"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."
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"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.
They do raise this in their discussion part: "Fourth, vaccines are only active while pathogens are inside hosts, but drugs can remain active in environmental reservoirs [89], suggesting that the strength of selection for resistance may differ for drug and vaccine resistance. However, drug resistance readily evolves even in pathogens that lack environmental life stages such as HIV [8]."
That's not really how it works, First, vaccines prevent infection in the first place so the virus never has a chance to replicate and mutate, unlike antibiotics which are given after infection and there are a massive number of bacteria and only the most resistant survive. Second, there isn't anything about vaccine acquired immunity thats different from infection acquired immunity, so any evolutionary pressure would already be there.
Don't the vaccines put evolutionary pressure on the virus to mutate in order to escape them? I'm thinking of the hospital superbugs which are resistant to antibiotics.
They actually do adress this, in what i thought was the weakest part of the paper, the "non-key factors" section.
Fourth, vaccines are only active while pathogens are inside hosts, but drugs can remain active in environmental reservoirs [89], suggesting that the strength of selection for resistance may differ for drug and vaccine resistance. However, drug resistance readily evolves even in pathogens that lack environmental life stages such as HIV [8].
Vaccines are very different from antibiotics. Antibiotics are single molecules that bind a very specific target. A single mutation of a single protein can render an antibiotic useless. Vaccines induce the immune system to generate a repertoire of antibodies, each of which binds in a different way and each of which is then selected and "evolved" (hypermutation) for increased efficacy. And each individual person creates a different starting and ending repertoire of antibodies. A single mutation, or even a large group of mutations, does not so easily side step all this diversity of antibody types/binding modes. Moreover, we have evidence that the idea that vaccines increase the likelihood of variants is just wrong. We do not see that effect for mumps, polio, smallpox, or any other virus. Moreover, delta appears to have arisen in India, which at the time had vaccination rates very close to zero. Again, providing strong evidence that vaccines are not applying selective pressure for more virulent strains.
Immunizations are, ultimately, subject to the same problems of evolved avoidance as antibiotics.
The current approach to treating diseases reminds me of the story of how the Yugoslav army shot down an F-117. They had spotters telling them when the F-117 got close, they operated radar that could almost, sorta see them, and they relied on a proximity fuse, a generous damage radius, and a helluva lot of luck. We may currently be able to determine roughly what an infection is, and how it's likely to behave, but we're far, far from being able to determine any of this with sufficient accuracy.
What's really needed is a combination approach, but even a combination approach is useless until we understand more about how bacteria evolve...
I remember reading this article over a year ago, while trying to understand why vaccines are unlikely to stimulate the same evolution of resistance as incomplete application of antibiotics does. The article provides good overview and solid explanation behind this observation.
My layman's understanding that it is because vaccines do not directly "fight" the weak spot of the virus, but rather stimulate a multi-modal response of one's own immune system, so the evolutionary pressure generated is not different from the one of a "natural" response. It sounded reasonable and reassuring.
However, I then read somewhere else (cannot really find a link now) that such logic does not fully apply to the current breed of mRNA vaccines. Specifically because the immune response they stimulate is not a multi-modal, but rather narrowly focused and tied to a very specific "configuration" of the virus. So from this perspective they are more akin to a drug rather than classic vaccine. This sounded reasonable and plausible as well.
But there is another layer to this onion! Because the vaccine, through induced immune response, so very narrowly "target" probably the most critical part of the virus, every vaccine "escape" will likely transform the virus in the direction of reduced virulence. The useful model suggests that when part of mutational "budget" is spent on extended contagiousness, the less of it remains for potential fatality. There was also some explanation why this is more applicable to viruses than to bacteria. Something about horizontal gene transfer, if I remember correctly. So, even though the immune escape in this case is, probably, as likely as with drugs, it may actually be a desirable thing, bringing us closer to a harmless, unnoticeable variety of SARS-V-2.
While I don't think this logic supports vaccine mandates currently introduced, it could alleviate some concerns held by some people and work toward increasing of voluntary uptake.
It is a pity that instead of expanding on a very solid base provided in the article, and using the opportunity to educate people and make them thinking, the editors seriously misread their audience and decided to slap that religious statement across. For many, this outright invalidates the whole content, which is understandable and unfortunate.
Antibiotics are, by and large, reactive. Vaccines are, by and large, prophylactic.
I am the furthest thing from an expert in this field, but the herd immunity from vaccines provides an entirely different protection than a 'toolset' of working antibiotics.
My naive understanding is that if you have 100% vaccine coverage, it's simply way more unlikely that a virus or bacterium can catch a foothold of reproduction that would even make possible the mutations that result in resistance. And then you have viruses like influenza that are so widespread and elusive that they change annually. But we've gotten really good at responding to that rapid change as well.
There are reasons to believe, and some experience to point to, that this effect doesn’t work with vaccines as much as it does with antibiotics.
It’s a long story, but part of the reason is that bacteria evolve resistance in the presence of the antibiotic, while here, the virus would need to randomly evolve it in the unvaccinated, then sustain useless adaption for a while until it gets the opportunity to infect a vaccinated person.
This is incorrect. A vaccine is not an antibiotic; the presence of one does not cause virulent strains. Vaccinations trigger the body's immune response to the virus; nothing else. They provide for a more effective response faster, but do not otherwise provide any forcing function.
Mutations and variants occur all the time as the virus reproduces. Variants are not a response to any vaccine; they have appeared primarily (entirely? I haven't been following all of them) in regions where the vaccine is not yet widely available because that is where the virus is able to multiply (and thus mutate) the fastest.
Vaccines are very different to antibiotics. Antibiotics are agents which kill bacteria, whereas vaccines train the body to respond to infection using its own antibodies. Vaccines do nothing once you've been infected: they're about increasing your body's immune response to an infection down the line.
Additionally, most of the diseases we vaccinate against are caused by viruses. Whilst it's possible for viruses to mutate, this isn't a huge problem because we can simply modify the vaccine to use the new strain (hence why the flu vaccine is given annually). This doesn't apply for antibiotics: we need to find a new agent, which may not exist.
But that is the point being made. These two are not similar.
Antibiotics are a general purpose thing. Using them on trivial cases can increase antibiotic resistance which is bad for the cases where we really need antibiotics.
Vaccines are specific. You can't accrue "vaccine resistance" as a catch all thing by applying vaccines to everyone. You may create pressure for a virus to work around specific vaccines, but the only risk is that we will need to adjust the vaccine. Unlike with antibiotics where we really just need to try and find a new alternative.
>Why would vaccination increase the likelihood of new mutations, or mutations surviving better?
Our immune systems are general enough to face a wide variety of viruses, infections and strains.
When one is vaccinated, it gets prepared for that particular strain of a particular virus. The cost is that it could become more vulnerable to other infections... it's the cost/benefit of specialization vs generalization. Reference: https://pubmed.ncbi.nlm.nih.gov/14970928/
The reason is that the immune system is highly optimized and it is optimized to be flexible enough to save enough individuals for the next generation. It is not optimized to save each and every individual against all possible infections. That is unnecessary, as far as evolution is concerned.
Having said that, vaccines generally don't weaken individuals to a slightly different variant of the same virus. It should rather strengthen it. The immune system expects the virus to mutate so it prepares for the mutations to an extent. In fact, a category of vaccines called live-attenuated vaccines are basically weakened strains of the same virus (these can sometimes mutate into dangerous strains, eg. https://www.the-scientist.com/news-opinion/polio-vaccination..., but that's a different discussion).
This notion appears to go against all the expert advice against (ab)using anti-biotics. Sure, less infections means less chance for mutations, but due to the fundamental forces at play, the resistant mutations will spread faster through the resistant population and eventually become the prevalent strain.
Unless you can eradicate the virus or bacteria completely (mass effective vacination), the tools we create to fight them are really only delaying the inevitable.
>If some variants do evolve that escape the vaccine, odds are good that they will be less dangerous than the original, not more.
From my understanding, this is not the case. It's pure chance whether a mutation is advantageous or disadvantageous. If you are looking on a per-mutation basis, then sure, it's likely the mutation is disadvantageous. But at a population level, it's likely that atleast one advantageous mutation will emerge reasonably quickly when we are talking about something at the scale of several thousands of infections.
"(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.
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