes.com/sites/joshuacohen/2021/11/03/if-appro...
  - fsh 5y ago
    The Novavax vaccine is a recombinant protein vaccine and only contains the spike protein: https://mvec.mcri.edu.au/references/novavax-covid-19-vaccine/ https://mvec.mcri.edu.au/references/novavax-covid-19-vaccine...
    - mdp2021 5y ago
      ...plus the 'Matrix-M1' adjuvant - saponin from tree bark. And, if you wish, polysorbate 80 to assemble the spike proteins into nanoparticle "parcels". In fact, I think the Novavax particles should be radial bunches of spike proteins tied at their "tail" - see e.g. https://www.nytimes.com/interactive/2020/health/novavax-covid-19-vaccine.html https://www.nytimes.com/interactive/2020/health/novavax-covi... Adequately technical and well done is the description at https://www.sciencemediacentre.co.nz/2021/09/14/what-do-we-know-about-the-novavax-vaccine-expert-qa/ https://www.sciencemediacentre.co.nz/2021/09/14/what-do-we-k...
    - angelzen 5y ago
      Thanks for the correction and the great link.
- warning26 5y ago
  Sinovac and Sinopharm, the Chinese vaccines that may or may not actually work, are also inactivated.
ak217 5y ago
The nucleocapsid is inside the live virus - it's not accessible from the outside. So we don't currently know of a way to train the human immune system to bind to it to kill live virus particles. So while it's important to understand the role of the nucleocapsid in infectivity, it's not actionable for vaccine technology. Conversely, there is currently no evidence that the spike can be "highly compromised" without reducing infectivity. The spike has to bind specifically to ACE2 in order to enter the cell. As long as that's true, vaccines can continue to target live virus using the ACE2 receptor binding domain in the spike protein.
dekhn 5y ago
I lived through the entire HIV cycle (from first announcements in the press to the current situation). There weren't really any credible origin stories for HIV for years after the discovery of the virus and the syndrome it causes (AIDS). Eventually (more than a decade later), a reasonably good origin narrative evolved, but not until there were plenty of now-discredited origin theories: https://en.wikipedia.org/wiki/Discredited_HIV/AIDS_origins_theories https://en.wikipedia.org/wiki/Discredited_HIV/AIDS_origins_t...
- jacquesm 5y ago
  It's a pretty sobering thought that HIV took 40 years to get to 37 million people confirmed dead, and that COVID-19 took only two years to get to 5 million confirmed dead.
  - FjolsvithAase 5y ago
    Especially sobering when those 5 million dead preempted death by other causes! Meaning that people weren't surviving long enough to die by influenza or motorcycle accident.
  - maxerickson 5y ago
    The official statistics start the clock in the 1980s when HIV became widespread enough to get noticed, but it probably infected humans quite a lot earlier. (which I think that period is probably relevant in the comparison to COVID)
  - thaumasiotes 5y ago
    > It's a pretty sobering thought that HIV took 40 years to get to 37 million people confirmed dead, and that COVID-19 took only two years to get to 5 million confirmed dead. The transmission mechanism for one of them is "being in the same room with the other person", and the transmission mechanism for the other is "having gay sex with the other person". [1] Almost everyone had pre-existing behavioral immunity. If you can only infect a tiny portion of the population, you can only cause a tiny number of deaths. [1] This is not the primary transmission mechanism in Africa, but it's pretty much the exclusive mechanism as far as the Western history of AIDS goes, with the runner-up being "receive a blood transfusion from the other person".
etiam 5y ago
Amazing work, and it would be gratifying to see Doudna bag another Nobel prize, to be awarded in a year when the celebrations aren't markedly subdued by rampant disease. As important as the posted story demonstrates the N protein to be, it's probably not a good idea to direct a vaccine towards it without a much deeper understanding of the consequences. Derek Lowe's wonderful column in the same magazine touched that point earlier this year, in https://www.science.org/content/blog-post/antibody-dependent-enhancement-and-coronavirus-vaccines https://www.science.org/content/blog-post/antibody-dependent... See the last paragraph under the subheading "ADE and Coronaviruses" for a very brief account of candidate vaccines (against the closely related SARS-CoV) which included the N protein tending to make the disease worse. For those who have already read that story, but not recently, you may want to check back on it, because I see now that Derek has added an update and more references: "There was trouble after immunization with a nucleoprotein-directed vaccine, but ADE could also be seen with some of the Spike-directed vaccine candidates as well - see reviews here, here, and here." Not sure exactly what you, zmmmmm, mean by a "compromised" spike protein, but if it's something like one that is not well neutralized by antibodies raised against epitopes from the early generations of SARS-CoV-2, this post recently would be relevant https://news.ycombinator.com/item?id=29004006 https://news.ycombinator.com/item?id=29004006
hyperpallium2 5y ago
The known is practically nothing compared to the unknown. What we know is inconceivably less than a rounding error. Appearing to know is essential for our social hierarchies. So... here we are.
rapjr9 5y ago
>So far most of the emphasis has been on the spike protein and its cleavage mechanisms. This is something that bothers me about science, why has most of the emphasis been on the spike protein? Has that prevented many researchers from looking for other mechanisms that increase infectiousness? Maybe not in this case, but it seems really difficult to tell what science believes are facts and what are assumptions. I think that if you could identify all the assumptions in science and test them you would find rich material for groundbreaking research. One assumption that seems to be universal is that old science is correct, that it has "stood the test of time", except that often nobody tested it and a lot of it is turning out to be wrong. Those old folk had a tendency to make things up and no one at the time checked them on it because they were an authority unto themselves. I'd like to see any statements that are assumptions specifically highlighted in research papers. There is a little of this in security research papers but not in other research as far as I can tell. How might it be possible to tell how much of "what is true" is actually based on assumptions? Maybe a semantic mining of research papers using an AI could identify assumptions and list them as interesting areas for further testing and research? To start with any statement that doesn't have a citation is a candidate for being an assumption. Also statements like "it is well known" without a citation. Maybe a dependency of logic upon an unsupported statement could be used to find assumptions.

by zmmmmm 5y ago

mdp2021 5y ago

Forthcoming vaccine Valneva will be based on inactivated virus. Nucleocapsid preserved.

angelzen 5y ago
Novavax has also applied for approval in Canada, UK, Australia and NZ, and possibly already received EUA in Indonesia. https://news.ycombinator.com/item?id=29111197 https://news.ycombinator.com/item?id=29111197 https://ir.novavax.com/press-releases?category=2 https://ir.novavax.com/press-releases?category=2 https://www.forbes.com/sites/joshuacohen/2021/11/03/if-approved-the-novavax-covid-19-vaccine-could-help-reduce-vaccine-hesitancy-in-the-us/ https://www.forbes.com/sites/joshuacohen/2021/11/03/if-appro...
- fsh 5y ago
  The Novavax vaccine is a recombinant protein vaccine and only contains the spike protein: https://mvec.mcri.edu.au/references/novavax-covid-19-vaccine/ https://mvec.mcri.edu.au/references/novavax-covid-19-vaccine...
  - mdp2021 5y ago
    ...plus the 'Matrix-M1' adjuvant - saponin from tree bark. And, if you wish, polysorbate 80 to assemble the spike proteins into nanoparticle "parcels". In fact, I think the Novavax particles should be radial bunches of spike proteins tied at their "tail" - see e.g. https://www.nytimes.com/interactive/2020/health/novavax-covid-19-vaccine.html https://www.nytimes.com/interactive/2020/health/novavax-covi... Adequately technical and well done is the description at https://www.sciencemediacentre.co.nz/2021/09/14/what-do-we-know-about-the-novavax-vaccine-expert-qa/ https://www.sciencemediacentre.co.nz/2021/09/14/what-do-we-k...
  - angelzen 5y ago
    Thanks for the correction and the great link.
warning26 5y ago
Sinovac and Sinopharm, the Chinese vaccines that may or may not actually work, are also inactivated.

ak217 5y ago

The nucleocapsid is inside the live virus - it's not accessible from the outside. So we don't currently know of a way to train the human immune system to bind to it to kill live virus particles. So while it's important to understand the role of the nucleocapsid in infectivity, it's not actionable for vaccine technology. Conversely, there is currently no evidence that the spike can be "highly compromised" without reducing infectivity. The spike has to bind specifically to ACE2 in order to enter the cell. As long as that's true, vaccines can continue to target live virus using the ACE2 receptor binding domain in the spike protein.

dekhn 5y ago

I lived through the entire HIV cycle (from first announcements in the press to the current situation). There weren't really any credible origin stories for HIV for years after the discovery of the virus and the syndrome it causes (AIDS). Eventually (more than a decade later), a reasonably good origin narrative evolved, but not until there were plenty of now-discredited origin theories: https://en.wikipedia.org/wiki/Discredited_HIV/AIDS_origins_theories https://en.wikipedia.org/wiki/Discredited_HIV/AIDS_origins_t...

jacquesm 5y ago
It's a pretty sobering thought that HIV took 40 years to get to 37 million people confirmed dead, and that COVID-19 took only two years to get to 5 million confirmed dead.
- FjolsvithAase 5y ago
  Especially sobering when those 5 million dead preempted death by other causes! Meaning that people weren't surviving long enough to die by influenza or motorcycle accident.
- maxerickson 5y ago
  The official statistics start the clock in the 1980s when HIV became widespread enough to get noticed, but it probably infected humans quite a lot earlier. (which I think that period is probably relevant in the comparison to COVID)
- thaumasiotes 5y ago
  > It's a pretty sobering thought that HIV took 40 years to get to 37 million people confirmed dead, and that COVID-19 took only two years to get to 5 million confirmed dead. The transmission mechanism for one of them is "being in the same room with the other person", and the transmission mechanism for the other is "having gay sex with the other person". [1] Almost everyone had pre-existing behavioral immunity. If you can only infect a tiny portion of the population, you can only cause a tiny number of deaths. [1] This is not the primary transmission mechanism in Africa, but it's pretty much the exclusive mechanism as far as the Western history of AIDS goes, with the runner-up being "receive a blood transfusion from the other person".

etiam 5y ago

Amazing work, and it would be gratifying to see Doudna bag another Nobel prize, to be awarded in a year when the celebrations aren't markedly subdued by rampant disease. As important as the posted story demonstrates the N protein to be, it's probably not a good idea to direct a vaccine towards it without a much deeper understanding of the consequences. Derek Lowe's wonderful column in the same magazine touched that point earlier this year, in https://www.science.org/content/blog-post/antibody-dependent-enhancement-and-coronavirus-vaccines https://www.science.org/content/blog-post/antibody-dependent... See the last paragraph under the subheading "ADE and Coronaviruses" for a very brief account of candidate vaccines (against the closely related SARS-CoV) which included the N protein tending to make the disease worse. For those who have already read that story, but not recently, you may want to check back on it, because I see now that Derek has added an update and more references: "There was trouble after immunization with a nucleoprotein-directed vaccine, but ADE could also be seen with some of the Spike-directed vaccine candidates as well - see reviews here, here, and here." Not sure exactly what you, zmmmmm, mean by a "compromised" spike protein, but if it's something like one that is not well neutralized by antibodies raised against epitopes from the early generations of SARS-CoV-2, this post recently would be relevant https://news.ycombinator.com/item?id=29004006 https://news.ycombinator.com/item?id=29004006

hyperpallium2 5y ago

The known is practically nothing compared to the unknown. What we know is inconceivably less than a rounding error. Appearing to know is essential for our social hierarchies. So... here we are.

rapjr9 5y ago

>So far most of the emphasis has been on the spike protein and its cleavage mechanisms. This is something that bothers me about science, why has most of the emphasis been on the spike protein? Has that prevented many researchers from looking for other mechanisms that increase infectiousness? Maybe not in this case, but it seems really difficult to tell what science believes are facts and what are assumptions. I think that if you could identify all the assumptions in science and test them you would find rich material for groundbreaking research. One assumption that seems to be universal is that old science is correct, that it has "stood the test of time", except that often nobody tested it and a lot of it is turning out to be wrong. Those old folk had a tendency to make things up and no one at the time checked them on it because they were an authority unto themselves. I'd like to see any statements that are assumptions specifically highlighted in research papers. There is a little of this in security research papers but not in other research as far as I can tell. How might it be possible to tell how much of "what is true" is actually based on assumptions? Maybe a semantic mining of research papers using an AI could identify assumptions and list them as interesting areas for further testing and research? To start with any statement that doesn't have a citation is a candidate for being an assumption. Also statements like "it is well known" without a citation. Maybe a dependency of logic upon an unsupported statement could be used to find assumptions.