Lecture 10: "Vaccines"

hello i'm richard young your host with fakunda batista and lena feyen for mit's course on covid19 sars kobe 2 and the pandemic yesterday pfizer announced that its rna vaccine against covet 19 is highly efficacious exceeding expectations and providing hope that the pandemic will come to an end in the foreseeable future today we have the pleasure of hearing from dr kazmakia corbett who's a research fellow and the scientific lead for the coronavirus vaccines and immunopathogenesis team at the national institutes of health vaccine research center and who has been working on a very similar rna vaccine against coven 19. this class of vaccines is new and exciting they can be developed quickly and bode well for our response to future pandemics dr corbett is a viral immunologist and obtained her phd in microbiology and immunology at the university of north carolina at chapel hill in 2014. she then joined the nih's vaccine research center and worked on development of a universal influenza vaccine which will soon be in clinical trials dr corbett's work now focuses on developing vaccines against the coronaviruses this includes mrna 1273 developed in a partnership between nih and the biotechnology company moderna this vaccine is currently in a phase three trial the final phase to determine its efficacy against coven 19. dr corbett thank you so much for joining us today absolutely um thank you for the kind invitation um i am very happy to be um sharing some of this work particularly as you said with the news that came out yesterday around pfizer's mrna vaccine candidate so i um i i generally give very very specific talks around our particular vaccine candidate that we're co-developing with madonna mrna 1273 but i wanted to start um this talk um because it is um to a more broad audience with just a clipping that i got from um from youtube around how vaccine development works and how the vaccine development process for cobit 19 has been so rapid vaccine development can generally be split into three phases in exploratory research scientists experiment with different approaches to find safe and replicable vaccine designs once these are vetted in the lab they enter clinical testing where vaccines are evaluated for safety efficacy and side effects across a variety of populations finally there's manufacturing where vaccines are produced and distributed for public use under regular circumstances this process takes an average of 15 to 20 years but during a pandemic researchers employ numerous strategies to move through each stage as quickly as possible exploratory research is perhaps the most flexible the goal of this stage is to find a safe way to introduce our immune system to the virus or bacteria this gives our body the information it needs to create antibodies capable of fighting a real infection so the best way to speed things up is for many labs to work on different models simultaneously this race to the finish strategy produced the first testable zika vaccine in seven months and the first testable code 19 vaccine in just 42 days being testable doesn't mean these vaccines will be successful but models that are deemed safe and easily replicable can move into clinical testing while other labs continue exploring alternatives whether a testable vaccine is produced in four months or four years the next stage is often the longest and most unpredictable stage of development clinical testing consists of three phases each containing multiple trials after a successful phase iii trial a national regulatory authority reviews the results and approves safe vaccines for manufacturing every vaccine has a unique blend of biological and chemical components that require a specialized pipeline to produce to start production as soon as the vaccine is approved manufacturing plans must be designed in parallel to research and testing this requires constant coordination between labs and manufacturers as well as the resources to adapt to sudden changes in vaccine design our best strategy is for labs around the world to cooperate and work in parallel on different approaches by sharing knowledge and resources scientists can divide and conquer any pathogen vaccine to them so as that video stated this entire vaccine effort around coronaviruses has been a really conservative effort with multiple labs across the country um the field is wide open and um there are three basic levels of vaccine development largely the pre-clinical testing phase and then the clinical testing phase and then the manufacturing phase so i'm going to talk a lot today about the pre-clinical testing phase that has driven this rapid vaccine response across the field so by way of introduction to coronaviruses which if you are attending this meeting on a regular basis you probably felt fairly well understand that coronaviruses are a large family of viruses that have pandemic potential and so what does that mean it means that these viruses that generally dwell in animal reservoir just like about 23 other viral families have the potential to jump from their animal reservoirs into humans so this has been happened happening with coronaviruses um it started with the sars epidemic over 10 years ago that tallied over 8 000 cases worldwide and then the mars epidemic that started in 2013 that has since tallied over 2 000 cases worldwide so history does repeat itself but also science generally should guide us and with that our close collaborator ralph barracks laboratory um published a series of papers stating that sars like viruses like we have now in this pandemic soros cov2 are poised for human emergence and so we knew that these viruses were poised for human emergence and the universe has now responded with a big ol itolia cell the 2019 human emergence of sars kobe 2 has now turned into a global pandemic that as of about two nights ago when i made these slides had tallied over 50 million cases worldwide so here we are in a global pandemic that could really only be subsided with some level of high-level herd or community immunity as you may very well know in the united states we have now hit our third wave of coronavirus um covet 19 cases this red blip here on the far right of this graph starting in around mid-september shows the case is starting to increase and if we think about what is called herd immunity or population immunity we need about 60 or 70 percent of that in um so that we can return back to normal activity it is notable that even at a one percent case fatality rate over 40 million people would succumb to cobit 19 globally shall we let the virus continue and thus a vaccine is needed to prevent the dynamics of the global pandemic and so what would a vaccine do well firstly um on a um on the individual level a vaccine could reduce the severity of cobit 19 illness and ideally prevent infection from a community standpoint vaccines have the ability to reduce transmission and thus make it safer to resume our normal activities what does it mean to have from a community standpoint and what is population immunity well if you take this graphic of these stick figures that are aptly colored um in a non-immune population where all of the people are blue um if a virus is put in is set free into that population there will be high levels of transmission where people in red will get infected and some may even succumb to the viral infection in an immune population however where some of the people are green you can see that the green people have do not have the ability to get infected with the coronavirus because they are immune and what's interesting about this scenario also is that the red people that were not immune are somewhat protected because of their distance from um between each other and so there's this level of about 70 of that type of green immunity that is needed to really allow for us to get back to our normal activity and so how do you really want to elicit herd immunity the way that you probably most likely hear about it and the way that it got sort of a a bad name is via media where they were describing herd immunity being induced by infection as i said the outcomes of herd immunity being introduced by infection could potentially increase disease severity and the amount of transmission obviously and also there are variable antibody responses that people acquire following a natural infection with sars kobe 2. and so we don't really understand really how viral infection might elicit immunity there's also vaccination so i have here um different types of vaccine platforms whether it be introducing the body to a protein or introducing the body to a virus like particle or nanoparticle or even gene based delivery which i will get into some detail today because that is the strategy for which we are using with with our collaborators at moderna nevertheless no matter how you elicit or give a vaccine to people in a population this is called rationally designed vaccines and so it's rationally designed because you are giving a um a substance to a person and that person will elicit a immune response to that particular protein or vlp or what have you and that immune response will then prevent infection or disease later antibody responses can also be given directly so you've probably heard about plasma therapy that is um in in phase three clinical trial right now as well but um the daughter so to speak of plasma therapy are monoclonal antibodies that i won't talk to you today um to you about today but the beauty of monoclonal antibodies is that they can be used also um prophylactically or therapeutically um and and the immune responses are are being tested for several monoclonal antibodies as uh right now in phase three clinical trial and so we know that we want to most effectively elicit population immunity by vaccine and um this was reasonably stated in this particular to find treatments for the sick and the vaccine to protect the healthy this ends with most or all of us being immune to this virus and ideally that's through a vaccine can solutions that usually take years we are trying to move as fast as we possibly can we found in a matter of months it is an extremely revolutionary approach to get into a phase one clinical trial 66 days after the sequence of a virus is released is a world record and so how did we get to a so-called world record the way that we were able to use sardis cov2 vaccine development as a proof of concept around rapid vaccine development was by using what we call pandemic preparedness the approach that we took particularly in our laboratory was the prototype pathogen approach that states that one might do research on a known virus within a given virus family in the case of the coronavirus family we chose the mers coronavirus to use as our prototype pathogen generate enough knowledge around that particular virus so that it could be applied widely to that viral family and then ideally for a pandemic response you would want to develop that counter to measure or vaccine through a phase one clinical trial and while we did not do that in this particular case with mers we did have enough generalizable knowledge around mers coronavirus vaccine development that allowed us to move fairly quickly in this vaccine response that benefited the entire um rapid development of multiple vaccines so as we think about new technologies for transforming vaccinology we like to think about them in kind of two different bubbles the first of those is precision so this is utilizing uh technologies structure based vaccine design mapping vaccine responses and immune responses whether they be in um in the pre-clinical setting in animal models or in humans defining antibody lineages all of these things that really inform how to best make the vaccine antigen or the piece of the virus that you want to deliver to a person to elicit a vaccine response and then their speed speed is obviously important because we are witnessing that right now where you do need to be able to monopolize on a vaccine platform that has the ability to be manufactured fairly rapidly and generally speaking those types of platforms are tending mrna type platforms or dna type platforms or tending to transform vaccinology in that way and so in our vaccine preparedness for the pandemic threat of coronaviruses it was obvious that we needed a fast as i discussed vaccine technology to be able to be produced in vast quantities quickly reliable a vaccine technology that must be tested and uphold some level of manufacturability standard and then italicize universal if you came on this call prior to prior to the class the course starting you note that um i was asked about universal influenza vaccines for which i um have some history in in understanding and developing those as well so the way that we think about universal as yet for coronaviruses is italicized because it is not necessarily how we think about universal influenza vaccines but what i hope to show you today is that the idea around universal is more so around a plug-and-play method that might be preemptive that will allow you to move quickly um into human face clinical trial and so how do what how do we do this and what was our timeline for development and i'm particularly going to talk about the candidate mrna 1273 that our laboratory is developing in collaboration with moderna but there are several candidates that have taken a fairly similar rapid timeline to vaccine development as you are very well aware the first a report of a respiratory virus outbreak in wuhan china occurred in the latter parts of 2019. by january to 10th these sequences for what was then called 2019 in coronavirus were published online and then only 66 days later a phase one clinical trial with mrna 1273 modernis kobe 2 um vaccine candidate um um what happened in what is so called a world record to enter a phase one clinical trial and how do we do that because we really really really really spent time on the pre-clinical development of this vaccine in the anticipation of the pandemic thinking about a prototype pathogen approach using mers coronavirus and other coronaviruses and so the pandemic the prototype pathogen approach that we use utilized the vaccine target which is the coronavirus spike protein so on the left hand side of your screen you see a coronavirus that has this spike protein that is this trimeric protein that sits on the surface of coronaviruses on the right hand side of this of your screen you see a human cell that has a human cell receptor in the case of stars cov2 that cell receptor is called the ac2 cell receptor binding of the spike protein to the human cell receptor occurs via a receptor binding domain that i've highlighted here that receptor binding domain is housed in this head of the spike protein that is called the s1 region and then below that in the stock or the s2 region is where the fusion machinery lies so that is a very important point these spike proteins are called fusion proteins because their entire purpose is to allow for attachment to the human human cell but then also allow for the virus and the cell to fuse together and so that infection and replication can occur fusion proteins such as the coronavirus protein have been used um as vaccine antigens before and a proof of concept around stabilizing these proteins and what's considered to be a prefusion conformation to improve a vaccine potency came via the respiratory synthesial virus f protein so if you draw your attention to the right hand panel of this slide where you see two respiratory institutional virus f proteins one of which is elongated and called the post fusion conformation the second of which is more squatted and called the pre-fusion conformation looking at the red surfaces on these proteins these surfaces are where the neutralization sensitive epitopes lie for lay terms those are the surfaces that you want to present to the body and make sure that the body sees them so that the body makes really robust antibody responses so if you present this post fusion protein and its post fusion conformation those red surfaces are hidden and occluded and so the body cannot see them whereas the prefusion protein has those red surfaces displayed um via like show and tell to the body and this therefore when you give a vaccine in the prefugine conformation you can elicit more robust neutralizing antibody responses so we wanted to do the similar kind of thing with coronavirus spike proteins at the time when i came into the vaccine research center there were no coronavirus spike structures that had been solved and so we didn't really have intel on um the types of detail that uh or an um immunogenicity that a spike protein might be able to elicit because we didn't know what it looked like and therefore in collaboration with andrew ward's laboratory and jason mcclellan's laboratory we solved the first prefusion structure of human coronavirus hku1 spike protein at the same time the visor laboratory solved the structure of the mhv coronavirus spike protein and then there was this real onslaught of literature um where different laboratories were describing various coronavirus spike proteins and really trying to lay out the architecture of these spike proteins around um um the time of 2017 george gal's laboratory published cryo-em structures for mers and coronavirus stars spike mers sorry insarus coronavirus fight proteins we also at the same time published the spike protein structures for mars coronavirus and hidden in that paper also some sars and hku1 as well but you'll note that in our paper we described the immunogenicity along with the structures of those spike proteins and termed the spike proteins not just some spike proteins but rationally designed pre-fusion spike antigens because we were really interested in the utility of these um spike proteins as vaccine antigens and so how do you rationally design a spike protein and lock it in its prefusion conformation the first clue is to hone in on the part of the spike sequence that um uh is where the fusion peptide lays so this blue fp is the fusion peptide that region of the spike protein is called the s is within the s2 region and you can see that these coils look like the toys that you used to play with as a kid that spring up and down and so to lock it down um and without allowing that coil to spring on top of each other we needed to insert mutations into the backbone of the spike protein um in collaboration with jason mcclellan's laboratory namely with ninjong wong who's no longer in that laboratory but did a lot of this work we scan the spike protein for mutations that might be able to stabilize it in its prefusion conformation stumbling upon and i say that very loosely because it was several years of work uh two proline mutations that effectively locked the protein into its prefusion conformation and how do we know that that was happening well firstly um the s2p so-called expressed 50 fold greater than the mers of s wild type and also when you look at these proteins under a microscope what you see is that the s2p version is in its prefusion mushroom shape beautiful homogeneous while the s wild type version of the protein readily flips into its post-fusion conformation and um these two prolimitations have the ability to be transplanted into the backbone of other stars of our other coronaviruses as well inclusive of hku1 and also sars1 and several other ones but most importantly is that we were able to effectively stabilize the potentially emerging wiv1 sars coronavirus spike protein and its pu frisian conformation with those two p mutations and so by way of prototype pathogen design um or the prototype pathogen approach we would wanted to test the immunogenicity or how well does do these proteins elicit immune responses starting in a small animal model here we use the balp c mouse where we immunize at week 0 and week 3 and simply took a bleed um two weeks after that immunization comparing various different constructs the first is the golden child the mers s2p construct in its pre-fusion confirmation and then the mars s wild type which readily flips into its post-fusion conformation and then a mers s1 monomer and without belaboring the point the point of one of the reasons why we use that is because in previous approaches from our center the s1 monomer elicit very robust neutralizing antibody responses and so we wanted to really set that standard bar around eliciting antibody responses and so in testing those vaccine candidates in mice what we show is that in a dose-bearing way mars s2p elicit more robust autologous neutralization or neutralization against a virus that is for the same strain for which the spike protein was taken but it wasn't just for autologous neutralization it was also for homologous neutralization against multiple mers coronavirus strains and so now we had this s2p protein that elicited very robust neutralizing antibody responses but in the case of a pandemic developing a protein would take some time because of just the way that these proteins have to be manufactured and so we needed to use a vaccine platform that had the ability to be fast produced quickly in vast quantities was reliable so at least tested in humans um through phase one clinical trial and also italicized universal in that you could plug and play the type of therapeutic protein that you wanted into the system and really pull the trigger on manufacturing and so we did that we in collaboration with moderna which is a pharmaceutical company that uses messenger rna to deliver drugs inserted the mers s2p are again from our prototype pathogen into the backbone of their messenger rna vaccine platform which consists of purified messenger rna for the spike protein that is encapsulated in a lipid nanoparticle that lipid nanoparticle is then delivered into a muscle cell and the muscle cell reads that mrna and then essentially spits out spike proteins and the body produces an immune response to it to test this as a proof of concept um with mers s2p we delivered that protein via mrna in in the in an animal model in a mouse model that had a human dpp4 receptor so this mouse had the ability to succumb to a lethal dose of mers following challenge you can see that in the animals that were given pbs only that they um succeeded days following the challenge however animals that were given 1 or 0.1 microgram of mers s2p mrna survived that challenge and even at a very low dose of 0.01 microgram per mouse while the animal some animals did lose weight the animals did start to recover and did not fully succumb to the infection and um not only was it via weight loss that we saw this protection but also via the amount of virus that was replicating in the lung taking those lungs and looking at the amount of virus inside of them we showed complete protection at the modest 1 and 0.1 micrograms of mars s2p mrna also looking at uh a disease score called lung hemorrhage so this is just how much hemorrhage is inside of the lung whereas four is a score with a lot of hemorrhage and zero is no hemorrhage at all there was no hemorrhage at all in the lungs of the animals that were immunized with 1 or 0.1 micrograms of mers s2p mrna so what this showed us is that by proof of concept that mars s2p mrna could elicit dose dependent protection against lethal mars challenge and what's called 288 330 mice or mice that have the human dpp-4 receptor and so we were very confident in our ability to deliver spike proteins particularly the s2p protein via mrna and thus once the sequences for um sars kovi 2 came out on january 10th in collaboration with moderna we were able to rapidly in three days decide on a sequence for a mrna 1273 the mrna 1273 encompasses the sars cov2 spike protein anchored by its transmembrane region so that this each cell the cells have present the spike protein on the surface and um and also we were able to show in collaboration with jason mcclellan using those two proline mutations that we could effectively stabilize a secreted version of the spike protein which led to the structure of the sars cov2 spike being published in 37 days i want to just take a step back from the vaccine response to really just really hone in on all of that what i've said about the protein particularly because it's not just for vaccines that these high quality stabilized proteins are beneficial i'm telling the story about a particular vaccine candidate being developed by moderna but then there's also the use of this particular protein with those proline mutations to isolate antibodies with our between our laboratory and a small biotech company in canada called accelera where this this particular very potent neutralizing antibody um is being developed um by um eli lilly and it was shown yesterday um that it it was being used it can be used by emergency use authorization by the fda it was the first antibody to enter into phase one clinical trial in the united states also all across the globe um i don't have a very recent count but there were hundreds of diagnostic tests being developed with this particular sars cov2 s2p protein and it is of important note that five out of the six leading vaccine candidates that are currently in the pipeline also use the s2p mutation to stabilize their vaccine antigen despite whatever the backbone of their platform is including the pfizer bioin-tech vaccine as well and so um when we decided on the mrna 1273 sequence it was also only 37 days that we were able to confirm that the vaccine was eliciting animal response immune responses in uh in mice and the way that we confirmed that is by immediately when we decided on the sequence we and got the vaccine for modarna we immunized three different strains of mice given the standard two-dose vaccine regimen and testing the immune responses but both after the first dose and also the second dose the gist of these grafts is that you elicit a potent antibody response following one dose that is boosted following a second dose and it wasn't just that the antibodies bind to the spite protein but also and particularly at the one microgram which is a very modest dose elicit we elicit neutralizing antibody responses but that's after two doses what happens after one dose after one dose you can see following two weeks and then four weeks following one dose that 10 micrograms and one micrograms a list is about a 10 to the three ic50 neutralizing antibody titer so we're giving these fairly modest doses of mrna 1273 and we're eliciting neutralizing antibody responses that are um are that are robust and based on what we understood about mers should be protective therefore we wanted to test whether or not there was um this vaccine was effective at protecting against soros cov2 in a mouse model so again in collaboration with ralph barracks laboratory at the university of north carolina we use their mouse adapted strain of sars kobe 2. so this is a virus that they um tweet in the receptor binding domain so that it binds to um a mouse h2 receptor and then upon binding to the h2 receptor in a mouse has the ability to replicate in the lung and also in the nose so we tested for whether or not our vaccine mrna 1273 could decrease replication in both the lung and the nose and as you can see at one micrograms we do not see any viral replication inside of the nose i mean sorry inside of the lung and then in a dose um bearing way you see that there is viral replication and breakthrough starting at the 0.1 microgram dose also in the nasal turbinates three out of four of the animals that were harvested at this time point did not show any viral replication in the nose but that's after two doses and what about after one so seven weeks following one dose of mrna 1273 we were able to show that mrna 1273 protected after a 10 microgram dose or a one microgram dose in the lung with that being said that was very interesting data particularly as you think about the utility of vaccines in an outbreak setting so we moved our vaccine test up into a higher order animal where we now are testing in rhesus macaques giving um the zero and four week immunization and then testing whether or not there's protection following challenge with about 10 to the sixth pfu of soros cov2 four weeks following the second dose what you'll see in the slides following are two doses of mrna 1273 the first of which is a 100 microgram dose that is quote unquote clinically relevant and the dose that was moved forward into phase 3 clinical trial and then 10 fold less at a 10 microgram dose we looked at antibody and t cell responses and protection in the upper and lower airway i don't want to belabor the antibody responses or the temporal antibody responses here i want to really point towards the neutralizing antibody responses where obviously before vaccination we do not have any antibodies to sars kobe 2. following one vaccination you see this boost in antibody response that holds still until the four weeks following the first vaccination then with a boost of mrna 1273 there's an increase in the neutralizing antibody response where we get about a 10 to the three 10 to the fourth neutralizing antibody response that holds steady at least through four weeks following the second vaccination taking this time point i want to show you some data from a couple of functional assays so this is the ace2 binding inhibition at week four following the second vaccination where we are really just testing the amount of antibody that has the ability to block acetyl binding from the receptor binding domain there are several points to take away from these this graph the first of which is that we test it against a large panel of serum that's collected from people that are naturally infected and we're able to show that we elicit antibody responses that are above that of people that have been naturally infected and recovered from covid19 disease and this is a wide range of disease severe infections etc um it was very interesting to note that even with these uh what we thought would be a subprotective dose but 10 microgram dose of mrna 1273 we were still eliciting a fairly robust ac2 binding specific inhibition antibody response and we looked at our live virus neutralizing antibody titers because what i've shown you previously have been pseudovirus responses and the gold standard in the field is to really look at a live virus neutralizing antibodies to detect how a vaccine response might impede not just viral injury and attachment but also replication and so in this particular assay which is a nanoleuk assay developed by ralph barracks laboratory you can see that there's whopping 10 to the three live virus neutralizing antibody titers that far exceed that of convalescent serum as you can tell here there's about one third of people that actually fall out of having neutralizing antibiotic responses following natural infection so to see 100 of the animals um being above that was very exciting to us we also looked at t cell responses mostly because t cell responses can be correlated with safety signals particularly for respiratory virus of vaccines some data that have from previous vaccines um show that if you elicit a response that is more skewed towards th1 versus th2 you have less you're less likely to elicit a vaccine-induced enhancement response not to belabor the t cell responses at all but only to show that seven out of seven of the animals that got the 100 microgram dose of mrna 1273 do have a th1 cd4 response whereas only two of them have a ch2 response and as you can see it's really abysmal and and very low level um thd response so we do have this skewed towards th1 as we would we would like we're also eliciting th cells in these animals which is in line with what you would say about um and what you would expect sorry and regarding what we know about our antibody responses looking at the ability of the virus to replicate in these animals that have been vaccinated both in the lower airway and the upper airway the assay that we're doing here is subgenomic rna assay that um really detects nascent viral replication and you can see that in the lower airway 100 micrograms or even 10 micrograms is very well protective against rapid clearance of viral replication and then also what was very very very cool for us to see particularly at this time where no other vaccine in the literature had shown um robust protection in the in the in the upper airway via nasal swab we were able to show with the 100 microgram dose of mrna 1273 that by day two all of the animals um had cleared the virus from the nose and so what that signified to us is that not only does this vaccine have implications around protection of disease but there might be some implications around transmission as well and so on the other side of the spectrum so um there's the preclinical side of things and then there's also the clinical side of things in the general vaccine development process there would be some stepwise order to that but in this vaccine process because there needed to be a rapid fact vaccine developed very rapidly things were happening synonymously and almost at risk so at the same time that we decided on the sequences for mrna 1273 modern pulled the trigger on gmp production or production of of clinical grade vaccine so that we were able to go into phase one clinical trial very quickly even without having seen any of the animal responses now obviously the fda one wants to see the animal responses but we were not willing to wait that month before getting that data in order to start manufacturing with that modern was able to ship the clinical drug product 41 days after they started their production and then the phase one clinical trial started soon after i am going to summarize just very briefly for you um because i'm running out of time um the phase one clinical trials and then some of the vaccine landscape just in general for coronavirus so there were two phase one clinical trials for mrna 1273 the first of which um that one that started in seattle in 66 days was um with people aged 18 to 55 looking at three different doses of mrna 1273 and then in the second trial there was an addition of people who were over the age of 56 looking at 25 and 100 micrograms of mrna 1273 these volunteers got two doses of mrna 1273 and they will be followed for a year but the data that i'm going to show you today is going to be for antibody responses that are out to 57 days within the trial so these are just some of the prelim data from the preliminary reports so we are eliciting very robust s-specific antibody responses as you can see after the first dose and then um a boost of about a log of the ic of the endpoint titer for s-specific antibodies after a second dose those antibodies are notably not waning through day 57 and also notably in the upper quartile of what you see from a huma inhuman convalescent serum looking at the neutralizing antibody responses via our standard pseudovirus neutralization assay there are a couple of things that are of note the first of which is that you don't get 100 of of of vaccine neutralizing antibody responses until after a second dose um particularly in this and and even in the 100 microgram group but after a second dose of mrna 1273 you get neutralizing antibody responses that are also in the upper quartile of what you see for human convalescent sierra and while those were the younger adults that were enrolled in the first um clinical trial comparing their antibiotic their neutralizing antibody responses to people that are from age 56 to 70 and greater than 71 you can see that um the older adults elicit just as robust neutralizing antibody responses as younger adults which has some promise because as you think about vaccines they might not generally speaking vaccines may not have the same type of immune response in older people and the immune response sometimes is dampened in older populations and so in conclusion we were able to rapidly develop a vaccine using two proline mutations um to stabilize the uh spike protein in its pre-fusion conformation and a large body of work around a prototype pathogen mers coronavirus was able to inform how we moved forward with this vaccine candidate and delivering it by um messenger rna in collaboration with moderna and the vaccine candidate elicits um high is highly immunogenic and protective in animal models and also elicits robust immune responses in humans and um as of today the vaccine candidate is in phase three clinical trial that has completely enrolled 30 000 people now to give you just a slight and brief overview of the sars kobe 2 vaccine pipeline across the globe there are over um 200 vaccines that are at least in pre-clinical testing but i will focus on the vaccines that are in in human trial so there are 36 vaccines that are in phase one clinical trials so this is just to say assess safety and dosage expanded phase two clinical trials where additional safety analyses occur and um you try to pinpoint your dose for your vaccine there are 14 vaccines are in phase 2 clinical trial and then there are 11 vaccines that are in phase 3 clinical trial and these are the large-scale vaccine trials that assess efficacy and there are six vaccines from around the world not in the united states though that are approved for earlier limited use and no vaccine to date has been approved for full use focusing in on those vaccines particularly those um that are in a phase 3 clinical trial in the united states there's the moderna candidate which i told you about throughout this presentation then there's the pfizer bioin tech candidate which is very similar to the modern candidate in that it is a pre-fusion stabilized spike that is being delivered by mrna and lipid nanoparticle they are planning to enroll forty thousand um people um in the us and brazil and have recently expanded their um their trial to children as well there's the jansen and johnson and johnson vaccine that also uses the pre-fusion stabilized s2p spike they use a adeno 26 vector to deliver this vaccine and one of the really cool things about their phase three clinical trial is that they are testing a one-dose regimen as opposed to two dose resins like the other vaccine candidates astrazeneca is not using the pre-fusion stabilized spike but is delivering the full spike via their chad vector or chimpanzee adeno virus vector with about 40 000 participants in the united states and other large-scale trials across other countries and then lastly but certainly not least is novavax that is using pre-fusion stabilized spike nanoparticle in combination with their adjuvant matrix m with over 15 000 people already enrolled in the uk and their u.s phase 3 trial to begin soon all of the data that i show to you today is synonymous across most of these vaccines and that many of them are eliciting high level efficacy in small animal models and non-human primates eliciting robust neutralizing antibody responses and the front runners are expected to have full efficacy results soon and as as you may have heard on the news yesterday pfizer biontech's pre-fusion spike being delivered by mrna has shown to be um preliminarily 90 efficacious in their interim analysis of their phase 3 clinical trial and so what does that exactly mean these trials are randomized placebo-controlled phase 3 clinical trial there is a vaccine group then there's a placebo group and the volunteers know anyone associated with a trial know whether you are in the vaccine group or the placebo group the volunteers are closely monitored as they go about their normal daily lives and then as covid cases are diagnosed by the trial physicians they're tallied and the way that you get vaccine efficacy is that you tally more covid cases in the placebo group than the vaccine group so if you take the pfizer bioin tech example they get about 90 percent reduction in covid cases or disease in comparison the vaccine group in comparison to the placebo group here is just a slide that i i want to acknowledge everyone on the team at the vaccine research center who's been working with me for several years um the cobit 19 response out of the vrc has been a vrc wide effort um i'm probably leaving off names but um all of these people on this slide have been extremely helpful in in various ways um with deploying these this modern vaccine candidate and then with other efforts from the vrc we've collaborated very heavily with many laboratories across the united states ut austin and scripps must be named because they started with us with some of our structure studies that led to all of this work and also moderna which is manufacturing mrna 1273 and the advancement of vaccines has been overall and across the world a most like multi-institutional effort and so here's a couple of logos from various partners whether it be from pharma or non-profit institutions that are driving forward with driving these vaccine efforts for and with that i will take some questions gizmekia thank you so much it's such a timely presentation uh as you pointed out with yesterday's announcement of an interim analysis that uh appeared to give 90 advocacy why was the expectation for vaccine efficacy against this novel coronavirus so low well [Laughter] i think that so i'm i'm assuming that you're reading that people expected like a 70 or right because this is this is literally a first generation vaccine i remember like back in the day when i was younger and i saw the gardasil or hpv vaccine results and i was just like there's no way a vaccine could ever be that effective um so you know 70 and 80 percent what people expected is actually okay and what you would expect from a first generation vaccine that has you know only been in trial for a year um and we didn't really know what to expect because we don't have the knowledge around correlates of protection and all of these things so i think that as we stated uh our expectations we were being fairly modest um and also these mrna candidates in particular have have not gone into phase or clinical trials enough to us to know how they might work but i'm i mean i cried when i saw 90 so i'm extremely thrilled about what it means around the entire vaccine portfolio and essentially i think probably the take-home message is that if you're listening really robust antibody responses that you are probably going to have a good efficacy for these vaccines one of the students wants to know um why we test so many different doses of vaccines why do we explore the lower doses so extensively why don't you just go to a very high dose right away so that is such a layered question um i like to think of myself an act as an academic so i'll start on that side so from an academic standpoint testing very low doses allows you to assess breakthrough so blowing out the response can actually give you a false false hope around the vaccine but when you go down in your doses and you start to see for example at that point zero one microgram dose where we saw breakthrough but the mice didn't die and they still recovered that's actually very gratifying as you are in the pre-clinical stages because what that tells you is that um you have a very um efficacious vaccine and that you're not eliciting any bad responses by by having sub protection which sub protection might come up later in you know nature or what have you and then from a manufacturability and more on the pharmacies you want to test a lot of doses and pair your dosing down because if you can give 50 micrograms instead of 100 micrograms you can vaccinate double the amount of people across the world or 30 micrograms as i believe pfizer is doing as opposed to 100 of moderna the vaccine responses will be about the same right because there's this plateau but you'll be able to vaccinate three times as more people and so there is also the business aspect to it you pointed out their tremendous advantage to developing multiple vaccines simultaneously but in the future should the mrna vaccines prove to be safe do you see them as uh basically taking over in the way we develop vaccines against pathogens in the future i think that it is going to be hard [Laughter] shall the mrna vaccines prove to be eventually completely effective after the phase threes and when we look at durability with the timeline that these companies have been able to develop these vaccines in a pandemic response i think that it's going to be very difficult to convince people to develop other types of vaccines but other types of vaccines in the interim come in handy because mrna vaccines have to be stored at -80 so getting them to develop work to the developed world is going to be difficult um you probably won't be able to use mrna vaccines and maybe in certain types of populations where other vaccines might be able to use so there are still holes and technologies you know will continuously get better i just don't know how you're going to get better at least as far as i can tell um i think that what will happen with the other platforms is they will start to fill in some of the gaps and there will be instances where t cell responses for example cd8 t cell responses are more important for protection for different viruses and in that case an ad vector might be better you you made an elegant case for knowing a lot about the structure of a protein before you decide exactly what to put into a vaccine of this type do you see in the future uh adding additional components of this coronavirus to optimize its efficacy um probably not for optimizing its efficacy um but what i do see is optimizing its other things like its breath for example um so you know the n a um or they're sorry not the n i'm not i'm not in flu world i'm in coronavirus world um the end protein is uh is uh is more conserved across the coronavirus family than spike protein you might not get neutralizing antibody responses but as we learn more about the types of responses that might be brought i can um i think that people probably will monopolize on on using different types of proteins and there's some curiosity about the steps that the fda is making or that companies are making or the government to ensure that people of different ages races etc are all being tested in these trials i can't speak for the regulatory agency i am not an employee of the fda i am an employee of the national institutes of health and a close collaborator with one pharmaceutical company modern so i can speak from our perspective um we were very very very very keen on making sure that there was ethnic diversity in the phase three clinical trial actually it slowed up our phase three clinical trial because the ceo of moderna made a statement that we would not enroll essentially what are white men anymore and start enrolling more people from latino or african-american backgrounds etc and so um in the phase one clinical trial we had about four percent minority or something around that way and then eventually in the phase three clinical trial we have like over 30 percent 10 of which is african-american so the phase three clinical trial demographics mirror what you'd see in the u.s population which is what you want for a vaccine trial and i'm very happy with the results of that type of enrollment i do know that um i'm not sure how that affects regulation around who can get the vaccine i think probably the fda has to figure that out but to have that type of broad enrollment in your phase three and to be able to say that your safety and efficacy signals are generalizable across populations is a big deal well with that i want to thank you it does seem like there's a light at the end of the tunnel and we so appreciate you educating us on this vaccine and your work in it thanks so much because kazmakia thanks a lot for having me um this was fun i never really get to talk abroad so it's very fun to be here bye everybody

Channel: MIT Department of Biology

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Keywords: MIT, Massachusetts Institute of Technology, Biology, Science, Research, STEM, University, SARS-CoV-2, COVID, COVID-19, pandemic, coronavirus, virus

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Length: 56min 0sec (3360 seconds)

Published: Sat Nov 14 2020