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This episode was filmed on April 30, 2020. If we have more recent episodes about vaccinesor COVID-19, they will be linked in the description. You might have heard that the COVID-19 crisis won’ttruly be under control until we have a vaccine — though increased testing and effectivetreatments are gonna go a long way.

You might also be hearing that even thoughscientists are working on a bunch of different vaccines right now, it’ll be more thana year until we the public can have one — and that is a best-case. This is frustrating…so you would not bethe only person asking WHY WHY WHY this is. Well, there are good reasons. But to understand them, we first have to understanda bit about how the immune system works. And, like, that’s not super simple, butit’s also fascinating and weird and going to come in handy on more days than just thisone. So listen up. Our immune system has two main prongs: innateand adaptive immunity. But the key player here is the adaptive part. Our adaptive immune system responds to thingsthat make us sick, and remembers them for later so that it can keep us from gettingsick 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 pictureof 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 pathogenas a whole, it’s noticing and responding to specific proteins found on invaders floatingaround your body, or, in some cases, on the surface of an already-infected cell. Any protein that your immune system identifiesas 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 whiteblood cell called lymphocytes. Each lymphocyte recognizes a specific antigenthrough a structure called an antigen receptor. But how can your immune system have an antigenreceptor for a protein it’s never seen? Well, this is where it gets crazy. It’s basically a brute-force guessing game…likea computer program hacking a password: you try a gazillion words until one of them locksin and you can use that password to get into somebody’s account. Basically, your body makes /trillions/ oflymphocytes with a bunch of very slightly different receptors. And sooner or later, one of them is likelyto eventually lock onto any given bug. And once it does, it immediately explodesin population cloning itself over and over and over again into an army of two types ofcells. Some are effector cells that make virus-neutralizingantibodies or kill off infected cells to prevent the virus from replicating — they’re meantto 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 bodyagain. The goal of a vaccine is to skip right tothat memory part, without causing serious side effects in the patient. But there’s more than one way to do that…sothere 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-2virus. One option is live attenuated vaccines, which are the first type of vaccines ever discovered. They’re still used today for diseases likemeasles, mumps, rubella, and chicken pox. They contain living virus, but don’t worry– it’s been weakened. That’s what the “attenuated” part refersto. Attenuated viruses are created by breedingthem in an environment that is different from what they encounter in a human being, likein 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 theright memory immune cells we want. But it has spent so much time adapting toa 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 effortbetween 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 strongimmunity, 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 temperatureand protected from light, which can damage them. That makes them harder to manufacture anddistribute. Plus, in patients with a weakened immune system,the attenuated virus will occasionally replicate enough to actually cause an infection or evenspread to other people. To solve those problems, scientists developedour second kind of vaccine inactivated vaccines, where the pathogen is killed before it’sinjected into the human body. There are plenty of inactivated vaccines outthere, like the ones used for Hepatitis A and rabies. Inactivated vaccines are /much/ safer forpatients with a weakened immune system, but what makes them safer also makes them a littleweaker. The killed-off virus doesn’t replicate inthe body, so however much pathogen you put into the injection, that’s all the trainingthat 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 kickthat immunological memory back into gear. At least four inactivated COVID-19 vaccinesare currently in development, two of which, created by a pair of Chinese companies, havealready been approved for human trials. Live-attenuated and inactivated vaccines haveone 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 forsome 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 belikely to provoke an immune response, and then grow it up in bacteria or yeast. That means you only have to grow part of thething — which is much easier! But those antigens may not induce immunityby themselves – remember, for that to happen, the lymphocyte with the exact right antigenreceptor 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 naturallybrings in our immune cells and makes the antigen/lymphocyte meet-cute more likely. We use subunit vaccines for things like HPVor Hepatitis B. Right now, there are dozens of subunit COVID-19vaccine candidates in the work, and a lot of them are already scheduled for human trialslater this year. And multiple other types of COVID-19 vaccinesbased on even newer technologies are already entering human trials. But if that’s the case…why is it goingto take so long before one of these is available? How long are we going to have to wait?! No matter the technology, each vaccine needsto 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, scientistslooking to develop COVID-19 vaccines identify possible candidates in the lab. Once a promising candidate has been discovered,it’s time for the preclinical stage, where the vaccines are tested on cells in cultureand in animal models. These animal models are carefully selectedbased on whether a given animal gets sick in a similar enough way to humans to be scientificallyinformative. Regular mice which is the main thing we use seem to be relatively immuneto COVID-19, so there’s also an effort to make them more human-ish in their responseto the disease by giving them the human version of a protein the virus uses to invade ourcells. But even the genetically-engineered mice wehave so far only develop mild symptoms to COVID-19.

So researchers have also been using naturallysusceptible 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 preclinicaltrials, it can go on to Phase I, II and III human testing. Phase I trials are done on groups of fewerthan a hundred volunteers. At this stage, researchers find out whetherthe vaccine candidate actually produces enough of an immune response in a human being thatit makes sense to move forward with a bigger study. These trials both test to see whether thereare any serious and significant side effects, and they are also used to establish a safedose for the vaccine — though bigger trials will provide more feedback there as well. Phase II trials involve groups of severalhundred volunteers and a more sophisticated study protocol with a control group that getsa placebo. Here, scientists learn a lot more about thesafety, the right dose, and how those doses will have to be timed out. They also find out about the best way to administerit — 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 torule 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 lymphocytesare responding, but without a placebo and thousands of participants, you can’t actuallycheck whether the infection rate actually drops in the group that got the vaccine. So the researchers need to give the vaccineto a lot of people. Then they need to give them, and a placebocontrol group that didn’t get the vaccine, time to be in the world where they might naturallyget 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 thevaccine can finally be approved for public use. Normally, it takes a vaccine candidate tento fifteen years to complete all of these testing phases. Yeah, you heard that right. I mean, think about it: for Phase III alone, you haveto recruit /thousands/ of people and keep tabs on all of them to make sure your candidatevaccine is working. It isn’t a lack of money or researchersor 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, arounda 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 eighteenmonths figure. From there…producing and distributing thevaccine will require a lot of thought and work and also isn’t an instantaneous process. Researchers think this is about as fast aswe can possibly go. But you might be wondering, like, can’twe do anything to speed things up? The answer is yes, but it’s really complicatedand there are tradeoffs and we’ve got a whole episode on that coming up soon. But we do also have short-term if not permanent solutions tothe problem of COVID-19….things like physical distancing which has already saved…probablymillions of lives. And in the slightly longer term, scientistsare looking for treatments to help those who are infected, including in the WHO-organizedSOLIDARITY megatrial that we talked about in this video appearing up in the corner. A vaccine is our long-term hope, even thoughwe can’t be sure when any of these candidates will be ready. The good news is, we have really effectiveways of creating new vaccines. So we are pretty hopeful that one of theseis going to come through. And if there’s a good thing that’s comingout of this pandemic, it’s unprecedented international cooperation between researcherswho want everyone, everywhere to be safe from this disease. It shows that working together… actuallyworks. Thanks for watching this episode of SciShow. What we do here is only possible with thehelp of our patrons. Our amazing community gets the chance to interactwith members of our team on our patron-only Discord, and there’s other neat perks too– like exclusive bloopers. If you’re interested in helping out, checkout patreon.com/scishow. [♪OUTRO ]

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