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MMRF » 2018 Vaccine Development Conference #03: The Rules of Immunity [2018-06-27. Tobias R. Kollmann. HVP/USC]

2018 Vaccine Development Conference Session #03: The Rules of Immunity [2018-06-27. Tobias R. Kollmann, Marie-Paule Kieny. HVP/USC]

2018 Vaccine Development Conference – Session #03: The Rules of Immunity — Tobias R. Kollmann, Marie-Paule Kieny.

Context

Organized in conjunction with the Human Vaccines Project, the 1st Annual Conference on the Future of Vaccine Development was a one day event which took place at the USC Michelson for Convergent Bioscience on June 27, 2018.

By bringing together some of the world’s leading scientists in the fields of immunology, genomics, bioinformatics, and bioengineering, the Future of Vaccine Development annual conference aims to explore how the convergence of new technologies across disciplines is impacting the future of vaccine development. The conference will also honor the three inaugural winners of the Michelson Prizes for Human Immunology and Vaccine Research, both via their respective presentations and the remittance of their prizes during the Awards dinner ceremony following the conference itself.

Transcript

    Participants:
  • Tobias R. Kollmann, MD, Phd, Professor of Pediatrics; Head, Division of Infectious Disease. University of British Columbia, Vancouver, CA.
  • Marie-Paule Kieny, PhD, Director of Research @ Inserm (Institut national de la santé et de la recherche médicale), former Assistant Director-General for Health Systems and Innovation at the World Health Organization (WHO).

Marie-Paule Kieny: So let’s go to the next, the second talk from Tobias Kollmann. So Doctor Kollmann is an investigator at the British Columbia Children’s Hospital. And he’s currently division head of the Pediatric Infectious Disease in Vancouver. His expertise centers around newborn infectious diseases, immune ontogeny and early life vaccine responses employing cutting edge technology, like systems biology, to extract the most information out of the typically small biological samples obtainable in early life. So as you know, you have 20 minutes.

Tobias Kollmann: Thank you, and I was under that I would be reminded when the 20 minutes are up. All right, and how do I move this thing forward? The green thing in the middle, okay. I don’t have to explain this to you in this room that vaccines work, and this is just showing three vaccines that we typically give to children, the haemophilus influenzae, pneumococcal, and rotavirus vaccines.

On the left side you see the numbers of lives – of cases prevented on the right side. On the left column you see the number of lives saved just these three vaccines. To the right you see the amount of money that’s estimated to be saved, again, just through vaccines. Vaccines work, there’s no question about this, but as Wayne already alluded to, we don’t really understand how they work.

For most vaccines we don’t have a clear understanding of the mechanisms of how they protect for some vaccines. For those that we don’t have the mechanism we at least have a correlative biomarker that we can measure on how they work. But for very important diseases that Wayne already alluded to, some of those infectious, others cancerous, autoimmune allergies and also emerging diseases, we’re not anywhere close to actually designing a vaccine based on insight on how they should be working, and that is a problem.

Therefore, the mission, as Wayne has already alluded to for the Human Vaccine Project, is to design, and to discover and decipher the rules that drive the immune response to vaccines, and target them against major global threats, and they’re not just all infectious as you heard in the beginning.

So this is the mission of the Human Vaccines Project. And the solution to overcome the problem you heard part one for that, which are about the parts, the immunome, and the very impressive work from Jim Crowe’s group. And what I’m going to talk to you about right now is how the other part, mainly the rules, how do these parts function. How do they work together, come together?

Wayne already showed the slide that much of what I’m going to show you right now would not have been possible even five years ago, so this is very much dependent on technological innovation, and a visionary approach to this that you just saw in Wayne’s talk as an example. So that’s what I’m going to focus on right now.

The way we approach this, and this is nice as a segue way to the questions that were just asked is, we were setup to capture as much information in an individual in relation to a specific vaccine as you could potentially do. So this includes blood leukocytes that’s most often studied in these assays, but we also include lymph nodes, bone marrow and more soon to come, mucosal tissue sampling to have an idea of what’s actually going on across the various tissues.

And then apply every possible approach to capturing the host response to a vaccine, and in a broad unbiased way using what is typically called omics assistance biology. So RNA for transcriptomics, proteomics, metabolomics, both in plasma as well as in the cells, epigenomics, the microbiome and various targeted assays including very fine granule detailed analysis using single cell analysis. And we’ll see Richard I’m sure will talk about this in a little while.

And then we couple this with information that we get out of the same individuals using the tools that Jim just showed you, mainly the human immunome. And then we put the parts and the rules together and identify how do they actually work together. We’re going to do this using vaccines initially as probes to perturb in a defined setup, the immune system.

With this we’ll hope to identify not just the rules that happen, or the changes that happen in the individual going forward, but also how past history, and Jim already alluded to some of this, imprints itself on the response today, and we’re going to do this across populations. And in these key populations we’re targeting not just young healthy adults, but the vulnerable infants and the elderly as well, developing world populations including pregnant women and others as they are relevant for a specific vaccine.

And it really is going to be a three dimensional space where we look at the results using high intensity information and technology across populations, across the entire age spectrum, and across the different vaccines to understand the rules that govern the response to all vaccines, not just to a single vaccine.

So the ultimate goal for the Human Vaccines Project is this. One dose of a vaccine given to anyone anytime anywhere providing lifelong protection. And you may say that this is similar to what Jim described, a foolish approach, a foolish goal, and it may still seem completely out of reach. What I’m going to show you today is that we’re pretty close to actually reaching some of that. Maybe not all of it at once, but it has moved into the realm of feasible similar to deciphering the entire human immunome.

The best example that we setup when we first met about five years ago, for a current vaccine that with a single shot provides protection, for as far as we know right now, up to 10 years, which is the longest period that we’ve studied this, is the human papilloma virus vaccine. This is the paper that just came out a few weeks ago, and there’s a whole special issue coming out comparing single dose, to two dose, to three dose trials across the world using various different versions of the human papilloma virus vaccine.

The day that that’s coming out there’s that single dose likely is enough to provide clinically relevant protection for at least a decade if not life. The reason that this is a good model is that it’s also an inactivated vaccine, so it’s safe to be given to immune compromised subjects, the very young, the very old, and pregnancy.

The problem with the human papilloma vaccine I’ve seen is indicated here by a paper by John Tsang a couple years ago that’s not – this graph was made specifically for the human papilloma virus vaccine, or HPV. The problem is that it’s so good of a vaccine that everybody responds to it, and almost everybody is protected. If you have a vaccine that’s this good you’re not going to be able to decipher what makes it work, or doesn’t make it work, and extrapolate this to other vaccines. So lack of variability or low variability is actually a handicap in this setup even though it’s a gold standard for a vaccination.

So we looked around and discussed this amongst ourselves, and identified the hepatitis B vaccine, that’s currently licensed from birth to old age in all populations around the world, as a very good alternative because the hepatitis B vaccine, Is similar to the human papilloma virus vaccine in the sense that structurally there is some similarities. There’s also differences obviously, but it’s importantly very variable in response to the vaccine. About 30 percent of subjects respond to the first dose only, then require up to three doses to get close to 100 percent.

So this is actually a pretty decent model that we have a wide spectrum of responses. And because of that we chose the hepatitis B vaccine as our first model in a demonstration study to identify how do we best approach deciphering the rules that put all the things together that you would like to know about a vaccine, and eventually get back to the gold standard there, the human papilloma virus vaccine.

So our demonstration study that I’m going to briefly mention today in outline only was meant to just demonstrate feasibility first of all, establish a platform, and provide data to allow us to plan going forward in the next step to then target the gold standard human papilloma virus vaccine, or a more difficult target such as the influenza vaccine and other vaccines as they come up.

The study setup was rather complicated. I’m not going to go through the details, but it involved enrolling at this point only 15 subjects just for a demonstration pilot. Multiple blood samples, large volumes that includes the sequencing of the entire human immunome, as you just heard from Jim. It also included the invasive tissue sampling, as I mentioned, lymph node, and it will soon also include bone marrow and mucosal tissue sampling including the microbiome as a potential variable in the response assessment.

And this is just an example. This on the right side is our first subject. On the top you see her getting blood draws, which we’ll then process. I’ll show you this in a minute. Then swabs for the microbiome. On the left side you see our setup for the lymph node biopsy, which to our surprise at least, this is to note, this is the first vaccine study that actually took tissue invasive samples including the lymph node of the recipients around the vaccine.

And this is the, to our surprise, the study subjects actually were thrilled to watch themselves being biopsied on the ultrasound screen. The same is not quite true for the bone marrow aspiration at this point, but we’re working on that. And then we process, in this case I’m just going to show it for the blood, we process the blood in a whole wide range working with experts in each of these domains from around the world, conducting not just whole blood transcriptomics, but single cell transcriptomics.

And this is done at the Craig Venter Institute by Richard Scheuermann and his group, and you’ll hear him talk in a little while. We also work with folks at the Institute of Pasteur who have a very fancy setup that’s broadly implemented around the world, and through the True _____ System at the _____ _____ study. We do an next generation sequencing, as you heard from Jim already, identifying the immunome working with folks at the Scripps Research Institute. And plasma proteomics and metabolomics is done in part and collaboration with Wyss Institute and Dave Walt. And there’s others that are part of this team effort. Like one group alone would not have the topnotch expertise needed to actually do this optimally.

And then we put it all together. And I’m not going to show you data right now because, as I said, this was only meant to be a pilot study, but I’ll get back to this in a minute. But the point of putting it all together was actually a big hurdle. A, it’s a lot of data, but that’s not the major hurdle, but to use tools that actually make sense out of this data. Here an example, if you just measure a biomarker. Pick whatever one you want out of the thousands, close to 100,000 biomarkers that we’re capturing, and correlate this to the vaccine response in an individual.

We put them together, each one of those by themselves as expected. Wasn’t able to differentiate groups. But the moment you put them together you can actually start seeing groups parse apart. And this integrated multivariate analysis here only shown for two parameters. Imagine you do this for 100,000? What you’re going to come across is to recognize that you’re capturing a picture of a process within the host that actually tells you a biological narrative in fine granular detail that actually starts making sense. These are not just snapshots from one angle or two. These are snapshots from 1,000 different angles.

And with this, the story that emerges from this integration approach is very surprising, and it’s tremendous. And the results I’m not going to go into the detail right now. I only gave you a preview of what we think this might lead us to is that not the responses to the vaccine so much as the baseline standards at the time of vaccination. Predict your final vaccine outcome.

All the studies, most of the studies that have been conducted using a similar or a more intensive sampling approach, and integrative analysis approach, focused on response to the vaccine as finding a signal that predicts vaccine outcome. But actually it’s the baseline, immune baseline that predicts this better than anything else. That’s not entirely novel, but it has huge impact if you think about how to go forward in identifying the rules of immunity in response to vaccination.

One thing that this already alludes to is that if the pre-vaccine status predicts a final outcome, you should be able to determine the most important parameters of this, miniaturize it in a system that allows this to be done in the field in a rapid manner. And then decide in the spot what vaccine is the best vaccine for the given individual in front of me. Or, with existing vaccines you can decide does this person need one dose, two doses, three doses.

With this you’re not just going to reduce the cost of vaccine implementation for public health systems, but for a vaccine evaluation going into the future for new vaccines you’re going to reduce the cost of trials because you’re going to get back to what Wayne showed you in the beginning. You’ll be able to cut down the number of individuals that needs to be studied from the tens to hundreds of thousands to tens to hundreds.

And you also reduce the risks associated with vaccine development because you can target subjects that are likely to respond or not respond, and you can therefore reduce the risk for potential failure of the vaccine, or adverse events. And most importantly, for us at least at this point trying to put the rules together of how does immunity work. You can actually begin rational vaccine design based on a database and on a background that is much, much better than what we used to have even five years ago.

But this is true for most vaccines that we currently have in place. Hepatitis B is one of them. I already told you that the human papilloma virus vaccine is so good that nearly everyone responds. Now what is it about that vaccine that makes it so good? Not a clue. There’s lots of hypotheses, and there’s people in this room who know this way better than any of us, and you’ll hear from them. But the best fit approach is now that we can give both vaccines to the same person, or different people, and figure out what are the differences in response to those vaccines using the exact same tools that I just showed you.

So within the same system we will be able to dissect why, for example, something as good as the papilloma virus vaccine, or something not as response inducing as the hepatitis B vaccine, differ from each other. And with that, we will be able to describe comprehensively the vaccine induced immune response, understand what the best response looks like, and best may differ from vaccine target to vaccine target, and/or from population to population. And then aim to replicate this as the one mechanism that is true for all recipients. And with that, really decipher the rules of immunity for vaccine design.

And the goal there for of a single dose providing lifelong protection across all populations is certainly within reach. It’s not going to be right around the corner, but it is within reach. And I think I’m going to briefly mention this is obviously, as I mentioned already, a huge team effort. Multiple institutions from Craig Venter, to Pasteur, Scripps and the Wyss Institute, and others in the Human Vaccines Project, and our team at UBC that’s been heavily involved in this as pretty large as well.

But I want to thank all of the folks from the Human Vaccines Project that are here today that have made this even possible. And we really feel, some of the words Jim described to all of us and 20 years ago at the beginning, the verge of the Human Genome Project hitting the road, and this is exactly where we’re at right now. So we’re very much looking forward to sharing the exciting years to come, and the exciting data to come with you in the next few years. Thank you.

Marie-Paule Kieny: Thanks a lot, Tobias. You actually being short, so we can have a lot of discussion.

Tobias Kollmann: That goes with I think we did complete this demonstration trial ahead of time, and on budget as well. It’s becoming a pattern.

Marie-Paule Kieny: Absolutely. It’s becoming a pattern. Not to criticize Jim because he went overtime, did you go over budget Jim also? Yes, let me just put one comment. You know, having been in my previous life involved in a lot of discussion about public health vaccination, large scale vaccination, I think that the ideal of having personalized vaccines is something that will be very difficult to implement. It will be very difficult to produce them in the right quality. It will be difficult – you know, the price of it.

So you can think about it for if it’s a therapeutic vaccine against cancer. Potentially yes, you can talk about personalization, but in terms of protecting large population against infectious diseases seems difficult. But I would imagine that what you would then try to do when you have these rules of immunity, instead of designing a hepatitis B vaccine that would work for each individual people try to see how you can make the hepatitis B vaccine like the HP vaccine, and what needs to be changed in order to get there. So what’s the idea about that?

Tobias Kollmann: So first of all what you said in the end is very much true. That the initial goal is going to be trying to reach for the lowest hanging fruit, which is to make all vaccines work in everybody. That’s the goal. Looking ahead you may not want to have all vaccines work exactly the same way in everybody. There is reasons where sometimes you might want to have not 100 percent response because you might want to have a different immune response in different populations. So that’s part one, we might not want this for everyone.

But what you pointed out was a similar almost ethical hang-up on my end to say that, “You know what? For $20,000 we can give you your personal footprint from head to toe, genome, immunome, everything.” That’s not feasible. And is it ethical is a different question. But, and this is the piece where people who are in machine learning artificial intelligence, and Richard is going to talk about this in a minute, but chime in, if you do this for those like populations and/or individuals that can afford it and you keep that data about each individual, and you build a database that’s becoming more and more rich in its fine granular detail, you’ll be able to extract meaning that is going to be useful for even population for which we cannot do this on an individual level.

So a personalized medicine, even if there is public health resistance for the same reasons that you just pointed out, I think can still be used as a vehicle to support public health implementation across the financial barriers that are certainly in place. I don’t know if that addressed – begins to address your question.

Marie-Paule Kieny: Yes, let me just come back to you. I had a first question down there, yeah.

Male: Yeah, so I think in your study design it looks like you’re looking at key titers after three doses. That’s not right. It looked like I saw three doses and then looking at the titers. Because you’d really be missing the key differences between the response to HPV and HBV vaccine in terms of longevity of the response, and also the strong response after a single dose. So I wonder if you could address that issue.

Tobias Kollmann: Yeah, so this is – the graph may have been misleading. We look at it after every single dose. So the data that I just showed you that predicts the response pre-vaccine baseline, was actually not only in relation to a month post the third dose, which is the gold standard and that’s why we did that, but also to the titers in the few individuals that respond with just one dose of hepatitis B. So we do what you just suggested at every single dose for hepatitis B.

Male: Now if we kept looking at one dose long-term. It’s really the long-term is what –

Tobias Kollmann: Absolutely, and this is where this becomes an issue right now. So this is where doing this in the same person over time is going to be coming up in the future. But obviously can’t do this in six months because we only had nine months really to complete the whole study. That long-term question is in the planning stage right now. But you’re right, that is the goal, single dose, and then follow them over time.

Marie-Paule Kieny: Stanley?

Male: Yeah, well obviously age is going to be important because as we all know infants are not responding the way older people are and don’t have the lymph nodes that older people do. But the point I would also make is that where I could see what you’re doing as being extremely important, it’s comparing populations, different populations. Because as you know, there are real differences between vaccinations in the developing world population and developed.

And I don’t understand what the difference are, I mean that would be very important. Even rotavirus, which people were talking about the microbiome et cetera, but the microbiome may be a reflection of other things. And so I look forward to your data on other populations.

Tobias Kollmann: Thanks for making that point Stan, but we are looking forward to that data. That’s precisely where we’re heading.

Marie-Paule Kieny: Go ahead.

Female: Yeah, kind of building on that, and on Marie-Paule’s question. In the public health context where you want to know what the rules of the road for an infant, but by necessity ethically your volunteers are all adults.

Tobias Kollmann: Um-umm.

Female: No?

Tobias Kollmann: Um-umm.

Female: Are you trying this on three year olds?

Tobias Kollmann: Yeah, so we just completed over in the process of conducting the study in newborns, and over the first few days of life. And it’s important this a HIPC and NIDA funded study. That does not include yet lymph node bone marrow and all those biopsies, but includes blood and that’s an important piece to point out there. The studies that I’ve just shown you, and this was a major criticism in the beginning, how can we translate this to a very small even premature infants where you can get, let’s say, half a milliliter of blood, or a milliliter of blood, or two milliliters of blood at most.

We’ve miniaturized the entire platform that I just showed you to work with less than five microliters of blood. We can’t do the whole immunome, which is obviously because that’s the number of frequency of B cells that needs to be in there. But everything else you see in there works with five microliters of blood, and we’ve proven that to work. So – go ahead.

That’s just if you sort your volunteers out between C-section and non-C-section?

Tobias Kollmann: Mm-hmm, yes. As Dan already pointed out, there is differences not just across populations, but even within a population, and those differences that have major impact on your early life trajectory, C-section being one of them. Because really birth is a major inflammatory process by nature. That’s just normal. Will have major impact on whether you have labor or not before we get the sample, fully understood, fully agreed.

We’ve been doing this for over 10 years right now in these early life populations. We at least know some of the variables that we’ll have to capture, and C-section, breast feeding and the likes are major, major variables that we’re trying to capture.

Marie-Paule Kieny: Okay, we take Nataly as the last one.

Female: So there’s two possibility to look at. Either you only classify individuals to see _____ _____ _____ so that you can see _____ of said population for vaccination, or you reset everybody to the same level for the induction of the _____ _____.

Tobias Kollmann: If I may without – I’m not sure. I’m not going to steal your thunder Richard. Precisely the point. The data that we’re already getting out of this demonstration project, and that literally it was only meant to be a feasibility study, but we were surprised to see that integrating it across, similar to Wayne’s slide with 10,000 data points. For 10 subjects we’re already getting major signals out of there. And the signal that we’re getting suggests that if you will give an innate immune stimulus before you give the vaccination you would standardize the response to the vaccine.

So adjuvant and antigen don’t always have to be in the same dose. And obviously this is at this point a hypothesis that we’re in the process of testing, but the data that’s emerging out of this little demonstration pilot already strongly suggests that that would be the case. And that would get along with what Stan already pointed out. Difference in the population they’re not just genetic, they may also be due to exposures to a different microbes and infections.

It’s kind of like an innate immune set point change. So if we can control the set point, change the baseline, we can do – have everybody respond to a given vaccine after we adjust the baseline standards. It’s exactly the probable final rule that’s going to come out of this.

Female: And to doing [inaudible].

Tobias Kollmann: Oh yeah, except if the agencies – that’s – go ahead, yeah.

Marie-Paule Kieny: Okay, thanks a lot. Thanks again, Tobias.

Transcript curation: Alison Deshong

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