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This episode was filmed on April 30, 2020. If we have more recent episodes about vaccines or COVID-19, they will be linked in the description.

You might have heard that the COVID-19 crisis won't truly be under control until we have a vaccine -- though increased testing and effective treatments are gonna go a long way. You might also be hearing that even though scientists are working on a bunch of different vaccines right now, it'll be more than a year until we the public can have one -- and that is a best-case. This is frustrating...so you would not be the only person asking WHY WHY WHY this is.

Well, there are good reasons. But to understand them, we first have to understand a bit about how the immune system works. And, like, that's not super simple, but it's also fascinating and weird and going to come in handy on more days than just this one.

So listen up. Our immune system has two main prongs: innate and adaptive immunity. But the key player here is the adaptive part.

Our adaptive immune system responds to things that make us sick, and remembers them for later so that it can keep us from getting sick a second time. Vaccines aim to jump in, before an infection, to teach the adaptive immune system what an infectious agent, or pathogen, looks like, so we don't get sick with it at all. A vaccine shows your immune system a picture of the scary invader, and then it remembers it as a baddie.

It's actually more complicated than that. This is all happening at a molecular level...your immune system can't “see” anything, it doesn't have eyes. So isn't actually responding to the pathogen as a whole, it's noticing and responding to specific proteins found on invaders floating around your body, or, in some cases, on the surface of an already-infected cell.

Any protein that your immune system identifies as worthy of action is what we call an “antigen.” And the cells that are going to respond when antigens are identified is a type of white blood cell called lymphocytes. Each lymphocyte recognizes a specific antigen through a structure called an antigen receptor. But how can your immune system have an antigen receptor for a protein it's never seen?

Well, this is where it gets crazy. It's basically a brute-force guessing game...like a computer program hacking a password: you try a gazillion words until one of them locks in and you can use that password to get into somebody's account. Basically, your body makes /trillions/ of lymphocytes with a bunch of very slightly different receptors.

And sooner or later, one of them is likely to eventually lock onto any given bug. And once it does, it immediately explodes in population cloning itself over and over and over again into an army of two types of cells. Some are effector cells that make virus-neutralizing antibodies or kill off infected cells to prevent the virus from replicating -- they're meant to stop the present infection.

The other type can hold a grudge for years – memory cells that will mount an attack should the pathogen ever infect your body again. The goal of a vaccine is to skip right to that memory part, without causing serious side effects in the patient. But there's more than one way to do that...so there is more than one type of vaccine.

And because COVID-19 is a relatively new disease, it's worth trying a little bit of everything to see what actually sticks against the SARS-CoV-2 virus. One option is live attenuated vaccines, which are the first type of vaccines ever discovered. They're still used today for diseases like measles, mumps, rubella, and chicken pox.

They contain living virus, but don't worry -- it's been weakened. That's what the “attenuated” part refers to. Attenuated viruses are created by breeding them in an environment that is different from what they encounter in a human being, like in low temperatures or in a different species of animal.

When that virus is then given to a human, it still retains the tell-tale antigens of its dangerous ancestor that will produce the right memory immune cells we want. But it has spent so much time adapting to a changed environment that it's not very good at virusing inside a human any more -- so it won't replicate enough to cause disease. One project in the works to produce a live attenuated SARS-CoV-2 vaccine is a joint effort between the Indian Serum Institute and the.

US-based drug research company Codagenix. It's already undergoing animal testing, and the companies may launch human trials in the fall. Live-attenuated vaccines usually produce strong immunity, and they tend to be one-and-done -- no booster shots.

But they also have some drawbacks. They need to be kept at a low temperature and protected from light, which can damage them. That makes them harder to manufacture and distribute.

Plus, in patients with a weakened immune system, the attenuated virus will occasionally replicate enough to actually cause an infection or even spread to other people. To solve those problems, scientists developed our second kind of vaccine inactivated vaccines, where the pathogen is killed before it's injected into the human body. There are plenty of inactivated vaccines out there, like the ones used for Hepatitis A and rabies.

Inactivated vaccines are /much/ safer for patients with a weakened immune system, but what makes them safer also makes them a little weaker. The killed-off virus doesn't replicate in the body, so however much pathogen you put into the injection, that's all the training that your immune system is going to get! That means multiple doses will be necessary, and with some inactivated vaccines, you may may later need periodic booster shots to kick that immunological memory back into gear.

At least four inactivated COVID-19 vaccines are currently in development, two of which, created by a pair of Chinese companies, have already been approved for human trials. Live-attenuated and inactivated vaccines have one thing in common: to make them, you first need to grow a lot of the pathogen in a lab. But that's not always easy, because for some germs, this process is just too expensive, time-consuming or dangerous.

Which brings us to subunit vaccines. Subunit vaccines only use /part/ of the pathogen. Researchers choose an antigen that will be likely to provoke an immune response, and then grow it up in bacteria or yeast.

That means you only have to grow part of the thing -- which is much easier! But those antigens may not induce immunity by themselves – remember, for that to happen, the lymphocyte with the exact right antigen receptor must randomly come across the exact right antigen. So many subunit vaccines use adjuvants, which are substances that will attract our lymphocytes, usually by inducing some inflammation.

And that's because inflammation naturally brings in our immune cells and makes the antigen/lymphocyte meet-cute more likely. We use subunit vaccines for things like HPV or Hepatitis B. Right now, there are dozens of subunit COVID-19 vaccine candidates in the work, and a lot of them are already scheduled for human trials later this year.

And multiple other types of COVID-19 vaccines based on even newer technologies are already entering human trials. But if that's the case...why is it going to take so long before one of these is available? How long are we going to have to wait?!

No matter the technology, each vaccine needs to go through a trial process before getting approved for human use. That process is time-consuming for a reason, as it establishes both that the vaccine is safe, and that it actually works. So let's walk through vaccine trials!

First, in the exploratory stage, scientists looking to develop COVID-19 vaccines identify possible candidates in the lab. Once a promising candidate has been discovered, it's time for the pre-clinical stage, where the vaccines are tested on cells in culture and in animal models. These animal models are carefully selected based on whether a given animal gets sick in a similar enough way to humans to be scientifically informative.

Regular mice which is the main thing we use seem to be relatively immune to COVID-19, so there's also an effort to make them more human-ish in their response to the disease by giving them the human version of a protein the virus uses to invade our cells. But even the genetically-engineered mice we have so far only develop mild symptoms to COVID-19. So researchers have also been using naturally susceptible animals, like Syrian hamsters,.

Rhesus macaques, and ferrets. Working through this menagerie can take time, even if you identify a candidate vaccine pretty quickly. Once a candidate /does/ succeed in pre-clinical trials, it can go on to Phase I, II and III human testing.

Phase I trials are done on groups of fewer than a hundred volunteers. At this stage, researchers find out whether the vaccine candidate actually produces enough of an immune response in a human being that it makes sense to move forward with a bigger study. These trials both test to see whether there are any serious and significant side effects, and they are also used to establish a safe dose for the vaccine -- though bigger trials will provide more feedback there as well.

Phase II trials involve groups of several hundred volunteers and a more sophisticated study protocol with a control group that gets a placebo. Here, scientists learn a lot more about the safety, the right dose, and how those doses will have to be timed out. They also find out about the best way to administer it -- like through a nasal spray or an injection.

If all goes well, it's time for Phase III, which involves double-blinded testing on groups of thousands of participants. Having a bigger group makes it possible to rule out dangerous, less common side effects that may have slipped through the cracks in earlier trials. But this is also the first trial that aims to test how effective the vaccine will actually be.

Previous trials are looking to see if lymphocytes are responding, but without a placebo and thousands of participants, you can't actually check whether the infection rate actually drops in the group that got the vaccine. So the researchers need to give the vaccine to a lot of people. Then they need to give them, and a placebo control group that didn't get the vaccine, time to be in the world where they might naturally get infected to determine the efficacy of the vaccine.

If you make it this far, and it is effective, congrats! A successful Phase III trial means that the vaccine can finally be approved for public use. Normally, it takes a vaccine candidate ten to fifteen years to complete all of these testing phases.

Yeah, you heard that right. I mean, think about it: for Phase III alone, you have to recruit /thousands/ of people and keep tabs on all of them to make sure your candidate vaccine is working. It isn't a lack of money or researchers or work...

TIME itself is a necessary part of the process. The amazing good news though is that for COVID-19, this process is being accelerated on an unprecedented scale. At the time this video is in production, around a hundred vaccine candidates are already being researched.

And only a few months after the first outbreak, many of them have already entered Phase I human trials or will do so very soon. Even with this accelerated pace of development, it takes time to find the correct dose...or doses...to make sure the vaccine will work, and be safe enough for us to tolerate. That's why you hear that one year to eighteen months figure.

From there...producing and distributing the vaccine will require a lot of thought and work and also isn't an instantaneous process. Researchers think this is about as fast as we can possibly go. But you might be wondering, like, can't we do anything to speed things up?

The answer is yes, but it's really complicated and there are trade-offs and we've got a whole episode on that coming up soon. But we do also have short-term if not permanent solutions to the problem of COVID-19….things like physical distancing which has already saved...probably millions of lives. And in the slightly longer term, scientists are looking for treatments to help those who are infected, including in the WHO-organized SOLIDARITY mega-trial that we talked about in this video appearing up in the corner.

A vaccine is our long-term hope, even though we can't be sure when any of these candidates will be ready. The good news is, we have really effective ways of creating new vaccines. So we are pretty hopeful that one of these is going to come through.

And if there's a good thing that's coming out of this pandemic, it's unprecedented international cooperation between researchers who want everyone, everywhere to be safe from this disease. It shows that working together… actually works. Thanks for watching this episode of SciShow.

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