Vaccines of the Past, Present, and Future

we have another okay [Music] so [Music] that's up [Music] all right it's 3 30 so we will go ahead and get started i want to thank all of you who are here and all of you who are on zoom joining through the webinar for being here today this is the first new frontiers series seminar we have had in a year and a half since february 2020 um and so it's really exciting to be able to do this again with all of you here and to use technology to be able to bring in people remotely as well and most exciting to have you here for dr lisa maurici from tulane university those of you on zoom just to know if you can't hear if you have questions just drop them in the chat or q a and we'll be sure to address them as quickly as we can um so dr lisa morissi is associate professor in microbiology and immunology at the tulane university school of medicine she earned her bachelor's in biology from mississippi state university her master's in marine science from university of san diego may be a bit of a surprise and then a phd in infectious disease and immune immunity from uc berkeley she's been recognized with a number of awards for teaching mentoring and research she has over 50 peer-reviewed publications millions of dollars in funding from the nih and other agencies um and i have to say i invited her a bit selfishly because i heard her give the keynote lunch talk at louisiana academy of sciences virtual meeting last year maybe some of you also attended that and it was one of the best talks i had heard on vaccine development and i thought she would be a fantastic start to our year to give us a great overview of some of what we've been hearing and learning about she's been a great guest today we've probably worn her out visiting with the university's incident response team this morning fye class a little bit later this morning so i just really want to thank you for being here and appreciate all the time you spent with us and i hope you can join me in welcoming her to louisiana tech [Applause] well thank you so much dr newman for that very nice introduction and also thank you to dr kennedy and dr calderon for inviting me here today and hosting me here today it's a real pleasure i'm born and raised in louisiana um and this is my first visit to louisiana tech and uh it's been it's been really great so so thanks so much for having me um i thought i'd uh talk with you guys a little bit about the history of vaccines and then maybe dive into a little bit of some of the research that i'm doing at tulene in terms of vaccine development i know it's a very timely topic and hopefully one that you guys will find interesting and as fascinating as i do so i know we're dealing with a pandemic right now but i wanted to remind you all that you know pandemics have really occurred throughout human history and probably one of the best examples of a pandemic is is the black death which i'm sure many of you have heard about and in the mid 1300s you know the black death was the deadliest pandemic or at least thought to be the deadliest pandemic in human history and thought to have killed up to 200 million people and there was a uh uh an autopsy finding that was uh described in the early the pathogenic 1900s found in such abundance considering the acute and quickly developing nature of the pulmonary process the surprising thing is not that so many patients die that even a few recover so this was a horrific disease it was caused by yosemite pestis a bacterium that's transmitted by a flea that bites the host and it can result in what's known as bubonic plague and then of course without the availability of antibiotics back then the the spercenia pestis could then disseminate to the lungs and cause what's known as pneumonic plague and that mnemonic plague could then be spread from person to person um and it's thought that there were about 300 plague outbreaks in the 14th to 17th centuries so you know i know we're dealing with one right now that's really wearing us out but can you imagine you know dealing with outbreaks over centuries and then of course there was another awful uh disease known as smallpox which was caused by a virus and it you know it was really the first disease that we were able to prevent uh with vaccination beginning in the early 18th century and so as far back as the 15th century there was something known as variolation where individuals would notice that people who perhaps were um you know exposed to smallpox uh that they may not come down with a severe form of the disease if they were inoculated with the pustular material from an individual who had smallpox and of course that was a very risky technique because you were actually transferring the virus from one individual to another but it turned out that very elation had a fatality rate of about two to three percent um if you caught the very formal small box however if you were not very elated then smallpox had about a 30 mortality rate so a very very uh scary disease and so individuals were really desperate for anything that they could do to protect them from this virus and we really uh you know credit uh edward jenner uh in 1796 with the development of the smallpox vaccine because jenner had relied on earlier uh um observations of variation and then he had observed that milkmaids who worked with cattle were exposed to cow pox and they would develop a mild from a cow pox but they would never get smallpox and so he made that really uh clinical observation well maybe if you know i take the carbocox virus and inoculate that into individuals i can protect them from small blocks and that turned out to be the case and that's how we get our get the you know the name vaccine because vaca is the latin woman for cattle and it was finally in the 1940s that our first sort of freeze-dried formulation of smallpox vaccine became available we were able to use that to immunize the globe and we were able to eradicate smallpox from the face of the earth in 1977 so a tremendous feat and one of the greatest achievements really in in human history and then of course if we um you know bring a role you know bring that forward a little bit and think back to something that's perhaps occurred in our times i was just talking to dean kennedy about this you know polio was something that that terrorized um our older generations and so it was something uh this was a virus that was transmitting female orally and you know it it was one of the scariest things to think about getting polio i'm showing you here a picture of what is known as the iron lung um and so these were basically you know the old ventilation or ventilator type systems that we had available to try and help people breathe and so everybody knew somebody that was afflicted by polio and can you imagine you know seeing your neighbor or your loved one developing you know paralysis or even dying disease it was something that was you know really feared and uh this is this is one of my favorite pictures this is showing you uh you know parents lining up in the gyms uh of the schools with their kids you know desperate for the vaccine so this is in uh this is 1957 when jonas salk developed the heat inactivate heat and activated version of the vaccine and made that available and what that did is it prevented the severe manifestations of polio and then albert savin followed that with a live polio vaccine that was that allowed us basically to eliminate polio from the western hemisphere and you now only find polio in very small pockets of the world like pakistan and other places but again another tremendous accomplishment with a vaccine and so vaccine development really surged after um after these early discoveries and developments and um this is just showing you life inspect life expectancy uh for humans and you can see that you know most people hope to live you know to their 60s and then after vaccines were developed you know we live well into our 80s and 90s and even longer um and this is really because vaccines have made such a difference in in life expectancy in the human population and it's thought that really the only other public health intervention other than vaccines that's had such a dramatic effect is access to clean water so again vaccines remain one of our greatest tools at preventing infectious diseases and just to you know kind of drill that point home a little bit more if this this is just a list of the impact of vaccines in the 20th and 21st centuries you can see um basically again eradicating smallpox and polio more than 90 reductions and many other diseases that were either life-threatening or scarring or really debilitating so things like diphtheria and tetanus measles lumps just to name a few and so you know the vaccines that i just talked to you about or what we think of as traditional vaccines so one one drug for one body like to call it and so we we knew that there was an infectious organism that was um you know threatening us and we would either take that organism and weaken it somehow um and and and administer that as a as a vaccine and so some examples of that are the measles or those attenuated or weakened viruses that would inject as the vaccine and then again polio vaccine developed by saban that's actually taken early and then other versions where you would take the virus and you throw it up in these large batches and you would inactivate it and uh you inject that inactivated form of the virus into someone and examples of that are again socks polio vaccine and sort of the annual flu vaccines that we get every year are developed this way and the way these vaccines work um just as a little bit of a refresher for those of you that that have had immunology or may not have had immunology but you know how do these vaccines work so the idea that that a vaccine takes advantage of is basically that our immune systems can develop memory they remember when they see foreign or dangerous things and they have what's called a memory response to those substances and so what i'm showing you here are just b cells so we our bodies have two types of cells that we traditionally think of in the acquired or adaptive immune response we have b cells that make antibodies and we have t cells that can that can see infected cells and so this this picture is just showing you um that if you were to be infected for example with an organism your naive cells will recognize that and they'll proliferate and they'll make antibodies to that and some of those cells will establish memory cells that can then respond if they see that virus or that microbe again and so a vaccine basically mimics that but in a safer way so the vaccine will mimic that first infection but we're injecting you with something that's safe or safer than the uh the virulent uh form of disease of the pathogen and that will again induce an antibody or be your t cell response in the body and then booster doses or if you were to see the infection thereafter that would it would boost that response and so now you're making even more memory cells and you're making even more antibodies and we can hopefully maintain those antibody levels at a high enough level to uh to protect you and if those antibodies lean over time then we have b and t cells that remember retain memory and if they see it again they can react again and make more antibodies for us and the t cells can go and find infected cells and so this you know our immune response is pretty amazing and it's actually known that that the memory response to the smallpox virus to the smallpox vaccine excuse me and the virus but but the memory response in people's bodies lasts 75 years or greater just to show you the power of our immune system so a single dose of that live attenuated smallpox vaccine pretty much convert lifelong immunity to individuals and that of course brings me to the present-day pandemic right and so we're talking about um you know vaccine development for for the coronal viruses and how do we tackle something that you know is sort of somewhat new some something that we weren't ready for or we hoped to be ready for um but that may have taken us by surprise and so i'm sure all of you are aware that you know in april 2020 the united states government you know issued operation warp speed and in hindsight i kind of wish they hadn't used the term warp speed because i think it gave people the impression that the vaccines were rushed and they weren't rushed and i'd be happy to talk with you guys about why that is um all of the safety standards were followed for these vaccines as they are for any other vaccine but they were expedited in the financial mitigation they had mitigated the financial investments of the of the pharmaceutical companies by government backing of the studies but anyway operation war speed you know aim to deliver 300 million doses of a safe and effective vaccine for coca-19 by january 2021 as part of a broader strategy to accelerate development manufacturing and distribution coca-19 vaccines therapeutics and diagnostics diagnostics and this was collectively you know known as medical countermeasures and so we're thinking how in the world you know are we going to produce a vaccine this quickly and so just to give you an idea of sort of the task at hand so traditionally those traditional vaccines that i just talked to about those weakened or inactivated versions of vaccines you know development of a vaccine in 12 months would be unprecedented because those vaccines typically take about 10 years from discovery to licensure and most of them fail and it took 28 years to develop a vaccine for influenza and most was the fastest vaccine that we ever developed and it took four years so now we're trying to develop a vaccine against a new pathogen in a very short timeframe so how do we do that well one of the things that we have been working on in the vaccine field for quite some time are technologies known as plug and play and so when i describe those traditional vaccines where we take the virus we isolate the virus and we grow up large batches of the virus and then we either weaken it or inactivate it and then we inject that into people that takes a very long time to produce so you might imagine the flu vaccine that we get every year we have to start right away for next year because it takes us that long to grow up that much of the virus and inactivate it and put it in the vials and ship it off so that it's ready for flu season so those types of technologies while they've been great and they've helped us eradicate some of the most horrific infectious diseases of our time they weren't going to work when a new virus suddenly jumped the you know the animal from one animal into humans and then circulated the globe as a pandemic and our virologists and our experts have been telling us for a very long time that we're overdue that this is going to happen you can imagine we have transatlantic flights and we have people all over the world in less than 24 hours so what happens you know in another part of the world can very quickly affect the other end of the globe and so we have been working on technologies known as plug-and-play technologies that could rapidly respond pandemics so let me let me tell you what those are so what we mean by plug-and-play is as opposed to developing a vaccine where that vaccine is a is that is that microbe and you inactivate it or you weaken it and you take a piece of it which is known as a subunit vaccine um these plug-and-play technologies are based on basically either nucleic acids so messenger rna vaccines which we'll talk about in a second dna vaccines which haven't panned out for several reasons and then add your virus or other viral vectors which are similar to live weakened viruses but instead of taking it from a pathogen we take it from some wimpy virus like a virus that just causes a common cold and we're not worried about it causing severe disease in us and then what we do with those viruses is we genetically modify them so that they can't replicate in our bodies and so they're simply serving as a delivery vehicle for genetic material and that genetic material in the case of the messenger rna or in the case of the animal virus that's delivering the genetic material to us that is from the pathogen of interest and so what you're doing is you're delivering the instructions to our cells to make an antigen a protein of interest from a pathogen that's attacking you so that you can mount an immune response to that um so let's let me show you a little bit more about what i'm talking about one of the reasons we lucked out with sarge's cool v2 the virus that causes kuva 19 is that we had already had some experience with sars before so we've had other incidents of stars and stars like coronaviruses causing disease in small epidemics and outbreaks in other parts of the globe and so we already knew how sars conveys our host cell and we knew that sars invades our host cell by using its spike protein that decorates the surface of the coronavirus to latch onto ace2 which is a receptor in our host cells and by spike latching onto h2 that allows the virus to invade our host and invade our cells and so we we knew very quickly that if we could generate an immune response to the spike protein we can block its entry into into the h2 receptor um and so what basically the messenger rna vaccines do is they take a snippet of messenger rna that's made in the laboratory that encodes the instructions for making spike protein and they formulate that messenger rna into lipid nanoparticles and it's those lipid nanoparticles that help deliver that messenger rna into our cells and then once it's in our cells the the the protein machinery in our own bodies that sees our own messenger rna that makes the proteins in our own bodies sees another piece of messenger rna in this case it's the one the vaccine just delivered and they say oh this one says to make spike protein and they go about making spike protein and it gets presented on the surface of the cell and then our immune system says wait a minute that's not what i want to mean right that's my proteins we don't have anything like that and they attack it and so we get antibodies and immune responses to the spike protein through that messenger rna technology delivering the instructions for the spike protein to our host cells our cells are just going about business like like usual and that messenger rna it's a drop in the ocean right our cells contain thousands if not hundreds of thousands of copies of messenger rna at any one time so this messenger rna that's getting delivered by the vaccine it's a drop in the ocean and once that protein is made that messenger rna is degraded it's eliminated it doesn't hang around i'm sure many of you know that rna is highly fragile and it's degraded very easily and i'm showing you the messenger rna technology here in this diagram but you can imagine the adenovirus works very similarly it's a particle by nature and it delivers the genetic material to the cell and works in much the same fashion and so um you know the lipid nanoparticles are are really the key to the mrna success so the mrna uh vaccine platform is not new it's been in development for 30 years 30 years vaccinologists and biologists have been trying to get messenger rna to work as a vaccine the key to its success were the engineers right so the bioengineers the biomaterials folks who created lipid nanoparticles that was the key to the success of the mrna vaccines because otherwise they never would have been able to get the messenger rna into the cells it would have been degraded before that um and so i have a list here of what these lipid nano particles typically consist of and you think you can see that they contain the same thing our most of our cells contain so cholesterol and phospholipids and other sugar components and salts there's nothing in these liquid nanoparticles that that you know that we have any any reason to be concerned about their safety and they're used in numerous applications other than vaccines and so i just want to say to you guys keep up the great work louisiana tech because without uh you know innovators like yourselves who are developing biomaterials and doing these types of bioengineering work the vaccine field would have been stuck we would have been stuck and we would not have been able to get the messenger rna into the cell and it was really this this nano technology which i know you guys are really great about um that helped help the field alone and so i just you know i know there's been a lot of misinformation out there about these vaccines and i know people feel like they've been rushed and that they're not safe um i can assure you they did not skip any safety steps they went through the same rigorous clinical trials the same assessments in any vaccine they were just expedited and the financial backing was there and the participants were there and the caseloads were there we were very quickly able to determine if the vaccines worked which is not the case with most diseases we don't fortunately we don't live in a world where there's lots of infectious diseases going around in this case there was we were able to tell very quickly that the vaccines were affected in the clinical trials and this is just a recent assessment of you know cases of basically hospitalization among different age groups and you can see the vaccines are highly effective highly effective at keeping you out of the hospital so the vaccinating room is basically a flat line um these vaccines will save your life they will keep you out of the hospital they will keep you from dying from coping yes we're hearing a lot about breakthrough infections but breakthrough infections we can deal with right we can deal with a mild disease we don't want to get hospitalized and die from this thing and that's what these vaccines were meant to do and that's what they're doing a really great job of and i just couldn't i just couldn't end my my um you know my summary of the coveted vaccines without debunking a few myths for you guys um because i know every one of you guys have seen something on social media you know making statements like this let me just say this the vaccines do not integrate into your dna i hope i convinced you that just showing you how the messenger rna works messenger rna does not even access the compartment in our cell when the dna is housed once it gets in and that protein is made it's rapidly degraded it doesn't linger in the body they don't cause infertility and they are safe for use in pregnant women despite what you may have heard numerous pregnant women have had the vaccine gone on to give healthy children healthy babies in contrast the virus can have devastating consequences in pregnant women um no no scientific basis for the infertility plans none whatsoever it's completely false and in fact coded the virus can cause reproductive issues in men that is scientific fact the message rna vaccines do not contain fetal cells or tissue they're not propagated in anything like that um they don't cause choline they can't right i just showed you they don't even contain any of the virus it's simply the instructions for making a part of the virus there's no way it can cause kilo 19. they don't carry microchips to track you and i hope i can convince you that they weren't pushed so we've been really really fortunate with these code vaccines i i really uh hope you guys appreciate you know the decades of research that the engineers and scientists put into making these plug-and-play platforms so that we could rapidly respond to to some type of pathogen that might surprise us um but you know there are limitations still with vaccines you know how how can we make them better how can we improve them and what do we do about the great majority of infectious diseases for which we don't have vaccines so i like to call these the big three right so hiv tuberculosis and malaria we have vaccines for malaria we have vaccines for tb we've done extensive vaccine development for hiv and we're still we still don't really have anything that's great so um the vaccines that's used for tuberculosis is used globally we don't use it here in the united states and it protects young children from the disseminated form of tuberculosis but it doesn't really do a good job at preventing pulmonary tb in adults so we need a really good vaccine so why is it why is it that our traditional vaccines and and really even our vaccines we think against covenant 19 why do they work so well well it turns out that pretty much the majority of infectious diseases that we have vaccines are still antibodies those those antibodies that our b cells make that latch on to the micro and either block its entry into it into the cell or promote clearance by other white blood cells antibodies seem to be sufficient for protection in these situations against these diseases but things like hiv malaria and tb these are what we consider sort of really sophisticated intracellular pathogens they've learned how to manipulate ourselves to survive inside the cell and so our traditional vaccines haven't worked as well um and so what we know about uh you know sophisticated uh intracellular pathogens is that t cells are required to clear those the t cells have to survey the body and find those cells that are infected and clear you know clear the infection and it turns out that our that most of our vaccines that we've successfully developed today they all skew the response towards antibodies which is great because the antibodies are sufficient for protection but they don't work for diseases like hiv and malaria and tb because again antibodies they can't see inside the cell you need t cells to recognize those infected cells and the other reason sometimes organisms escape antibodies is they mutate or they change and so whatever it is on their surface that the antibodies see they're changing that so that the antibodies become less effective we've seen some of that with cova 19 but fortunately the vaccines are still really really effective at preventing severe forms of disease so yeah you might get a little bit of a breakthrough infection mild to moderate you know symptoms you don't feel well for a little while but it's going to keep you out of hospital because those antibodies are still seeing that spike protein even though it's mutating a little bit hiv on the other hand mutates dramatically and so the minute you have an antibody response to it it's changing and you can't neutralize it or block it the next time around and so why is that why you know why do vaccines skew towards antibodies well one of the reasons is that as we've moved past using live vaccines so we'll talk about small clocks and polio where we have sort of weakened versions of the virus that we inject into the body you know those vaccines were highly effective and helped us eradicate those diseases but they're also a little risky because they do come with some risk of infection so if someone's immune compromise for example when we inject a live vaccine into a new compromised person it maybe could cause disease in that individual we have a lot of people now who are being compromised in our world so we want to get away from live vaccines um and so one of the one of the things that we've done is we've developed in addition to these plug and play platforms we've developed what are known as sort of subunit vaccines so we use just pieces again of the organism and then when we inject those into the body the problem is that our bodies are smart and they can distinguish between sort of just a small piece of the organism they don't they don't respond to it as well as if they respond to the whole organism and so what we've had to do is we have to put what's called an adjuvant into the vaccines and adjuvants basically provide the danger signal to the body to tell the body what i'm injecting you with is you should mount an immune response and and these adjuvants tend to dictate the type of immune spot so they can polarize it towards an antibody or they can polarize it towards a t cell and some do both and so it turns out that most of our our vaccines that we've used you know up until this point have been formulated with aluminum hydroxide which is a salt basically and what aluminum hydroxide does is when you add it to a vaccine it does a very good job of stimulating high titers of what we call igg antibody and so if you look at this this table i know it's a little hard to see but what we're showing you is all the different vaccines to date the type of vaccines so these traditional vaccines are they live are they inactivated or are they subunits and you'll see that typically inactivated and subunit vaccines have to be formulated with aluminum hydroxide to provide that danger signal and what that does is it polarizes the immune response to antibodies and again that's been very helpful traditionally and has helped us protect against these diseases but what it doesn't do as you can see here from the table it doesn't give you very good t-cell production and it also doesn't give you really good antibodies in the mucosa so in the lung or in the gut for example or in the reproductive tract um and so we you know why is that so how does an adjuvant has an adjuvant like alan woke so um we finally really appreciated in the mid 1990s that our innate immune response so meaning sort of the white blood cells that patrol our blood and our tissues are what signal and drive our bnt cell response and so what they do is they recognize either an injury or an infection through signals and those signals are what are known as pathogen-associated molecular patterns in the case of an infection so microbes have these pathogen-associated molecular patterns things on the microbe that we our bodies don't have and so our white blood cells can recognize those pathogen-associated molecular patterns and it's it's the danger signal and that's what adjuvants are meant to mimic they mimic those danger signals and so what what that what that allows is it allows our white blood cells in particular dendritic cells which is a cell type that will take up these these foreign substances and these these pathogen-associated molecular patterns that tell the dendritic cell okay you need to respond to this and so what we'll do is it'll take that take that material up and it will mature and will become activated and it will migrate to our lymph nodes where it will then activate the t cells to recognize that material okay and so what adjuvants are doing is they're driving this innate immune response um and as you'll see um that can depend on what on what the initial response is so there was a really important paper in 2006 by some of the premier immunologists of our time rafa ahmed and richard lavelle and volley palendron and what they did is they said wait a minute if if innate immune responses and these signaling pathways drive being t cell responses um maybe that's why some of my vaccines are really good and some of our vaccines aren't that great and so they took the yellow fever vaccine which for vaccines is an incredible vaccine one dose of the live attenuated yellow fever vaccine can provide lifelong immunity much like the live attenuated smallpox vaccine and so they worked backwards they said well what is the live attenuated yellow fever vaccine doing that makes it so amazing it induces antibodies and b cells and cd4 t cells and cd8 t cells which are two different types of t cells and so they work backwards and they realized that the yellow fever vaccine was signaling to our immune cells through multiple pathways through multiple what are known as pattern recognition receptors and it was this response that was synergizing to stimulate a really robust acquired immune response so a really robust b and t cell response and so i'm just showing you i know this is a very complicated figure but these are all just internal sensing pathways that our cells use to recognize these pathogen-associated molecular patterns and so if you trigger just one you know the cell's not too concerned but if you trigger multiple pattern recognition receptors through multiple pathways like the live yellow fever vaccine does you get a really great downstream adaptive immune response and so the nih sort of recognizing this this you know this sort of game-changing discovery issued a strategic plan for adjuvant development in vaccine design and so they recognized that alan was limiting alan was probably just providing one signal and that signal was leading the antibodies and it was missing all the signals that could lead to t cells and other desired responses and so they uh developed a strategic plan to tackle this and they have a number of different mechanisms they have an adjuvant discovery program an adjunct development program and molecular mechanisms of combination adjuvant so figuring out how different combinations can change the response from an antibody to t cell or perhaps even getting both and so what i'm showing you on the next diagram alan for example signals through what's known as the inflammasome pathway or is at least thought to things like bacterial lipopolysaccharide which is what causes septic shock syndrome there's a detoxified form of that in this mpl it signals through a pattern of recognition receptor known as toll-like receptor iv and so alan tends to skew the response to antibodies and mpl tends to skew the response to t cells and if you mix the two which is what adjuvant system o4 is aso4 you get both you get antibodies and you get t cells and asl4 is now part of gsk's hpv vaccine so you might imagine with human papillomavirus again a virus that needs to invade ourselves that antibodies and t cells would probably be a really good thing and so it turns out that azimuth is very good and so at tulane we are also working through this adjuvant development program we have two adjuvants that we've developed there um i'm showing you the first here so this is the mlt adjuvant which is um is basically a detoxified and collide enterotoxin and so it's thought to function in the inflammasome as well as perhaps other pathways we still don't really understand fully how it works but basically it's a detoxified toxin derived from a bacterium and then the other one is this outer membrane vesicle adjuvant which are uh are basically um derived from the surface of gram-negative bacteria so as bacteria grow they shed these vesicles and these vesicles are loaded with pathogen molecular patterns but they're much safer than using it using an entire bacterium and it turns out if you stimulate dendritic cells with outer membrane vesicles they're really really good at activating those dendritic cells i mean you can see in comparison to yellow fever so yfax there's yellow fever they're even better than the yellow fever vaccine at stimulating basically the surface marker expression so cdc86 and cd25 is an indication of activation and maturation of dendritic cells and you can see that the outer membrane vesicles in this data set are stimulating really robust um you know up regulation of these markers and so we were we were pretty confident that outer membrane vesicles would work at uh stimulating um basically t cell responses and and that's what this next figure is showing you so basically what we can do is we can mix peptides so just pick a peptide from your favorite microbe mix it with outer membrane vesicles deliver that in the formulation and you can get really good both cd4 which are known as helper t cells and c8 which are known as cytotoxic t cell to this agile and this was really amazing because up until this point there was no known adjuvant or really no non-replicating non-living vaccine that could elicit cytotoxic t cells cda t cells um and the ombs as i showed you they're just you know shed off the surface of the bacterium they're not alive they're not replicating and yet they're able to drive um you know t cell responses and so how might we um you know improve current vaccines with something like the only advent well all of us in this room have been vaccinated with um dtap so dtap is a subunit vaccine that's formulated with alum and it provides for antibody and mediated protection against diphtheria tetanus and pertussis those are all caused by toxin production and the antibodies neutralize the toxin and protect us from disease unfortunately this little critter here is florida pertussis which is the you know the organism the bacterium that causes whooping cough or pertussis and it's it's still able to colonize our upper respiratory tract um despite the fact that this vaccine elicits really good antibodies and it's thought that um t cells are actually needed to come in and clear this organism and so what we did is we just mixed the lees with dtac and you can see we removed the response from about 10 of um cd4 t cell response up to about 47 and a half percent um so simply adding that little leads to an hour formulated vaccine we were able to shift the response to hopefully a better response that could could then lead to clearance of border telepertussis another organism that we work on is this is this bacteria called bermudario pseudomalaya which causes the disease meliodosis and some of you may have heard about it because just as recently as last month the cdc was warning folks of these unusual bacterial deaths here in the united states meliodosis is usually endemic to other countries we don't really find it here and yet we had two individuals die and it's thought it was from something that perhaps they imported from another country and so i'm showing you here uh a picture of the organism invading uh the host cell so much like a virus for their pseudomalia can get into the host cell and once it's inside our cells it can survive and replicate and it never has to leave the cell and so you can imagine that antibodies don't do much against an organism like this this is the same thing with malaria and tuberculosis once they're inside the cell antibodies don't really do anything good and so you need t cells and so what we were able to show is that we could use an ov adjuvant um vaccine that basically uh gave the same protection as a live attenuated strain um against a fully lethal challenge with this organism um and so that was a really a really uh great finding and so now what we can do is we can look back at this table and we can start filling in the t cell column now you know we have an adjuvant that we can add to substances that will now give us a t cell component which is great but there are other um there are other problems with with current vaccines and you might remember actually let me go back to the table you might remember i mentioned not only do they not illicit t-cells you know they don't really elicit responses in the mucosa right and so the way it's thought that we're that we're protected from things like cova-19 and vaccines is we get enough antibody in the blood that it moves into the mucosa and circulates there and protects us but what would be really good is if we could get immune responses in the mucosa themselves to stay there and to protect us from invading pathogens and so um you can imagine that you know with a respiratory pathogen for example there's always in coca-19 is the best example there are many manifestations of the disease it can stay in the upper respiratory tract it can move down into the lungs it can get into the blood and spread to other organs and so protecting against you know severe disease disease in the lungs or other organs these vaccines are really good at but how do we get you know how do we get it to stay in the mucosa and protect from breakthroughs and other infections and so one of the one of the more interesting discoveries on the last um i'd say decade is that parental vaccination can be an effective means of inducing protective mucosal responses so traditionally we've thought that to get a protective immune response to the lung we would have to immunize ketone easily or to get a protective response in the gut like the oral polio election we would have to deliver it orally and you know for for the many sexually transmitted diseases that initiate a reproductive tract you know we don't want to be immunized there right so we we like injection in the arm but if we can drive immune responses to the mucosa that would be even better and this is one of the reasons why the whole infertility thing with the kuva 19 vaccines frustrates me so much it's like we've been working on trying to generate immune responses in the reproductive tract for a long time with vaccines it's really hard to do so the fact that they're saying that code 19 vaccines cause infertility like we can't even get it there so it's it's so far-fetched but this is this was a really you know uh interesting finding that we could actually drive what's known as mucosal tissue resident memory t cells um with uh with with vaccines if they were accidented correctly or if they were given by an appropriate route like intradermal administration or even intramuscular and so instead of the t cells these memory b and t cells staying in the lymphoid organs or staying in the bone marrow they're now staying in the tissues that are most vulnerable to infection like the lung like the gut like the reproductive tract and so that dmlt adjutant is really good at doing this and so this this is the um this is as far as i am aware um this is in collaboration with my good colleague dr james mclaughlin at tulane this is the first example of any adjuvanted uh vaccine attempt that can actually elicit mucosal responses in the reproductive tract um others have shown that you can do it in the lung in the gut but we're showing here with the mlt that we can actually get it in the um in the reproductive tract and we're comparing it to another adjuvant known as cpg which which doesn't do it so different adjuvants have different properties that can change the way a vaccine behaves and dmlt is really great because it elicits two types of cd4 t-cell helper responses one is called a t-helper one which can activate our white blood cells to kill pathogens that might be inside of them and the other is that it activates and recruits neutrophils to a site of infection which can also you know counter microbes and it reinforces the epithelial barrier so it can protect our guts and our lungs and our mucosa from damage and promote healing so it's a really promising advent and this is a paper we publish showing that we can actually uh protect against pseudomonas or indigenosa which is a bacterial infection in the lung by stimulating these t helper 1 and t helper 17 immune responses or t cell responses in the lung and protecting these mice against challenge you can see they go down very very fast but the vaccine that's adjuvanted with the mlt can give them some sort of protection and then finally you know i've talked a lot about you know these adjectives promoting t cells and and also the ability of the mlt to drive responses to the mucosa um but i think you know it's also important to show that these adjuvants also can induce antibodies because we know some of our best vaccines you know do induce antibodies and so we we compared it to allen we even combined allen with another adjective in the cpg so they signal through two different pathways and they give you really good antibody responses and our dmlt and our ob adjuvants alone give better antibodies than even the combination and so we think that these are going to be very very um promising adjuvants going forward and so you know i guess i told you a little bit about the history of vaccines and i told you a little bit about current vaccines and i told you a little bit about you know the research that we're doing at tulane to try and improve vaccines and change the way vaccines are developed going forward and so i think you know the future has a lot a lot of promise in terms of vaccines we've made huge leaps forward in the last decade or two and so i think we're going to see a lot of um you know increased focus on on these these plug-and-play technologies um so that we can rapidly respond to a new pandemic because there there will be another one unfortunately you know this is this is the world we live in um you know as as a as as zoonosis diseases that jump from animals into humans become more frequent we're going to deal with more pandemics going forward and so i think these plug and play technologies like the mrna vaccines um you know hold tremendous promise being able to rapidly respond to those but i also think we're going to see us taking advantage more advantage of these subunit technologies because now we're not relying just on allen we have numerous other adjuvants in development like the ones that we're working on at tulane that we can use to sort of customize the vaccine response based on what type of response we want and where we want it and so we can actually develop vaccines that will elicit tissue resonant memory so we can drive immune responses to the reproductive tract or to the lung or to the gut simply by injecting it into your arm which would be an amazing feat and then also you know i think um you know unfortunately we're going to have to improve our communication about vaccines because as we've seen 19 there's been a lot of vaccine hesitancy and a lot of misinformation um and it's you know i've seen some of the stuff that's been spread on on social media and i really go wow that sounds scary and i'm a vaccinologist and i'm reading that's how real it looks you know it's it i i get it it's scary because they're making it look really real like valid and yet um you know i hope that i've convinced you that most of that stuff is just nonsense and it's up to us as scientists and you guys next generation scientists you know to be communicators to communicate your knowledge and um and to do your own research and to understand the science and to follow the data and results and so with that i'll just like to acknowledge you know my group at tulane who helps us with all his work um particularly particularly dr james mclaughlin in his lab um also uh dr john clements our former chair of the department of microbiology and immunology dr lucy freitag dr chad roy and then also i want to thank my you know my funding sources so we've been um we received a lot of support from the department of defense who um really is interested in protecting their military and their in their service members from diseases but also making sure they're getting the safest vaccine we possibly can get um and the nih and iaid um and then tulane the l.a cats and mercado center who funded us for some work on on um covered vaccines looking to see if we can drive that protective immune responses to the spike protein to the upper respiratory tract and i might have a little early but i'd be happy to take any questions the audience might have and thank you guys so much for your attention yes and lack of shock yeah thank you so much for the question so i'll repeat it for our folks on the zoo webinar so the question was when you encounter individuals who are hesitant to get the mrna vaccines or even the johnson johnson vaccine because of the anaphylactic or allergic reactions that they're hearing about you know what advice can you offer them and um so what i'd like to share with you is um you know what what's thought to be the allergic uh component or the component that's stimulating the allergic reaction is the polyethylene glycol component in the in the lipid nanoparticle shell for the mrna vaccines and then it's polysorbate i believe in the johnson johnson vaccine and so these allergic reactions are extremely rare uh i think the it's about on average uh five cases of the allergic reactions per one million doses given so these are extremely rare allergies that uh that you know some folks have developed to that component and so what they what they'll do is and because of that they make everybody um even if you you don't know that you have an allergic um an allergy to one of these ingredients they'll make you wait you know 15 minutes 30 minutes if you report that you have allergies to a lot of things and they'll monitor you and everyone has epinephrine on hand and they can give you an injection if you do start to feel like you're having a reaction so they can treat it um and so it is i i really believe that these you know these messenger rna vaccines are some of the safest vaccines we've ever developed and for those those allergic reactions um are the or some of the more severe things that we're saying with the vaccines they're extremely extremely rare and folks with other allergies can get these vaccines no problem it's just a specific allergy to that ingredient you're welcome do you see increased reactions given they're not getting better yeah that's a great question thank you for asking so the question is how close are we to getting these adjuvants into clinical trials and do we see a more enhanced um sort of reactorgenicity or toxicity because they are stimulating multiple pathways and driving more more of a rigorous immune response and so uh i can tell you dmlt is the more advanced adjuvant it was developed by john clements at tulane and it is already in multiple clinical trials and you can you can pull up you know a number of papers on pubmed that report safety and efficacy of the mlt in human uh volunteers for a number of like diarrheal diseases for example um and so dmlt is definitely you know farther along what we're doing with the ml team is we're looking at its ability to really drive things to the mucosa so that we can partner it partner it with other vaccines and development to prevent diseases in the long run the gut or the reproductive tract and show that dmlt might be really good at helping enhance the protection there um for the outer membrane vesicles it's our younger um adjuvant in development it's um myself and dr mclaughlin have developed that and we've put it through um pretty much every model um you can think of other than humans so we've done monkeys we've done um wax worms which happen to be highly sensitive toxicity we've done human cells we've done mice and so um we have clinical trials for the buccal various pseudomalley i've actually hopefully planned phase one in like 2022. um and so the onlb adjuvants and the vaccine for meliodosis are getting manufactured as we speak and um and and the reason um i didn't mention it the reason you know you have to do safety trials with any vaccine is is you know the very thing that you said anytime you add a component to a vaccine you're going to change the way that the body recognizes it and reacts and so you have to do those safety trials and make sure it's not too reactogenic absolutely yes [Music] yeah i'm sorry i missed the word that you said did you say deaths okay so the question was um we're hearing reports that the coup and 19 vaccines are causing deaths um and so uh you know i think it's it's one of those things where you know nothing is scrutinized like a vaccine and so you're going to have people dying every day from natural causes or from you know chronic conditions or what have you right and so even if we weren't distributing the vaccines on such a large scale those those folks you know probably would have died right on that on any given day and so the fact that they got the vaccine the day before someone says ah they got the vaccine and you know they died from the vaccine and that's that's simply not true what what we know is that if the vaccines were causing death then the vaccinated population we would be seeing increased deaths in in the vaccinated population relative to the unvaccinated population and it's the opposite right the unvaccinated are dying and they're dying from cover 19 and the vaccinated are protected and yes you know people are going to just like you know anything you know you could go ride a bike one day and you know the next day you could die and it could be like oh they they died because they moved their bike yesterday no they it's not related right and so that's what's happening yeah yes yes sir do you have any group of patients that you say should not get vaccinated for example someone that has an immune system response difficulty and we have a family member who has nine decisions and she has a very severe case of it that's been going on and she's had relapses on it is she an example of someone that should or should not get the vaccine yes sir thank you for the question so the question was are there any groups of individuals that you would recommend don't get the vaccine and the example you used as a loved one who has lyme disease who as you know it could be you know any type of inflammation could trigger the chronic manifestations of wine and so it's anything that might trigger information could be dangerous in that situation so i do want to clarify i'm not a clinician i'm a phd so i'm a scientist and so i don't you know i can't give medical advice um but what i would what i would encourage your loved ones to do and i would encourage any of you to do is to you know to talk with your health care provider about you know about your condition before you get a vaccine um there could be a lot of things to talk about in terms of whether you may or may not um you know want to get the vaccine for example maybe maybe that individual has had other vaccines and has done fine with those vaccines in that case perhaps they could um but again you know i i don't want to give medical advice in anyone's especially when i'm not a physician and two you know the circumstances for any one person could be could be variable and so their doctors is who knows the best and can really advise them um you know in terms of the vaccines but what i can tell you is that you know really the only contraindication for the mrna vaccines that i'm aware of are is if you have an allergic reaction or you know you're allergic to polyethylene glycol you're welcome yes yes thank you for the question so the question was um so we're hearing a lot about booster doses and booster vaccines for coca-19 do we expect it to become sort of an annual thing um and so you know uh it's it's it's probably going to become somewhat common that that that we're dealing with you know this virus circulating for quite some time right so if you guys think about influenza that causes the flu every year you know influenza is an example of a virus that undergoes sometimes slight changes which are which is known as antigenic drift and then it can undergo dramatic changes that's known as antigenic shift and so small changes you know the vaccine from year to year does a pretty good job of protecting us because we can kind of gauge what's circulating in one part of the world and then we vaccinate the americans here based on what we observed and we can sometimes we miss and sometimes we get it right and that's why the flu vaccine efficacy means you know it sometimes it's really good and sometimes it's not so good and it's because the virus is mutating so we don't think slash kobe 2 is going to mutate as much as flu but we do see that it's mutating right that's what viruses do but it seems like that spike protein is limited in how much it can you take because you can imagine if it mutates too much it's not going to be able to bind east to and if it can't mine h2 it can't infect us so it's somewhat restricted in that sense so communicate a little so what we think is that these vaccines are going to be very good at still protecting us against this virus no matter what mutant throws at us fingers crossed and that over time you know the virus will as as more and more people not only here in the united of mellow states it will sort of find an equilibrium with us and we have we have common cold coronal viruses that circulate now none of us really think about them or pay much attention to them because they just cause a common cold and we're hoping eventually sars cody too will become just like these other common cold coronaviruses where it does nothing more than cause a common cold but until it gets there you know and we can't really we don't know if that'll be 10 years or 100 years it may be the next flu where we just have to deal with it every year we have a flu season we have to maybe boost our immune response with an annual booster just to keep us out of the hospital and we might get a mild illness but you know we won't have to worry about it killing us yeah thank you um so the question was you know if we're dealing with viruses like the flu virus and coronary viruses that are always mutating you know how how can we as researchers design vaccines to stay ahead of it and i think this is where these plug-and-play technologies are going to be really helpful because what we know about protection against flu is that it's usually antibodies to two components on the surface of the virus so we may be able to you know rapidly plug and play depending on what's circulating those two components of the mrna and get much more effective food vaccines than what we currently have because remember what we currently have is based on growing the virus by the time we grow it when it takes us a year it's changed and we can't rapidly switch um with the plug and play technologies we can and so even with these variants the you know the pharmaceutical companies you know pfizer violin tech and modern are already changing the messenger rna instructions to match the delta variant the problem is by the time they roll it out you know crew of ours is going to change to something else and we won't see the delta variant it'll be something else and and you know we may not need it so in other words for the coronavirus because the mutation is somewhat restricted it still seems like just boosting the response to the original is good enough to keep us out of the hospital against any variant frozen a great question oh thank you yeah do you recommend a certain vaccination okay so the question is do i recommend a certain carbon vaccine so my you know my answer has always been um you know get the vaccine that's available to you all three of the vaccines that are you know authorized here in the united states the pfizer the moderna the johnson and johnson they're all highly effective at preventing severe disease hospitalization and death there's some differences in breakthroughs there's some differences in um in you know those reported efficacy numbers from the clinical trials but the number that matters is that they're all keeping you from getting severe disease and so you know in terms of differences you know the modern and the physical mrna vaccines the johnson johnson is that agno virus vector the johnson and johnson's a single dose mrna are two doses so some of you may feel like i don't want to go back for a second though so go get the johnson johnson you won't have to um although we're all going to probably need booster doses at some point and so yeah i'm a fan honestly i'm a fan of the mrna technologies um it doesn't mean i don't think that johnson johnson is a great vaccine but i just think you know i love nanoparticles i work with them the vesicles are nanoparticles i just think they're really they're you know we've been working on for so long they're some of the safest and most effective vaccines we've ever produced so i'm a big fan okay so this is uh so do i see widespread adoption that messenger rna vaccines yeah yeah you know i do i think i think they can serve a real you know i don't think they're i don't think they're the answer for every disease right so there are organisms like some of these complicated intracellular bacterial infections like tuberculosis you know whether an mrna vaccine would ever prove efficacious for tuberculosis i'm not i'm not convinced of that but they're really good at what they were meant you know sort of what they were designed for and that's rapid response to something that is spreading by the respiratory route and is about to take out you know humankind and it's like what can we plug in very quickly and start making very quickly um i think they definitely serve have proved their worth in that capacity the question is how do we overcome ambulance and i i appreciate your question i do it's frustrating you know as a scientist but you know i think one of the things is as scientists we're trying to you know test test our hypothesis you know work in a lab keep our heads down do do our research and we're not taught to communicate our science as well and to be advocates for science and you know i really think all of us need to do a better job of that we we need to we need to educate folks we need to share what we know and we you know there are there are certain you know there are certain people that it doesn't matter what you tell them they're not they're not going to be swayed but there are people in the middle that we can reach that just have heard some things that scare them and they're just not too sure and if you just talk with them and share your knowledge with them and just have a conversation with them and say man i get why you're scared that sounds scary to me too but let me let me tell you what i know and what i heard and maybe you know maybe you can research it and you'll find most of these myths you can easily just google it and you know 10 sources of debunking the myth come up um but people get really frightened very easily and so yeah those are the people we hope to reach yeah you know i think we were really oh so the question was you know how long really does the memory response b and t cells um you know last to the covered vaccines and you know i think what we've always appreciated is that live vaccines so yellow fever smallpox you know a single dose can give lifelong protection um but it also has to do with you know what are you trying to protect against and how quickly does the pathogen replicate right so in the case of smallpo

2021-10-07 21:44

Other news