 It's always a little challenging to be speaking about research, particularly right after lunch. But I hope that the panelists who have joined me and some of you out in the audience upon whom I will call, will really be able to talk about how this relates to the challenges that we're facing in the field and how this will change what we're trying to do. As I was thinking about it, what we're asking technologies to do largely is to help us bridge the gap between what is controlled today to elimination, whether we're replacing drugs and drug strategies or we're replacing diagnostics with somewhat different tools that will accomplish different goals or potentially introducing entirely new constructs like a malaria vaccine. Now, this concept of bridging that gap is really important because over the day and particularly last night we had almost two conversations going. One was a control conversation, what we're doing today to control malaria. And then the other one was an elimination conversation in which we're talking about the infectious reservoir and different strategies that are going to have to be taken. Ultimately, these will need to be combined. It will need to be one strategy. But we're not quite there yet. And so the job of this panel is to really address what innovation can bring. And I really want to emphasize that for whether it's polio or smallpox, even Rinderpist had moments where innovation saw some of the problems that they were facing. And I think that is actually accentuated when it comes to malaria. So let me ask Chris Plow to start off. I was fortunate to engage with him as he was leading some of the work on malaria on drug strategies. So I know who to call. Thanks, Gina. So I'll try to set the stage a little bit for conversation about drugs and also some of the other technologies and tools in the pipeline. But I first want to go back to the notion of the Gina just brought up about control versus elimination and what we're talking about doing here. So when I was a medical student working in Kenya in 1986, loosely supervised by somebody sitting here who was in the military at the time, we went out and did a survey pricking the fingers of adult men in western Kenya in a village called Saraditi and checking under the microscope who was infected. We surveyed 100 men, none of them had symptoms of malaria, and 90% were walking around with plasmidium fulciferum parasites in their blood. So we've known this is the case for a long time in Africa where there's a lot of malaria, people build up immunity, people can tolerate parasites after enough years of exposure without being sick. So we talked about the asymptomatic reservoir. What's a surprise to us is that we always thought that in lower transmission settings, Asia, Latin America, this would be very rare. Anybody who is experiencing infection should get sick because they don't have immunity. But with some very sensitive diagnostic tools, molecular diagnosis, we're learning now that perhaps as much as 40% or more of people on the Thai Myanmar border, for example, might be walking around with asymptomatic parasites. And this really changes the dynamic of surveillance, drugs, and ultimately even vaccines, what we want these tools to do. So with that as background, I will say that the diagnostic tests that are being used to show these kinds of shockingly high levels of infection in Asia are not something that we can roll out, not something that community health workers can collect the samples and do. It involves drawing a couple of mills of venous blood, you actually have to centrifuge the sample out in the field, do some other fancy things and plunk it in liquid nitrogen. That's not scalable. So what we're trying to do is take technologies that are very promising, tests that can do exciting new things, and really get them to a stage where they're robust enough to work in the field in scalable conditions. And Paul Labari will talk more about some of these technologies in just a minute. If we're trying to use drugs, one of our earlier speakers mentioned targeted mass treatment, where it's basically using drugs to eliminate all the parasites in the human population. The reason I put the eyes of the hippo up there, as opposed to the tip of the iceberg, is to give you the sense of this very large amount, this very large reservoir that you can't see. The eyes of the hippo represent the clinical malaria. It's just a more tropically appropriate analogy. I'm glad you told us what that was, because it's not entirely obvious. Those are the eyes of the hippo. That's the malaria you can see, the clinical disease. And what we have to tackle if we want to eradicate malaria is everything that's under the surface of the water. So if we're going to be using drugs to treat people who don't have symptoms, and that's what we're talking about now, that's being piloted along the Thailand-Myanmar border, and soon in other parts of Myanmar as well as Vietnam, I think, and Bangladesh, and elsewhere in the world, these drugs have to be extremely safe because you're treating people who aren't sick. They need to be effective in Southeast Asia against artemiscent resistant parasites, and ideally they should be administered in a single dose. So they're something that you can give in a campaign and not to have to have people coming back when people aren't sick, they're not as motivated. So there's been progress with some promising new drugs that are in early stages of clinical testing. A lot of this work is supported through the Medicines for Malaria venture, notably with some partners in the pharmaceutical industry, Novartis in Glass of Smithcline come to mind. None of these candidates yet are ideal. To finish when the very long-acting drug the U.S. military has also been involved with is something that requires some testing before it's safe to use. Others have multiple doses, so we really are years away from having a drug that's going to be widely available for elimination indications. Vaccines, again, we're not talking just about the clinical disease, the eyes of the hippo. There is a vaccine that I'm sure Ashley will talk about, RTSS, that's moving toward licensure that has efficacy against clinical malaria. We don't know what that vaccine will do to the risk of transmission. And so I'm sure we'll hear more about next-generation vaccines building on the success of RTSS from Ashley. There's been some really interesting results recently from a very different approach with vaccines taking the whole organism that's been irradiated in the mosquito, something that was tried at University of Maryland 40 years ago. If you give 1,000 infected bites from irradiated mosquitoes, basically using the mosquitoes, a needle and a syringe, to immunize with an attenuated whole organism vaccine, eventually you can get protection. So we've been involved in some tests with scenario Steve Hoffman is here and recently in a study done at NIH, much of their support for this, by the way, from NIH in a very small study, 100% protection was achieved against experimental challenge. So this is now moving into the field. There are many obstacles to getting this ready to go for elimination, but something that completely abrogates infection, that prevents not just the clinical disease above the surface, but the infection below the surface is what we're going to need for elimination. So that's the kind of approach that will be needed. There are more kind of high-tech approaches just from a finger stick of blood the same way you get blood for a rapid diagnostic test or for microscopy. You can actually now get genetic information from the whole genome of malaria parasites and there are ways of then analyzing that information to try and predict the parasite migration patterns, where parasites are genetically communicating with other populations and potentially highlighting areas of risk. When I talk about this kind of work, I'm challenged by people from the Gates Foundation, for example, is this information that the NMCP directors are clamoring for right now that the people in the field need. And so I think the onus is on researchers to show how this kind of information can be actually made useful to make decisions right now on what's needed for controlling and eliminating malaria. But I want to come back to something that we've been talking about intermittently throughout the day and that's the political will. I think even with some of these higher-tech approaches, high-throughput molecular surveillance to map infection or drug resistance, we shouldn't underestimate the political will benefits of a pretty modest investment in capacity development in the malaria endemic countries. We're looking here at some pictures from training workshops both in the lab and in the field with surveillance in Myanmar. And there's just a tremendous amount of ownership and buy-in you can get from working with the local partners to analyze samples in the country, not ship them out and to establish the capacity for surveillance. And I think ultimately for this to work in the long term, as we've heard in the finance discussion, the countries are going to have to invest. And if this is seen as something that the development partners are doing and kind of owning, it's hard to imagine how we're going to get the kind of local buy-in that we need for the long-term success. So I really want to emphasize that. And I will just say, apropos the last discussion on the upper right there, you're looking at somebody who was once living and working on the border, attempting to overthrow the Burmese military, standing next to a brigadier general who is a malariologist and one of our partners now on malaria control and elimination. So I think if this can work at an individual level, I would hope it could work at a military-to-military level between the U.S. and Myanmar. And my last slide just to kind of finish up then kind of takes a step back to highlight the importance of cross-border collaboration and cross-sectorial cooperation. On the bottom left is a border post between China and Myanmar. On the upper area there is a refugee camp on the China-Myanmar border. And then on the bottom right, there's a river crossing. And a kilometer away from the official border crossing, you have people coming back and forth from the jade market in China into Myanmar. And this just, again, highlights the importance of having tools that can be used in these kind of settings and refugee camps and in areas where there's not much infrastructure. And on the bottom right, the building on the far right there is actually the Ministry of Health of the Kachin Independence Organization. So this is an area of Myanmar that neither the military nor the civilian government has access to, but working with the Chinese CDC, you can work on this in this part of the world. And we're beginning to do surveillance here. So as we talk about these tools, I think we always have to bring it back to what's really going to be scalable out there in the places, in the border areas where we need to be working. Great. Thank you. Won't you pass it down to Ashley? Thank you. We've seen a huge shift in the focus of malaria vaccine development over the last few years. Back when resources started to flow into translational R&D for malaria vaccines around, you know, 2000, the focus was really on developing vaccines that could minimize the disease and death in the highest burden population. So young African children exposed to felsiparum malaria. And there's been a, as we've discussed today, you know, a big shift towards not just focused on that population, but more broadly the role that vaccines could potentially have in elimination or eradication of malaria. A lot of the gains that we've seen over the last 15 years have been down in the absence of a vaccine. And so we shouldn't take for granted that a vaccine is absolutely essential. And I think the next slide I find is a really, you know, great example of what a vaccine could have done to leverage some of the gains that have been made by other interventions over the years. So this is a very nice review article that looks at 75 different resurgence events in 61 countries from the 1930s to the 2000s. And the main take-home message from this article is that almost all of these events, over 90% of them, were attributed in part to weakening of control programs. So you can see pretty much across the board here, and there's more examples in the paper, but if you look across the top three, these are all parasite prevalence data. The others are on malaria cases. But if you look across the top there, the impact of various other interventions to get transmission down to very low levels has been proven over and over again. But as soon as you pull back, then the parasite comes back with the vengeance and within a few years you're back where you started. So we really do look at this data in the context of the role that a vaccine could have had to harness those gains and leave those individuals when you were maybe forced to move out of those populations, political well-died resources were limited, that you could have left those individuals with an immunity that they would have carried with them independent of their behavior during the days and the intervening months and years. So I think this is a really good example of how we see vaccines for elimination, really leveraging what can be done with other tools to get transmission down to very low levels and then have vaccines really do the job in terms of preventing reintroduction and reinfections. So I think our timing was probably as bad as it could have been in terms of the first malaria vaccine technology roadmap, which was an effort that involved hundreds of people around the world to define what are the real goals for malaria vaccine development. And this was published back in 2006 with a lot of involvement from WHO, many of you in this room, to really define what are our goals? What are we trying to achieve from malaria vaccines? And the strategic goal was a highly efficacious vaccine against Plasmodium falciparum malaria that could be implemented in young African children by 2025, and then a landmark goal of 2015 to develop a partially efficacious vaccine, 50% efficacy against severe disease and death. And that's what we were working for. I think it's sort of from 2000 on, this was really the main focus, this was solidified in this roadmap in 2006, and then of course in 2007 the field began to shift as the call for a renewed focus on elimination and eradication came. So over the last few years we've been working very closely with WHO, all of the other funding agencies, the Gates Foundation, USAID, EU and others to define a new set of priority goals that are really aligned with where the field is today in terms of not just thinking about vaccines to minimize disease and death, but more long term the role vaccines might have in elimination and eradication. So the original landmark from 2006 still stands and RTSS GSK vaccine that we've been very heavily involved in developing a path malaria vaccine initiative has the potential to achieve the landmark goal if it receives a positive recommendation as early as next year. So that landmark is still in play, but now the goals going forward are really focused around two endpoints. One, a vaccine with high level of protective efficacy against clinical malaria. This is both falciparum and bivax malaria. And then goal two is really the new one which focuses on vaccines that reduce transmission of the parasite that are going to be particularly important for supporting future elimination and eradication efforts. In alignment with this roadmap, the WHO has led a process to define what are called preferred product characteristics to give further guidance to vaccine developments on what the key parameters are for vaccines that could be favorably reviewed for pre-qualification, things like the number of doses, how those doses are administered, the thermostability of the vaccine and what have you, and those preferred product characteristics should be available over the coming months and will be important in guiding future decisions and investments in malaria vaccine development. So we've got long-term goals with the roadmap which is really important for us to have. In terms of the short-term goals, in the next few years obviously the 2015 landmark goal with RTSS, we're all watching that. The preferred product characteristics that I mentioned to guide the development of vaccines that are going to meet those new technology roadmap goals. And then the regulatory approval process for transmission blocking vaccines is a challenge. We've made a lot of progress over the last few years working with FDA including some discussions in the last few months to define what the pathway would be to license a vaccine that doesn't provide a direct immediate benefit to vaccine recipients but provides a community effect through high coverage and high efficacy and we may get a chance to talk about that a little bit more when we talk about some of the key challenges. I think in the midterm, hopefully we're going to do this before 2020, maybe in the next couple of years, evidence that the high level of efficacy that's needed to support elimination agenda could be achieved hopefully before 2020 including with platforms that are really fit for purpose for implementation in endemic settings. Just to finish, this is the global malaria vaccine pipeline. We're starting to see some new transmission blocking vaccine candidates coming on. Those are shown in yellow here. These were not on the road on the pipeline a few years ago. These are vaccines designed to induce immunity that can block human to mosquito transmission, the herd immunity effects I mentioned. Very heavily represented a prerecitic vaccines as you might expect can prevent infections as well as provide a direct and immediate benefit. So the best of all cases really these are all shown in pink. And then in blue you have the blood stage vaccines which are really primarily focused on the individual benefit from prevention of clinical disease. And we've definitely seen a somewhat of a waning in the pipeline for blood stage vaccines as there's been a resurgence in the focus on elimination and eradication. I think a point I wanted to make on this is really the importance of a portfolio based approach to achieving these malaria vaccine development goals. Until you get through phase 2B data, we really do advocate strongly that investments are made in the context of a portfolio that enables trade-offs to be made as new data emerges and that we don't commit ourselves too early to a single vaccine approach and certainly until it's reached proof of concept in the field and then of course it makes perfect sense to advocate for a product specific investment in alignment with a specific target product profile as we've seen with the RTSS vaccine. So with that hopefully that's a helpful introduction. Great. Thanks for setting that stage, Ashley. Sorry? Thanks for setting that stage. Great. Now, Paul. Thank you. The world of diagnostics. Great. Thank you, Stephen. Thanks, Gina. Thanks, Katie and the rest of the CSIS team for setting this up and inviting me to be on the panel here. I think many of you guys were thinking that you might make it through an afternoon of elimination discussions without seeing a single iceberg, but scrolling through a few more slides here, we'll get to it. There we go. There it is. The iceberg. And very similar to the eyes of the hippo, I think the iceberg is a great way to describe what Ellen referred to as defense above the water. Very successful efforts over the last couple of decades in attacking the clinical side, but the offense needed for the asymptomatic reservoir is really going to require new tools and a transition or a bridging period, as Gina's been referring to. Good question. Last night we talked about the advances in technologies and the ridiculous amount of new tools that are available. And perhaps it's easy to have one lulled into the thinking that maybe we don't need new tools in the area of diagnostics. I think this is a good example that Lisa White's been using to describe how inadequate current RDTs actually are in detecting the asymptomatic reservoir. So what you have here is a cohort of PCR-positive malaria specimens that they've detected the DNA to prove that each of these specimens can, in fact, transmit the disease. And yet the RDTs in the bag represent all of the negative tests from that cohort, and there's only two positive tests in that cohort. Now, I'm not quite clear on whether this is representative of all RDTs. I suspect this had to do with the specific commercially available RDT chosen. But I think in general that the statistics I've seen is that up to 90% of the asymptomatic DNA positive tests out there are, in fact, RDT negative. And so I would argue that, in fact, we really do need some advances in the world of diagnostics in order to see that lower part of the asymptomatic reservoir, the lower part of the reservoir underwater. The question is, how would we use them if I could advance? There we go. How would we use those tests? Well, if you look at the upper part of this graphic, this is a framework the diameter team created to help work through the discussion of how diagnostics are used. And the symptomatics or the clinical cases are covered really in the control phase through passive case detection. People are walking into a clinic. And that's relatively not so complex as compared to all of the different use scenarios for how diagnostics get used in the elimination context when you're seeking that asymptomatic population. We call those active infection detection because you have to actively go out and find these people. It gets more complex. We talk about reactive where you're reacting to an index case or proactive where you might be going into an area of unknown malaria and trying to find out whether that's a hot spot or not. It gets even more detailed than that. I won't go into the details, but it is a much more complex set of use scenarios. And sometimes the actual performance characteristics for one use scenario might be in contrast to the use or the performance requirements for another use scenario. So building good target product profiles is really key to product development in this area and getting the users of those tests involved. At the bottom, we have laboratory testing. And as you go for the asymptomatic cases, the actual parasitic density goes down. So whereas historically microscopy has been an excellent gold standard in the control phase, it is, in fact, a static measure of a dynamic infection. And in fact, we really do need reference tests, laboratory tests that are capable of 10 times to 100 times or even better limit of detection than currently available with microscopy. So how are we doing in that pipeline? Well, it's not a very rich pipeline compared to vaccines. And I think we've got a lot more work to do. This is a pipeline. It's an abbreviated pipeline, representative of some of the leading technologies that are under development and working through towards commercialization. And it's a lot more rich than it was, say, five years ago. A lot of good money has gone into R&D. Working through this, you can see there's really three categories. We really do need true positive point-of-care tests. So you can go out and conduct that active infection detection with a test and treat people on the spot. You don't want loss to follow up. You don't want a three-day gap. So the positive test at the point of care is really important. The IDT initiative led by the Gates Foundation, the diameter team at PATH, is the managing partner of this initiative, is advancing an HRP2 or an antigen-specific infection detection test. Using the form factor of R&DT is why? Because this is an accepted form factor. It's got an ease of use that's hard to beat. We want to get more of these out there. We want them more sensitive so that we can support the active infection detection. Isothermal methods have come a long way. Are they really point-of-care tests? Well, there's a lot of gray area there. You've seen some commercialized lamp tests and also a lot of more research going into isothermal looking at Vivex, higher throughput tests, other isothermal methods listed there, helicase-dependent cross-priming amplification. I think really exciting, although it may be a few years out, is the idea of being able to have a non-instrumented or an electricity-free disposable version of molecular. There are some efforts in the product development pipeline focusing on that. There you would have the ease of use of an R&DT. You throw it away after you're done, but you have the accuracy of a laboratory-based test. For a true positive lab test, as I said, you really do need very, very sensitive reference methods. And in the pipeline are PCR for both DNA, which is a high volume, high blood volume test, as well as PCR for RNA, which allows a much smaller, even a finger stick volume of blood. If you're going to have an HRP2 infection detection test, well, you really do need reference standards that are even more sensitive in the laboratory. And so that's why we have the HRP2Q ELISA reference method there. And then finally, there's the same in quality control and manufacturing that you can't quality inspect something that you can't measure. And if our goal is eradication and the elimination of parasites from the human reservoir, then you actually do need a tool to measure that. And so you absolutely need a true negative laboratory test, where you can go out, take specimens, and demonstrate that a population in general is negative and that transmission hasn't occurred for a number of years. And serology is an excellent measure of that if you start looking at age-specific co-parts. So with that, my last slide here. Oops, we're cycling through. I don't know what happened. Give me a second. Just a few take-home points. There's really no silver bullet. Hopefully one of my slides indicated that there are many use scenarios and probably no one tool is going to fit all the needs in the way that RDTs have been really instrumental in a one-size-fits-all for control recently. New tools can create temporal and cost efficiencies for malaria, that should say malaria elimination programs. Unfortunately, the market forces are insufficient to drive innovation. And we've seen this with RDTs. We've in fact seen the opposite, where the market forces have been a force against innovation. And unfortunately, it may be the case that the scale of the markets or the economies of scale that we're used to seeing with RDTs may not apply in an elimination context, depending on how many countries are adopting the same tactics and therefore the same tools. So it's something I think we want to do some market shaping to make sure that we can try to achieve the same economies of scale. User-friendliness, you can't underestimate that. And I think going with platforms that are familiar can get you an operational sensitivity much better than platforms that are difficult to use. And then finally, there's a lot of innovation piled up. Right now, a lot of that has to do with unknowns. We still don't know everything about the heterogeneity of malaria and the differences between how tactics and tools may be used and successful in one area and not another. And so I think we still have to do some basic research and also move that up to the level of new policy and consensus at that level in order to drive innovation. Great. Thank you. Now, do we have a microphone? Great. If you could hand it to Dr. Steve Hoffman up here. He's in the middle right in front of me. And the question for you, Steve, is, first of all, in terms of acceptability, you are working with a novel classic approach which requires IV formulation. I'd love to hear what kind of response you've had from people in country where you're doing studies about the acceptability of that kind of a strategy, which is very different from any other vaccine. And then could you comment on what engaging with research community in Africa and Asia, wherever you're doing your studies has been like, because you're taking a very different approach to working in product development. Well, how long do you want me to talk for? You get a minute. So let me just go back about to 2009 when there was a meeting convened by the WHO in Senegal about whole parasite malaria vaccines. And there were a number of individuals from institutions that you may have been associated with before and others who stood up and said, it is impossible. We will never accept a vaccine that is IV, for example. Right. What we call now direct venous inoculation. And the next morning, seven African scientists from seven different countries stood up and said, you give us a vaccine that works. We're going to figure out how to administer it. As you well know, we've been studying our vaccine, which is given through a 25 gauge needle of 0.5 ml in Mali, in Tanzania, in Equatorial Guinea. And so far, we haven't gone to children, but we will soon be an infant. In Mali, they've given 500 consecutive injections in less than 10 seconds without a miss. 60% of the injectees don't even know that they've been injected. So I think the answer is, and I would like to extend that. You mentioned about the target product profile and so on. The target product profile has to start with being sensitive enough. A vaccine has to start with being effective in us. And the idea that in the 21st century, we have a job of getting a highly effective malaria vaccine or a non-PCR, highly sensitive diagnostic or a drug that works in a single dose for all parasites. And my view, and as you well know it, and its scenario has been, let's get that first. The idea that we can't figure out how to engineer getting that to people, I think is just to try to start with practical and then move towards effective when you don't have effective is not the way that we've chosen to go. So the answer is that our colleagues in Africa who are clamoring for this have never once said we can't do it. They just said, let's see if it works and if it works, we'll figure out how to do it. Great. Thank you now. Lift your hand. No, no, no, lift your hand. Michael, could you take the microphone please? So you will notice we've had people talking about drugs and diagnostics, vaccine strategies, and wait, wait, you got up, you got up. Sorry, the back of my head is kind of ruined. It's okay. All right. And because we couldn't keep on inviting more people, we can't hit absolutely everything happen. It's a very rich field right now. But there's a very important area that's not on the table, which is vector control. And I didn't want to talk about insecticides because hopefully there's insecticides being worked on to replace or offer alternatives for insecticide resistance. But if you could address a little bit of the novel paradigms like spatial repellents, et cetera, just let the group know the richness of what's coming along. Okay. Thank you, Virginia. I have to apologize. In the last session, it was a shameless attempt to get the names of the mosquitoes on the record here. And fortunately, we do have Fred and Martin. We'll be talking in the next session about entomology. I think it's often forgotten that there is a lot of innovation going on in the vector control field. So right now I'm doing some work with the Innovative Vector Control Consortium. There is work with insecticides, as you said. Just to make one point, though. Although vector control is more than 60% of GMAP of our investment in malaria, when you look at the global insecticide industry, the pesticide industry for agriculture is about 54 billion per year. With vector control, it's less than a billion. So we have the same issues with MMV, MVI. It's the public-private partnerships to develop these new products. So there is a lot of work going on with new formulations, new insecticides, et cetera. But for innovative products, there is work going on. And a lot of this was started, again, from the AFPMB, the Armed Forces Past Management Board, in their deployed warfighter protection program. But looking at treated materials, repellents, spatial repellents. And we have a number of projects now with IVCC looking at push-pull strategies where you have a spatial repellent combined with a trap to push the mosquito into a trap. There's other work going on with attractive toxic sugar baits, trying to get the mosquito, interrupting the mosquito's life when she is looking for a carbohydrate meal. Some other things with swarming, et cetera. So there are a number of little niche issues going on. But I think what's important to stress is that we will never have a magic bullet, as Paul put up here. We will never have a magic bullet like we had with DDT, like we had with pyrethroids. Everything now, I think, moving forward will be much more niche products. Things that you can use, not globally, but in certain situations, spatial repellents save for funerals in Africa. Topical repellents or treated clothing for rubber taffers in Burma. So much more niche products. And this requires people. And I'm glad that the very first session with Alan and Bernard mentioned the issues of systems and capacity building. Because without the environmental health technician, environmental health officer, the public health entomologist, we don't have the capacity to adapt these new tools that are coming to a specific situation. So we often joke about the gray hairs and the no hairs in our business. And fortunately, I think there are a lot of good young entomologists coming up for the next generation of public health entomologists that can really develop these innovative vector control tools, thinking that we will not have something at the magic bullet that we had for our generation and previous generations. Thank you very much. So to bring it back to the panel, clearly there are a series of innovations and probably more than we can swallow. There's a pipeline so that we can optimize and choose the best of what will work well and what will be acceptable and what will be usable. Has industry remained engaged? And let me just ask you to opine that, because we've gone from a control scenario to an elimination scenario. And there's unknowns about what the scale of manufacturing is required and who's going to pay for it because you're not dealing with treatment of acute illness for which people are willing to pay. These are different public health strategies. Has industry remained enthusiastic and engaged? And let me start. We'll start with diagnostics. Sure. Thanks, Gina. Has industry remained engaged? Or are they? Are they engaged? Well, I think that's actually two different questions. So the first question, as I said, there's been disincentives to innovation driving down the price of RDTs, rapid diagnostic tests over the years have certainly provided a disincentive. And I think so that's where some of these in-between players like PATH with Gates Foundation funding can create that incentive through product development partnerships to recreate that. So in fact, getting them back engaged is part of our product development plan. And in fact, although I can't disclose who we're working with right now, we certainly are working with some of the same players who have the broad distribution reach and a history of high quality and have the R&D capabilities to move forward with new tools. Ashley. You know, our TSS will, whatever will happen will happen. What about the pipeline following? Are those academic constructs or is industry engaged? Yeah, I think when we think of industry I really group it into two because I think they're so different. I think pharma and biotech, you know, are very different industrial partners that we work with. So I think our experience with pharma, obviously with GSK has been there's been a commitment to malaria vaccine development all the way up through the senior management, which I think is critical. We haven't seen that with other large pharma. So we've tried to engage with biotech artists and Concernofi and you get tremendous enthusiasm with the scientists and you'll get so far but when push comes to shove there isn't the commitment there to put the resources onto these projects. So I think you need the commitment all the way up to the top if you're working with large pharma. With biotech it's very different. I think there's a lot of enthusiasm in biotech in sort of proving their technology and because we have these fantastic challenge models and exciting space for them to work in in terms of proving that their technology can do something in such, you know, preventing infection in challenge models and what have you. However, working with biotech, you know, you've got groups with new technologies don't always have the most experience in manufacturing their product and that can lead to some delays and challenges. So we see industry as critical particularly for platforms but it's a very different space. He's extremely enthusiastic. Pharma is concerned about success because success comes with a huge obligation and they understand that and they have to manage it. So I think they're very different but for us clearly, you know, these commercial partners are critical to what we do and of course then we also rely on the academics to bring through novel target antigens key assays and model systems and things to support that. And I think that's where the PDP model works so well that we bring all of that together. You've got to bring together a GSK doing assays at Hopkins with some new antigens coming through somewhere else and bring all that together and that won't happen. I don't think that'll happen organically without somebody driving it and that's really what we see as one of our roles. Chris, I know you don't work for MMV but you're aware of their portfolio specifically for the CERCAP single dose radical cure type drugs is industry engaged? Well, I think, yeah, broadly for drugs, industry is engaged but you asked two questions, are they engaged and are they enthusiastic? And so, you know, industry is engaged to some extent and there is some enthusiasm in my experience sometimes that's a personal thing where the family member of a CEO spent time in Africa and got interested in malaria that's how Pfizer kind of got into looking at quark and azithromycin where you see the enthusiasm tempered though I think there's a much lower risk tolerance for risk and it's not going to be a big blockbuster for cholesterol lowering or electrical dysfunction or whatever when it's something like malaria so anything that can be done to mitigate risk whether it's liability for vaccines or whether it's kind of looking at markets up front for vaccines or drugs is going to help because I think the level of enthusiasm is just marginal for these products and it doesn't take very much for the pharma companies to pull back so like the Gates Foundation has done for and others for vaccines and even I'm sure this is true for diagnostics the more we can kind of get out ahead of anticipating who's going to pay for it what are going to be the risks to the manufacturer and how can we kind of increase their comfort will be important to do So the question then becomes because at some point I mean pharma generates innovation and innovative ideas product development partnerships creates a group of people who can do different components and have historically done so but eventually some kind of company needs to manufacture product fix and so that it is usable and the question is in 2014 basically almost 2015 what should we be thinking about doing to make this whole enterprise more successful let me just open it up to you first and then we'll see what other ideas people in the room have let me remove money from it yes we need more money let's just take that as a given we used to speak of pilot lot manufacturing for vaccines being a huge barrier I think there's lots of providers of that kind of capacity in fact they're competing with each other we used to have problems with protein manufacturing and the appropriate folding that's not a problem we used to have problems with quality control or the diagnostics and more systematic approach was taken to make sure that the ones that were out there are good quality we didn't have a pipeline for drugs now there definitely is one you didn't show the picture but there's definitely one what would make I'll take a first I'll take a first step at this I think we need to think of it not as just research and development moving to development moving to commercialization with perhaps a tech transfer from an academic to somebody who has market share I think we have to think of the overall architecture of the vision of what's needed and engage all of the parties including the policy makers and the regulators early on in the conversation engage them as members of that if not advisors to members of that product development partnership because I think what can very often happen is that you get to the point where the technology is there you've validated it to your specifications and then you find out that's the stopping point that there isn't this receptive energetic population market ready to receive it so I think especially in the case of of new tools aimed at tactics that are influx and still being developed and validated I think we need to engage everyone and make sure that they move forward and lock step together so it sounds like the kind of what you're saying is we need to think harder and be smarter about what we're asking for and mean it because if we keep asking for a variety of things and then end up not using them we won't have too many times at bat that industry will say no we don't really believe you and that's where we used to be 15 years ago so I kind of worry about because I see all this wealth of innovation different kinds of constructs from a field operational view that's a little overwhelming I would think are there any people here that are worried about how you're going to take on all this innovation who's going to pay for it train for it and is it worth it how you make that decision or are you all fine with it someone yes Steve so I'm actually not clear on what you're saying so if we start with diagnostics and say we just heard we need a highly sensitive easily executed diagnostic we don't have it okay I mean so we're not asking for a symptomatics it means highly you know you have to recognize parasitemia at a level below you know the most sensitive thick blood smear for two or four parasites for microliter but practically 50 parasites per microliter so you need to have that we have test PCR that we can do that with right now but it's not practical so the question then becomes are you know we heard about a program are we engaging all the people that we could in such a program do we have all the technical experts working on it that they could be and then you raise the question is how do we do it all right so what's the incentive well the incentive really is only going to be that you know UNICEF the Gates Foundation the world community is going to buy this stuff because there's nobody out there going to pay for it otherwise so you have two types of clarity of what the strategy is and I think that's what these documents GMAP and GTS where if we're clear that the strategy is elimination and that's what we're moving to that there's missing that will solve problems that people aren't grappling with yet that's a huge transition we need to make that we haven't made yet and that's kind of the point I was trying to get to okay I mean so I think that that's important you know and it's the same thing whether it's for vaccines or drugs what you needed for you know we need a drug vaccine that's 100% protective for life in one dose okay that you give under your tongue right but it's not going to happen you know in my lifetime exactly the person with the red tie behind you please say hi yourself I'm Roman Makaya the ambassador of Costa Rica I find this a topic fascinating you've been talking about level of enthusiasm for developing this type of technology and if the enthusiasm isn't there then you need a proxy for enthusiasm how can you achieve that there's been discussion on for example patent extensions that in other words if you developed a drug or a patent a vaccine that fits certain criteria you would get sort of a coupon to extend a patent of your choice so it wouldn't necessarily be you wouldn't necessarily be making your money on the malaria vaccine you'd be making your money on extending your patent on a very lucrative drug and you know however this is paid for there has to be a transfer of investment or wealth from the rich to the poor because the base of patients is not going to be able to pay for this so getting the incentive right is critical we've seen it with orphan drugs where drugs weren't developed for rare diseases malaria isn't a rare disease but in the orphan drugs situation giving a monopoly a temporary monopoly on the treatment of the disease created the incentive so what is the incentive for malaria I mean there has to be something that attracts investment into this field and I'd like to hear you know what other ideas have been discussed and which ones do you think most likely to succeed in creating that incentive others? I'm Bob Guads recently retired from the NIH and I suppose my fact of the appointment is the Collegium Medicum of the Agalonian University and I'll give a nickel to anybody who knows where that is it's 40 years from essentially from the publication of the concept of transmission blocking immunity and now we have a pipeline just to show you how long these things take but that's not my interest I'm an entomologist we don't know anything about the vectors in the Mekong Mike mentioned dires 20 years ago, 10 years ago you would have said dires is the vector all over the place in most of Cambodia it's almost impossible to find dires now it's a forest mosquito the forests are gone there are 26 potential vectors in Cambodia and minimus may be the most important but who knows what we don't have amongst all these entomologists you talk about are biologists every entomologist now gets up and says well here is the molecular structure of such and such but if that mosquito landed on their hand they wouldn't know what it was we need to appropriately train people we have a question down here my name is Wilson Magaya from Zimbabwe I heard something about materials that can be treated and such small interventions and I'm wondering why we do not have those on the ground I came across a blanket that was tested by in Africa University and we tried to sell it as a private sector drive and we're told we needed who approval we needed to get certain paperwork but the chemical that was being used is already approved it's EPA approved here in the US and the university actually made a blanket infusing that chemical now to interest the big funders here we couldn't get any interest in it the question then is the discussion here seems to be happening here we have researchers in Africa who are trying these small things is it possible to take maybe 5% or 1% of all R&D funds and put them into these small things that can actually be done now and people try them out and say they work or not thank you and I think there are some limited funds for that kind of concept testing sort of the grand challenges exploration Canada or grand challenges exploration when there's a malaria topic there's a lot of innovation to test concepts but clearly just as innovation comes from academia in the US and Europe we also need to look for innovation coming from academia in Africa and Asia so I think that's a really good point yes Michael you want to respond to that Michael just respond to that by the way you need the microphone because otherwise people really can't hear and it's a very isolated blanket and not to say that we're completely useless but it has gone to the vector control advisory group for WHO so it is under consideration by WHO now and again coming back to the issue of niche we're thinking of this not for general populations so much but for South Sudan for CAR for displaced populations outside the house so again coming back to what I said earlier we may not have this one magic bullet but the niche products that I think will in total when you add them up will make the difference having just two minutes left I want to highlight this chair how different the discussion is today than it was 14 years ago when I first became involved in this field there's a pipeline there's a pretty robust pipeline and concepts there are pools of money for development not of all of them but for those that meet certain criteria there's probably innovation money for testing of smaller concepts and I think compared to where we were in 2000 when none of the tools that are being used today were being used we weren't using long lasting bed nets we weren't using insecticide treated bed nets we weren't using RDTs the companies would call us that we have them no one will buy them we weren't using ACTs remember this is before that painful article came out in the Lancet saying WHO is killing babies because there's no recommendation for this these are innovations that now are old but they weren't being used at that time it doesn't take a lot of vision to look at the pipelines that have been described in this very humble small session and realize that it is quite likely that the tools that we will be using 10 years from now will be quite different and will perform differently than those that we're using today and so the challenge is really one for all of us because managing that kind of innovation influx is going to test every single part of the system but hopefully it could make it much more effective and ultimately much more efficient and I think that's the promise for the future thank you very much