One empirical subquestion I’m interested in (in case anybody reading this is very knowledgeable about human immunology, which seems plausible) is whether we have strong in-principle reasons to believe that our immune systems, with sufficient coaxing, is capable of producing antibodies for arbitrary diseases.
This seems like a necessary but not sufficient condition for developing vaccines that work against arbitrary novel diseases, and may become increasingly relevant if we’re more worried about manmade than natural pandemics.
This is an interesting question which I have thought about a little before, but stopped given infohazards risks from thinking too hard about ways in which this might be possible outweighed the actionability of such insights. For a variety of reasons, which includes this reason, I am a fan of pushing fast response passive immunoprophylaxis platforms and other countermeasure approaches such as the receptor-competition based ones, it seems that whatever we are worried about, such approaches would be robustly good.
Short answer (mostly based on undergrad immunology and vaccinology): yes there could be things.
There are different potential reasons for why active immunisation might not work for a given pathogen, the most obvious one being that we cannot induce antibodies that manage to bind to (neutralising) areas on pathogens. This may be because of us only having a limited set of B/T cell receptor genes (and even less flexible MHC receptor (present pathogen peptides to immune cells) genes which might be relevant for inducing immune responses) which might mean that induction is difficult—but these genes vary across the population potentially exactly for the reason that the population is protected from getting wiped out by one specific pathogen. This is somewhat seen in HIV where some individuals are able to develop neutralising antibodies and most others don’t—question is whether sequential immunisation with more and more complex antigens (to achieve antibody evolution to penetrate HIV glycan shields) can get us to neutralising antibodies for everyone or not.
Another mechanism (discussed by Tessa) might be that antibody-dependent disease enhancement. If any neutralising antibody induction by active vaccination is accompanied by non-neutralising antibodies which may cause ADE for a given pathogen this might be bad. I think this is somewhat a technical challenge, but there might be pathogens which feature unique mechanisms that make overcoming this very difficult.
Not an expert, but Antibody-Dependent Enhancement (ADE) shows that we are not guaranteed to produce useful antibodies for arbitrary diseases. In fact, we can produce antibodies that make a disease worse!
This happens in dengue, where there are different serotypes of the disease and antibodies for one serotype can be non-neutralizing for others, but “original antigenic sin” (I find this term quite funny) means that we don’t generate new ones and the infection is enhanced because the non-neutralizing antibodies recruit macrophages, which dengue likes to replicate in.
Here’s a Derek Lowe post from December 2020 on ADE, which also notes examples in HIV, Ebola, and coxsackievirus. I was in fact a bit worried about ADE with SARS-CoV-2 early in the pandemic, since spike protein immunization against feline coronaviruses has sometimes led to ADE.
Definitely not expert enough to confidently answer this, but I thought the answer was obviously yes—I don’t think there are any diseases where it doesn’t happen as a natural part of response. (Even HIV is mostly fought off quickly, but in cases where it spreads, it infects enough immune cells that it persists and eventually destroys the immune system.)
So for example rabies has a ~100% fatality rate without vaccination, but immune systems are expressive enough to produce antibodies with vaccination.
I’m not personally convinced by directly empirical evidence that it hasn’t happened so far → this isn’t possible, since the space of pathogens that’s evolutionarily plausible is presumably a lot narrower than the space of possible pathogens, including engineered ones.
Interesting though not super important piece of information: Rabies is ~100% fatal once symptoms present, but there is evidence that even without vaccination, some humans have been exposed and survived, they just didn’t realize it.
One empirical subquestion I’m interested in (in case anybody reading this is very knowledgeable about human immunology, which seems plausible) is whether we have strong in-principle reasons to believe that our immune systems, with sufficient coaxing, is capable of producing antibodies for arbitrary diseases.
This seems like a necessary but not sufficient condition for developing vaccines that work against arbitrary novel diseases, and may become increasingly relevant if we’re more worried about manmade than natural pandemics.
This is an interesting question which I have thought about a little before, but stopped given infohazards risks from thinking too hard about ways in which this might be possible outweighed the actionability of such insights. For a variety of reasons, which includes this reason, I am a fan of pushing fast response passive immunoprophylaxis platforms and other countermeasure approaches such as the receptor-competition based ones, it seems that whatever we are worried about, such approaches would be robustly good.
Short answer (mostly based on undergrad immunology and vaccinology): yes there could be things.
There are different potential reasons for why active immunisation might not work for a given pathogen, the most obvious one being that we cannot induce antibodies that manage to bind to (neutralising) areas on pathogens. This may be because of us only having a limited set of B/T cell receptor genes (and even less flexible MHC receptor (present pathogen peptides to immune cells) genes which might be relevant for inducing immune responses) which might mean that induction is difficult—but these genes vary across the population potentially exactly for the reason that the population is protected from getting wiped out by one specific pathogen. This is somewhat seen in HIV where some individuals are able to develop neutralising antibodies and most others don’t—question is whether sequential immunisation with more and more complex antigens (to achieve antibody evolution to penetrate HIV glycan shields) can get us to neutralising antibodies for everyone or not.
Another mechanism (discussed by Tessa) might be that antibody-dependent disease enhancement. If any neutralising antibody induction by active vaccination is accompanied by non-neutralising antibodies which may cause ADE for a given pathogen this might be bad. I think this is somewhat a technical challenge, but there might be pathogens which feature unique mechanisms that make overcoming this very difficult.
Not an expert, but Antibody-Dependent Enhancement (ADE) shows that we are not guaranteed to produce useful antibodies for arbitrary diseases. In fact, we can produce antibodies that make a disease worse!
This happens in dengue, where there are different serotypes of the disease and antibodies for one serotype can be non-neutralizing for others, but “original antigenic sin” (I find this term quite funny) means that we don’t generate new ones and the infection is enhanced because the non-neutralizing antibodies recruit macrophages, which dengue likes to replicate in.
Here’s a Derek Lowe post from December 2020 on ADE, which also notes examples in HIV, Ebola, and coxsackievirus. I was in fact a bit worried about ADE with SARS-CoV-2 early in the pandemic, since spike protein immunization against feline coronaviruses has sometimes led to ADE.
Definitely not expert enough to confidently answer this, but I thought the answer was obviously yes—I don’t think there are any diseases where it doesn’t happen as a natural part of response. (Even HIV is mostly fought off quickly, but in cases where it spreads, it infects enough immune cells that it persists and eventually destroys the immune system.)
So for example rabies has a ~100% fatality rate without vaccination, but immune systems are expressive enough to produce antibodies with vaccination.
I’m not personally convinced by directly empirical evidence that it hasn’t happened so far → this isn’t possible, since the space of pathogens that’s evolutionarily plausible is presumably a lot narrower than the space of possible pathogens, including engineered ones.
Interesting though not super important piece of information: Rabies is ~100% fatal once symptoms present, but there is evidence that even without vaccination, some humans have been exposed and survived, they just didn’t realize it.