Thought I would plug a really fascinating recent preprint. It is entirely a theory paper but it makes sense of several interesting things that have been seen about the fact that type A blood is a risk factor for infection, type O blood is protective, and only a fraction of infected people infect most new people. If you have the ability to read biomedical literature I recommend it wholeheartedly along with all its references.
“Modelling suggests blood group incompatibility may substantially reduce SARS-CoV-2 transmission”
Short version: it is possible that transmission of the virus from one person to another is substantially hampered by blood transfusion incompatibility. Type O blood individuals become ‘universal viral donors’ able to maximally infect most people, while being at substantially lower risk of infection from non-type-O individuals.
It has already been established that HIV, SARS-classic, and measles virions produced in tissue culture from cells expressing the type A antigen can be deactivated by serum containing anti-A antibodies, albeit at a lower rate than using antibodies specifically raised against the viral proteins. The ABO antigen is not a protein, but instead is a polysaccharide that is used to decorate many other proteins. If the viral spike protein incorporates an ABO antigen in its glycosylation it can be bound by antibodies, some of which will neutralize it. This would ONLY affect the incoming viral inoculum, not any virus produced in your own cells.
The data in the paper suggests a risk to type O inviduals of getting the virus from a type A individual of about 40% baseline.
This would also be complicated by ‘secretor’ status. About 80% of the European population puts the ABO antigen on proteins on all their cells rather than just blood cells, but 20% are ‘nonsecretors’ who only put it on blood cells. These people would fail to put the ABO antigen onto virions and transmit as if they were type O ‘universal donors’ but still get infected with heightened risk factors if they have non-O blood type status. This would also imply that the rate of getting infected by someone of an incompatible blood type who was a secretor would actually be only about 20% of baseline.
An implication of this work is that spread should be slower in populations with a greater *diversity* of blood types—a more even mix of A, B, and O—and that superspreaders should preferentially be nonsecretors and type O individuals.
Needs in vitro work and careful contact tracing epidemiology to back it up. But it makes way too much sense...
Note that this paper is just a mathematical model, without any actual data, so our default stance should be skepticism. The mechanism seems unlikely, but not impossible. Respiratory droplets apparently do contain whole cells (source), so a way this could happen would be if transmission involves not just virus particles in droplets, but infected whole host cells; in that case, the surface markers of those cells could make a big difference to the initial immune response.
No, I am talking about actual ABO antigen on actual virus particles, and specifically probably on actual spike protein.
The ABO antigen is not a protein, unlike the Rh antigen (the positive/negative factor—which is not empirically relevant for disease risk unlike ABO). It is a motif of a few sugars hooked together (three particular sugars in a chain for O, and two different branched 4-sugar motifs for A and B) that is used as a component of polysaccharide chains used to decorate proteins via glycosylation. It winds up attached to loads and loads of membrane proteins made by cells. In a nonsecretor it winds up on surface proteins of blood cells and endothelial cells only, in the other 80% of the population it winds up on surface proteins on all cells.
The spike protein is COVERED with glycosylation sites. They are places on the protein that polysaccharide chains defined by the particular enzyme milieu of the cell get added. Like many glycosylated proteins they’re rather variable molecule to molecule and not precisely genetically predetermined by the protein sequence, though the protein certainly biases particular types of chains to wind up on particular pieces. In the case of the spike protein, these chains actually significantly help make sure that there’s very few places on the protein that an antibody can bind without needing to bind to the sugars, since the sugars are the same sugars that you decorate your own cells with and you thus cannot generate an immune reaction against.
If you look at the references of the paper above, you will see it has been experimentally determined for SARS, measles, and HIV that the ABO antigen winds up decorating the spike/fusion protein and that anti-A antibodies can neutralize particles created in tissue culture that expresses the A antigen. It doesn’t neutralize nearly as vigorously as antibodies raised against the protein proper, but a whole lot of the particles get neutralized in in vitro experiments. Presumably they bind to sugar chains near the receptor binding site and just physically block it from being able to touch its receptor.
So, virions made in your own body are effectively cloaked by glycosylation. But if an incoming inoculum includes a bit of glycosylation that you have antibodies against—an incompatible ABO blood type—antibodies might be able to bind to and neutralize a reasonable fraction of incoming viral particles before they are able to infect you and make virions that have your own ABO sugars.
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I am quite aware that this is only modeling. The feature is that the risk factors of different blood types line up with what you would expect if there was this blood type incompatibility of spread in which getting the virus from someone with an incompatible blood type was only 40% as likely as from someone with a compatible blood type, and that this could explain a component of the extreme dispersion seen in which some people barely spread the disease and some spread it quite freely. Definitely requires in vitro and careful contact tracing work to follow up on and see if the blood type associations are somehow a fluke with a different mechanism.
What’s the practical implication if true? Presumably it implies things like “You’re type A so you go to the type O butcher’s shop, or have an office meeting with a Type O colleague, and everyone is safe?” Does that mean that type A people become more valuable because there are less of them and they match easier? What about type B? Are ABs worse than As or are they now superstars? Etc.
Does this mean that blood relatives are in general more likely to infect within-household than friends or spouses, since their types match more often? Any implications? Etc.
Important to note that the author suggests that the best fit from observed blood type disease risk differences to a model like this would indicate that getting a virus from someone with an incompatible blood type would be about 40% as easy as getting infected from a compatible blood type.
One might be able to make arguments about intra-familial transmission versus extra-familial transmission rates with more math than I have time for right now.
In this model, if you ignore secretion status, type O people would be hardest to infect but most likely to spread. In the US about 45% of the population is type O, about 40% is type A, about 11% is type B, and about 4% is type AB according to the first source I found. You get the following fractions of the population being easy to transmit to and receive from for each blood type:
O—to 100%, from 45%
B—to 15%, from 56%
A—to 44%, from 85%
AB—to 4%, from 100%
If you assume that you are 40% as likely to spread to someone of a noncompatible blood type, you get a ease-of-infecting-others score for each type of: O = 100%, B = 49%, A = 66%, AB = 42%. Assuming you don’t know their secretion/nonsecretion status.
If you take into account non-secretors, then this is all slightly wrong and you actually have most non-O people slightly less infectious than that and some people who are A, B, or AB with their usual higher risk of getting infected but who transmit like type O. This is me—I am a type A nonsecretor and thus would be more vulnerable to transmission from a full 85% of the population, while being good at transmitting to 100% of the population. Such individuals might be more likely to be important nodes in the network.
If you look at the paper they show that the biggest result of this kind of an effect on an epidemiological model is that the more diverse the population is in terms of blood types—a more even distribution of A, B, and O—the slower spread happens, and the more homogenous a population is in terms of blood type the faster it happens regardless of which blood type is dominant.
No. It is already known that type O people are at lower risk of disease, with higher risk to type B then higher still to type A then highest to type AB, and that when you do a GWAS study for associations with disease the ABO locus is one of exactly two loci that fall out as very important. The question is, is that due to some intrinsic degree of resistance to disease brought on by the ABO locus or is it due to this sort of transmission incompatibility? To know you need to figure out actual pairs of people you know transmitted to each other and see if particular pairwise patterns of blood types are more likely than others (which has never been done), and test the virions themselves to see that they can be neutralized by anti ABO antibody levels that you find in mucous membranes (though this is highly likely given previous work on other viruses).
Thought I would plug a really fascinating recent preprint. It is entirely a theory paper but it makes sense of several interesting things that have been seen about the fact that type A blood is a risk factor for infection, type O blood is protective, and only a fraction of infected people infect most new people. If you have the ability to read biomedical literature I recommend it wholeheartedly along with all its references.
“Modelling suggests blood group incompatibility may substantially reduce SARS-CoV-2 transmission”
https://www.medrxiv.org/content/10.1101/2020.07.13.20152637v1
Short version: it is possible that transmission of the virus from one person to another is substantially hampered by blood transfusion incompatibility. Type O blood individuals become ‘universal viral donors’ able to maximally infect most people, while being at substantially lower risk of infection from non-type-O individuals.
It has already been established that HIV, SARS-classic, and measles virions produced in tissue culture from cells expressing the type A antigen can be deactivated by serum containing anti-A antibodies, albeit at a lower rate than using antibodies specifically raised against the viral proteins. The ABO antigen is not a protein, but instead is a polysaccharide that is used to decorate many other proteins. If the viral spike protein incorporates an ABO antigen in its glycosylation it can be bound by antibodies, some of which will neutralize it. This would ONLY affect the incoming viral inoculum, not any virus produced in your own cells.
The data in the paper suggests a risk to type O inviduals of getting the virus from a type A individual of about 40% baseline.
This would also be complicated by ‘secretor’ status. About 80% of the European population puts the ABO antigen on proteins on all their cells rather than just blood cells, but 20% are ‘nonsecretors’ who only put it on blood cells. These people would fail to put the ABO antigen onto virions and transmit as if they were type O ‘universal donors’ but still get infected with heightened risk factors if they have non-O blood type status. This would also imply that the rate of getting infected by someone of an incompatible blood type who was a secretor would actually be only about 20% of baseline.
An implication of this work is that spread should be slower in populations with a greater *diversity* of blood types—a more even mix of A, B, and O—and that superspreaders should preferentially be nonsecretors and type O individuals.
Needs in vitro work and careful contact tracing epidemiology to back it up. But it makes way too much sense...
Note that this paper is just a mathematical model, without any actual data, so our default stance should be skepticism. The mechanism seems unlikely, but not impossible. Respiratory droplets apparently do contain whole cells (source), so a way this could happen would be if transmission involves not just virus particles in droplets, but infected whole host cells; in that case, the surface markers of those cells could make a big difference to the initial immune response.
No, I am talking about actual ABO antigen on actual virus particles, and specifically probably on actual spike protein.
The ABO antigen is not a protein, unlike the Rh antigen (the positive/negative factor—which is not empirically relevant for disease risk unlike ABO). It is a motif of a few sugars hooked together (three particular sugars in a chain for O, and two different branched 4-sugar motifs for A and B) that is used as a component of polysaccharide chains used to decorate proteins via glycosylation. It winds up attached to loads and loads of membrane proteins made by cells. In a nonsecretor it winds up on surface proteins of blood cells and endothelial cells only, in the other 80% of the population it winds up on surface proteins on all cells.
The spike protein is COVERED with glycosylation sites. They are places on the protein that polysaccharide chains defined by the particular enzyme milieu of the cell get added. Like many glycosylated proteins they’re rather variable molecule to molecule and not precisely genetically predetermined by the protein sequence, though the protein certainly biases particular types of chains to wind up on particular pieces. In the case of the spike protein, these chains actually significantly help make sure that there’s very few places on the protein that an antibody can bind without needing to bind to the sugars, since the sugars are the same sugars that you decorate your own cells with and you thus cannot generate an immune reaction against.
If you look at the references of the paper above, you will see it has been experimentally determined for SARS, measles, and HIV that the ABO antigen winds up decorating the spike/fusion protein and that anti-A antibodies can neutralize particles created in tissue culture that expresses the A antigen. It doesn’t neutralize nearly as vigorously as antibodies raised against the protein proper, but a whole lot of the particles get neutralized in in vitro experiments. Presumably they bind to sugar chains near the receptor binding site and just physically block it from being able to touch its receptor.
So, virions made in your own body are effectively cloaked by glycosylation. But if an incoming inoculum includes a bit of glycosylation that you have antibodies against—an incompatible ABO blood type—antibodies might be able to bind to and neutralize a reasonable fraction of incoming viral particles before they are able to infect you and make virions that have your own ABO sugars.
---
I am quite aware that this is only modeling. The feature is that the risk factors of different blood types line up with what you would expect if there was this blood type incompatibility of spread in which getting the virus from someone with an incompatible blood type was only 40% as likely as from someone with a compatible blood type, and that this could explain a component of the extreme dispersion seen in which some people barely spread the disease and some spread it quite freely. Definitely requires in vitro and careful contact tracing work to follow up on and see if the blood type associations are somehow a fluke with a different mechanism.
Interesting.
What’s the practical implication if true? Presumably it implies things like “You’re type A so you go to the type O butcher’s shop, or have an office meeting with a Type O colleague, and everyone is safe?” Does that mean that type A people become more valuable because there are less of them and they match easier? What about type B? Are ABs worse than As or are they now superstars? Etc.
Does this mean that blood relatives are in general more likely to infect within-household than friends or spouses, since their types match more often? Any implications? Etc.
Important to note that the author suggests that the best fit from observed blood type disease risk differences to a model like this would indicate that getting a virus from someone with an incompatible blood type would be about 40% as easy as getting infected from a compatible blood type.
One might be able to make arguments about intra-familial transmission versus extra-familial transmission rates with more math than I have time for right now.
In this model, if you ignore secretion status, type O people would be hardest to infect but most likely to spread. In the US about 45% of the population is type O, about 40% is type A, about 11% is type B, and about 4% is type AB according to the first source I found. You get the following fractions of the population being easy to transmit to and receive from for each blood type:
O—to 100%, from 45%
B—to 15%, from 56%
A—to 44%, from 85%
AB—to 4%, from 100%
If you assume that you are 40% as likely to spread to someone of a noncompatible blood type, you get a ease-of-infecting-others score for each type of: O = 100%, B = 49%, A = 66%, AB = 42%. Assuming you don’t know their secretion/nonsecretion status.
If you take into account non-secretors, then this is all slightly wrong and you actually have most non-O people slightly less infectious than that and some people who are A, B, or AB with their usual higher risk of getting infected but who transmit like type O. This is me—I am a type A nonsecretor and thus would be more vulnerable to transmission from a full 85% of the population, while being good at transmitting to 100% of the population. Such individuals might be more likely to be important nodes in the network.
If you look at the paper they show that the biggest result of this kind of an effect on an epidemiological model is that the more diverse the population is in terms of blood types—a more even distribution of A, B, and O—the slower spread happens, and the more homogenous a population is in terms of blood type the faster it happens regardless of which blood type is dominant.
So we can test AB-blood populations for antibodies and compare that to the general population, and you’ll know quickly if this theory is right or not?
No. It is already known that type O people are at lower risk of disease, with higher risk to type B then higher still to type A then highest to type AB, and that when you do a GWAS study for associations with disease the ABO locus is one of exactly two loci that fall out as very important. The question is, is that due to some intrinsic degree of resistance to disease brought on by the ABO locus or is it due to this sort of transmission incompatibility? To know you need to figure out actual pairs of people you know transmitted to each other and see if particular pairwise patterns of blood types are more likely than others (which has never been done), and test the virions themselves to see that they can be neutralized by anti ABO antibody levels that you find in mucous membranes (though this is highly likely given previous work on other viruses).