Reason that it was not one of the most devastating epidemics in the history of humanity is because that particular flu decided not to be very lent. We dont get a vote. But the Gates Foundation has mathematical modelers that estimated that, had it been anything like the 1918 flu, 33 million, 37 Million People would have died, and we would not be having this conversation because we would be dead. What happens when these sort of things occur is if they dont kill a lot of people, we just move on, especially when it comes to influenza, which people seem to think is just a word that means i dont feel well. For the first question, i would like to ask tony, maybe you can explain why we would want universal vaccines, how does this work, and how is the pandemic different from what we get every year, and where are we . Ok. Thanks, michael. Very briefly, because i know we have a lot to talk about, but the situation with influenza, as many know, is that unlike a virus like measles, which, if you have a measles virus and you get vaccinated against measles, or you get infected with measles, then you are protected, essentially, for life, for the simple reason that measles does not change from year to year or from decade to decade, whereas influenza is very unique in that it is a virus, a group of viruses. There are different kinds of influenzas that tend to drift from season to season. You need to get vaccinated each year, and you try to anticipate the right match between a vaccine antivirus that will be circulating. Every once in a while, as michael alluded to, you have a very dramatic change, either by mutations or evolutions, from animal influenzas that jump species. It is a big change. The viral inflections we deal with, polio, smallpox, measles, etc. Dont do that. So we are dealing with a continual moving target from season to season and the threat of a pandemic. The title of this session is the quest for a universal flu vaccine. When we talk about a universal flu vaccine, it really is an aspirational goal, the quest being to make a vaccine that induces a response in the body, to the part of the virus that does not change from season to season or decade to decade. The scientists throughout the country and world have been able to identify components of the influence of that really do not change much at all. The critical issue is getting a vaccine to induce a response against that part. A universal flu vaccine is not going to be, today we dont have it and that we flip a switch and then the next month or year we have it. It is a process. If you look at the display of influenza as, they are in two different groups and there are 18 different ages. There is a lot of wiggle room you will have to cover. The quest on the road to a universal flu vaccine will be to take one of the influenzas in group 1, lets take h one, and we know it changes a bit from season to season, to make a vaccine that would cover all the iterations of h1. The next iteration would be all the influenzas in group one. There is group two, with h3 and it. It will be a stepwise process with the ultimate aspirational goal of having a vaccine that you could give relatively infrequently, compared to now. It would cover the broad array of the influences that we would be experiencing. Thats in a nutshell. The things i have done as a journalist is constantly write stories telling people to get flu vaccinations, but they really kind of suck. People always say to me, why should i get a flu vaccine . I would say 23 is better than 0 . As far as my mouth goes, that is true, but im wondering i wrote something for a report that many of you have access to, the vaccine report on influence and we put out last year, and i talked to literally dozens of people in this field, and not one person i asked them all this as good as we can do . At least one question. Is not one person said yes. Not one person said we are as close to doing it as we can do. Im curious, why are we so bad at protecting ourselves from what many people consider the sort of most likely virus to cause the most damage to humanity . I am going to let anyone of you who wants to answer this do so. Thanks, michael. I wish the narrative would have come up on the video coming through, because it was called a sense of urgency to address this problem. There are still 650,000 people around the world dying every year from seasonal influenza, and if we take the scenario that the Gates Foundation modeled, which says if we have another outbreak like we did today, we would have 33 Million People dead. Not only that, that virus would have been seeded all around the globe. And then we start releasing vaccines. We are still behind the gun on the tools we use to make the vaccines. We have reasonable vaccine foundations, and we can make them better by adding highdose vaccines that are not fully utilized. A lot of people across the world do not have access to the vaccines at all. I think the sense of urgency needs to be there, but also the fact that we need to leverage the tools we have and envision what that universal flu vaccine is in a very rapid, urgent pace to t there. For part of my life, i taught at stanford, and people use this word in Silicon Valley that i mostly hate, but im going to use it now disruption. Why dont we blow the system up . Obviously we cant turn off the spigot and say everyone in the world should get this new vaccine we have not given yet, but there must be some way that we grow vaccines mostly in eggs, the way we did in 1947. We live in a world where i can download whatever song i want onto my phone at command, and we grow vaccines the way we did 70 years ago. What is going on with that, peggy . I think i can talk on my own. I never knew that about you it certainly is the case that we are behind where we have to be in terms of the urgency of this threat and how we are harnessing advances in science and technology, and how we are mobilizing society to recognize the magnitude and scale of the problem before us. Clearly, disruption comes with uncertainty, and it comes with uncertainty on many levels uncertainty within the Scientific Community and how we do science, regulatory uncertainty, which i know something about, and also uncertainty about adoption and access and all of that. I think one of the things is, and i think hopefully one of the messages coming out of this panel is, its time to stop talking. Its time to act. We have talked about these issues for a very long time, and that has taken the place of action sometimes, i think. But in terms of why we are still growing it mainly in eggs, i think part of it is that its just the way weve always done it. Its the way we know we will get some kind of vaccine into the marketplace. And theres always the hope that in the meantime, other work will be going on and we will have the breakthrough and the aha moment clearly is not going to happen. It is also that we have not had the sense of urgency. Do we need to have lots of people die for that sense of urgency to occur . The incredible thing is lots of people do die every year, and yet we are not mobilizing. To be more positive, since i cant really answer the question of why it has taken us so long, because i think it shouldnt have, and there really is not a good excuse, the science has had to move forward. Gaps in the science bill persist, including our understandings of immune protection in addition to understanding the nature of this particular virus, which has its complexities. Certainly part of the problem has been that it is much safer for a company to just keep doing what its doing than trying to do something new. But also, we have not funded all the work that needs to be done. On an optimistic note, there is a lot going on, and tony is leading efforts, and there are of her efforts from the Gates Foundation, european research, horizon 2020. But we are also not collaborating, and that needs to be addressed. We needs just we need to start sharing knowledge. We need to identify where the gaps are, how we can fill those. We need to identify, what are the rats we are stuck in that we have to get out of, and how are we going to use all the capabilities of science and Technology Today and the energy of our society and the Scientific Community to get the job done . This collaboration issue seems particularly interesting and urgent to me, because there is a vast amount of data out there. A lot of it just falls by the wayside. If you do a study and it is not published, then it goes away. Yet there may be good data. I think casey has something to say about that, about openness and collaboration . Can you hear me . Yes. I dont need a mic. Good day. I think isolation is our enemy, and there are opportunities to expand transparency and expand a culture of transparency and open data sharing that i think could unlock breakthroughs and create new insights to accelerate our progress. We are the sole philanthropy on the group, and we really build into our dna a bravery about asking really hard questions. For example, we have been asking, what is the role that publication bias may play in limiting our progress going what are the opportunities for funders in this space to meaningfully collaborate, to build code funding opportunities and build strategies together . What are the ways by which there can be cohorts in a collaborative session and less as individual contributors . One of the programs i think michael is alluding to we established a new collaboration with the center for open science and the Public Library of science to really create new incentives for researchers to publish no and the negative null and negative findings. If we can shed more light on data that is not published, can we create new incentives to bring that those analyses to the front and shed more light on them . I think it would be wonderful. This new program we are starting, we are asking researchers to open the file drawers, pull out the floppy disks, whatever they have, and we will pay them to reduce that opportunity cost and to draft to those manuscripts and work and help them get those published because we think there are a number of opportunities ahead of us if we shed light on opportunities. Im curious, it is a pr issue in some ways. People talk about the flu i had the flu, i feel fluish, and 80 of that time, i am making that number up, they dont have a lot bit a lot of time. I had a bug. I wont call it the stomach flu, but most people would call it that. Is the problem we dont have appropriate nomenclature . There is complacency on that side, as well. Peggy mentioned the institutional architecture that keeps innovation from happening. I think those things are connected. People say the disease isnt so bad, i had the flu, i got over it. The vaccine isnt so great, fair enough, ill take it. There is that piece, as well. But the Vaccine Institute is in washington. Innovation is one of our pillars and we teamed up with aspen last year. The idea was a Diverse Group of thinkers, science, philanthropy, industry, journalism to take on issues in vaccination and not surprisingly, given the 100th anniversary of the 1918 pandemic, that was the issue. That is where the speech with video came from. But that is where the urgency came from, and the recognition is we need to do some things differently. There was a discussion about the cascade from communication to coordination to collaboration to convergence, and we need to work our way down the pipeline to make sure we are actually getting all the way to the end to bring in as much as possible to take on this problem. The complacency really israel. Reflecting back on when i was in government, not in the last administration but a few administrations back, and i was developing Public Health preparedness programs, and i went to fema to talk to them about doing a tabletop exercise around preparedness for biological threats and we were going to do a flu pandemic scenario and they said we dont do infectious disease. We do hurricanes, we do floods, earthquakes, all kinds of disasters, but disease outbreaks . I encouraged them to participate and it was incredible to watch them as events unfolded and realizing how much this kind of an outbreak would undermine all of the essentials of civic life, how it would undermine their own ability to mobilize and respond to needs, and also, the recognition of the Economic Costs and productivity costs in addition to the medical concerns and ultimately the loss of faith in people in government and leadership, because of the failure to be able to provide vaccine in a timely way and other things, so people still dont think enough about what this really means in our daily life and what the impact our, even though every year impacts are coming even though every year, we are suffering a lot of preventable deaths, illness, and disability. That is on why i asked the dark question, do something really that have to happen . It seems one of the curses of the Public Health world is if you guys do your job well, everyone goes along but if you dont or do your job well and people get sick anyway, somehow you just failed. Im not sure how you get around that. Id like to take a half step back and maybe tony is the person to address this, cor rick. Can you give a better sense of how far we have come on our approach to a universal vaccine in the last decade . We really didnt we didnt really have a real confidence in the scientific asus basis that we could produce a response or even what component of the virus, if you had an immune response would actually broadly cover. When we had the evolution of structure based vaccine design, when we used cryo ems to look at the molecular configuration of the stem, one of the big targets of a universal flu vaccine, certainly not the only target, but one of the targets if you look at the hemaglutin in molecules, if you metabolically construct it, it is like a head, which is a mushroom cap with a broccoli cap with a stalk. Part of the body the part the body makes an immune response against is the head. When it sees influenza, it much prefers to make a response against the head. When that gets it right, that is good news because you will get protected. The sobering news is that is the part that does the mutations i mentioned a bit ago. The stalk or the stem doesnt really change much at all. That is potentially good news. The challenging news is the body doesnt readily make an immune response against that because it is not immuno dominant and it hasnt been studied well. Now that we know that if, in fact, you make a response against the part of the virus that doesnt change, that when you look at the response body makes and test it against an array of viruses, you get a much broader coverage than against just that particular head of the hemagglutinin, which likes to change from season to season, whereas the stem stays the same relatively speaking. That is not something we knew 40 years ago. That is something that just now is beginning to appreciate. What investigators are doing and not the only target is to take the stem and get rid of the distracting head, and stabilize that stem and put it in a way, not growing it in eggs, not growing the virus at all, but getting the protein and sticking it on a self assembling nano particle that is much more immunogenic. You dont have to grow it, you can make a lot of it, and if you do it right and partner with industry, that is the kind of thing that doesnt have the vicissitude of growing an end. Egg. The critical challenge, and it relates to one of the things peggy said, is in order to make the transition from getting out of the tried and true egg growing, which we know gives us results that can be beneficial, weve done well with that, to something that has to be much better. You have to prove that this works, and then youve got to go through all of the clinical trials, phase one, phase two, phase three, and show this particular product is going to be good over a period of years. That alone if it works perfectly is going to take a decade. Im not a representative of the industry but ill pretend i am one. I make a flu vaccine every year and it protects people to the degree why the hell when i go spend 400 million to do this thing which may be great . That is where the federal government comes in. Seriously, what happens you bring up an excellent point. Our responsibility to the Public Health and not the profit line has to be able to push the process to the point where industry will find it to be a benefit to do that. If you sit back and the company that has been growing eggs for thirty years to spontaneously change without any incentives, it is not going to happen. Can i add . It is not that the field is not active. For 40 years or more, there have been concepts and approaches and it has eb and flowed, the amount of energy from biotech and from large pharma. In the 1980s and 1990s, the target had a lot of energy focused around there. Been funding became available from government in 2005 and 2006, so a lot of new ideas cropped up, but they were still focused on the framework that the government put out saying it should be an ha based antibody vexing. Dear vaccine. We have been learning so much about vaccines through the field that we have had a dogmatic approach that an antibody is the only thing that will save the day for influenza and now the resume of science from investigators, and studies showing how the breadth of an immune response is critical for so many of these lifelong or long durable vaccine or immuno responses. The energy now, trying to pull that into an influenza vaccine approach is out there, but what i think peggy said is we are seeing a lot of silent approaches, where there might be 40 different approaches on companies in the pipeline attempting a broadly reactive universal or crossreactive as very different labels are putting on it for funding primarily, they are kind of siloed. You dont see them leveraging the. Of knowledge weve of what we have learned. We are not conducting really large efficacy trials, understanding the details of the immune response. We are not comparing the new Tech Knowledge hes we are technologies against each other. Where redistributed 100 50 million doses in our country every year, we dont know how many people are getting vaccinated, how many are delivered to people, which doses they got, and what the outcomes were. We can learn how to improve our vaccine. There are opportunities today with wealth of data that has been created for years that is being ignored because it is not hold up into some larger brain trust for 40 Different Companies to leverage and make the best vaccine approach or even for us to determine which vaccines we have today are working or not. If we uncloaked the poorest performing vaccines on the marketplace today, it might be very revealing to tell us which technologies we have that allow us to go deeper into the technologies to determine why they are more extractive. There are more effective vaccines today. We are afraid to reveal the truth because we dont have the capacity to spread those vaccines widely once we learn the truth. We need to build that brain trust. We need to move as quickly as possible and as urgently as possible to get these technologies that address speed, and the effectiveness of the vaccine. The council of economic advisers from the white house put out a report in line with an executive order from the white house saying we need to Prioritize Development of vaccines for him to windsor that are fast, so right now, they are mediocre and slow. A mediocre and fast vaccine is even better than a mediocre and slow vaccine, but we can make better and faster vaccines, but 361 billion every year is our Economic Cost for seasonal influenza. In a pandemic that goes into the trillions of dollars. We have to take that sense of urgency, Economic Cost, the societal disruption, and the lives lost into perspective and think, how do we gather this information and share it in a targeted way to accelerate the development of a better, fax or faster vaccine . Conclusions of this group last year we came to was we need a new entity. We need Something Special to do this because i wont say we are spinning our wheels, but we are not accomplishing what we could accomplish, and many people think we will not do that unless we do something very fundamentally different. Im assuming you are on board with that, bruce . That is the ultimate conclusion, from communication to convergence and bring those things together in a coordinated way. In addition to the research dr. Faucis group supports, there are pieces of this puzzle. Youve made an argument there is more to what we have now, but given the urgency, and that was the overarching theme of the report, we need to do things in addition to what is happening. What else can we do . Have family bring new ideas to this space . We need a Garry Marshall moment. Ulcers were the territory of surgeons, then came the observations that there is a bacteria there and with antibiotics and peptobismol, ulcers have gone away, Gastric Cancer has gone down and researchers are doing something else. Im sure ive gotten this wrong for the people at milken, but im looking at this logo. We need strands from different places to solve this on top of the work going on. Im not exactly sure how we do that, and i have one other question that has been bugging me, and maybe im wrong about this. I know there are a lot of people doing great flu work, but young, smart, phd students and postdocs go where there is funding. The funding exists, but there is greater funding and other areas. I dont run into an endless number of people at Stanford Medical School who are doing flu research. They are doing neurology there are a lot of things they are doing. This doesnt seem like its principally one of the most important issues on students or brilliant young researchersminds. Had we change that, or am i wrong . How do we change that, or am i wrong . A year ago, the foundation teamed up to put out a grand challenge for this and acknowledged all this stuff is going on, the importance of the basic research, but are there other people we dont know from other fields who may have a solution to this problem that dont know they might have a solution . Thats a step forward. There is lots of interest in that. They are trying to forge better disciplinary interdisciplinary collaboration. In parallel with what weve heard about thing also, it is not sexy anymore. It probably hasnt to excite the creative thinkers. In addition to what we are so good at, in parallel, there might be a need for an urgent call for an entity of excitement out there that is completely disruptive that is not beholden to bureaucratic strings and processes. The hiv field was galvanized when we put a lot of money into it. So lets talk about reality whats reality and the easy way to get grad students excited about something that isnt sexy is to put ita gown on it by having a lot of money. There has been movement by members of congress to increase the universal flat flu vaccine by a billion dollars over five years, 200 million each year for five years. You will get people excited not to do the same thing they are doing. You will get new people with new ideas that are disruptive, and looking at it from different angles. When you have an infusion of resources, that is how the field changes because that is what happened with hiv. And when people pair. We were talking about the early days of hivaids, and the activists moved the Research Agenda in powerful ways, the people who going to science want to make a difference, and if we really put this in the context of the burden of disease and what it means, you talk about pr before, we havent done a good job of that and that will help generate the resources and will draw on the best instincts of people going into science want to make a difference in this country and around the world. I think we are being terrible pr people. We are flew in and we are saying the flu isnt sexy. Flu ambassadors and we are saying the flu isnt xsexy. Thousands of people died last year and they died this year and they will buy next year. We seek a transformative product. I think we can absolutely, in parallel with the pursuit of an iterative process, in parallel we can and this. We need to set an ambition for a vaccine that is broadly protective. It is once in a lifetime. It is durable. It is for everyone on this planet, and it eliminates this annual scourge and it eliminates the pandemic threat, and i think weve all been talking about the need for urgency. We are talking about a lot of increased passion in our field and i think that is very important, but weve really been asking ourselves and our communities the hard questions. Are we organized in the right way to harness the new scientific insight and discussion . Are we organized in the right way to make Permanent Progress and meet this goal . That is one of the reasons we asked the Vaccine Institute and the Aspen Institute to interrogate this issue. The results were quite clear. There is no clear mobile owner of the problem, and there is no clear global owner of the solution. It is hard to imagine how we will make Permanent Progress. From a worldwide perspective, if that doesnt have some kind of ownership, i think this fragmentation, this problem, the scale of it requires unprecedented collaboration. It requires a new model for global collaboration and dedicated leadership, and an ecosystem that is going to engage and support it. I agree with all that. Flu lab is an exception, but it seems to me when i throw around in the field, for lent offers philanthropers want to make a splash, and they dont want to make a splash on something everyone thinks is boring. Dont tell me it isnt boring. Dont you dare. Weve got to get you trained. laughs you dont have to train me. The people i talk to who have a lot of money, their eyes glaze over when you say this stuff. You are an exception to this. What weve all been talking about is a twotrack system where we do what we have been doing because we have no choice. We arent going to ditch that system right now, but we develop something more powerful and permanent, and that requires a different kind of entity. I wonder who is going to run that entity because i dont think the government is probably answer the answer. Else because a government representative. Think you are right on that. I have at least 25, 30 areas i am focused on. Where you saw a lot of mobilization, even in the hiv world with separate entities, focus on hiv vaccines there is no single entity, single focused entity on influenza and if there was a single focus on influenza, that target and that timeline would bring the best science, bring the best interdisciplinary thoughts. We are in this room, we are backs and knowledge its comic immunologists vaccinologists and immunologists, but we are not the others who bring critical insight on how you construct and deconstruct an ageold problem. And had these vaccines for 70 years, so this is an ageold construct that requires creative chefs to come out of the kitchen to deconstruct the carrot cake and make it look like Something Different but the best caret cake youve eaten in your life. You need that for the influenza vaccine. We also need to not forget that influenza for influenza, vaccines are the only part of the solution. If you want to get sexy in influenza, you stay in the vaccine if you going to the diagnostic space, the therapeutic space, those are the early steps that will make a huge impact on bending an epidemic or foreseeable pandemic outbreak. We have to have that single focus entity, focus on stopping influenza not only on making a vaccine. Did you want to, case we havent figured this out already, this is very complicated not only from a scientific and Public Health standpoint, but a perception standpoint. It is certainly not boring when you delve down and see the ultimate impact accumulative each year as well as the intermittent time we get a pandemic, but let me tell you how things fall into a different category. It is the diversity of what influenza means to the community. For some people, they get the flu the real flu. They get better. There is this perception that if it is so serious, how come people get the flu each year and it isnt a catastrophe . When you are dealing with a disease like hiv, if you get hiv, it is serious whether you are young, middleaged, old. If you get cancer, thats bad, weather you are young, it is intermediate. But with influenza, for some people it doesnt impact them at all. There isnt anyone afraid of influenza. You going to a focus room and asked are you afraid of getting hiv, cancer . Absolutely. Are you afraid of getting the flu . Dont bother me. That is how people perceive the flu. We are responsible for a variety of diseases, creating countermeasures, malaria, ebola, zika. You go to the drc where i went to a week and half ago to visit our sites and ask someone are you worried about influenza . They laugh about laugh at you. They dont vaccinate against influenza because theyve got enough albums with malaria, tuberculosis, and ebola. We have a perception, a misconception that it is not a serious disease that hundreds of thousands of people die from it each year and when you get a pandemic, millions and millions of people. We really do have a problem of how the world perceives influenza and it will be very difficult to change that unless you do it from within i dont care what your perception is, we are going to address the problem. In a disruptive way. In the long run, over time, if the 2009 pandemic had been much more deadly, without have ended up being the better thing for humanity . Come on, be honest. Would it have been . No, because we had not as serious as the 1918, but we had a pretty bad pandemic in 1977 and 1968. That didnt change much. But was not before dont have some technological tools now at our disposal that we didnt have them . Absolutely. Absolutely. The center is that when there is a major crisis, it focuses resources and significant mobilization follows. It doesnt necessarily mean we are using resources and the best way possible, because it is done in the most crisis and there is throwing money at things that sound good without them being thought through, and there is what we used to call the ushape d curve of concern. An initial increase in resources and other problems emerge, than everything drops off. We have been in that through many outbreaks and flu to some degree as well. Part of what casey was pointing out and others on this panel, we need this time to be different and we need to really organize ourselves in a way where there will be accountability for sustained action and not just response. So lets talk about the science a little more. A controversial person but interesting to me, has written that he thinks we ought to have a vaccine such that if you take off in a plane from hong kong and are infected, by the time your plane lands in new york, there ought to be a vaccine assembled and deliverable to you. How crazy is that . How far are we from that . Will we ever get there . Im not going to say how far away but i dont think that is to that isnt crazy. If we moved it synthetic aced vaccines, we remove the dependencies of thinking the vaccine has to be something we have to grow into something else, an egg, cell, insect cell, any dependence on growth. Syntheticbased, those sequences can be rapidly shared around the world. Enzymes that can synthesize the small fragments of messenger can be made in a shoebox size system right now, which is translatable into 3d printer four Inkjet Printer like. Putting those in a system to print those on a patch that is selfadministered, the technologies are out there. We havent demonstrated their effectiveness and ability for a vaccine, but it is not too crazy to think that an outbreak of a virus could occur in china somewhere, we could get the rna sequence from that, being it to a number of regional centers, if not local or in your home at some point, and print
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