We know the primary antigens for most infections (S. aureus, E. coli, etc). Most vaccinations are inactivated antigens, so what’s stopping scientists from making vaccinations against most illnesses? I know there’s antigenic variation, but we change the COVID and flu vaccines to combat this; why can’t this be done for other illnesses? There must be reasons beyond money that I’m not understanding; I’ve been thinking about this for the last couple of weeks, so I’d be very grateful for some elucidation!
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S. aereus have cell surface proteins that bind and inactivate antibodies.
E. coli modulates it cell surface to become extra slippery, prevention immune cells to grab it. It also release molecules that suppress immune cell’s ability to communicate with each other (basically doing biological equivalent of jamming).
Same way the immune system evolved to fight pathogens, pathogens also evolved ways to fight back.
A big part is funding and effort. Pre-COVID mRNA vaccines had been in development for 30 years, with the first human trials for an mRNA vaccine being started in 2001.
The COVID vaccines are the fastest any vaccines have been pushed through safety protocols, but that was on the back of that 30 years of research.
So up until 5 years ago, developing a vaccine took decades and many millions of dollars, and there are only a few people in the world qualified to do that work.
Which means vaccine development is selective by nature. You only develop vaccines for pathogens that are major concerns.
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The cost of clinical trials is one more thing. And more specifically, excessive and outdated paperwork and procedures.
I just got prescreened for a(nother) vaccine study yesterday. This was after delays on another vaccine study I was waiting for got put on hold (who knows how many costs have been incurred for that vaccine).
It took over 3 hours. It should and could have taken 1 hour, but they presented the same information and asked me the same questions probably 5 times between prescreens on phone, and in person. I was seen by one staff who left the office 5 times for every step or question he got confused at, and was seen by two NPs and a PA to do a blood draw (i.e. expensive high level medical staff that could’ve been done by a lower level medical professional).
That time burden also drives up recruitment costs. The staff told me they usually just get retirees who have time to show up. That must shrink the recruitment pool.
At the end of this trial, I will probably just provide one useful (summarized) data point and it will probably cost thousands of dollars.
The COVID vaccine (one of the trials of which I was in) effectiveness could be summarized in one graph. Each person really only provided one critical data point on that graph (i.e. what date did you get COVID after being vaccinated), despite maybe hundreds of raw data points and extra health information collected on each individual. The remaining data can be useful, but 99%+ of the trial’s value was in that data column.
I understand the importance of safety, but the slowness was excessive and counterproductive, in my scientific opinion. I work with plant science, and sample sizes that have gone into the 100,000s, because some experiments only cost a few cents per data point. You can do a lot more things when costs are that low and you get that much data. All that money getting extra information on every individual could and should be spent getting more individuals, in my opinion.
I wouldn’t be surprised if the speed of the COVID vaccine trials actually saved a lot of research dollars.
There are many potential answers to your question. Much of them ultimately boil down to “is anyone willing to invest >$100 million to get this vaccine through clinical trials” and “how feasible is it to develop a vaccine against this pathogen”
Some pathogens have such small risk groups that the cost of R&D would take many lifetimes to be recouped.
Some pathogens have readily available therapeutics that, for one reason or another, are preferable to a prophylactic vaccine.
Some pathogens are just so good at evading immunity, that we’ve yet to develop an effective vaccine.
Money realistically it takes forever to get one though the regulatory process; for good reasons.
Government’s were willing to through heaps of cash to a COVID vaccine and skip nearly ever safety requirement to get it out the door. Without a pandemic you’re not going to convince the FDA to greenlight anything in a year.
Ok, as others have said, money is a big one. One aspect of this is that clinical trials get very expensive when you have to wait around for people to get sick. So if the disease you are trying to immunize for doesn’t have a lot of cases, it’s hard to run a large trial.
Non-money factors include the fact that we’ve already got vaccines for the diseases that are easiest to vaccinate against and the ones that are still around have some level of immune evasion or hyper variability, or molecular mimicry that make it difficult to provoke a long lasting protective response.
There’s also stability and distribution concerns. Modern vaccines need special storage which make it harder to plan for and pay for large immunization campaigns.
One answer that I haven’t seen yet is that a lot of vaccine candidates make all the sense in the world to work, and they may even work well in animal models. Then when they’re tried in humans…they just don’t work well.
There are all sorts of potential reasons why that might be, and those reasons will vary for each pathogen. But I distinctly remember a whole bunch of papers with promising data about a vaccine candidate that would peter out in clinical trials.
The immune system is incredibly complex, and there are a lot of different mechanisms in which bacteria can infect you and there are a TON of parts to the immune system. Like thousands probably when you consider everything that’s happening inside and outside of all your different cells. Though antibody antigen is the premise, there are way, way, way more steps and complexities to pathogenicity and immunology than just this. Kinda like saying “your heart beats and pumps blood” is a way over simplified statement that ignores that brain, electrolytes, neurotransmitters, PNS, CNS, hydration, preload, after load and so many other things.
Some ways that pathogens can evade immunity include: are antigen masking, where bacteria can hide the antigens for entry into the cell until they are at the cell itself, viruses replicating intercellularly and causing your cells to hide their “red-flags” that let your NK cells are infected (MHC molecules), so they never really being detectable by your immune system, some have systems that essentially can inject toxins directly into your cells. Some pathogens can change their antigens very frequently and stay latent in your body this way forever so no vaccine could really address that. There are also a variety of signaling molecules infected cells release to initiate your initial immune response (like IL-6 and TNF-alpha) and some bacteria and viruses inhibit these. There’s way more examples too, but those are a few I can think of off the top of my head.
If you are interested in immunology I recommend watching the Ninja Nerd immunology videos for a nice foundation!
The simplest answer to why we can’t make vaccines to a lot of things is they have evolved ways to survive our immune system one way or another. Herpes viruses lay dormant in our ganglia but also have gene products that interfere with immune function. Some bacterial pathogens will change the antigenic makeup over time so antibodies made for one form become useless for the next form. There are many ways viruses and cellular pathogens manage to survive in a human in the presence of the immune system. When you learn about the different ways they do this it is quite remarkable and varied. Even going so far to make enzyme that break down antibodies. Not surprisingly a pathogen in our body will need to have some way to cope with the immune system to continue to survive in that environment.
Other things are just not practical to make vaccines to. The common cold although an annoying illness is not deadly and lasts only a week. However what is called the common cold is caused by many different strains of rhinovirus, about half of all colds, coronaviruses about a quarter and the rest are made of other viruses. So there is not one vaccine to make for this but many many vaccines. Given the illness is not severe and the immune system clears it, making a vaccine is not that practically useful. These viruses evolve and change as well so you would need to be constantly updating the vaccines for many viruses.
Many other viruses may not make us very ill and thus a vaccine would not be worthwhile. Further there are viruses that infect us, such as some in the HPV family (not the strains that cause cancer or warts) that do not cause any sort of disease we are aware of. But we know they infected an individual based on the presence of antibodies to them.
Most often though the things that are pathogens that you might want to make a vaccine are pathogens because they can evade the immune response. Thus not as easy as making a vaccine for the flu. Other pathogens are rare so the economics are not there to make a vaccine. In other cases we do have vaccines, for rabies for example, that we don’t routinely give to people because rabies exposure is not hugely common. The vaccine is give to those who might expect a higher chance of exposure such as those working with animals that might be rabid for example. And it is given when there is a suspected exposure. We have a vaccine for anthrax but most people are not likely to ever contract this disease so we don’t routinely vaccinate people for it.
If it can be prevented by easier and cheaper means, then there’s no real pressure to develop a vaccine for it. That’s the main case for foodborne pathogens like E. coli. But also not everything can be vaccinated against, microbes and viruses are wily little fuckers and some adapt much too easily for a vaccine to ever be viable.
Vaccines are a way of artificially activating the immune system to protect against infectious disease. The activation occurs through priming the immune system with an immunogen. Stimulating immune responses with an infectious agent is known as immunisation.
Vaccines do not work for all illnesses.
For a vaccine to be effective, you need a couple of elements. You need not only any antigen, you need an antigen that’s conservative enough so that it is present on all variations of the given pathogen and also won’t change any time soon – this is why for example you need to get a flu shot every year, the virus changes so much that the antigen the vacine is no longer present or HPV vaccinations have so many antigens and still don’t cover all known subtypes.
The antigen must also be available to the body soon after the infection. Even if an antigen is present on every variant of a pathogen and doesn’t change if it’s present, for example, only in the core structures of it, the exposure to your immune system will be too low to trigger an immune response quickly enough. For example, we use the capsule and core antigen of the Hepatitis B virus for diagnostics (deciding if it’s a new or old infection, active or dormant, etc.), but we don’t use it in the vaccine since it wouldn’t trigger an immune response fast enough.
The antigen needs to trigger a big enough immune response. Even if you have a conservative enough antigen that is available to the immune system, it doesn’t necessarily mean it will trigger a strong enough reaction to trigger immune memory, the reason we vaccinate in the first place. This can sometimes be mitigated by additives to the vaccine that can trigger a stronger immune reaction, or by combining the antigen with a bigger molecule so it’s easier picked up by the immune system, but here again, we run into technical limitations and the compatibility of the antigen with such methods.
And lastly, the antigen needs to be stable enough on a chemical level to be able to be put into a vaccine. The first versions of the COVID-19 vaccine needed to be kept at low temperatures up to the moment of injection. This was a technical challenge that limited the spread of the vaccine in the beginning. So if you can’t find an antigen that can be somewhat stabilised in the solution of the vaccine, it isn’t viable as well.
Taking all this together is actually very hard to find a good antigen for every pathogen out there, which is also why sometimes researchers look for cross reactions. Looking at antigens from complete different organisms that could trigger the production of antibodies that also react to the antigens of a given disease – a couple of years ago there was hope they found a conservative antigen in cammels that would give you permanent immunity to the flu but in the end it didn’t worked well enough.
The infections you mentions are from bacteria. Vaccines are usually made for viruses. To say that bacteria are WAAAAY bigger than viruses would be and understatement. We use antibiotics for bacterial infections.
https://www.who.int/news-room/feature-stories/detail/vaccine-efficacy-effectiveness-and-protection
Vaccine effectiveness if we go with even 80%. Then we look at something like E. Coli and the fact that not even is all E. Coli hazardous, as only the toxin producers are.
Then the vast majority of people who get E. Coli poo for a day at worst and then its over.
The next set is that unlike viruses which don’t habe antibiotics, E. Coli is subject to such, and the antibiotics are highly effective generally.
With some 30 deaths a year, which necessarily include people who were in shape to die from just about anything.
So even if you could design a vaccine that worked, at best, you’d be looking at saving what? 24 people. Who would probably die within a year anyway?
Further the effect of the toxins is the real problem and being vaccinated means your body fights the infection. All those poo people I mentioned earlier? They defeat E. Coli as easily as one would with a vaccine. But the bacteria still kicks out some toxins before it dies.
So you basically destroy coli in a day all the time.
Also, vaccines reproduce generally, the same effect of what occurs when you get an illness and develop immunity.
People who get e. Coli can get it again pretty well, because again the symptom problem is toxins whether you beat it or not.
So, most people are already “vaccinated” against it and still get it. Meaning the liklihood of an effective vaccine is about as low as it gets.
What you cannot vaccinate against as of any science I know about, is toxins. So the only real valuable “vaccine” against some of these issues would be a non-existent Toxin Vaccine.
A big factor is money though . It is much easier to demonstrate the cost benefits of treating a disease than it is to demonstrate those of avoiding one. We all know that COVID cost the world so much, but that’s with the benefit of hindsight and knowing that COVID became a pandemic.
One other mechanism I haven’t seen mentioned is that for quite a few bacteria, in particular I’m thinking S aureus and N meningitidis but there could be others, they have complex glycans present on the surface which can actually be very similar to those on our own cells which makes it difficult to stimulate the immune system to create antibodies against because it has been trained during infancy to tolerate these antigens to reduce the risk of autoimmunity.
some bacteria have lots of strains (they have different proteins on their surface), this makes it hard to train the immune system to recognize that bacteria, in the end, for some infections you would probably need a vaccine that has an absurdly large number of different antigens
secondly, not all antigens cause your immune system to “memorize” the pathogen. For example sugars found on bacteria, the body recognizes them, it then fight the bacteria, but it doesn’t memorize them
Looking at this from another point of view from the other posts – antigenic determinants are what your immune system looks at when it is mounting a defense. Antigenic determinants are limited in size, so there is crossover between species. Years ago there was research into a vaccine against the bacteria that causes dental cavities (Streptococcus mutans). The researchers found that the vaccine caused rheumatic fever. It’s the same thing as multiple strep throat infections can cause rheumatic fever. Heart muscle looks like Streptococcus bacteria to your immune system. So, the vaccine induced the immune system to attack heart muscle.
No, actually money is the limiting factor. Research and development is expensive and elucidation of every mechanism for every vector is time consuming, as well. However, AI is on the scene and will rapidly transform the process.