3 ms·

How do antibiotic resistant infections work? I ask as a lay person.

criticaltinker 5y ago
Here are very accessible peer-reviewed primary sources that will answer your question and give historical examples [1][2]. [1] Why does drug resistance readily evolve but vaccine resistance does not? https://royalsocietypublishing.org/doi/pdf/10.1098/rspb.2016.2562 https://royalsocietypublishing.org/doi/pdf/10.1098/rspb.2016... [2] The adaptive evolution of virulence: a review of theoretical predictions and empirical tests https://www.cambridge.org/core/services/aop-cambridge-core/content/view/30EC8AB1717BF7A173CF5E051DBB498F/S003118201500092Xa_hi.pdf/_div_class__title__The_adaptive_evolution_of_virulence__a_review_of_theoretical_predictions_and_empirical_tests__div_.pdf https://www.cambridge.org/core/services/aop-cambridge-core/c...
- newbamboo 5y ago
  Second link was really helpful. I found this part interesting and potentially relevant, “reducing the risk of death for infected hosts reduces the cost of virulence, causing an evolutionary increase in virulence (Gandon et al. 2003, 2001b). Vaccines that either block infection or block transmission, on the other hand, have no effect on virulence evolution” Especially considering Dr Fauci’s recent statements on how the COVID vaccines do not block transmission. https://m.youtube.com/watch?v=AuO_OfjlPUI https://m.youtube.com/watch?v=AuO_OfjlPUI Putting these together then it seems like we should expect the result of our vaccination efforts to be increased virulence in strains such as Delta variant. Is it possible the Delta variant itself was somehow the result of our intrepid and swift vaccination efforts? I’m having a hard time understanding why more people aren’t talking about this given the obviously well established scientific literature you’ve cited.
  - criticaltinker 5y ago
    I'm glad you found the reference helpful. > Is it possible the Delta variant itself was somehow the result of our intrepid and swift vaccination efforts? The variants can arise under neutral genetic drift, ie pure random chance via naturally occurring mutation. But the widespread dominance of these variants is very plausibly connected to the mass vaccination efforts. Here is another good paper on the subject, in case you haven't already seen it [1]. > I’m having a hard time understanding why more people aren’t talking about this Me too, but to be fair these are complex second and third order effects that only gained traction in the scientific literature within the past decade or so. Right now everyone is mostly focused on first order effects - eg "will the vaccination help/harm me?" Quotes from [1]: - "Our modeling suggests that SARS-CoV-2 mutants with one or two mildly deleterious mutations are expected to exist in high numbers due to neutral genetic variation, and consequently resistance to vaccines or other prophylactics that rely on one or two antibodies for protection can develop quickly -and repeatedly- under positive selection." - "Our work suggests that it is likely that standing genetic variation alone has already produced a substantial population of viruses with single and double nucleotide changes that confer nAb resistance. These variants will establish quickly in the population under selection pressure. In fact, there is already a precedent for this behavior, as one such selective sweep occurred early on in the SARS-CoV-2 pandemic when the D614G mutation rose to nearly 80% frequency in under 6 months [33]." [1] Risk of rapid evolutionary escape from biomedical interventions targeting SARS-CoV-2 spike protein https://pubmed.ncbi.nlm.nih.gov/33909660/ https://pubmed.ncbi.nlm.nih.gov/33909660/
    - newbamboo 5y ago
      So this makes it sound like we might be headed for semi-annual or even quarterly boosters. “one possible solution to the problem of immune evasion by SARS-CoV-2 that has been proposed is to develop a new vaccine update every year, similar to influenza [42]. In practice, such a solution will only work in the face of a moderate pace of evolution of SARS-CoV-2 and a low degree of clonal diversity among various clades of SARS-CoV-2 as they evolve to evade the current crop of vaccines. Further, if within-host evolution of SARS-CoV-2 contributes to population-level immune evasion, the valley-crossing mechanism described in this paper could accelerate the emergence of vaccine-resistant strains in the months following vaccine deployment. To the extent that new strains of SARS-CoV-2 are antigenically distinct, this may also lead to increased risk of antibody-dependent enhancement (ADE), as one mechanism for ADE involves antibodies that bind to the pathogen but fail to neutralize it [43]. Finally, our work suggests that immune evasion requiring one to two mutations occurs within months, raising the prospect that this phenomenon will further shorten the duration of natural immunity, which is already limited by the relatively short duration of the humoral [44,45] and cellular [46] responses to SARS-CoV-2 infection. Further studies are required to understand the risk immune evasion poses to a strategy of annually updated vaccines.” I wonder if this is why Dr Fauci is emphasizing the need for therapeutics as higher priority than vaccines at this point? I should say though, mathematical biological models like the ones in this study are not something I feel very well equipped to evaluate. How often are such models wrong? What are the incentives for the company associated with these authors, “Fractal Therapeutics”? Obviously Harvard is Harvard, but I just can’t understand why smart people aren’t talking about this stuff. Murti-Bing pills?
majormajor 5y ago
Similar thing. What's important to note, though, is that the mutations are blind to their environment. The virus or bacteria doesn't see an antibiotic or antibody and say "I need to adjust this aspect." It's just constantly changing as it reproduces, and some of them may end up winning a battle that the original did not. And then they spread from there as would any strain. From the purposes of the virus, an unvaccinated person in a poor country without access to vaccines isn't better or worse than one in the US who's simply refusing. It doesn't know. They're both opportunities for the virus to keep replication and so keep (randomly, blindly) mutating. If the odds of reproducing in a way that escapes people's current antibodies, and making your way outside the host (because a mutation the immune system adapts to before it can be spread dies there) are 1 in ten billion, say... and you leave 7 billion people in the world unvaccinated... suddenly those odds aren't so great. (Numbers entirely fake here, but basically, less likely events become more likely as more time goes by, if you keep giving them opportunities to happen.) A key advantage of a vaccine over an antibiotic is that it can potentially stops the problem before it starts whereas antibiotics are generally given if you already have a nasty infection. So the amount of virus that's exposed to the immune system in a vaccinated person will be lower, and throttled more quickly, giving less time for it to get lucky, IIRC. But nothing about that would magically necessarily stop a virus that's still spreading like wildfire in a large unvaccinated population from coincidentally developing new traits that help it out. The goal is to vaccinate a large enough population quickly enough that this "spreading like wildfire" situation stops, so we reduce the mutation rate of the virus.
- newbamboo 5y ago
  So that says right in the abstract: “When vaccine resistance has evolved, these generalities have been violated.” So as long as mutations like the epsilon variant don’t occur (they do right?) and as long as vaccines are prophylactic against infection (not the case given need for boosters is Israel, right?), there’s nothing to worry about? Sorry if I’m being dense.

Here are very accessible peer-reviewed primary sources that will answer your question and give historical examples [1][2]. [1] Why does drug resistance readily evolve but vaccine resistance does not? https://royalsocietypublishing.org/doi/pdf/10.1098/rspb.2016.2562 https://royalsocietypublishing.org/doi/pdf/10.1098/rspb.2016... [2] The adaptive evolution of virulence: a review of theoretical predictions and empirical tests https://www.cambridge.org/core/services/aop-cambridge-core/content/view/30EC8AB1717BF7A173CF5E051DBB498F/S003118201500092Xa_hi.pdf/_div_class__title__The_adaptive_evolution_of_virulence__a_review_of_theoretical_predictions_and_empirical_tests__div_.pdf https://www.cambridge.org/core/services/aop-cambridge-core/c...

newbamboo 5y ago
Second link was really helpful. I found this part interesting and potentially relevant, “reducing the risk of death for infected hosts reduces the cost of virulence, causing an evolutionary increase in virulence (Gandon et al. 2003, 2001b). Vaccines that either block infection or block transmission, on the other hand, have no effect on virulence evolution” Especially considering Dr Fauci’s recent statements on how the COVID vaccines do not block transmission. https://m.youtube.com/watch?v=AuO_OfjlPUI https://m.youtube.com/watch?v=AuO_OfjlPUI Putting these together then it seems like we should expect the result of our vaccination efforts to be increased virulence in strains such as Delta variant. Is it possible the Delta variant itself was somehow the result of our intrepid and swift vaccination efforts? I’m having a hard time understanding why more people aren’t talking about this given the obviously well established scientific literature you’ve cited.
- criticaltinker 5y ago
  I'm glad you found the reference helpful. > Is it possible the Delta variant itself was somehow the result of our intrepid and swift vaccination efforts? The variants can arise under neutral genetic drift, ie pure random chance via naturally occurring mutation. But the widespread dominance of these variants is very plausibly connected to the mass vaccination efforts. Here is another good paper on the subject, in case you haven't already seen it [1]. > I’m having a hard time understanding why more people aren’t talking about this Me too, but to be fair these are complex second and third order effects that only gained traction in the scientific literature within the past decade or so. Right now everyone is mostly focused on first order effects - eg "will the vaccination help/harm me?" Quotes from [1]: - "Our modeling suggests that SARS-CoV-2 mutants with one or two mildly deleterious mutations are expected to exist in high numbers due to neutral genetic variation, and consequently resistance to vaccines or other prophylactics that rely on one or two antibodies for protection can develop quickly -and repeatedly- under positive selection." - "Our work suggests that it is likely that standing genetic variation alone has already produced a substantial population of viruses with single and double nucleotide changes that confer nAb resistance. These variants will establish quickly in the population under selection pressure. In fact, there is already a precedent for this behavior, as one such selective sweep occurred early on in the SARS-CoV-2 pandemic when the D614G mutation rose to nearly 80% frequency in under 6 months [33]." [1] Risk of rapid evolutionary escape from biomedical interventions targeting SARS-CoV-2 spike protein https://pubmed.ncbi.nlm.nih.gov/33909660/ https://pubmed.ncbi.nlm.nih.gov/33909660/
  - newbamboo 5y ago
    So this makes it sound like we might be headed for semi-annual or even quarterly boosters. “one possible solution to the problem of immune evasion by SARS-CoV-2 that has been proposed is to develop a new vaccine update every year, similar to influenza [42]. In practice, such a solution will only work in the face of a moderate pace of evolution of SARS-CoV-2 and a low degree of clonal diversity among various clades of SARS-CoV-2 as they evolve to evade the current crop of vaccines. Further, if within-host evolution of SARS-CoV-2 contributes to population-level immune evasion, the valley-crossing mechanism described in this paper could accelerate the emergence of vaccine-resistant strains in the months following vaccine deployment. To the extent that new strains of SARS-CoV-2 are antigenically distinct, this may also lead to increased risk of antibody-dependent enhancement (ADE), as one mechanism for ADE involves antibodies that bind to the pathogen but fail to neutralize it [43]. Finally, our work suggests that immune evasion requiring one to two mutations occurs within months, raising the prospect that this phenomenon will further shorten the duration of natural immunity, which is already limited by the relatively short duration of the humoral [44,45] and cellular [46] responses to SARS-CoV-2 infection. Further studies are required to understand the risk immune evasion poses to a strategy of annually updated vaccines.” I wonder if this is why Dr Fauci is emphasizing the need for therapeutics as higher priority than vaccines at this point? I should say though, mathematical biological models like the ones in this study are not something I feel very well equipped to evaluate. How often are such models wrong? What are the incentives for the company associated with these authors, “Fractal Therapeutics”? Obviously Harvard is Harvard, but I just can’t understand why smart people aren’t talking about this stuff. Murti-Bing pills?

majormajor 5y ago

Similar thing. What's important to note, though, is that the mutations are blind to their environment. The virus or bacteria doesn't see an antibiotic or antibody and say "I need to adjust this aspect." It's just constantly changing as it reproduces, and some of them may end up winning a battle that the original did not. And then they spread from there as would any strain. From the purposes of the virus, an unvaccinated person in a poor country without access to vaccines isn't better or worse than one in the US who's simply refusing. It doesn't know. They're both opportunities for the virus to keep replication and so keep (randomly, blindly) mutating. If the odds of reproducing in a way that escapes people's current antibodies, and making your way outside the host (because a mutation the immune system adapts to before it can be spread dies there) are 1 in ten billion, say... and you leave 7 billion people in the world unvaccinated... suddenly those odds aren't so great. (Numbers entirely fake here, but basically, less likely events become more likely as more time goes by, if you keep giving them opportunities to happen.) A key advantage of a vaccine over an antibiotic is that it can potentially stops the problem before it starts whereas antibiotics are generally given if you already have a nasty infection. So the amount of virus that's exposed to the immune system in a vaccinated person will be lower, and throttled more quickly, giving less time for it to get lucky, IIRC. But nothing about that would magically necessarily stop a virus that's still spreading like wildfire in a large unvaccinated population from coincidentally developing new traits that help it out. The goal is to vaccinate a large enough population quickly enough that this "spreading like wildfire" situation stops, so we reduce the mutation rate of the virus.

newbamboo 5y ago
So that says right in the abstract: “When vaccine resistance has evolved, these generalities have been violated.” So as long as mutations like the epsilon variant don’t occur (they do right?) and as long as vaccines are prophylactic against infection (not the case given need for boosters is Israel, right?), there’s nothing to worry about? Sorry if I’m being dense.