10 ms·

Why does drug resistance easily evolve but vaccine resistance does not?

171 points by gwern 9y ago

clarents 9y ago
My understanding is that we're unable to created effective vaccines against RNA viruses as RNA replication doesn't have the built-in "checksum" mechanism that DNA has. When DNA replicates, because the two strands of the helix are essentially mirror images of each other, it is easier to create an exact copy without mutations. RNA, not having this property, allows for more mutations during replication. This increased mutation rate is what causes the viruses to change so quickly and what makes the vaccines we create quickly useless against the changed virus.
- dnautics 9y ago
  Flu, polio, and measles are rna viruses which are regularly vaccinated against.
  - clarents 9y ago
    Wow, you're right, I guess that kind of kills my theory. I knew that flu was which explained why there's a new vaccine every year and it's often not effective against the current strain. But I had thought that polio and measles were DNA viruses.
    - Fomite 9y ago
      You are partially right. Some RNA viruses are hard to vaccinate against because of their mutation rate, but it's not the sole arbiter of whether or not it's doable. There are other issues, like the existence (and lack thereof) of highly conserved antigenic targets.
saas_co_de 9y ago
"Here we argue that vaccines are less vulnerable to pathogen evolution than are antimicrobial drugs because of differences in the way drugs and vaccines work. We contend that two key features of vaccines have large, synergistic effects on the rate at which resistance arises and then spreads" "(a) Timing of action - For most infectious diseases, hours to days elapse between exposure to a pathogen and symptomatic infection in a host ... Pathogen replication during this incubation period creates opportunities for mutations to arise" "(b) Multiplicity of therapeutic targets within and between hosts - The benefit of combination therapy is based on the premise that resistance can only be acquired by the simultaneous acquisition of resistance to each component drug. The probability of simultaneous acquisition becomes vanishingly small as the number of drugs increases. A vaccine, however, often exposes the host immune system to multiple pathogen proteins (antigens), and multiple potential binding sites (epitopes) on each antigen. Epitopes are recognized and bound by components of the immune system analogously to how biochemical molecules would interact with a drug or its downstream products. This means that immunity is in effect acting like combination therapy, but with substantially more component effectors (and hence targets) than any drug cocktail." ------ "One set of differences between vaccines and drugs stem from the fact that vaccine effects are mediated through host immune responses while drugs effects are mediated through chemical pathways" They discount this as being a major factor but the only evidence they provide is that "resistance is seen against drugs such as solfonamides that also act indirectly." It could also be considered that the immune system is adaptive and its capacities evolve during a person's lifetime and that the collective immune system within a population group evolves depending on the spread (or lack there of) of disease within the population group. With vaccines we are triggering the evolution of individual and group immune systems in ways that we don't fully understand and so unlike with drugs where once resistance is formed we have to develop a new drug, individual and group immune systems continue to evolve even if the vaccines don't change. The same vaccine administered now may be triggering different responses than it did 100 years ago.
- chewbacha 9y ago
  Herd immunity affects timing and variation in the community affects multiplicity. You aren’t wrong but I believe you are restating the conclusions in another way.
dnautics 9y ago
The decreasing effectiveness of the flu vaccine suggests to me that the flu metagenome is evolving resistance to our vaccine generation strategy.
- philjohn 9y ago
  It's not, each year we have to guess which strains will be prevalent, and sometimes they get it wrong.
  - epmaybe 9y ago
    That brings up an interesting question: what does the CDC do to predict strain prevalence each year?
    - icegreentea2 9y ago
      They're tell you! https://www.cdc.gov/flu/about/season/vaccine-selection.htm https://www.cdc.gov/flu/about/season/vaccine-selection.htm Ars Technica also did a nice breakdown (with many related Q&As) https://arstechnica.com/science/2017/12/this-years-flu-season-is-upon-us-and-it-looks-bad-heres-what-you-should-know/2/#h1 https://arstechnica.com/science/2017/12/this-years-flu-seaso...
  - rflrob 9y ago
    Not only that, the strains they choose not to include will likely spread more effectively than the ones that they do. So even if the vaccine magically protected 100% of people against the most prevalent N strains, the (N+1)th strain will be the one that most people get. Did the CDC “guess wrong”, or are they doing their best to fight an impossible battle?
    - richardw 9y ago
      Is developing or producing the vaccine the costly bit? If producing, then what about creating more and patchworking them? It might reduce the monoculture type issue. I.e. everyone gets the worst two, then two of the next 8/16, whatever models best. I assume this has already been modelled to death but asking in case anyone knows.
lr4444lr 9y ago
Not a biologist here, but hoping maybe one can correct me on this: isn't it an important factor that in the immune system the signaling cells themselves have evolved to respond to variants of a given pathogen's protein marker, whereas drugs are always presenting the same chemical challenge?
- Xylakant 9y ago
  As far as I read the article and understand your question, this is indeed one of the factors that they mention. Each persons immune system reacts in a different way, posing a unique challenge to the pathogen.
mannykannot 9y ago
While I do not doubt that this difference exists in general, I am wondering if there is not, to some extent, an issue of terminology here. My understanding is that influenza vaccination is somewhat uncertain because antigenic shift and drift produces new, or not-recently-seen, strains. When a bacterium modifies its genome to survive an antimicrobial drug, we call that 'resistance', yet I guess the drug is still as effective as before against unmodified bacteria. While the mechanism is, in detail, different in the two cases, they both involve the pathogen modifying its genome to render the treatment less effective. Maybe the distinction is because, in the case of influenza, the strain changes are not in response to, and driven by, the treatment? HIV, however, seems to be very effective in mutating specifically in response to every candidate vaccine that has been tried against it.
- m3kw9 9y ago
  Exatly, the resistance due to evolution and new strains by passing vaccines is not very comparable
  - ianai 9y ago
    As a total amateur, it seems like the bacterial/viruses need only find one way to breakthrough your immunity. Your immune system has many more attack vectors to cover. The bacteria only need to be right once, but the immune system billions.
    - alextheparrot 9y ago
      The immune system is also layered - a single viral infection won’t necessarily kill you right away. If it does penetrate the initial layers, the immune system will continue adapting and fighting it on each new front. Eventually your entire body might even engage using things like a fever. In this way, it doesn’t need to be right initially billions of times, but capable once at one of many steps.
paviva 9y ago
Very good question and a very good answers in this article! I'll add one more reason not explored by the authors: antibodies don't "leak" in the environment, in contrast to the antibiotics which are everywhere. For example, if I'm vaccinated against S. pneumoniae (one of the bacteria that can cause pneumonia), the bacteria have to get inside my body to gain exposure to my vaccine-induced antibodies. This makes the emergence of resistance very unlikely because : (1) the number of bacteria that are exposed to the antibody is relatively small, because the antibody response is pretty fast and happens before the bacteria had a chance to multiply to significant numbers; (2) any bacteria clones who evolve resistance to the antibody remain susceptible to the myriad of other immunes peptides, to macrophages, and so on. In other words, as long as I survive my pneumonia, no resistance can ever emerge, because I will kill all the resistant clones through other means. Contrast this to antibiotics. I have pneumonia, I take antibiotics, I'm cured. However, I excrete those antibiotics in urine and stool. Outside of my body, enormous numbers of bacteria are exposed to minute doses of antibiotics. The number of surviving clones is likely to be very high, and those survivors do not face any supplemental threat. Thus, resistance to that antibiotic can be transmitted to later generations.
- pishpash 9y ago
  You don't excrete antibodies? I think you might be saying that antibiotics are passive strategies which are inherently overly broad and thus problematic.
  - IIIIIIIIIIIIIII 9y ago
    Antibodies are too large to pass through the filter in the kidneys. Lower molecular weight fragments of antibodies are usually reabsorbed in the proximal tubule of the nephron. Their fate mostly lies in catabolism, i.e. they are broken down and the components reused. Biliary excretion accounts for a very small amount of the elimination of IgG antibodies. [0] "Pharmacokinetics of Monoclonal Antibodies" http://onlinelibrary.wiley.com/doi/10.1002/psp4.12224/pdf http://onlinelibrary.wiley.com/doi/10.1002/psp4.12224/pdf
    - 9y ago
rapsacnz 9y ago
I like to use a conflict analogy: A drug is a weapon exploiting one weakness of the enemy. A vaccine is a visual identification of the enemy, passed on to special forces (your immune system). A single weakness can often be changed easily, but it's harder to shake off special forces.
exabrial 9y ago
Don't bacteria have a way of swapping genes that was discovered recently?
- jballanc 9y ago
  If by "recently" you mean 1946, then yeah: https://en.wikipedia.org/wiki/Bacterial_conjugation https://en.wikipedia.org/wiki/Bacterial_conjugation Unless you mean across species, in which case there are new and interesting ways that bacteria can swap genetic elements across species boundaries being discovered all the time. The first example was the original Griffith experiment in 1928, but the wiki article here: https://en.wikipedia.org/wiki/Natural_competence https://en.wikipedia.org/wiki/Natural_competence has a nice timeline of some of the more recent examples as well.
refurb 9y ago
I always figured it was because there were thousands of different types of antibodies generated against an immunological challenge (e.g. vaccine). The antibody simply finds a conserved binding site and it works. Therefore, they don't have to be the same. As a result, resistance doesn't form as the bacteria or virus would need to develop resistance to thousands of different antibodies, not just one.
- mirimir 9y ago
  This was my guess, before reading the article. A couple secondary hypotheses come to mind. First, resistance to monoclonal antibody based drugs[0] is more likely than resistance to vaccines. Second, resistance to single-epitope vaccines is more likely than resistance to complex multi-epitope vaccines. 0) https://www.medicinenet.com/monoclonal_antibodies/article.htm#list_and_types_of_monoclonal_antibodies_(fda_approved) https://www.medicinenet.com/monoclonal_antibodies/article.ht...

171 points by gwern 9y ago

My understanding is that we're unable to created effective vaccines against RNA viruses as RNA replication doesn't have the built-in "checksum" mechanism that DNA has. When DNA replicates, because the two strands of the helix are essentially mirror images of each other, it is easier to create an exact copy without mutations. RNA, not having this property, allows for more mutations during replication. This increased mutation rate is what causes the viruses to change so quickly and what makes the vaccines we create quickly useless against the changed virus.

dnautics 9y ago
Flu, polio, and measles are rna viruses which are regularly vaccinated against.
- clarents 9y ago
  Wow, you're right, I guess that kind of kills my theory. I knew that flu was which explained why there's a new vaccine every year and it's often not effective against the current strain. But I had thought that polio and measles were DNA viruses.
  - Fomite 9y ago
    You are partially right. Some RNA viruses are hard to vaccinate against because of their mutation rate, but it's not the sole arbiter of whether or not it's doable. There are other issues, like the existence (and lack thereof) of highly conserved antigenic targets.

saas_co_de 9y ago

"Here we argue that vaccines are less vulnerable to pathogen evolution than are antimicrobial drugs because of differences in the way drugs and vaccines work. We contend that two key features of vaccines have large, synergistic effects on the rate at which resistance arises and then spreads" "(a) Timing of action - For most infectious diseases, hours to days elapse between exposure to a pathogen and symptomatic infection in a host ... Pathogen replication during this incubation period creates opportunities for mutations to arise" "(b) Multiplicity of therapeutic targets within and between hosts - The benefit of combination therapy is based on the premise that resistance can only be acquired by the simultaneous acquisition of resistance to each component drug. The probability of simultaneous acquisition becomes vanishingly small as the number of drugs increases. A vaccine, however, often exposes the host immune system to multiple pathogen proteins (antigens), and multiple potential binding sites (epitopes) on each antigen. Epitopes are recognized and bound by components of the immune system analogously to how biochemical molecules would interact with a drug or its downstream products. This means that immunity is in effect acting like combination therapy, but with substantially more component effectors (and hence targets) than any drug cocktail." ------ "One set of differences between vaccines and drugs stem from the fact that vaccine effects are mediated through host immune responses while drugs effects are mediated through chemical pathways" They discount this as being a major factor but the only evidence they provide is that "resistance is seen against drugs such as solfonamides that also act indirectly." It could also be considered that the immune system is adaptive and its capacities evolve during a person's lifetime and that the collective immune system within a population group evolves depending on the spread (or lack there of) of disease within the population group. With vaccines we are triggering the evolution of individual and group immune systems in ways that we don't fully understand and so unlike with drugs where once resistance is formed we have to develop a new drug, individual and group immune systems continue to evolve even if the vaccines don't change. The same vaccine administered now may be triggering different responses than it did 100 years ago.

chewbacha 9y ago
Herd immunity affects timing and variation in the community affects multiplicity. You aren’t wrong but I believe you are restating the conclusions in another way.

dnautics 9y ago

The decreasing effectiveness of the flu vaccine suggests to me that the flu metagenome is evolving resistance to our vaccine generation strategy.

philjohn 9y ago
It's not, each year we have to guess which strains will be prevalent, and sometimes they get it wrong.
- epmaybe 9y ago
  That brings up an interesting question: what does the CDC do to predict strain prevalence each year?
  - icegreentea2 9y ago
    They're tell you! https://www.cdc.gov/flu/about/season/vaccine-selection.htm https://www.cdc.gov/flu/about/season/vaccine-selection.htm Ars Technica also did a nice breakdown (with many related Q&As) https://arstechnica.com/science/2017/12/this-years-flu-season-is-upon-us-and-it-looks-bad-heres-what-you-should-know/2/#h1 https://arstechnica.com/science/2017/12/this-years-flu-seaso...
- rflrob 9y ago
  Not only that, the strains they choose not to include will likely spread more effectively than the ones that they do. So even if the vaccine magically protected 100% of people against the most prevalent N strains, the (N+1)th strain will be the one that most people get. Did the CDC “guess wrong”, or are they doing their best to fight an impossible battle?
  - richardw 9y ago
    Is developing or producing the vaccine the costly bit? If producing, then what about creating more and patchworking them? It might reduce the monoculture type issue. I.e. everyone gets the worst two, then two of the next 8/16, whatever models best. I assume this has already been modelled to death but asking in case anyone knows.

lr4444lr 9y ago

Not a biologist here, but hoping maybe one can correct me on this: isn't it an important factor that in the immune system the signaling cells themselves have evolved to respond to variants of a given pathogen's protein marker, whereas drugs are always presenting the same chemical challenge?

Xylakant 9y ago
As far as I read the article and understand your question, this is indeed one of the factors that they mention. Each persons immune system reacts in a different way, posing a unique challenge to the pathogen.

mannykannot 9y ago

While I do not doubt that this difference exists in general, I am wondering if there is not, to some extent, an issue of terminology here. My understanding is that influenza vaccination is somewhat uncertain because antigenic shift and drift produces new, or not-recently-seen, strains. When a bacterium modifies its genome to survive an antimicrobial drug, we call that 'resistance', yet I guess the drug is still as effective as before against unmodified bacteria. While the mechanism is, in detail, different in the two cases, they both involve the pathogen modifying its genome to render the treatment less effective. Maybe the distinction is because, in the case of influenza, the strain changes are not in response to, and driven by, the treatment? HIV, however, seems to be very effective in mutating specifically in response to every candidate vaccine that has been tried against it.

m3kw9 9y ago
Exatly, the resistance due to evolution and new strains by passing vaccines is not very comparable
- ianai 9y ago
  As a total amateur, it seems like the bacterial/viruses need only find one way to breakthrough your immunity. Your immune system has many more attack vectors to cover. The bacteria only need to be right once, but the immune system billions.
  - alextheparrot 9y ago
    The immune system is also layered - a single viral infection won’t necessarily kill you right away. If it does penetrate the initial layers, the immune system will continue adapting and fighting it on each new front. Eventually your entire body might even engage using things like a fever. In this way, it doesn’t need to be right initially billions of times, but capable once at one of many steps.

paviva 9y ago

Very good question and a very good answers in this article! I'll add one more reason not explored by the authors: antibodies don't "leak" in the environment, in contrast to the antibiotics which are everywhere. For example, if I'm vaccinated against S. pneumoniae (one of the bacteria that can cause pneumonia), the bacteria have to get inside my body to gain exposure to my vaccine-induced antibodies. This makes the emergence of resistance very unlikely because : (1) the number of bacteria that are exposed to the antibody is relatively small, because the antibody response is pretty fast and happens before the bacteria had a chance to multiply to significant numbers; (2) any bacteria clones who evolve resistance to the antibody remain susceptible to the myriad of other immunes peptides, to macrophages, and so on. In other words, as long as I survive my pneumonia, no resistance can ever emerge, because I will kill all the resistant clones through other means. Contrast this to antibiotics. I have pneumonia, I take antibiotics, I'm cured. However, I excrete those antibiotics in urine and stool. Outside of my body, enormous numbers of bacteria are exposed to minute doses of antibiotics. The number of surviving clones is likely to be very high, and those survivors do not face any supplemental threat. Thus, resistance to that antibiotic can be transmitted to later generations.

pishpash 9y ago
You don't excrete antibodies? I think you might be saying that antibiotics are passive strategies which are inherently overly broad and thus problematic.
- IIIIIIIIIIIIIII 9y ago
  Antibodies are too large to pass through the filter in the kidneys. Lower molecular weight fragments of antibodies are usually reabsorbed in the proximal tubule of the nephron. Their fate mostly lies in catabolism, i.e. they are broken down and the components reused. Biliary excretion accounts for a very small amount of the elimination of IgG antibodies. [0] "Pharmacokinetics of Monoclonal Antibodies" http://onlinelibrary.wiley.com/doi/10.1002/psp4.12224/pdf http://onlinelibrary.wiley.com/doi/10.1002/psp4.12224/pdf
  - 9y ago

rapsacnz 9y ago

I like to use a conflict analogy: A drug is a weapon exploiting one weakness of the enemy. A vaccine is a visual identification of the enemy, passed on to special forces (your immune system). A single weakness can often be changed easily, but it's harder to shake off special forces.

exabrial 9y ago

Don't bacteria have a way of swapping genes that was discovered recently?

jballanc 9y ago
If by "recently" you mean 1946, then yeah: https://en.wikipedia.org/wiki/Bacterial_conjugation https://en.wikipedia.org/wiki/Bacterial_conjugation Unless you mean across species, in which case there are new and interesting ways that bacteria can swap genetic elements across species boundaries being discovered all the time. The first example was the original Griffith experiment in 1928, but the wiki article here: https://en.wikipedia.org/wiki/Natural_competence https://en.wikipedia.org/wiki/Natural_competence has a nice timeline of some of the more recent examples as well.

refurb 9y ago

I always figured it was because there were thousands of different types of antibodies generated against an immunological challenge (e.g. vaccine). The antibody simply finds a conserved binding site and it works. Therefore, they don't have to be the same. As a result, resistance doesn't form as the bacteria or virus would need to develop resistance to thousands of different antibodies, not just one.

mirimir 9y ago
This was my guess, before reading the article. A couple secondary hypotheses come to mind. First, resistance to monoclonal antibody based drugs[0] is more likely than resistance to vaccines. Second, resistance to single-epitope vaccines is more likely than resistance to complex multi-epitope vaccines. 0) https://www.medicinenet.com/monoclonal_antibodies/article.htm#list_and_types_of_monoclonal_antibodies_(fda_approved) https://www.medicinenet.com/monoclonal_antibodies/article.ht...