This article largely addresses the challenges of vaccine development for SARS-CoV-2.
It was extremely clarifying for me. It seems to have consulted several experts for opinions, but is written for close-to-layman reading.
Here are a few bullet-points, but I recommend the whole thing.
Th-2 type immunopathology, “in which a faulty T cell response triggers allergic inflammation,” plays a big role in bad vaccine response to SARS-CoV-2
Ralph Baric: “There is the potential for ADE, but the bigger problem is probably Th2 immunopathology”
Me: Th-2 responses are extensively documented in both severe COVID19 disease, and SARS-1′s bad vaccine responses. This makes a lot of sense. I would like to understand what is upstream of that, sometime.
Another likely problem: Complement system malfunction
“poorly functional antibodies that form immune complexes, activating the complement system and potentially damaging the airways”
Me: There is most likely a scientific term for this phenomenon. I’ll add it when I find it.
ADE is possible, but less than likely to play a major role
FIPV is a coronavirus where ADE is a major concern. But FIPV productively infects macrophages. I’ve seen no evidence so far that SARS-CoV-2 productively infects WBCs.
UPDATE: It looks like it isn’t productively replicating in WBCs, but it probably is fusing with them and telling them to apoptose. Receptor uncertain, but they were checking T-cells specifically, which are exactly the WBCs that get severely depleted in severe COVID-19. Consider me pretty convinced. Article, h/t CellBioGuy. (P.S. SARS-2 is much better at this than SARS-1.)
For RSV* (Respiratory Syncytial Virus) and SARS-1, bad vaccine response gets blamed on both Th-2 immunopathology and antibody complexes activating the complement system. This can lead to severe disease, including the infiltration of lung tissue by neutrophils (for both) and eosinophils (for RSV?).
For SARS-1, whole-S-protein vaccines seemed more likely to produce this detrimental enhanced immune response. S-fragments containing only the receptor binding domain offered protection, but did not produce this unwanted effect.
They are hoping that the same logic and fix goes for SARS-2, but are still waiting on the test results.
*Me: Side-tangent, but both SARS and RSV seem to be nasty lung infections with some propensity to form syncytia in severe disease. Heck, one of SARS-2′s novel mutations seems likely to be involved in increased syncytia formation. However, the viruses are not close relatives, and they seem to show different preferences for which particular lung cells they reshape into syncytia. I find it interesting that they ran into a similar bad reaction here.
All very interesting, thank you for writing this up. Don’t know enough to evaluate this, but it sounds plausible, and not very encouraging. Vaccines do not look promising, but perhaps further understanding of the disease will lead to other treatments that head off some of these complications.
Vaccines are still our best shot in the long-term.
I wouldn’t phrase it as “vaccines do not look promising,” but more as “SARS is relatively hard to vaccinate well.” I do think we’ll have a vaccine that works reliably, eventually. No other antiviral method has their price-to-effectiveness ratio.
We were able to find fixes to the problems with some SARS-1vaccines, and I think we’ll be able to route around these problems for SARS-2 as well.
This just means that I don’t expect vaccine development to be quite as fast as it would be for viruses without these known problems. Additionally, I suspect animal-testing could be crucial to the development of a safe vaccine, unless we’re willing to risk a few human lives in their stead (which, maybe we are).
And speaking personally, until the clinical trial results are in, I’m inclined to be cautious about taking vaccines that use large swathes of the viral S-protein, although I suspect some with smaller fragments will turn out to be fine.
Very delayed response, sorry. I suspect that by the time we have a vaccine ready to go on a mass scale, it won’t make a huge difference. People will return to life before then, for the most part. Not sure if the most vulnerable are able to get vaccines or if that is dangerous—if they can, it will make a difference for them. I don’t think it will eradicate the disease because not everyone will choose to get it (especially as it seems dangerous side effects could be a thing with this vaccine, due to the autoimmune response, and being comfortable about this will take years, and it isn’t clear how dangerous it is for most people), it would be a huge and imperfect effort even if we mandated it, and presumably the disease will change over time, requiring new vaccinations. So I don’t think a vaccine is going to be what changes things here. Obviously, it is still playing out, and the data about risks that comes out regarding both the disease and the vaccine, along with other practical issues, will affect the final outcome.
I did specify long-term, which for me meant time-frames of around a year to a decade out. Honestly, I suspect you’re largely right about the short-term.
Well, except I might be more optimistic about vaccination efforts. Effective vaccination pushes in the past give me some hope.
Also, the mutation rate is a good bit lower than the seasonal flu. SARS-CoV-2′s point-mutations per year is around 28 substitutions, which is about 1⁄2 as many as the flu. Or around 1⁄3 the rate, at ~1.1e-3 subs per site per year, compared to flu’s 3.3 subs per site per year. (Different genome lengths, hence the different answers.)
I’m inclined to be cautious about taking vaccines that use large swathes of the viral S-protein, although I suspect some with smaller fragments will turn out to be fine.
What would be the difference between a large swathe and smaller fragments here?
This article largely addresses the challenges of vaccine development for SARS-CoV-2.
It was extremely clarifying for me. It seems to have consulted several experts for opinions, but is written for close-to-layman reading.
Here are a few bullet-points, but I recommend the whole thing.
Th-2 type immunopathology, “in which a faulty T cell response triggers allergic inflammation,” plays a big role in bad vaccine response to SARS-CoV-2
Ralph Baric: “There is the potential for ADE, but the bigger problem is probably Th2 immunopathology”
Me: Th-2 responses are extensively documented in both severe COVID19 disease, and SARS-1′s bad vaccine responses. This makes a lot of sense. I would like to understand what is upstream of that, sometime.
Another likely problem: Complement system malfunction
“poorly functional antibodies that form immune complexes, activating the complement system and potentially damaging the airways”
Me: There is most likely a scientific term for this phenomenon. I’ll add it when I find it.
ADE is possible, but less than likely to play a major role
FIPV is a coronavirus where ADE is a major concern. But FIPV productively infects macrophages. I’ve seen no evidence so far that SARS-CoV-2 productively infects WBCs.
UPDATE: It looks like it isn’t productively replicating in WBCs, but it probably is fusing with them and telling them to apoptose. Receptor uncertain, but they were checking T-cells specifically, which are exactly the WBCs that get severely depleted in severe COVID-19. Consider me pretty convinced. Article, h/t CellBioGuy. (P.S. SARS-2 is much better at this than SARS-1.)
For RSV* (Respiratory Syncytial Virus) and SARS-1, bad vaccine response gets blamed on both Th-2 immunopathology and antibody complexes activating the complement system. This can lead to severe disease, including the infiltration of lung tissue by neutrophils (for both) and eosinophils (for RSV?).
For SARS-1, whole-S-protein vaccines seemed more likely to produce this detrimental enhanced immune response. S-fragments containing only the receptor binding domain offered protection, but did not produce this unwanted effect.
They are hoping that the same logic and fix goes for SARS-2, but are still waiting on the test results.
*Me: Side-tangent, but both SARS and RSV seem to be nasty lung infections with some propensity to form syncytia in severe disease. Heck, one of SARS-2′s novel mutations seems likely to be involved in increased syncytia formation. However, the viruses are not close relatives, and they seem to show different preferences for which particular lung cells they reshape into syncytia. I find it interesting that they ran into a similar bad reaction here.
All very interesting, thank you for writing this up. Don’t know enough to evaluate this, but it sounds plausible, and not very encouraging. Vaccines do not look promising, but perhaps further understanding of the disease will lead to other treatments that head off some of these complications.
Vaccines are still our best shot in the long-term.
I wouldn’t phrase it as “vaccines do not look promising,” but more as “SARS is relatively hard to vaccinate well.” I do think we’ll have a vaccine that works reliably, eventually. No other antiviral method has their price-to-effectiveness ratio.
We were able to find fixes to the problems with some SARS-1vaccines, and I think we’ll be able to route around these problems for SARS-2 as well.
This just means that I don’t expect vaccine development to be quite as fast as it would be for viruses without these known problems. Additionally, I suspect animal-testing could be crucial to the development of a safe vaccine, unless we’re willing to risk a few human lives in their stead (which, maybe we are).
And speaking personally, until the clinical trial results are in, I’m inclined to be cautious about taking vaccines that use large swathes of the viral S-protein, although I suspect some with smaller fragments will turn out to be fine.
Very delayed response, sorry. I suspect that by the time we have a vaccine ready to go on a mass scale, it won’t make a huge difference. People will return to life before then, for the most part. Not sure if the most vulnerable are able to get vaccines or if that is dangerous—if they can, it will make a difference for them. I don’t think it will eradicate the disease because not everyone will choose to get it (especially as it seems dangerous side effects could be a thing with this vaccine, due to the autoimmune response, and being comfortable about this will take years, and it isn’t clear how dangerous it is for most people), it would be a huge and imperfect effort even if we mandated it, and presumably the disease will change over time, requiring new vaccinations. So I don’t think a vaccine is going to be what changes things here. Obviously, it is still playing out, and the data about risks that comes out regarding both the disease and the vaccine, along with other practical issues, will affect the final outcome.
I did specify long-term, which for me meant time-frames of around a year to a decade out. Honestly, I suspect you’re largely right about the short-term.
Well, except I might be more optimistic about vaccination efforts. Effective vaccination pushes in the past give me some hope.
Also, the mutation rate is a good bit lower than the seasonal flu. SARS-CoV-2′s point-mutations per year is around 28 substitutions, which is about 1⁄2 as many as the flu. Or around 1⁄3 the rate, at ~1.1e-3 subs per site per year, compared to flu’s 3.3 subs per site per year. (Different genome lengths, hence the different answers.)
What would be the difference between a large swathe and smaller fragments here?