IMM TRANSCRIPT PRIMARY IMM. PART 1 OF 2 PDF

You guys have not seen the recordings from Friday there are two and because I recorded the second half It's you know the most recent one comes up to the top It's going to appear when you first open the folder that I'm just it jumps in another thing So just scroll to the bottom of that page the first...

You guys have not seen the recordings from Friday there are two and because I recorded the second half It's you know the most recent one comes up to the top It's going to appear when you first open the folder that I'm just it jumps in another thing So just scroll to the bottom of that page the first one's at the bottom I'll go in and label one part one and part two so you do know obviously part two was recorded later But just for the 30-minute difference. That's why I was so behind on everything last week All right, so we did talk about this is some evidence showing that we do have data to support adding in vaccination does save lives This is specifically talking about rotavirus, which we will talk about a lot more next semester with micro, which is fantastic here We did talk about the other different types of vaccines in general and just some fun facts to know about those other types Subunit vaccines are usually made from the most antigenic component because like it sounds it's a subunit It's a piece of a vaccine or a piece of a pathogen that we used to make a vaccine And so we pick the most antigenic because again, it's going to trigger an immune response and that's the whole goal of vaccination Bacterial vaccines can be made from whole bacteria Secreted toxins or even capsular polysaccharides. It really depends on the nature of the specific vaccines and then we talked about conjugate vaccines This is when we enable high affinity antibodies to be made against carbohydrate to antigens So in a previous slide when I was talking about a different bunch of the different subtypes I did kind of lump them all together This just provides a little bit more elaboration and clarification on the different subtypes here specifically and they are facts You know, that's why they're kind of bolded So this one is talking about macromolecular complexes with separate epitopes can be recognized by B and T cells that make effective vaccines This is showing a B cell receptor is binding on to the polysaccharide part of a vaccine conjugate here shown here That has been labeled with a protein toxoid here Obviously it will endocytosis bring it in the conjugate is internalized and degraded where we present it on MHC So it continues on you guys are very familiar with the fact that B cells are antigen presenting cells They'll present it to T cells to in turn activate each other You guys are very familiar with all this information now here, too And by presenting that toxoid derived peptide to the T follicular helper cell and in turn sends activation signals to the B Cell thus producing antibodies from a plasma cell which can then bind on to That anti anti polysaccharide loaded with that kind of toxin here And so it's just again just highlighting based on what you guys know How vaccines work using the immune system of everything that you guys know So the continuation to if you didn't notice from this previous picture it continues on but for the sake of you guys being able To see it reasonably without glasses. I expanded that one here, too So how do we make vaccines more effective? I used to have a lot more memes and this lecture is pretty much just a straight meme lecture But students complained that there were too many memes so we've toned the memes back, but I have a whole vaccine meme folder but here, you know, there's a lot of Incorrect foundational information about vaccines on the internet and things like this like if vaccines were healthy you could put it on a spoon and eat it Well, if you know broccoli was healthy, we could inject it. It'd be fine So, how do we make them more effective I do a lot of testing behind vaccines here, too Also, please don't for like I know you guys are smart enough You're going to med school to not do things that people tell you what's new on the internet But just in case any of us felt susceptible to the tide pod challenges things like that, please, please don't inject broccoli This is not gonna be challenging you to show that broccoli is safe Please don't inject broccoli like you can do so much better things with broccoli We add adjuvants to it No rabbit holes We may we add adjuvants to vaccines that I had mentioned it if you listen to the recording I mentioned the word adjuvants earlier in the vaccine her at the lecture and now we're actually defining what they are We add them to vaccines to activate and enhance the immune response to a pathogen Because there are some features of vex there like some features of pathogens where sometimes the immune system just doesn't recognize it And so it's basically like we put a little something in there to irritate, you know response to the piece that we've injected so an adjuvant Unfortunately, it's also the reason why we're more likely to experience side effects with vaccines because again We are literally adding in an irritant You guys have heard how oysters make pearls sand and dirt get inside it irritates them They start coating it, you know with that pearlescent material That's how we get a pearl and so it's a very similar concept We're trying to irritate the immune system. So we put a piece of it's not actually saying please don't tell people that dr Della says there's sand and vaccines. There's not but it's the same concept that like with an oyster was making a pearl We put sand in the irritate it just a little bit to let the immune system know that this is what we're about to go try to fight so an adjuvant is an ingredient used in some vaccines usually The things like the subunit to conjugate things like that where it's not the whole virus like a live attenuated or a killed vaccine here It helps create a stronger immune response and people receiving the vaccine. So it does produce a stronger immune response overall However, you're more likely to experience side effects and my favorite fun fact with vaccines the side effects that you are experiencing It's not the vaccines itself. It's your immune system Like I was reassured if I go get a vaccine and there's redness or like soreness or like I have a fever the next day It's letting me know my immune system loves me and is activating and doing its job So I always get reassured when I get back symptoms But the side effects that you think about site soreness injection like when you get tetanus and you like hurt smooth your arm the next day It's telling you that it's working that your immune system is activated, which is the whole point of this We're gonna fight this eventually. We need to mount an immune response to it here Some vaccine components by themselves can serve as adjuvants others are things that we've added in So pertussis component like from Bordetella pertussis and the DP DTP vaccine, which is diphtheria tetanus and pertussis Acts as an adjuvant by itself and it is a component of the vaccine Which is really nice and it's another reason why they combined those three together Other adjuvants can include alum. So aluminum salts This is a keynote because anti-vaxxers see the words aluminum freak out and think we're injecting pure aluminum into people's bodies That would be kind of cool, but we're not that would kill you We use aluminum hydroxide aluminum phosphate aluminum packed potassium sulfate as you guys know with sodium chloride What is sodium by itself? It's very explosive Okay, in case you didn't know sodium by itself is very explosive and what is chlorine? Like if you think about it It's mustard gas basically, but it's it's a toxic gas. But when we put it together we get sodium chloride. What do we get? Salt the most amazing thing to put on french fries So as you guys know when we alter chemical structures, even just a little bit by making it a salt It is very safe and well tolerated And there's a lot of safety studies on that in case you were curious you can actually you can google it on the internet They have all of this information out there You just have to look for it CDC does have a very nice list of all the different adjuvants including links to safety studies where they did determine if These components were safe before adding them to vaccines. And so there's additional one here, too This was another one that was a safety review of an aluminum salt pharmacokinetics. So how the body Metabolizes it and works with it in vaccines. So we do have the data out there Unfortunately a lot of people don't know to look at PubMed and actually how to read a scientific paper So these are present and future adjuvants for use in human vaccines And it's not even a huge list because there's a lot more out there There's tons of grants trying to create new adjuvants every year ones that are safer I've seen some that are actually trying to isolate parts of lipopolysaccharide So that it's not the full molecule but pieces of it to try to irritate the immune system since we know The innate immune system loves LPS and will respond very quickly here. I do not expect you should know these This is just to point out we have a lot of different types. We know how they work We know what class they're in we know what vaccines they're in this information is readily available. We're doing all kinds of really cool Components overall, but there are a lot of different types of adjuvants Also, I do want to mention because there was some concern on the exam Included Humira on a question that that answer choice was correct Like I'm not gonna try to trip you up like because you guys like well is Humira a monoclonal antibody I did include that in the stem. You thought I was testing you on that part I wasn't with things like this if you see a hypothetical question on an exam where I provide an example of this I'm not trying to quiz you. Oh, it was AS04 not AS03 or AS02 or something like that I will be testing you on a concept of the definition. So like I tell you oh this molecule known as ABCD 12345 Increases an immune. It's out of two vaccines and it increases the immune response to a vaccine. This is the best example of a what I Want you to get that like I'm not gonna have you guys be like, oh did I make this up? Like am I being tested on the drug name? No I'm testing you on the concept and I will have teach it's called teaching in a statement and Wendy hates when I do that Where I provide information to you that's telling you like a teaching statement that it is an adjuvant basically You will see something like that on the exam So you can flag that now you don't have to memorize this but I'm not gonna like try to trip you up and be like Oh, it was ASO 2B now if I give you something and I tell you it works by boosting the immune system I've usually gone and googled and found an actual adjuvant and included that in the question So I'm not trying to trip you up on the concept. I want you to know the definition But this is an example of that's what I'm describing Did you know there's more aluminum in breast milk like actual aluminum in breast milk seven grams milligrams? Formula has 38 milligrams and soy formula 117 Milligrams and in all the vaccine administered in the first six months of life, which is 4.4 milligrams So when people argue that, you know, it's not natural. We shouldn't be doing this. It's coming from breast milk breast milk is natural Some formulas are mostly natural soy It comes from soy plants. It's natural We're exposed to aluminum all the time So really don't need to fear monger about that because again, it's very safe well tolerated and tested Genome sequences of human pathogens have opened up new avenues for making vaccines So now that we've also been able to go through and synthesize and just look at the entire genome sequences for every possible pathogen We're finding more and more things that we can make vaccines for do not panic about this Picture you guys kind of me. Can you what what concept what starts with a C just to narrow you down. Thank you complement I don't know how to ask that question We do know that there are certain bacterial toxins that are constantly trying to fight back with our own bodies immune systems to override it and prevent things from happening and in This case there's a bacterial lipoprotein named F HbP found with the Syria gonorrhea and meningitides that can actually bind onto factor H as part of the complement pathway and help Inactivate c3b Thus blocking activation of complement pathway and phagocytosis like the obstinization and things like that here So it cleaves it and damages that we know that and by learning more about how the different pathogens work their sequences They're you know ways they subvert our immune system We can then go in and make targeted therapeutics to then fight the ways that they're fighting back against us So it's just you know, really nice warfare here And so in this specific example because we learned that F HbP blocks complement And we still want complement to work. We can actually go in and create antibodies and vaccines to that F HbP Thus blocking it and preventing it from working Giving our immune system a chance to do its job normally, too So it's really cool now that we learn a lot more in science about you know All these different pathogens and all these advancements. We make better targeted therapeutics including vaccinations, too and so Influenza is a complicated when we talk about shots to the most part you guys are not getting shots all the time Unless you're like severely immunocompromised you get a bunch of series when you're a kid by the time, you know, you're you hit college Yeah, you get the series from a ninja tidies and things like that But it kind of takes off you get your tetanus shot once every 10 years unless you've you know Recently been exposed or say hypothetically you go out and play with a wild animal Please don't and you get exposed to rabies. We've got a rabies shot stuff like that But frequently you really are not getting a ton of vaccines but the ones that we do talk about every year frequently influenza and COVID too is because both of those viruses unfortunately are very good at what they do and they mutate quite rapidly and kind of deviate from the immune response that we've built up Over and over and over again and because of that We have to fight back so we constantly have to make a new flu vaccine and unfortunately That's just you know, the nature with upper respiratory viruses that are very good at what they do Influenza rapidly evolves and so we frequently have to get a booster every single year. So this is just kind of highlighting what's happening Let's say hypothetically here. We have four incidents on the surface of this first influenza virus. You have ABC and D It spreads to I'm gonna use the entire first row Sorry, you guys I'm gonna make you guys sick Nathan Went somewhere and got the flu and he came to class because he's like I can't miss class It's important which I appreciate but please stay home if you're sick Comes to class and his first infection has ABCD on the surface of it, but then he coughs Oh, no, I'm so sorry. I Also don't know your name Okay contracts it and every time it jumps from person to person There's a chance for it to mutate based on just what it exposes to your immune system how it tries to fight back It develops a point mutation. So instead of having This D antigen here. We're now getting E expressed on the surface. Oh No, you're sitting very close to your friend You cough on her she gets sick. It changes now But we have E and F now and then oh no You had to cough a really far distance, but you like really aimed Sabrina got sick We just have a now on the surface So our body the only thing it recognizes now from this virus is this a antigen from Nathan's first breath So Sabrina was really mad that Nathan started this she figured it out. She's very smart. She's like I tracked this I knew what was happening. She goes back and coughs on Nathan Her virus, you know look like this Maybe it was really not prepared for what's going on and it mutates again and now all four of these antigens are not anything You know we've experienced before and thus it continues to spread and again, it's just random It's point mutations that occur every time it's spread. That's why it was so important. We did the two weeks to fought in the curve which failed Horrifically, but only in the premise behind it the premise is sound the execution was terrible one The virus takes a little bit longer like it would have been more effective if we did a month however, that's not feasible if we think about a public health standard, so it was crappy, but the goal with that was to limit the spread and to keep other people from getting infected because every time someone else gets infected it Mutates and it changes and it's just random. It could be a point mutation that makes it less effective at spreading great It dies off or evolutionarily. It's one that allows it to spread better if you guys ever played like plague ink on your phones I think they still make it you can mutate and change things and some can get better some can get worse You mix around and play around with it. It's just point mutations that occur It's impossible to predict and so the whole goal of that was to keep it from spreading and keeping other people from getting it because the more and more it spread the more and more mutated and change the point that like original things that we had to protect it weren't effective anymore and so the whole point like what they're trying to do now with h5n1 That's circulating is to quarantine and isolate keep it from spreading keep it from developing mutations That will make it more suited for human spread And so that's the premise behind a lot of this is with enough people getting it and spreading it It's going to be dangerous. And so unfortunately influenza does rapidly mutate. That's why we see pandemics with it all the time same with Covid too as an upper respiratory. So all this is just showing you that with each subsequent Infection, there is the risk of point mutations that will change it to the point that eventually It doesn't look like what we have an immune response for and so that's frequently why we need immune boosters for influenza every year too This was talking about the h1n1 pandemic. You guys were babies when this came out Y'all were all alive, right? By 2009, I hope so. Okay, I Was in high school. This is a big thing. Everyone was freaking out about it But the cool thing about influenza is we know so much about it. We already know a lot of the sequences We've already predicted kind of the things that could happen AI has been really advanced full with that which has been fantastic here But also because we know how influenza works. We already have like a template vaccine for it It's very very easy to start manufacturing Stuff for it. So if your family members are all of a sudden either like you're gonna be a doctor or you're a doctor now Here's a news article in h5n1 explain what's happening to me right now We're just trying to limit the spread to keep it from picking up point mutations that will make it better at jumping between humans But they're already working on vaccine templates. We already have something ready to roll out They're just building up enough stock that should it become a pandemic or spread or anything like that We have vaccines available to treat. We also have antivirals that we can use towards influenza So it's not something it's be concerned and be cautious, you know practice basic, you know Sanitary functions wash your hands before eating touching your face putting on your makeup If you're sick, don't go around other people stuff like that It's not anything to be scared about because we do know enough about it that we can get in front of it But it can be really dangerous than individuals who are immunocompromised susceptible to upper respiratory They already have like COPD other things going on are more at risk But it is very quickly to start rolling out vaccines, especially with influenza So it is not anything to be wildly concerned about I would just be cautious and informed But no fear mongering and anything over here, too And so it was again even in 2009 2009 we were able to quickly and rapidly Deliver a vaccine that got control of it and we didn't have to worry about it. Just fantastic You also do not have to memorize this either, but we have a lot of different candidates about against vaccines And this was talking about stars could be too I know we all talked about the RNA ones here But there were a lot of other ones that were being tested at the same time, too They were looking at not replicating vectors replicating inactivated virus They were trying to come up with an attenuated viral one, too They have a lot of different options. So science does have a lot of templates for a lot of different things So anytime any kind of novel thing comes out science is already, you know decades ahead It's just it was not aware to the public because the public doesn't care about something until the public is told to care about something Whereas heard about it in the news And so we did have a lot of different vaccines kind of behind the scenes and even now with they have the orobouche virus That's spreading in the Caribbean. We're seeing some cases in the United States and people are concerned about it They're already working on a vaccine for that Science is a little bit advanced which is kind of nice The other thing is to people argue we rushed the COVID vaccines The COVID vaccine is actually older than I am technically if you look at all the behind the scenes data On when we discovered all this technically mRNA was first discovered back in 1961 significantly before I was born but we had actually started testing it in humans or not humans. I'm sorry rats We first proposed in 1990 and started doing rat studies with using mRNA as a vaccine back in 1990 And so there's just a lot of stuff behind the scenes because again, the general public didn't care about it at the time But science has been working on this for a hot minute here, too We actually even injected mRNA and as a vaccine into humans in 2009 it was targeted for cancer. They were trying to do a vaccine against a specific type of cancer Unfortunately, it didn't work better than a placebo So that fell through but nobody in that trial died from the vaccine Unfortunately, some did die from cancer because they weren't able to control it But they have done many studies here and even using it for additional I'm sorry. That was the first mRNA here as a cancer treatment. treatment. They use it as a vaccine by definition here in 2017 We've had a lot of data and studies behind the scenes making sure they were good and actually the first ramp up of it was during the original SARS, which was like Here ish, right? Here ish, right? Yeah. Oh gee SARS was 2011. No, it was MERS. Oh gee SARS was I Should know this, huh? Yes, it's yeah, too. That was like 2003. Maybe Hmm not on the graph But anyway, they had started proposing a template for COVID in the SARS-CoV viruses in the early 2000s They were had a better template for by the time MERS came around in 2012 And so we had a lot of studies behind the scenes. It's just the general public didn't see it So when they see something suddenly something published, they're like, oh We rushed it. No, it was going on behind the scenes The general public just didn't know about it, too The only thing we rushed was the red tape in the paperwork because if you guys are not sure how grants work You spend six months writing a grant They have like two or three due dates per year You submit you find out six months later if you were even scored and then you find out like three months after that if you Even get funding and then you don't get a funding until like a year later and it's absurd The only thing they really sped up was you know The paperwork behind the scenes and people kind of moving that faster through because science gets bogged down by paperwork all the time Unfortunately have yet to make a vaccine against pathogens that establish chronic infections just because again They're hiding out somewhere in the body. There's a latent reservoir. It's a lot harder to treat and target those guys But that explains why we have issues like Making a vaccine against HIV, although we have tried and we are actively still trying here, too These are some diseases for which effective vaccines are not yet available, but we are, you know, really trying our best for it And so they are still working on a better measles vaccine here and this is specific subtype Hepatitis to other diarrheal disease. There are a lot of different pathogens that cause diarrhea We don't have a successful tuberculosis vaccine yet or even schistosomiasis But they are actively trying because these are global public health burdens It would make sense to try to roll out a vaccine Although I am happy to admit we have some good stuff on Ebola now, too They have a moderately decent Ebola vaccine because that was always something I was like Irrationally afraid of because like viral hemorrhagic just does not sound like a pleasant thing to experience Here are the available types of vaccines for humans. No, you don't have to memorize this either I wouldn't try to intentionally trip you up on it Like, oh is the tetanus vaccine toxoid or not? No. The premise is I want you to know how they work I might ask you like, oh, is this a toxoid like by giving you the definition things like that? But we have so many different options available, which is fantastic And a lot of these are ones you might not even experience, too Like you're not going to get your cineopestas vaccine unless you've been exposed to it potentially or like might encounter it to you or you're in an area where there's high rates of Spread because again, we're not trying to give you too many things if you're not gonna like you're not gonna give you a rabies vaccine Unless you're like a vet or you have a habit of going around wild animals and petting wild animals And if you do you should probably tell your doctor that you like doing that I tried to get the rabies virus vaccine and they didn't give it to me I tried my best stuff, but we have a lot of different options out here too same with yellow fever You're not going to get yellow fever unless you travel to potentially you travel to a country where it's Spread and actively found and in that case they make you get a yellow fever vaccine And so vaccine development actually does face greater public scrutiny than drug development does which is insane to think about even though People don't think it occurs. It really does Another fun fact too as fewer children were vaccinated against measles virus the incident of measles infections increased We're actually seeing spikes in measles cases and even outbreaks now in communities, especially communities with high rates of anti-vaccine Advocates just due to the fact that when people stop vaccinating There are susceptible populations now who can get vaccine preventable illnesses And so we are tracking active increases in spikes This is only from 2002. The data is significantly worse recently. So I don't include that because I don't want to cry But we do see increases in vaccine preventable illnesses, especially when we start to decrease vaccination And this was just basically this is all started over a dude who lied for money I don't know if you guys are familiar with Andrew Wakefield people still cite it despite the fact that it was retracted But he went through and basically took a lot of money from some lawyers to say that vaccines cause autism And his study was wildly flawed and has been debunked some like notorious things He picked 12 children that he basically like recruited from his like kids birthdays parties and like from their school they didn't have any informed consent so these children who were developmentally disabled and Probably leaning towards that direction were tested and had invasive treatments like blood draws biopsies without any informed consent that this was happening Which is important in any kind of human research. So they had unethical invasive tests on children So they didn't have any ethical clearance to he falsified data when one of the points didn't meet his metrics He threw it out and cherry picked what results he wanted to show 10 of the 12 authors and for like have thankfully asked to be retracted here to and retract the paper And it was an incredibly difficult study Most of the children he did select were already showing signs of neurodevelopmental issues before they even assigned them to the study So it was just massively flaw. There's lots of breakdown on it here, too But the study has been debunked many times over but unfortunately it's still pervades and people still cite this and say he showed That vaccines cause autism which he didn't even if you go through his actual conclusion on the paper I do have a copy of the retracted version. He even says it's a possibility. He doesn't even say he proved anything He just says it's a possibility Even though it was a horrifically designed study But we go through a lot of different Testings for it to show that they are safe to try to debunk the stuff that he claimed here too And so you guys don't know about this But in any time we do any kind of new medication or vaccine research There's basic research, you know Whether people are building proteins in a lab for hours on end awful Then they pick which ones might potentially be a good drug or treatment Then we move into preclinical animal testing and this is showing you the number of ones that drop off as we go through into Experiments and realize they don't work we move them eventually we'll move into phase one We're testing these items in patients in a very very small subset to make sure it doesn't cause death or anything super serious With COVID the first time people to sign up and get vaccines were scientists and their families who agree to be part of the phase one Studies here, too Then we start to increase the number of volunteers to the hundreds because at this point We're trying to document any large-scale side effects same with phase three and we're also looking for does this work better than a placebo? Because there's no point in advancing the research and the studies if the vaccine doesn't do anything to protect it any more than someone Who just got a saline injection or an injection of just the adjuvants and so eventually by the time you actually get FDA approved Drugs it is narrowed down immensely because most drugs fail out by phase two and then even in phase three You'll see a lot more failouts. They submit the data to the FDA and if it's still mixed they won't approve it But eventually we usually get one FDA approved medicines after millions of possible combinations from way back when and so even then we do Post-approval research and monitoring which is really cool. So we do wildly test them and we continue to test them I don't know if you guys saw the news about phenylephrine this weekend, but they might pull phenylephrine which is in cough and cold meds It's believed to be a nasal decongestant but new studies and like they've done a lot to follow up on that very good placebo controlled studies show Phenylephrine is no better than a placebo and clearing sinuses and nasal decont like nasal congestion And so they may actually just pull phenylephrine because what's the point of having the drug on the market? If it doesn't actually do what it's supposed to do So we will continue to do monitoring even after things get approved by the FDA and made public To everyone here. And so again, I would go through and loosely know the phase studies There is a question on this here too Like kind of what what state like which phase would this kind of fall under if I gave you an example here, too But anyway phase two we're frequently look at the most common side effects How are the immune system are the volunteers immune systems responding and then again with phase three? It's a lot larger hundreds or thousands of volunteers, you know, is it safe? Is it effective? Is it better than the placebo before we end up going through to that FDA license which requires it to be safe and effective and The benefits of it significantly outweigh the risks You guys can watch this video later But if you've never heard of a randomized double blind placebo controlled study This is the ideal in science where double blind means to people don't know what's going on because there can be sometimes things I'm like, hey like here I'm gonna give you this these pills They're both the same color, but you know, you're gonna feel you're gonna feel so much better like when you take this She's gonna believe that she's gonna be better just because of my behavior towards her People pick up on like, you know If I'm like really telling you you're gonna feel better. It's a fitting in your brain. You're like, oh, I'm gonna feel better She said so she's a scientist. She knows what she doing. She's wearing a white coat. I Could have given you the placebo Could have given you the regular drug but because of that belief and so the double blind The person also giving the drugs or administering it has no idea what's going on There's someone distanced from there so that I can't affect in my behavior towards the two individuals Which one is which which is great because then it's blinded We don't know what's going on. And so they are blinded to it, too They're not going to respond based on that placebo or the suggestion and then two we will also use Compared to a placebo and usually it is a saline placebo or saline with the adjuvant just to make sure it's not the adjuvant producing The effects not the actual vaccine itself and then we go through just kind of measure and monitor What side effects occur and is it more effective than those that received a placebo which is fantastic. Also, it's randomized So we don't know it's not like every other person goes to this group versus that group Computer algorithms completely randomize it and we just you know Usually 50% go here 50% go there, but it's randomly assigned I'm gonna skip through that past that When we add a vaccines the US recommended immunization schedule, this is not a one-person decision This is a committee upon committee upon committee of decisions It's usually gone through through the advisory committee on immunization practices a sip which is made up of medical and public health experts including members of the American Academy of Pediatrics the American Academy of Family Physicians Immunologists microbiologists public health officials and they all sit down together and they hash it out and they fight and they argue and it is messy as Physicians and future physicians you guys are more than welcome to serve on this It's actually a great committee especially if you guys go into allergy and infectious diseases It is a phenomenal opportunity to serve for the community too But they go through all this data and collectively as a group Make the decision to add it and do the benefits outweigh their risks and things like that And so once they go through that and the CDC director reviews their final decision Then it is added into the immunization schedule overall. So it does go through many testings before we just don't like we just like Through darts and then just wherever they ended up. That's how we put it in there There's scientists and there's physicians behind the scenes going through all the data and the science behind why we do it When why do we give booster shots? Why do we give three or four shots? For ice type switching and affinity maturation. That's why so we go through and explain all of that here, too So how do we address the argument that vaccines aren't tested the way they are administered since multiple vaccines are often given at the same Time we actually have tested them There's lots of papers on the internet that you can find and here's a source kind of listing all the different ones of how they're tested Together but think about it if I get a new vaccine tomorrow any vaccine I've previously already gotten in my body is being tested with the new vaccine because I'm adding a new vaccine into the body That's already received every other vaccine. So there's lots of you know ways of arguing it, but we do test all these guys here I think a lot of people don't think to Google the sub, you know acronyms and things like that They're like, oh, I Google chickenpox and meningococcal. Did it work? Sometimes you need a little bit more information like flu miss was the nasal flu. They tested with MMR and varicella So you got a lot of different options out there. There is a lot of science and data If you want to find those sources you can They are tested together extensively And again, we do continue to monitor them after we release stay hypothetically We mean there's still the chance that you miss side effects interface three You try your best to get a wide range of people But again when you mass produce that there is the possibility that you find something you didn't originally know So they continue to monitor. That's why we have the VA ERS or vaccine adverse event reporting system It's open to the general public to submit any concerns They notice so they can be investigated because a good scientist is going to go through and investigate every clamps There have been people who reported that vaccines made them magnetic and that's why cars hit them and they were like they died by like getting hit by a car Because they were magnetic even though cars cars and that's the wildest one I've ever seen submitted to VA ERS So people can submit anything and they've made the egregious claims that cars are also not magnets either So by that logic, it doesn't work So you can submit anything and they go through and they still investigate even the wild claims that you know vaccines made them magnetic So they do test stuff like that here too That's the best way to report it physicians also have a reporting system that they can go through and report as well And we also keep post licensure monitoring overall just to make sure that nothing new doesn't appear or develop And they will continue to do safety assessments overall, too Like with COVID you guys got the vaccine very early on they asked you to sign up for v-safe Where you reported anything and any side effects and they checked in with you to see hey Did you get COVID after the vaccine like, you know two weeks later? Like how how long were the antibodies affected and stuff like that? Like I even reported after the Moderna I just had a really bad side effects to it I got a fever for two days and I just felt like funk I mean, I was relieved because I knew my immune system was doing its job, but I was miserable I reported that when I got my second shot I told him and I let them know and someone from the CDC called me a week later and asked me if I was okay And then walked me through like all the steps and just you know documented my instance so they could know If there was some bigger trend with that so they do actually follow up and police it in case anything happens Also are also scientists is this Queen Dr. Kismetki a Corvette. She's amazing. I am madly in love with her She is an assistant professor of immunology and infectious diseases at Harvard School of Public Health And the vaccine concept incorporated in mRNA 1273, which was Moderna Was designed by her team so she was the one behind the scenes who came up and also she has the best fashion sense and the like sleigh is constantly Phenomenal just insanely cool person very good speaker to like just Riveting human being but she was the one who came up with the template that we now use in the Moderna vaccine I probably just gave away an exam question, but Love this woman. So there's lots of biographies on her if you'd like to read about her, but she is amazing So that is all finally the part three of the vaccines. I really love this stuff I think it's important for medical students to understand about vaccines If you guys have any questions at any point there's no such thing as stupid questions and I'd love to be able to provide you with the information you need to make and formed decisions About your health and also be able to talk to everybody I hope you guys have watched the documentary by now I was thinking did a pretty decent job of not bashing any one group But also explaining that a lot of it is just fear-based a lot of people like people just don't understand They haven't if I haven't had a foundational immunology course They don't know how it works They hear things like natural killer cells and they think it's this horrific thing not realizing that natural killer cells are what we want To keep our body in check. That was the biggest one of the I thought it was silly But I can understand why they were scared But they saw increased rates of natural killer cells in patients blood After the COVID vaccine and people were freaking out like oh my god. These cells are gonna kill us like this is bad It's they just didn't know So a lot of it is fear and so it's addressing fear calmly and just you know providing the information Most people will make a good choice. It's just you need to be calm You need to you know validate that you know fear is normal their young parents They want to make the best decision for their families. They don't know enough They want to know more information and so kind of approaching with that really helps granted. There are some people out there who are Way out there and will always believe vaccines are going to kill you and they'll dox your address on the internet and share pictures of your Best friend's baby and all kinds of fun horrific things. So that still happens. Unfortunately, you will encounter those people, too That's a real-world story that I did in my social media for a while ago because a very true anti-vaxxer who believes everything is horrific So that I was poisoning babies. I was gonna kill my best friend's baby and shared my address on the internet. So This stuff happens still but for the most part people are very nice and kind It's important to have those discussions provide the information for them and really reassure them that the reason we have these vaccines is to prevent Illnesses and to save lives we care about the babies We care about you know people living and having good quality of life and the best way we can do that is by preventing diseases That have the potential to just destroy your life So very very important there. This is Phil courtesy of Abigail who's not here But there are a lot of Phil pictures that she sent I couldn't just decide on which one so we have a montage of Phil studying and looking at trees and houses Announcements you go office hours back to normal tomorrow. They will be in person from 4 to 5 you guys draw to know it is back There's a lot more this module. So stay on top of them This is still due despite the fact that we have class asynchronous and its research days Please make sure you do this before Friday It is the pathophysiology of HIV because today we're going to talk about Primary immunodeficiency disorders HIV is considered a secondary immunodeficiency disorder And so that's what we'll talk about in the recording which I will post ahead of class I imagine you're probably gonna listen to it after research days research days is a lot of fun because you get to see what all the Different professors are working on in terms of research see what's available here Especially if you come to be a medical student here You can see what available options there are for research for you guys to do Also, it's just really cool and just kind of see what the med students are doing and then like if you're doing to your track Pick out a mentor We do a lot of fun stuff here. So that's fun and that will be on Friday. And again, that is a bonus point I am a judge on Friday. So I will be here like all four hours I will be wandering around keeping track of who I see so feel free to come up to me If you're like hiding in the corner So I can document that you're here because this it's the last bonus point attempt for this class If you've already done the other one, you're not eligible for this one I do still hope you attend you get one possible point total towards homework and unfortunately I can't go above a hundred percent. So if you have perfect in all your homework Unfortunately, that won't be applied but those are the rules of the school that I can't abide by technically I'm not supposed to do extra credit either. We all do but I'm not supposed to So shh, but everyone knows we do it. So bonus point for attending and again one maximum one bonus point towards homework per person Collette I left your I left. Oh, no, I forgot his name her name what Cooper Cooper hiding in a bucket I think I have Cooper on the next PowerPoint to Speak Cooper in a bucket the whole time We are in primary immunodeficiency now, even though obviously we just finished up vaccines and this is the rest of the plan for the semester Please note hypersensitivity. So we have Wednesday off for Thanksgiving, but hypersensitivity. I'm also making it asynchronous So if you guys need to travel go home You can easily listen to it on part like from from wherever you go home so that you have time to actually have a week off To chill I do that on purpose. I'm pretty sure your Tuesday classes do too I'm also fairly certain the other Monday classes are fairly amenable to you know Going home to be with your family, especially if you have to travel far away So that's there and that's the rest of the semester overall and here are our learning objectives for today So there are a lot of slides today with scary-looking charts You do not have to memorize these scary-looking charts These are the specific disorder examples will be talking through I do need you to be able to read the charts though because you will See one question at least where I provide a chart for you And if you can follow yes or no and kind of you know go down the columns of the questions you can get to the right answer and so that is my Solution for not having to teach you every single possible primary immunodeficiency disorder if you can solve one with given Like a given chart and table you will get that one, right? So we'll go through what I mean because again, you're gonna see it you're gonna freak out But it is how we diagnose it's the charting It's the charts that we use in order to diagnose immunodeficiency disorders, especially if it's not that common We have categories that we used to sort So obviously the failure of the immune system this leads to a reduced ability to resist infection immunodeficiencies Like they sound are defects in components of the immune system. It's a decreased immune response You have two main categories primary and secondary Primary is a disease in which there's a failure of Immunological function due to a defect in one or more genes and coding components of the immune system It is usually genetic but can't be the result of randomly occurring errors and developments of point sense mutations In utero during fetal development, so you didn't get the genes for it specifically, but it still occurred during development Most of these guys become apparent by about six months old if they're more common sometimes they're very odd and just rare and like the symptoms aren't really anything not obviously really pointing to anything and so a Lot of times they can get missed too But around six months is when we start to see most of them because that's when the maternal derived antibodies start to disappear And so if the child just suddenly keeps getting sick over and over and over again It keeps having recurrent bacterial infections over six months old some things going on that's making them more susceptible to this So it is it is so diverse the term inborn error of immunity is now being used to describe primary immunodeficiency disorder So if you see the word ie I used people thought that primary just sounded bad Because it sounds like it's the main grouping even though we have environmental ones which fall under secondary So we call these because again it's going to be during development whether it's the genes that you inherited specifically or some sort of point Mutation or malformation with cell division when you were developing in utero, so that's why they call that inborn error of immunity Secondary immune deficiencies are caused by the environment after you're born infection therapeutic treatments So you can even be immunocompromised because you are on immunosuppressants for an auto a primary autoimmune disorder and things like that And so you have various issues with that too cancer will also put you under an immunodeficiency And malnutrition if you don't have the right nutrients or vitamins needed to help you know your immune system function you're going to be immuno immuno deficient overall just because You don't have the right nutrients you need to function so there are multiple causes behind the scenes, too HIV also falls under secondary immuno because it's environment It's a virus you contract later in life These guys can occur at any time in life depending on when the exposure to the causative factor occurs It's like a new mass amounts of radiation caused it Obviously you need a triggering event of the mass amount of radiation in order to develop that immunodeficiency Both of them however if you're comparing and contrasting both of them are characterized by recurrent or chronic infections The inability to clear infectious agents typically after standard antibiotic therapy because antibiotics are there also to help You know control it enough for your immune system to step in and finish off the job So again if you have patients who are just constantly and again, we've tested for you know The antibiotic is supposed to work Bacteria or virus or the bacteria is susceptible to the antibiotic and we still provide it and it still doesn't work something else is going on Or the presence of unusual infectious agents So if you get a patient comes into primary care who has a bacterial infection You have never heard about that. We never talked about in micro Probably not that common and probably something you should investigate further and so those are Similarities between both primary and secondary, but the major differences are primary is birth like during birth and development And secondary our environment after birth Rare primary immunodeficiency diseases reveal how the immune system works We've actually learned more about the immune system based on how it doesn't work when people have certain malformations genetically with these primary Immunodeficiency disorders we have actually identified over 100 different primary immunodeficiency disorders overall which is why I'm not going to have you memorize all 100 of them There could even be a new one that's discovered in the time that you guys are working You could even discover when you never know And so as we see specific defective genes that we identify We're able to kind of you know Figure out what the causative agent is and learn a little bit more that like oh if they have a defect in this gene and it Affects, you know these cell behaviors that gene is linked to these cells in their function So we've learned a lot actually through them to Immunodeficiency these are actually less the rare than originally thought they thought it was like, you know One in three or four million now there are some that can be one in a hundred chances of you getting it So there could be people in this class who have a rare Immunodeficiency disorder they do depend and they vary in rarities We'll talk about some that are most common. These are the ones we'll talk about in class But there are some other ones too. We talked about the primary ones since they're inherited They can be caused by dominant recessive or even X linked gene defects They do kind of all differ so there can be some where only women can track it because they have 2x chromosomes Or only males experience it because they have a Y chromosome It can get complicated when you have like client filters and other like *** xxy xyy and things like that Which can also affect your ability to diagnose it If it's a little atypical in the presentation, too So here are the main groups and you guys are expected to know The group and the immunodeficiency with it because this is how So say you discover a new one we can at least figure out what group it's in based on how it presents So group one are immunodeficiencies affecting cellular and humoral immunity group two are combined Immunodeficiencies with associated or syndromic features and we'll talk about what that means But usually it's kind of multiple together causing just severe You know everything gets taken out with these guys here, too Group three predominantly affects antibodies and antibody deficiencies group four is diseases of immune dysregulation So the immune system is activated But then doesn't function the way that it's supposed to group five is congenital defects and phagocyte number function or both Uh group six is defects in intrinsic and innate immunity like say we're taking out your macrophages or your neutrophils that could affect that, too Which can also kind of loosely tie into group five. So I am very nice when I present stuff like that group seven is auto inflammatory Which can be kind of considered considered like autoimmune But it's basically where we attack self and lead to just massive inflammation in the body And group eight is all of your complement deficiencies Obviously, there are a lot of different genes involved You do not need to memorize these guys here But it is kind of cool that we figured out kind of where a lot of these guys found within these groups Are affected by overall So we talk about group one and i'm just trying to get to a point at the charts on the next slide. So It will be okay i'll walk you through them Also, you can't really read them because they're so tiny because I had to squeeze it onto a powerpoint slide I'll make them bigger for the exam. So, you know what's going on group one affects cellular and humoral immunity So this this is a diagnosis chart Proposed by aai on how to diagnose Different immunodeficiency disorders that fall just within group one And so kind of when they're going through here too, like if it's severe and combined They can go through these guys here and they look does this one have decreases in cd19 counts? So you guys could imagine it affects, you know b cells Then we'll go down these guys here and like are you also missing nk cells? Cool, then you go down these guys here. So there are additional like testing you can do but this gives you the red Are the terms and diseases found within this chart so if you can read a chart like I say, hey, you know It is a severe combined in group one And you have normal levels of cd19 cool Then you guys go here and you read down this column And so basically that's kind of how I set you up for it here like here It's you know has low levels of t cells. You have normal b cells, but you have Normal nk cells. Cool. Then you go down here and read this here And so it gives you kind of just it narrows down the focus when we're diagnosing the various disorders So I would give you a chart like this and actually be one of the charts from this powerpoint and give you the information Needed so as long as you can answer the questions and read down the chart It'll get you to the answer area Okay Is everyone comfortable with this process because this is what you're going to do if you go into this field of practice They don't expect you to memorize all I mean grants if you work in this field for a very long period of time You might memorize them if you're really good But it's not expected for you to memorize them But it is expected for you to be able to follow a flow chart Of the different tests that you've done to start narrowing down what a patient's diagnosis is And so that's why I use this as an exam question To get you comfortable with practicing going through this process here, too We will talk about some of these look cd40 ligand deficiency falls into this category here So some of the names you are familiar with some of them you aren't you guys might remember zap 70 But there are deficiencies that affect zap 70 overall here, too There are some that affect your ability to have mhc class one So some terms may sound familiar But again, we will talk about very very specific ones too as we go through here, too So when we're knocking out the lymphoid lineage with group one It results in defective function of both b and t cell numbers. Although from that previous chart You can have some normal b cells too Functions or both so it may not always be equal either You could have normal levels of b cells, but they may not be able to function So, you know various aspects of a group one is kind of one of the broader categories I think if you talk about so an example of severe combined immunodeficiency disorders This is a specific example to know or scid This one was originally believed to be one disease But now it's actually kind of a group of diseases overall Caused by different defects in individual genes that have similar functional consequences in that we Pretty much wipe out the functioning of your entire adaptive immune response here, too And so because of that you lose the ability to have cell mediated lysis delayed type 1 hyper sensitivity can get affected which we'll talk about later Obsonization can get affected Antibody production is decreased antibody dependence mediated cytotoxicity gets decreased, too You also have you know difficulty with massive degranulation because if it requires IGE Produced by b cells and you're affecting your b cells You're in trouble there, too. And so there's a lot of overlap here, too The classic example of defects in combined lymphocyte lineage is cid. So it's the primary one described often The cid related defects may occur in genes like rag 1 rag 2 So as you guys know that would affect recombination machinery and the ability to make your t cell receptors and your b cell receptors That's a significant knock out here, too And so obviously that affects the ability to produce the variable regions of your immunoglobulin molecules in your t cell receptors You can also knock out cytokine receptors, too So that cells can't respond or function like think about you knocked out aisle 7 you talked about that heavily with b cells There's a problem with that too or your even ability to you know, lead to t and b cells So a lot of it makes logical sense kind of if you think about it here, too It can also affect, you know cell-to-cell interaction where you have normal levels, but they can't talk to each other So they can't activate each other and they can't function. And so those are consequences as well, too And so an example of one within cid is ada which is a little bit more common It's called adenosine deaminase deficiency or ada it is in a metabolic immunodeficiency disorder That is one of the causes of cid. So cid is a group of disorders And so this is the one example within we do know the inheritance pattern here It is caused by mutations in the ada gene and it counts for about 10 to 15 percent of all cases of autosomal recessive Cid among a non inbred population With this one, it's showing that both parents were carriers of the disorder And so males are in squares and females are in circles here And so the functional copy is in green the defective copy is in red. And so obviously again It's a random one and fourth meat Well, actually one half mutation at that point when anytime you flip a coin the chance of your child inheriting it here, too But you need both defective copies in order for it to display So you can also have generations of a family where maybe they only have two kids and both kids ended up becoming just carriers And so a lot of times too going back and looking at family trees and genetics to kind of figure out what the disorder is Can kind of narrow down what some of them are But this one this is one of the few ones where we can go back and actually do genetic testing to look for issues with ada Genes to see if a patient has developed it That way so we will stop there since it is at time Do you have any questions about that? Is everyone comfortable with the idea of the charts because if you look ahead There are many charts But for each group each group has a chart But because I don't expect you to memorize all of these different things I will provide a chart for you So as long as you can follow and you know I'll give you the information needed to go down the different combos or columns You can figure out what it is based on that We'll do some practice questions too for your end of the week quizzes