This is cool but I’m sorry, that’s not a vaccine - it’s a prophylactic.
A vaccine or inoculation is named because it creates a sustained adaptation to a targeted antigen. Something that boosts immune response is not an acquired adaptation! This would need to be re-upped every month or so.
Good for travel and brief encounters. Not an actual immunization.
Not too mention boosting cell growth factors can have unintended side effects like cancer! There are immune system cancers and I would be concerned about risks there.
I would also mention, just general auto-immune diseases. I would be very worried this could trigger those in people who wouldn't have gotten one otherwise.
What's interesting to me is that one of the biggest booms in pharma over the last ~10 years has been biologics / monoclonal antibodies that treat auto-immune diseases by SUPRESSING cytokines. Examples include TNF inhibitors like Remicade/Humira/Enbrel; or specific IL-XX inhibitors like Dupixent/Cosentyx/Skyrizi/Tremfya/etc; or interferon therapies for MS. These are increasingly used for a broad (unlimited?) set of autoimmune or inflammatory diseases and work by blocking specific cytokines to reduce immune overactivity.
What this treatment does is the opposite side of that coin, it mimics cytokines in order to PROMOTE an immune response.
Immune regulation is an area that deserves a lot more research, and there is going to be learning (harm) along the way. An increasing body of science is pointing to autoimmune diseases being triggered by traditional vaccines, which are then treated by the biologics above that increase the likelihood of other disease due to immunosuppression, which can now be treated(?) by a new immunobooster AKA universal vaccine?
This seems too good to be true. Respiratory infections kill and debilitate a lot of people. If cranking up the innate immune system all the time reduced illness with no downsides, you'd think evolution would have done it already, but it didn't, which makes me think there's probably a downside, and the fact that the innate immune system is only cranked up when a pathogen is detected is probably because the downside is worth it in the presence of a pathogen but not otherwise.
I was thinking the same thing. Perhaps the trade-off made by evolution is about saving energy?
In that case it shouldn't be a problem to boost the innate immune system, as long as you have surplus calories to spend. But it could be something else entirely.
It could be just "good enough" as it is. That is, as another poster commented, there is a Th1 or a Th2 reaction. And these in a sense compete. Only one appears to be active.
The current framework of our immune system could go back quite some time. Even to our mammalian cold-blooded ancestors, 200? mya. When I think of cold blooded, I think of creatures able to remain static and at rest for a long time, periods of low-energy usage. So maybe this framework comes from before warm blooded mammals?
And, if it works well enough that people can breed (which used to be 15 years to 30 years old), and if dying after, oh well. Why evolve better? Or maybe too much monkeying has downsides.
Look at sickle cell anemia. Quite beneficial with malaria parasites around, not so much without them.
Yes, i was thinking just this. Having been prescribed multiple immunocompromisers, turning up my immune system sounds terrifying. There's all these supplements and things that talk about boosting your immune system and i get probably most are unrelated, i don't have the time to get a degree in immunology to find out. Zinc does well enough for me, thanks. But if any immune boost started to increase my tnf-alpha or il-23 i'd be on the long and painful road to a terrible death. Or yet another high side effect medication.
Are you sure that availability of resources was a limiting factor during a large part of human evolution?
ie what has driven human population growth - a fundamental change in availability of natural resources or a fundamental change in how humans exploited them?
I'd argue it's the latter, and that's driven by accumulated knowledge - and before writing - the key repository of that was - old people.
Humans have selective adaptations to reduce resource competition between older and younger members of populations - examples are menopause and testosterone levels.
Part of the reason it benefited us that some but not all people become old is because people require more attention during two phases of their lives. Our biological evolution has prioritized care for the very young over the very old, with respect to a limit on resources (like attention), effectively until the modern age. In some cultures, for instance, those with teeth must pre-chew food for those without, or expected members to engage in ritual suicide at a certain age.
Except humans are a social species and the bands of humans who survived were the ones with the behaviors which kept elders around because of their benefits to our capacity for social learning.
You wouldn't have to do it all the time. Modern humans are much more likely to get a respiratory infection in the winter (I get sick once a year like clockwork). It could be worth stimulating your innate immune system for a few months every year during flu season. Or before traveling.
> cranking up the innate immune system all the time reduced illness with no downsides
But isn't that what the adjuants that are currently in nearly every vaccine do anyway. That is forcing the triggering of immune response when there wouldn't be none or very little response naturally?
No but it’s very good. Just upregulating an already existing system is the sort of thing that can evolve very quickly if there’s a big benefit to survival.
> If cranking up the innate immune system all the time reduced illness with no downsides, you'd think evolution would have done it already, but it didn't, which makes me think there's probably a downside,
Auto-immune diseases are the downside. There is no way that this ends up being safe or recommended for use outside of epidemic situations or short term occupational hazards.
They’re largely an artifact of civilization, with people living in close proximity to lots of other people, and to livestock. We haven’t had time to evolve for that new reality.
It's probably because maintaining the immune system at high levels costs more energy.
You probably know that antibiotic use is rampant in industrial livestock. But do you know precisely why?
Antibiotics aren't just given prophylactically to prevent infections; constant low doses actually *increase the animal's size*. The animals can put more energy into growing larger, and spend less on their immune system.
I don't know much about this, but wouldn't the description of this imply you're stimulating the body to be in an a long-term situation that would be commonly viewed as unpleasant (inflamed, maybe nasal drainage, that type of thing) with the positive tradeoff that you get fewer actual infections?
Yep! But you are also a mouse who has limited venues in which to complain.
I wonder if the vaccine causes inflammatory and other unpleasant responses when administered. If so, I wonder if those responses go away after the last dose, when the three months of protection begin.
Here are the two paragraphs that I found interesting:
> The new vaccine, for now known as GLA-3M-052-LS+OVA, mimics the T cell signals that directly stimulate innate immune cells in the lungs. It also contains a harmless antigen, an egg protein called ovalbumin or OVA, which recruits T cells into the lungs to maintain the innate response for weeks to months.
> In the study, mice were given a drop of the vaccine in their noses. Some recieved multiple doses, given a week apart. Each mouse was then exposed to one type of respiratory virus. With three doses of the vaccine, mice were protected against SARS-CoV-2 and other coronaviruses for at least three months.
> It also contains a harmless antigen, an egg protein called ovalbumin or OVA
Here's hoping the final product doesn't have a side-effect of inducing an allergy to the main component of egg-whites.
Although even if that happened... Would it only apply to the raw materials, as opposed to cooked products where the ovalbumin was denatured by heat?
Edit: No, wait! What about "safe to eat" cookie-dough, which uses heat-treated flour and pasteurized eggs as ingredients!? The might still have intact ovalbumin, and obviously I can't give it up.
AFAIK people with egg white allergy also have to avoid cooked foods.
My understanding (not a chemist nor doctor) is that it's specific bits of the protein that trigger the allergic reaction, so eve if the whole protein breaks down parts of it will survive and will cause trouble.
I suppose this is similar to how we use broken down bits of virus to trigger immune reactions with vaccines.
And what about people who eat actual raw egg? I routinely eat freshly-made cake batter (made with raw eggs; I just clean the bowl, I don't actually gobble tons of raw cake batter), for instance. It's perfectly safe because I live in a country where they actually check eggs for salmonella before selling them and people routinely eat raw eggs on top of things.
A new area of research has opened up. This approach may be more useful for treatment than prevention. It's not really a vaccine; it's more like an induced vaccine response. Keeping the immune system in that state full time might be a problem. But after an infection, that's what's wanted.
I think that "vaccine" is really not the right word to use for this; they sound as different as bandages and blood transfusions. But if it works as advertised, it could be useful if used in the right situation.
I do wonder if the kind of people who got vaccinated 10 times against Covid-19 will end up trying to get a sniff of this every month? Kind of like how we overuse antibiotics in cleaners. It seems like it would be best if saved for an "oh shoot" kind of situation.
The tradeoff might not be something unpleasant. For example, it might be that the immune system uses a lot more energy in this state, which would be bad for survival in the wild with limited resources but probably harmless or even beneficial for modern humans with abundant food.
Me neither, but I got something similar from the abstract that I was about to ask, so adding it here: "Following infection, vaccinated mice mounted rapid pathogen-specific T cell and antibody responses and formed ectopic lymphoid structures in the lung."
That latter term (ectopic lymphoid structure) comes up in connection with persistent inflammation where the immune system sets up camp near the problem point. Is this good or bad? Do these go away once the infection clears up?
These are pretty common, physiologic structures associated with infections. They can be just a handful of cells on a slide or be quite large, and I don't know what they found in these infections. I didn't read the original paper. The ectopic lymphoid structures go away after the infection resolves. It seems that the immune system has ways to set up mini lymph node architecture right by the site of infections, which is very sensible. The same process is going on in a more organized way in the draining lymph node in parallel. Research into these was really hot in the 2010s, but people don't seem to be as into them anymore (but my research has also transitioned to innate immunity from adaptive, so it's likely that I'm no longer in that universe).
In general, it doesn't surprise me that when you prime the innate immune system, the adaptive immune system works well. The problem is that pathogens have an incredible suite of tools ready to evade these mechanisms. The doses of the pathogens are typically insanely high too, which I do not think model natural infections well. Anyways, this is intriguing, so I'll take a look at the original paper one of these days. Vaccine research generally is so boring. It's like, we vaccinated, and it worked, or didn't, no mechanism.
Yes, I've had exactly this ever since my first COVID experience. If I come across anyone with even a tiny level of COVID or flu, it sets of inflammation in my lungs within minutes. Haven't gotten sick in six years now but this inflammation has happened probably one hundred times and is indeed quite unpleasant.
I think you have evolution backwards. There only needs to not be a reason we need it to survive long enough to reproduce. Or more probabilistically, there needs to not be a significant reproductive benefit to it.
And bear in mind that most people don't have a problem surviving colds and the like long enough to reproduce even with no vaccines at all, and that was probably more true for much of our evolutionary history when we were living much more isolated lives, and not cohabiting with chickens and pigs.
At scale, yes. Because human males have significantly longer fertility periods than females, the specific adaptations of men who are healthier into later life can be passed onto offspring. The same applies to women who reach menopause while they're still healthy are able to continue caring for family without the risk of expanding the population, albeit for their offspring.
While human evolution is not predictive, it has selected for a wide variety of survival-associated adaptations beyond the mere individual.
>There only needs to not be a reason we need it to survive long enough to reproduce.
Humans had life expectancy even shorter than our fertility period until recently and they developed as social species hundreds of thousands years ago, for which living beyond fertility period is beneficial (grandparents were invented by evolution too).
> And bear in mind that most people don't have a problem surviving colds
That’s modern people with access to antibiotics etc.
> that was probably more true for much of our evolutionary history when we were living much more isolated lives, and not cohabiting with chickens and pigs
For much of our evolutionary history people were eating animals, getting viruses with them.
> Humans had life expectancy even shorter than our fertility period
That's largely due to infant/child mortality. Once you reached reproductive age, life expectancy was roughly 50, plenty of time to have plenty of kids.
> That’s modern people with access to antibiotics etc.
Antibiotics don't help against viruses like colds. And we live a life that is has a higher degree of social connectivity than our ancestors, allowing for faster spreading of disease, so we're arguably worse off.
Yes, and to get there we use immunity that is activated on demand. Clearly that was better from evolutionary perspective than preactivation or always-on.
> Yes, and to get there we use immunity that is activated on demand. Clearly that was better from evolutionary perspective than preactivation or always-on.
I don't think you understand evolution. Neither needs to be "better" for anything other than survival to reproduction. Evolution isn't min-maxing in a video game.
I don’t think you understand it, if you cannot connect the dots. And of course “survival for reproduction” is oversimplification of what’s actually happening. Chances for survival to reproduce of some individuals are greatly influenced by survival of their relatives in the same group. The traits that help whole group to survive will win in natural selection, including those that extend survival beyond what’s necessary to reproduce to what’s beneficial for the group.
> I don’t think you understand it, if you cannot connect the dots.
This doesn't mean anything.
> Chances for survival to reproduce of some individuals are greatly influenced by survival of their relatives in the same group. The traits that help whole group to survive will win in natural selection, including those that extend survival beyond what’s necessary to reproduce to what’s beneficial for the group.
Which, of course, has absolutely nothing to do with whether current traits are optimized for perfection, or simply sufficient for continued reproduction. Again, evolution isn't min-maxing your video game character. I'm not clear why you have such strident opinions on something you don't understand very well.
If something clearly helps survival and not an improbable thing to develop, the chances are high we would already have it. But we don’t and most species don’t. It is not the default, there likely exists a reason why.
> If something clearly helps survival and not an improbable thing to develop, the chances are high we would already have it.
Well sure, but "not an improbable thing to develop" is doing a lot of work there. Again, everything complex is "improbable to develop," in the sense that evolution takes a lot of time and is very path dependent.
We could have paper shredders, blenders, toasters, water taps, and so on that just ran all the time, but our utility bills would be ginormous. Same thing for our bodies.
So does getting infected over and over. Much worse damage. Evolution isn't some magic thing that gives you the most optimal creature for a given metric. The only metric is procreation. Not longevity. Not a pleasant life.
Might be as simple as cost/effect in resource-constrained environment.
Inflamation uses up resources. When we were hunter-gatherers and had to survive ice ages - it wasn't a good idea to waste calories and vitamins just in case.
Better for 3 people out of 30 to die of flu than for all 30 to starve.
Nowadays the optimal trade-off might be completely different.
>wouldn't the description of this imply you're stimulating the body to be in an a long-term situation that would be commonly viewed as unpleasant (inflamed, maybe nasal drainage, that type of thing) with the positive tradeoff that you get fewer actual infections?
It might be worth it, at least during certain times of the year. For much of the winter, for instance, I already seem to have a lot of nasal drainage and other unpleasant symptoms for the whole time, along with the occasional actual infection which is much more unpleasant.
There's certain times when there's big flare-ups of infections such as flu, so maybe giving everyone an annoying vaccine during that time which gives them the sniffles would actually improve things overall.
People with severe allergies or at high risk would probably make the tradeoff even if side effects were a problem. If they're not a problem, I could see most people taking this regularly just to avoid the nuisance of respiratory infections.
What intrigued me the most is why their vaccine reduces allergic reactions too. If the allergic reaction is an immune response, why does administering the vaccine which increases immune response result in a decreased allergic reaction? I'd expect the opposite.
They say so in the article but you need a teensy bit more to make the connection. Here's the ELI5 version and then a link to too much detail:
You can have a Th1 or a Th2 reaction. One produces one kind of reaction and the other produces a different kind of reaction. And they both inhibit the other. It's a mechanism whose purpose (to the degree purposes exist) is to identify which kind of problem you have and apply as much energy as possible to that because they each fight different kinds of enemies. You'll see in the article they say:
> Allergic reactions are caused by a type of immune response known as Th2 response. Unvaccinated mice showed a strong Th2 response and mucus accumulation in their airways. The vaccine quelled the Th2 response and vaccinated mice maintained clear airways
Neither of these are immune (haha) to causing problems. Th1 was historically associated with multiple sclerosis. Obviously if your detection mechanism is broken you will create more and more of the wrong kind because of the fact one kind can beat the other with numbers but also because the wrong one won't even get the mis-detected enemy (which might not even be an enemy - and be harmless) out.
> Th1-type cytokines tend to produce the proinflammatory responses responsible for killing intracellular parasites and for perpetuating autoimmune responses. Interferon gamma is the main Th1 cytokine. Excessive proinflammatory responses can lead to uncontrolled tissue damage, so there needs to be a mechanism to counteract this. The Th2-type cytokines include interleukins 4, 5, and 13, which are associated with the promotion of IgE and eosinophilic responses in atopy, and also interleukin-10, which has more of an anti-inflammatory response. In excess, Th2 responses will counteract the Th1 mediated microbicidal action. The optimal scenario would therefore seem to be that humans should produce a well balanced Th1 and Th2 response, suited to the immune challenge.
> Many researchers regard allergy as a Th2 weighted imbalance, and recently immunologists have been investigating ways to redirect allergic Th2 responses in favour of Th1 responses to try to reduce the incidence of atopy
There's a lot of detail to it. After all, it's an emergent evolved device that we carry, but that's the rough shape of it. You can create one kind of immune response and simultaneously shut down another kind.
Allergies are not simply overactive immune response. It’s the wrong type of response. What’s really intriguing is how much we can do innate immunity that we have done relatively little with.
I'm pretty allergic most of the time (lots of birch cross allergies and dust mites), but sometimes when I'm sick the allergic reactions appear to go down. Allergies can be pretty weird.
I would speculate it's something like, if your innate immune system is running "hotter", it's going to reduce the amount of time it takes to clear anything it runs into, leading to less time spent inflaming anything, in a similar fashion to how it significantly reduced viral payloads, leading to negligible symptoms when the adaptive immune system batted cleanup.
Appears that it is trying to stimulate broad immunity .. instead of any one specific virus/disease. Artificial and overstimulation of our immune systems long-term can't be healthy. Definitely a tradeoff here.
> [greater activity within] our immune systems long-term can't be healthy
Not trying to be flip, but why? "Natural" isn't always better, and as the obesity epidemic has shown, our evolutionary past hasn't done a perfect job of preparing us for our current environment.
You might be right, but I'm skeptical that there is any non-extreme limit to something as simple and mechanical as our innate immune system.
We know that systemic inflammation is associated with all kinds of chronic diseases. I don’t know whether we have figured out which causes which, but I’d be wary of overstimulating the immune system too.
The immune system operates at level far below where we get "tired" -- worrying that we'll "use up" the immune system seems similar to worrying that exercise will "use up" our lifetime allotment of heartbeats.
The concern isn't "using up" the immune system, the concern is the immune system gets all revved up looking for something to kill, and not finding pathogens handy, attacks your own organs.
But this is talking about the innate vs. the adaptive immune system. I am not a medical professional, but it seems like the innate system is either maladapted or not. In any case, I don't think it's fair to assume that your "common sense" overrides my skepticism.
There are likely biological pros and cons between innate and adaptive, such that using the innate response for everything is not desirable.
The innate response is less targeted, less effective, and causes potentially damaging effects like inflammation. The adaptive response is more targeted and more effective, with the tradeoff that it needs to be learnt.
> Cant we say this applies to the flu vaccine? This almost validates why I skip it every year.
These two things have literally nothing to do with each other.
> I get sick after getting the flu vaccine and feel pretty bad for 1-3 days
I thought you skipped it every year? So did this happen like, once, and you don't actually have any real basis for comparison or understanding, here? Come on.
And you distinctly remember every single one of those 5-6 years getting sick immediately after, and getting the flu the same year? Again, come on now. This isn't even anecdata, it's just invented memories to push a conclusion you arrived at in your 20s with no actual understanding or basis of knowledge. I assume you think there are no benefits to having gotten the flu vaccine, if you do happen to get the flu after, either, for reasons that are surely backed by strong evidence and subject matter expertise, and not like, Facebook posts.
I don't know why people feel so compelled to invent stories about vaccines they hate but don't even vaguely understand, especially when the creative writing is so poor. It's such a weirdly pervasive thing in healthcare, that people think basic existence is the same as expertise.
It could also be useful in low doses to supplement, for example, a seasonal vaccine in a year where they are especially unsure about prevalent strains, or where their predictions were already proved wrong early in the flu season
you would think so! as a "vaccine skeptic", i think this kind of research is important and patients should be able to decide w/ their doctor which to pursue based on their individual condition. perhaps this tradeoff will be worth it in higher risk individuals.
3M-052 again? Oh, for fuck's sake. We've been down this road for 15 years now. Every funder who learns about the interferon cascade gets a boner. And then they go to animal trials and meet disappointment. If these guys can get to an IND, good on them, but 3M is really licensing the shit out of this one.
Meanwhile, if you've got spare millions laying around, have a look at ENA Respiratory. They've already done a Phase 1 in Australia (entirely admissable for the FDA). Turns out hypoxia creates and anxiety and old people have most of the world's wealth, so COPD is a lucrative market.
Another super interesting one is Lumen Biosciences - can't make oil from algae at a viable price point, but for sure they can hit pharma price points, even food supplement price points.
Depending on how bad it is for you, I can recommend thinking about turbinectomy. Had it done due to chronic, allergy related swellings, and it was life changing.
Have you considered just doing hyposensibilization therapy? No reason to go the way of surgery before trying that. Worked wonders for me and my array of allergies, dust mites among them.
I tried hyposensibilization therapy, and while it worked for seasonal birch pollen issues, it didn't work for dust mites, oral allergies, and chronically stuffed sinuses.
It basically means surgically removing parts of your chronically enlarged/swollen turbinates so that your airways are free again. Along with that I've had a nasal spur removed (slightly blocked airways); Septumplastic (had a slightly deviated septum that also inhibited airflow a bit); and while at it the ENT also recommended and did FESS (Opening/Widening some paths to the sinuses).
It was a pretty life changing surgery that finally allowed me to properly sleep again, and do exercises/run while breathing through the nose. For some people, the turbinates may become enlarged again after a while, but for me it's been great for two years already.
This is cool but I’m sorry, that’s not a vaccine - it’s a prophylactic.
A vaccine or inoculation is named because it creates a sustained adaptation to a targeted antigen. Something that boosts immune response is not an acquired adaptation! This would need to be re-upped every month or so.
Good for travel and brief encounters. Not an actual immunization.
Not too mention boosting cell growth factors can have unintended side effects like cancer! There are immune system cancers and I would be concerned about risks there.
I would also mention, just general auto-immune diseases. I would be very worried this could trigger those in people who wouldn't have gotten one otherwise.
What's interesting to me is that one of the biggest booms in pharma over the last ~10 years has been biologics / monoclonal antibodies that treat auto-immune diseases by SUPRESSING cytokines. Examples include TNF inhibitors like Remicade/Humira/Enbrel; or specific IL-XX inhibitors like Dupixent/Cosentyx/Skyrizi/Tremfya/etc; or interferon therapies for MS. These are increasingly used for a broad (unlimited?) set of autoimmune or inflammatory diseases and work by blocking specific cytokines to reduce immune overactivity.
What this treatment does is the opposite side of that coin, it mimics cytokines in order to PROMOTE an immune response.
Immune regulation is an area that deserves a lot more research, and there is going to be learning (harm) along the way. An increasing body of science is pointing to autoimmune diseases being triggered by traditional vaccines, which are then treated by the biologics above that increase the likelihood of other disease due to immunosuppression, which can now be treated(?) by a new immunobooster AKA universal vaccine?
This seems too good to be true. Respiratory infections kill and debilitate a lot of people. If cranking up the innate immune system all the time reduced illness with no downsides, you'd think evolution would have done it already, but it didn't, which makes me think there's probably a downside, and the fact that the innate immune system is only cranked up when a pathogen is detected is probably because the downside is worth it in the presence of a pathogen but not otherwise.
I was thinking the same thing. Perhaps the trade-off made by evolution is about saving energy?
In that case it shouldn't be a problem to boost the innate immune system, as long as you have surplus calories to spend. But it could be something else entirely.
It could be just "good enough" as it is. That is, as another poster commented, there is a Th1 or a Th2 reaction. And these in a sense compete. Only one appears to be active.
The current framework of our immune system could go back quite some time. Even to our mammalian cold-blooded ancestors, 200? mya. When I think of cold blooded, I think of creatures able to remain static and at rest for a long time, periods of low-energy usage. So maybe this framework comes from before warm blooded mammals?
And, if it works well enough that people can breed (which used to be 15 years to 30 years old), and if dying after, oh well. Why evolve better? Or maybe too much monkeying has downsides.
Look at sickle cell anemia. Quite beneficial with malaria parasites around, not so much without them.
> shouldn't be a problem to boost the innate immune system, as long as you have surplus calories to spend.
So I'd lose weight too? Sign me up yesterday.
Such as autoimmune disorders or other hyperinflammatory disorders?
Graves’ disease, lupus/SLE, psoriasis, type 1 diabetes, myasthenia gravis, Addison’s disease, Hashimoto, Goodpasture, etc.
Yes, i was thinking just this. Having been prescribed multiple immunocompromisers, turning up my immune system sounds terrifying. There's all these supplements and things that talk about boosting your immune system and i get probably most are unrelated, i don't have the time to get a degree in immunology to find out. Zinc does well enough for me, thanks. But if any immune boost started to increase my tnf-alpha or il-23 i'd be on the long and painful road to a terrible death. Or yet another high side effect medication.
Evolution just needs people survive long enough to reproduce. If they get sick afterwards, it doesn't care.
Evolution happens both sides - you and the virus/bacteria trying to live off you.
One of the risks of an always on response, is if something evolves to evade it - you have nowhere to go.
It's why taking an antibiotic at breakfast everyday is not a good idea.
Unless they are contributing to the survival of their offspring.
Which is one theory why grandmothers (post-menopausal women) are a thing
It can work the other way, too. Your offspring may be more likely to survive if you stop consuming resources once they become viable.
Are you sure that availability of resources was a limiting factor during a large part of human evolution?
ie what has driven human population growth - a fundamental change in availability of natural resources or a fundamental change in how humans exploited them?
I'd argue it's the latter, and that's driven by accumulated knowledge - and before writing - the key repository of that was - old people.
Humans have selective adaptations to reduce resource competition between older and younger members of populations - examples are menopause and testosterone levels.
Part of the reason it benefited us that some but not all people become old is because people require more attention during two phases of their lives. Our biological evolution has prioritized care for the very young over the very old, with respect to a limit on resources (like attention), effectively until the modern age. In some cultures, for instance, those with teeth must pre-chew food for those without, or expected members to engage in ritual suicide at a certain age.
The vast majority of human evolution happened in non-humans
Except humans are a social species and the bands of humans who survived were the ones with the behaviors which kept elders around because of their benefits to our capacity for social learning.
You wouldn't have to do it all the time. Modern humans are much more likely to get a respiratory infection in the winter (I get sick once a year like clockwork). It could be worth stimulating your innate immune system for a few months every year during flu season. Or before traveling.
> you'd think evolution would have done it already, but it didn't, which makes me think there's probably a downside
Couldn’t you apply this logic to any medicine?
> cranking up the innate immune system all the time reduced illness with no downsides
But isn't that what the adjuants that are currently in nearly every vaccine do anyway. That is forcing the triggering of immune response when there wouldn't be none or very little response naturally?
That’s adaptive rather than innate, as the article makes clear.
It’s only an imperfect vaccine — broad immune protection. Evolution probably has come up with a bunch of these.
Evolution is not a perfect optimizer.
No but it’s very good. Just upregulating an already existing system is the sort of thing that can evolve very quickly if there’s a big benefit to survival.
That’s not how evolution works.
> If cranking up the innate immune system all the time reduced illness with no downsides, you'd think evolution would have done it already, but it didn't, which makes me think there's probably a downside,
Auto-immune diseases are the downside. There is no way that this ends up being safe or recommended for use outside of epidemic situations or short term occupational hazards.
They’re largely an artifact of civilization, with people living in close proximity to lots of other people, and to livestock. We haven’t had time to evolve for that new reality.
It's probably because maintaining the immune system at high levels costs more energy.
You probably know that antibiotic use is rampant in industrial livestock. But do you know precisely why?
Antibiotics aren't just given prophylactically to prevent infections; constant low doses actually *increase the animal's size*. The animals can put more energy into growing larger, and spend less on their immune system.
I don't know much about this, but wouldn't the description of this imply you're stimulating the body to be in an a long-term situation that would be commonly viewed as unpleasant (inflamed, maybe nasal drainage, that type of thing) with the positive tradeoff that you get fewer actual infections?
Yep! But you are also a mouse who has limited venues in which to complain.
I wonder if the vaccine causes inflammatory and other unpleasant responses when administered. If so, I wonder if those responses go away after the last dose, when the three months of protection begin.
Here are the two paragraphs that I found interesting:
> The new vaccine, for now known as GLA-3M-052-LS+OVA, mimics the T cell signals that directly stimulate innate immune cells in the lungs. It also contains a harmless antigen, an egg protein called ovalbumin or OVA, which recruits T cells into the lungs to maintain the innate response for weeks to months.
> In the study, mice were given a drop of the vaccine in their noses. Some recieved multiple doses, given a week apart. Each mouse was then exposed to one type of respiratory virus. With three doses of the vaccine, mice were protected against SARS-CoV-2 and other coronaviruses for at least three months.
> It also contains a harmless antigen, an egg protein called ovalbumin or OVA
Here's hoping the final product doesn't have a side-effect of inducing an allergy to the main component of egg-whites.
Although even if that happened... Would it only apply to the raw materials, as opposed to cooked products where the ovalbumin was denatured by heat?
Edit: No, wait! What about "safe to eat" cookie-dough, which uses heat-treated flour and pasteurized eggs as ingredients!? The might still have intact ovalbumin, and obviously I can't give it up.
AFAIK people with egg white allergy also have to avoid cooked foods.
My understanding (not a chemist nor doctor) is that it's specific bits of the protein that trigger the allergic reaction, so eve if the whole protein breaks down parts of it will survive and will cause trouble.
I suppose this is similar to how we use broken down bits of virus to trigger immune reactions with vaccines.
And what about people who eat actual raw egg? I routinely eat freshly-made cake batter (made with raw eggs; I just clean the bowl, I don't actually gobble tons of raw cake batter), for instance. It's perfectly safe because I live in a country where they actually check eggs for salmonella before selling them and people routinely eat raw eggs on top of things.
Raw flour is just as dangerous. It can contain e coli and salmonella, among other bacteria.
Right, that's been mentioned elsewhere.
A new area of research has opened up. This approach may be more useful for treatment than prevention. It's not really a vaccine; it's more like an induced vaccine response. Keeping the immune system in that state full time might be a problem. But after an infection, that's what's wanted.
Some autoimmune diseases are a result of an immune system always on.
I think that "vaccine" is really not the right word to use for this; they sound as different as bandages and blood transfusions. But if it works as advertised, it could be useful if used in the right situation.
I do wonder if the kind of people who got vaccinated 10 times against Covid-19 will end up trying to get a sniff of this every month? Kind of like how we overuse antibiotics in cleaners. It seems like it would be best if saved for an "oh shoot" kind of situation.
Inoculation?
The tradeoff might not be something unpleasant. For example, it might be that the immune system uses a lot more energy in this state, which would be bad for survival in the wild with limited resources but probably harmless or even beneficial for modern humans with abundant food.
Me neither, but I got something similar from the abstract that I was about to ask, so adding it here: "Following infection, vaccinated mice mounted rapid pathogen-specific T cell and antibody responses and formed ectopic lymphoid structures in the lung."
That latter term (ectopic lymphoid structure) comes up in connection with persistent inflammation where the immune system sets up camp near the problem point. Is this good or bad? Do these go away once the infection clears up?
These are pretty common, physiologic structures associated with infections. They can be just a handful of cells on a slide or be quite large, and I don't know what they found in these infections. I didn't read the original paper. The ectopic lymphoid structures go away after the infection resolves. It seems that the immune system has ways to set up mini lymph node architecture right by the site of infections, which is very sensible. The same process is going on in a more organized way in the draining lymph node in parallel. Research into these was really hot in the 2010s, but people don't seem to be as into them anymore (but my research has also transitioned to innate immunity from adaptive, so it's likely that I'm no longer in that universe).
In general, it doesn't surprise me that when you prime the innate immune system, the adaptive immune system works well. The problem is that pathogens have an incredible suite of tools ready to evade these mechanisms. The doses of the pathogens are typically insanely high too, which I do not think model natural infections well. Anyways, this is intriguing, so I'll take a look at the original paper one of these days. Vaccine research generally is so boring. It's like, we vaccinated, and it worked, or didn't, no mechanism.
Yes, I've had exactly this ever since my first COVID experience. If I come across anyone with even a tiny level of COVID or flu, it sets of inflammation in my lungs within minutes. Haven't gotten sick in six years now but this inflammation has happened probably one hundred times and is indeed quite unpleasant.
Or worse. If it is so easy to activate, there must be an evolutionary reason why we don’t have it.
I think you have evolution backwards. There only needs to not be a reason we need it to survive long enough to reproduce. Or more probabilistically, there needs to not be a significant reproductive benefit to it.
And bear in mind that most people don't have a problem surviving colds and the like long enough to reproduce even with no vaccines at all, and that was probably more true for much of our evolutionary history when we were living much more isolated lives, and not cohabiting with chickens and pigs.
At scale, yes. Because human males have significantly longer fertility periods than females, the specific adaptations of men who are healthier into later life can be passed onto offspring. The same applies to women who reach menopause while they're still healthy are able to continue caring for family without the risk of expanding the population, albeit for their offspring.
While human evolution is not predictive, it has selected for a wide variety of survival-associated adaptations beyond the mere individual.
>There only needs to not be a reason we need it to survive long enough to reproduce.
Humans had life expectancy even shorter than our fertility period until recently and they developed as social species hundreds of thousands years ago, for which living beyond fertility period is beneficial (grandparents were invented by evolution too).
> And bear in mind that most people don't have a problem surviving colds
That’s modern people with access to antibiotics etc.
> that was probably more true for much of our evolutionary history when we were living much more isolated lives, and not cohabiting with chickens and pigs
For much of our evolutionary history people were eating animals, getting viruses with them.
> Humans had life expectancy even shorter than our fertility period
That's largely due to infant/child mortality. Once you reached reproductive age, life expectancy was roughly 50, plenty of time to have plenty of kids.
> That’s modern people with access to antibiotics etc.
Antibiotics don't help against viruses like colds. And we live a life that is has a higher degree of social connectivity than our ancestors, allowing for faster spreading of disease, so we're arguably worse off.
>Antibiotics don't help against viruses like colds
Yes. But they help fighting secondary infections, which are common.
If you made it to fertility age your life expectancy was much longer.
Yes, and to get there we use immunity that is activated on demand. Clearly that was better from evolutionary perspective than preactivation or always-on.
> Yes, and to get there we use immunity that is activated on demand. Clearly that was better from evolutionary perspective than preactivation or always-on.
I don't think you understand evolution. Neither needs to be "better" for anything other than survival to reproduction. Evolution isn't min-maxing in a video game.
I don’t think you understand it, if you cannot connect the dots. And of course “survival for reproduction” is oversimplification of what’s actually happening. Chances for survival to reproduce of some individuals are greatly influenced by survival of their relatives in the same group. The traits that help whole group to survive will win in natural selection, including those that extend survival beyond what’s necessary to reproduce to what’s beneficial for the group.
> I don’t think you understand it, if you cannot connect the dots.
This doesn't mean anything.
> Chances for survival to reproduce of some individuals are greatly influenced by survival of their relatives in the same group. The traits that help whole group to survive will win in natural selection, including those that extend survival beyond what’s necessary to reproduce to what’s beneficial for the group.
Which, of course, has absolutely nothing to do with whether current traits are optimized for perfection, or simply sufficient for continued reproduction. Again, evolution isn't min-maxing your video game character. I'm not clear why you have such strident opinions on something you don't understand very well.
There doesn’t need to be an evolutionary reason why we don’t have something. That’s the default!
If something clearly helps survival and not an improbable thing to develop, the chances are high we would already have it. But we don’t and most species don’t. It is not the default, there likely exists a reason why.
> If something clearly helps survival and not an improbable thing to develop, the chances are high we would already have it.
Well sure, but "not an improbable thing to develop" is doing a lot of work there. Again, everything complex is "improbable to develop," in the sense that evolution takes a lot of time and is very path dependent.
What's the reason
Systemic cost.
We could have paper shredders, blenders, toasters, water taps, and so on that just ran all the time, but our utility bills would be ginormous. Same thing for our bodies.
Or the risk of autoimmune disease?
Yep. And probably increased allergies. Possibly decreased fertility. And who knows what else.
Yes that's the obvious one
Maybe it would made the immune system age faster if it is "used" too much.
Inflammation is certainly not "free". It causes systemic damage.
So does getting infected over and over. Much worse damage. Evolution isn't some magic thing that gives you the most optimal creature for a given metric. The only metric is procreation. Not longevity. Not a pleasant life.
Might be as simple as cost/effect in resource-constrained environment.
Inflamation uses up resources. When we were hunter-gatherers and had to survive ice ages - it wasn't a good idea to waste calories and vitamins just in case.
Better for 3 people out of 30 to die of flu than for all 30 to starve.
Nowadays the optimal trade-off might be completely different.
>wouldn't the description of this imply you're stimulating the body to be in an a long-term situation that would be commonly viewed as unpleasant (inflamed, maybe nasal drainage, that type of thing) with the positive tradeoff that you get fewer actual infections?
It might be worth it, at least during certain times of the year. For much of the winter, for instance, I already seem to have a lot of nasal drainage and other unpleasant symptoms for the whole time, along with the occasional actual infection which is much more unpleasant.
There's certain times when there's big flare-ups of infections such as flu, so maybe giving everyone an annoying vaccine during that time which gives them the sniffles would actually improve things overall.
People with severe allergies or at high risk would probably make the tradeoff even if side effects were a problem. If they're not a problem, I could see most people taking this regularly just to avoid the nuisance of respiratory infections.
What intrigued me the most is why their vaccine reduces allergic reactions too. If the allergic reaction is an immune response, why does administering the vaccine which increases immune response result in a decreased allergic reaction? I'd expect the opposite.
They say so in the article but you need a teensy bit more to make the connection. Here's the ELI5 version and then a link to too much detail:
You can have a Th1 or a Th2 reaction. One produces one kind of reaction and the other produces a different kind of reaction. And they both inhibit the other. It's a mechanism whose purpose (to the degree purposes exist) is to identify which kind of problem you have and apply as much energy as possible to that because they each fight different kinds of enemies. You'll see in the article they say:
> Allergic reactions are caused by a type of immune response known as Th2 response. Unvaccinated mice showed a strong Th2 response and mucus accumulation in their airways. The vaccine quelled the Th2 response and vaccinated mice maintained clear airways
Neither of these are immune (haha) to causing problems. Th1 was historically associated with multiple sclerosis. Obviously if your detection mechanism is broken you will create more and more of the wrong kind because of the fact one kind can beat the other with numbers but also because the wrong one won't even get the mis-detected enemy (which might not even be an enemy - and be harmless) out.
The too-much-detail: https://pmc.ncbi.nlm.nih.gov/articles/PMC27457/
> Th1-type cytokines tend to produce the proinflammatory responses responsible for killing intracellular parasites and for perpetuating autoimmune responses. Interferon gamma is the main Th1 cytokine. Excessive proinflammatory responses can lead to uncontrolled tissue damage, so there needs to be a mechanism to counteract this. The Th2-type cytokines include interleukins 4, 5, and 13, which are associated with the promotion of IgE and eosinophilic responses in atopy, and also interleukin-10, which has more of an anti-inflammatory response. In excess, Th2 responses will counteract the Th1 mediated microbicidal action. The optimal scenario would therefore seem to be that humans should produce a well balanced Th1 and Th2 response, suited to the immune challenge.
> Many researchers regard allergy as a Th2 weighted imbalance, and recently immunologists have been investigating ways to redirect allergic Th2 responses in favour of Th1 responses to try to reduce the incidence of atopy
There's a lot of detail to it. After all, it's an emergent evolved device that we carry, but that's the rough shape of it. You can create one kind of immune response and simultaneously shut down another kind.
Allergies are not simply overactive immune response. It’s the wrong type of response. What’s really intriguing is how much we can do innate immunity that we have done relatively little with.
I'm pretty allergic most of the time (lots of birch cross allergies and dust mites), but sometimes when I'm sick the allergic reactions appear to go down. Allergies can be pretty weird.
Well yes, as allergies mean the immune system is acting weird and sees harmles things as a threat.
I would speculate it's something like, if your innate immune system is running "hotter", it's going to reduce the amount of time it takes to clear anything it runs into, leading to less time spent inflaming anything, in a similar fashion to how it significantly reduced viral payloads, leading to negligible symptoms when the adaptive immune system batted cleanup.
IN MICE should be added to this title
No need: this is always the top comment
Appears that it is trying to stimulate broad immunity .. instead of any one specific virus/disease. Artificial and overstimulation of our immune systems long-term can't be healthy. Definitely a tradeoff here.
> [greater activity within] our immune systems long-term can't be healthy
Not trying to be flip, but why? "Natural" isn't always better, and as the obesity epidemic has shown, our evolutionary past hasn't done a perfect job of preparing us for our current environment.
You might be right, but I'm skeptical that there is any non-extreme limit to something as simple and mechanical as our innate immune system.
We know that systemic inflammation is associated with all kinds of chronic diseases. I don’t know whether we have figured out which causes which, but I’d be wary of overstimulating the immune system too.
calling the immune system simple and mechanical is completely wild, like half of americans have some kind of medically diagnosable immune dysfunction
The immune system operates at level far below where we get "tired" -- worrying that we'll "use up" the immune system seems similar to worrying that exercise will "use up" our lifetime allotment of heartbeats.
The concern isn't "using up" the immune system, the concern is the immune system gets all revved up looking for something to kill, and not finding pathogens handy, attacks your own organs.
Normally when your immune system is on high alert for a prolonged period of time, it can lead to more false positives and trigger auto immune issues.
But this is talking about the innate vs. the adaptive immune system. I am not a medical professional, but it seems like the innate system is either maladapted or not. In any case, I don't think it's fair to assume that your "common sense" overrides my skepticism.
There are likely biological pros and cons between innate and adaptive, such that using the innate response for everything is not desirable.
The innate response is less targeted, less effective, and causes potentially damaging effects like inflammation. The adaptive response is more targeted and more effective, with the tradeoff that it needs to be learnt.
Cant we say this applies to the flu vaccine? This almost validates why I skip it every year.
I get sick after getting the flu vaccine and feel pretty bad for 1-3 days... then I get the flu anyway because they picked the wrong ones.
The normal vaccine is very different. The inmune system learns how to block one virus or bacteria and go to rest until the virus or bacteria appears.
This looks like the inmune system is keep at the emergency level for 3 months.
> Cant we say this applies to the flu vaccine? This almost validates why I skip it every year.
These two things have literally nothing to do with each other.
> I get sick after getting the flu vaccine and feel pretty bad for 1-3 days
I thought you skipped it every year? So did this happen like, once, and you don't actually have any real basis for comparison or understanding, here? Come on.
Did it for a few years in my 20s. Then did it for a few years from family peer pressure. Then did the covid thing.
Probably n=5 or 6 out of 18.
And you distinctly remember every single one of those 5-6 years getting sick immediately after, and getting the flu the same year? Again, come on now. This isn't even anecdata, it's just invented memories to push a conclusion you arrived at in your 20s with no actual understanding or basis of knowledge. I assume you think there are no benefits to having gotten the flu vaccine, if you do happen to get the flu after, either, for reasons that are surely backed by strong evidence and subject matter expertise, and not like, Facebook posts.
I don't know why people feel so compelled to invent stories about vaccines they hate but don't even vaguely understand, especially when the creative writing is so poor. It's such a weirdly pervasive thing in healthcare, that people think basic existence is the same as expertise.
It could also be useful in low doses to supplement, for example, a seasonal vaccine in a year where they are especially unsure about prevalent strains, or where their predictions were already proved wrong early in the flu season
you would think so! as a "vaccine skeptic", i think this kind of research is important and patients should be able to decide w/ their doctor which to pursue based on their individual condition. perhaps this tradeoff will be worth it in higher risk individuals.
Until they mandate it...
> Until they mandate it...
When, specifically, do you think that has happened? I'll wait.
3M-052 again? Oh, for fuck's sake. We've been down this road for 15 years now. Every funder who learns about the interferon cascade gets a boner. And then they go to animal trials and meet disappointment. If these guys can get to an IND, good on them, but 3M is really licensing the shit out of this one.
Meanwhile, if you've got spare millions laying around, have a look at ENA Respiratory. They've already done a Phase 1 in Australia (entirely admissable for the FDA). Turns out hypoxia creates and anxiety and old people have most of the world's wealth, so COPD is a lucrative market.
Another super interesting one is Lumen Biosciences - can't make oil from algae at a viable price point, but for sure they can hit pharma price points, even food supplement price points.
Study: https://www.science.org/doi/10.1126/science.aea1260
https://sci-net.xyz/10.1126/science.aea1260
Hopefully this wouldn't trigger autoimmune conditions.
In mice?
3 weeks old story;
Some discussion: https://news.ycombinator.com/item?id=47080267
What a time to be a Mice!
as someone with chronic nasal allergies, would this work for me?
Depending on how bad it is for you, I can recommend thinking about turbinectomy. Had it done due to chronic, allergy related swellings, and it was life changing.
TIL! I have dust mite allergies, how will this help?
Have you considered just doing hyposensibilization therapy? No reason to go the way of surgery before trying that. Worked wonders for me and my array of allergies, dust mites among them.
(one who recommended surgery here)
I tried hyposensibilization therapy, and while it worked for seasonal birch pollen issues, it didn't work for dust mites, oral allergies, and chronically stuffed sinuses.
It basically means surgically removing parts of your chronically enlarged/swollen turbinates so that your airways are free again. Along with that I've had a nasal spur removed (slightly blocked airways); Septumplastic (had a slightly deviated septum that also inhibited airflow a bit); and while at it the ENT also recommended and did FESS (Opening/Widening some paths to the sinuses).
It was a pretty life changing surgery that finally allowed me to properly sleep again, and do exercises/run while breathing through the nose. For some people, the turbinates may become enlarged again after a while, but for me it's been great for two years already.
Didn‘t we something similar with antibiotics?
At first they helped against a broad spectrum of bacteria but then the bacteria evolved.
Damn you Darwin and your evolution.
I want my body to be a product sold to me by a corporation.
In mice
Gotta start somewhere!
Good news! Also, AI thumbnail defies all physical laws.