 Good morning. Let's get started. Let me do a self-introduction. My name is Greg Yan-Yan. I'm a professor in public health, so I don't come here this seminar very often, as I travel quite often for my further international research. I'm really delighted to introduce our seminar speaker Dr. Mark Benedict. Mark received his bachelor's degree from the University of Florida, and also PhD from the University of Florida. And after that, he did a post-doc at the University of Arizona. This is Mark with K-Level, so on the general transformation of drosophila and mosquitoes. And then he did a short post-doc at the Emory University. Today, Mark worked at the UCDC Center for Disease Control for a long time. And a couple years ago, Mark moved to the IAEA International Atomic Energy Agency, an engineering agency, working on the mosquito control in Sudan using the sterile male mosquito technology. So Mark's interest is on the mosquito genetics, ecology, and the control. So he has done a wonderful work in this area. His author and co-author for more than 80 publications has consulted to a number of mosquito control programs, including the Geeks mosquito control program using genetic modification approach and the WHO vector control programs. I'm really delighted to have Mark to come to UCI to give a talk about a program in the public health. And Mark's talk is about unification of the vector pole, vector direction, ground route. Just one announcement after a seminar, there are a few students and invited to go to lunch with the seminar speaker. So I think the place is called Steelhead, probably somewhere in the University Town Center. Okay, bye. So I have to start off by thanking Guy Young for the invitation and for the opportunity to speak to you. But I have to confess that I've totally given up the probability that I'm ever going to get a Nobel Prize for anything. But for many of you, it's not too late. You're very young, you're just starting your careers. And so I'm going to give you an idea. I'm giving ideas a way that are no good to me anymore. I'm going to give you an idea about how you can pursue your Nobel Prize. And the key, I think, if you think about Nobel Prizes, is not just merely coming up with a good idea, not just coming up with something clever and throwing it out there, but it's really coming up with an idea that has a lasting impact upon peace, upon science, whatever the particular prize is. And so what I want to talk to you about today is just an idea that I think is important in the context of malaria elimination. And I'm going to say some rather negative things about current efforts to control malaria, but I want you to consider them that I'm addressing them in the context not of the good that they do for the individuals who are receiving protection, but in the context of my topic, which is malaria elimination. And so if I say something negative and you go, well, people are being saved by this, it's not that I have any problem with people being saved. It's that if we're talking about the long-term goal of malaria elimination, we may have to think a little differently. And the little differently is what I want to convey to you during this talk. The other thing I should say is that other chaos will reign after about 15 minutes of my talk. When I'm going to give you an assignment, I'm going to break you up into groups and I'm going to ask you to do something. And you are going to teach yourselves what otherwise I would have to teach you, because if you teach it to yourselves, you're going to be much more engaged with the concept and you're going to see why it makes sense as opposed to me just telling you. Okay, so malaria elimination, right goal, right direction, wrong road, question mark. To an extent, that's a question that you are going to have to come away from this talk answering to some extent. And the reason I say maybe we're heading in the right direction, maybe we have the right goal is illustrated by this map of the fine university from my hometown of Atlanta, Georgia, Georgia Institute of Technology. And if we want to get to the library in this campus, we can take Plum Street, which is right here. Plum Street goes right for the library. It's headed in the perfect direction. If we go to the end of that, we're almost there. The problem is if we take Plum Street, we cannot get to the library. In fact, we have to take the road that's further west, Atlantic Drive, in order to get there. And so this is just an illustration of what I'm saying. We're heading in the right direction, we've got the right goal, but maybe the road we're taking will not get us where we want to arrive. Do we have a pointer of some sort? Okay, maybe I can use the mouse. So I know many of you are not, you're not deeply steeped in malaria or vector-borne diseases, so I'll give you a very brief introduction. Malaria is a parasite that the transmission cycle of which involves three components, a human in which the gametocytes develop that are taken up by mosquito upon a blood meal. The mating occurs in the mosquito, the parasites move to the salivary glands and then upon feeding on a second human being, the infectious stage is transmitted to the human. So you have to have these three components in continual circulation or transmission ceases. Without the parasite, obviously there's no malaria. Without vector mosquitoes, there's no malaria obviously without people, there's no malaria. So that provides numerous opportunities that people are trying to exploit to interrupt the transmission cycle throughout the world. I say throughout the world that actually most of the risk of malaria is in tropical and subtropical regions. The real focus historically in terms of the emphasis for malaria interventions is sub-Saharan Africa. But it cannot be under-emphasized that Asia and South America also have significant malaria problems. So here we have this disease. It's got multiple vulnerabilities. It's spread throughout the world. It leads to the deaths of at least one million people each year, most of those in Sub-Saharan Africa. So it's a serious problem. There's no question about it. In spite of all these vulnerabilities for the parasite, for the mosquito and personal protection that people might implement, it's a tough problem to solve. Welcome Bill and Melinda Gates. Bill and Melinda Gates were made aware of the problem of malaria and they decided that to allow malaria to continue to kill people after a year was not acceptable. And therefore they decided to bring the very formidable resources of the Bill and Melinda Gates Foundation to gather together not only their funds but also to get the cooperation of WHO, Rollback and Lary and these other organizations to also pool together with the very laudable, if difficult, goal of malaria elimination. And initially they articulated a view of increasing the funding for malaria control in the near term in order to make gains in the long term that were much more economical. So what is shown here are two different graphs in which they proposed very high expenditures against malaria in the short term with the long term result that the number of cases out here and we are talking long term 2040 would be lower than if the support for malaria control were reduced in the near term. The number of cases in the end would be greater. The denominator that they were facing this improved version of malaria control was cost per case averted which was $17 in their vision versus $28. But not only did they propose increased funding against malaria in the near term to lead to greater efficiencies later they went beyond that and this is where they became controversial and that they actually proposed that if such decreases in the number of cases could be accomplished that those arrows point to what? Zero. So they began to think and to widely promote the idea that not only malaria control but malaria elimination might be possible. When I say elimination what I mean is a regional or an area wide elimination of transmission. Eradication would be the global cessation of transmission. That's formidable not only is there one malaria parasite but there are four different parasites transmitted by many mosquitoes. So this is a big job. But they put the idea of eradication back on the table and because they were bringing so many dollars to the picture it got attention of many people. The way that they proposed that this could be accomplished was to begin reducing the burden of malaria transmission in the near term. Once that significant burden of malaria had been attained that sustainable control would be put in place eventually eradication would be accomplished. And how did they propose to do this? Develop new tools. The Gates Foundation is very technology oriented so they want new insecticides. They want more effective drugs. They want new repellents and so on and so on. Any out years these tools would be implemented in some way to lead to eradication. That's all well and good thus far. There are two tools against mosquitoes that are very effective. Indoor residual spraying of insecticide on the walls of dwellings. Mosquitoes come and rest on the walls and then die. The other one is ITNs insecticide treated nets which is simply a bed net treated usually with pyrethroid insecticide. The mosquitoes are less prone to feed. There is some mortality. And both of these have been shown to be very effective. So having effective tools, albeit not totally effective, useful tools was considered to be a key part of the program. It's interesting though, even though these tools appear to be very simple from a social aspect, they're very difficult to implement. There are questions such as should people buy the nets or should the government give them the nets? Who should sleep under the nets? Should the mother and the child? Should they be given to everyone in the household even though they are at great risk as the mother and child might be? So there are multiple questions. On top of that are the other considerations of insecticide resistance, which is appearing widely, drug resistance of the parasites and so on. So we're a little bit weak, quite honestly, in terms of the tools that we have. Even though we know they're effective, they do not totally eliminate malaria transmission. So what if you go into the literature and you begin to read about the different programs that are attempting to reduce malaria. What you'll find are descriptions of many different activities that are going on. But I would argue that if we're talking about elimination of malaria, they fall short of being adequate. So what I've shown here is just an excerpt from the WHO for the Rollback Malaria Program, which is a global program by which reductions in transmission are intended to occur. And what you'll notice on this side right here are several very laudable goals in terms of activities and outcomes. Countries with lowest achievement toward the Abuja targets, which I'm not going to talk about, they catch up to some previously defined goals. Coverage of interventions, and that's primarily and or residual spraying and insecticide-treated nets, reaches 80%. One-third reduction in the under five-year-old mortality rate and so on and so on. All of these things are very good. My question to you is do these goals and accomplishing these goals have anything to do with elimination? And the problem is that malaria is a very difficult disease to remove from the transmission cycle because of its cryptic nature in people. You can have asymptomatic carriers of parasites, of the fact that there are often numerous mosquitoes that transmit it, and you have people moving around who carry the parasites. So if we go back to this graph, the question is do those arrows that the decrease in the number of cases indicate will they actually ever reach zero with regard to malaria? And there's an analogy I like to use for malaria. Malaria is like English ivy, and those of you who have ever worked with English ivy trying to get rid of it know that you can pull ivy, pull ivy, cut ivy, you can fill garbage cans with ivy, and the next season, you'll come right back up and you're right back where you started. And that is very analogous to the current situation with malaria. We're seeing tremendous advances in terms of the number of bed nets distributed, the number of dwellings being sprayed with insecticide, the number of diagnostic tests being performed, the amount of drugs being distributed. But if you're talking about elimination, then you have an English ivy situation. And the question is, if these tools do not completely remove the reservoirs of the malaria parasite and the means by which they are transmitted, we are faced with a situation where we're doing the same activity year after year with no hopes of actually reducing, in a permanent sense, malaria transmission with durable solutions. Okay. So these are things that I think are unquestionable. The exercise I'm going to have you do contradicts to some extent does, but it's to make a point. So I think these things are widely agreed upon. The existing donations are not sufficient for near-term, global, sustainable control. There just is not enough money currently to go around. What does that mean to you? That means that somebody is making a choice about where the money goes and how it is used possibly at the expense of other countries. So the resources are not sufficient. Bill and William Gates Foundation predicts, and I think most donors agree, that the amount of donations will eventually decline. There simply is not enough moral will, if you will, to continue donations at the present levels, much less increase them indefinitely, unless a solution occurs so that the amount of funding for malaria control can eventually be reduced, then we will be back where we were ten years ago. The existing tools are not sufficient for eradication. Only in very special circumstances, islands, areas of low transmission, epidemic, malaria, and so on are the existing tools really adequate. For locations where there's hyperendemic malaria, few would argue that the current tools we have are good enough. That means we've got to come up with more, right? Or they have to become more efficient through some modification. At this point I've described, and I hope you understand, it's a pretty blink scenario if we're talking about malaria eradication. Because we don't have the tools, we don't have the money, so here is your opportunity for your Nobel Prize. That is figuring out a way forward. And in order to help you come up with a way forward, I've advised a very artificial exercise that I want you to complete in approximately 15 minutes. And I had thought originally that I would divide you into small groups, but because of the configuration of the room, I'm going to give you some handouts. I will set up a scenario. I want you to come up with a solution to the scenario. And then at the end of 15 minutes, we'll discuss what your solutions were. And I will be available to give you advice as you go along. Now I think we only have 25 sets of handouts. So some of you are going to have to share. So if you're sitting next to somebody you don't actually absolutely import, work with them. So you'll have to divide these up. There are three sheets. And they describe the setup for this exercise. Okay, what I've drawn here is a hypothetical region. The Democratic Republic of China. Okay, it's corny. I know that. And I've set up a scenario here where there's malaria transmission in these villages. And your assignment as a program manager for using the available resources is to eliminate malaria transmission for the maximum number of people. The way I've set this up, in these villages, in each of the villages, there are different numbers of people as indicated on the village, the little hut. The prevalence of people who carry parasites in each village is 5%. I don't know who they are necessarily, but they're 5%. Your objective is to protect the maximum number of people by going through this very simple exercise. Now what's the nature of what you've got to work with? The villages are distant enough that infected mosquitoes or mosquitoes that carry parasites are not moving between villages. Okay? People move between the villages but only by the roads. The likelihood of a person coming into a village who is infectious is the same as the prevalence of parasites in the adjacent village. So if I come from a village that has 5% prevalence, the chance that I will introduce that parasite into the village is 5%. One person enters each village by each of the roads almost each month. If you enter a village and you have the parasite, I set it up so that the likelihood of infection is 100%. Each household contains 5 persons, so that means there's 20 dwellings in each of these. When immigrants come into a village, you know who they are and where they came from. A village becomes malaria-free only after one year of no malaria transmission. And it can become malaria-less again only by reintroduction. Okay? So these are the basic ground rules. Now, I'm going to give you resources in this simple model. You have resources that you can spend. You can carry over anything that's unspent the next year that you can't overspend your budget. You can spend your money on accurate diagnosis, which 100% accurately diagnoses the presence of parasites. You can spend your money on long-lasting nets, which fully protect everyone sleeping under them. But you have to purchase at least one for every two people in a household, or you can spend your money on drugs. A person treated with drugs becomes unaffected, unaffected, but he could become unaffected the next month. And we're only going to give drugs to those who have been diagnosed as having parasites. So what I want you to do, I've given you a cheat sheet on the second one, showing you what the annual costs or the cost of, like, drug treatment and diagnosis is. I've also given you the cost of distributing bed nets. And what I want you to do, mostly in groups, I hope, is you're going to have some people who are going to latch on to this very quickly and say, oh, this is easy, I know how to do this. And you're going to have others who are like, oh, I don't know what he wants me to do. So please, work together. And what I want you to do is come up with a quick budget not only for each year, which is temporal, but stationally, which will address which of the villages you will try to protect when. So the way you win this game, as it were, is to protect the most people possible. Questions. So I'm going to give you 10 minutes to think, how would you come up with a solution for this problem? All right. Go for it. A challenging exercise, especially since you had to complete it very quickly. But in fact, this is very similar to what people, I think, granted, they have more time, but this is very similar to what people have to do. They have limited resources. They have to decide where to deploy and how effective it's going to be in the long term. So now I have a question for you to determine who the winner is. Hands up if you protected at least 100 people permanently. 100 people? Yeah. At least for the duration of this project. At least 100. Yeah. Okay. 200. They got 200. Several of you. 300. Okay. 400. Still not forward. How many did you get? Come on, man. 500. Okay, great. 600. 700. 800. Excellent. How many did you end up protecting? Well, I'm not going to defend this right, but I have 1100. 1100. I think it is possible to protect almost everyone. Can you describe briefly how you did it? Yeah, I first went for village A just because it's 200 to protect diagnosis tree, which I assume that's protecting too. And then also with since I didn't have that much left, I put up the L-L-I-N for village C which was, that was 300 people so far. The next year I took I had 150 left over the dollars that is and then I went for village I which was the second largest and I yeah, I diagnosed and treated J also. Okay. So that was 300 people. And then the last year I just set up L-L-I-N with village K, D, D, F, and E because I figured there's a lot of traffic between sort of outliers, huh? Yeah. Okay. I'm not sure you did it right either. Okay. Because the diagnosis and treatment only protects people for a month. So you would still have to consider it before coming in. Right. The point though of the exercise of this is that you didn't have enough resource to do everything at once, right? You couldn't just distribute bed nets everywhere and give everybody protection. You break the transmission cycle. So somehow you've got to divide this up between the different villages in order to isolate them to bring some form of control. And when I did this exercise with my colleagues at the CDC actually one of them did come up to protect everybody, following the rules which I understand is quick. So it is possible to protect everybody. But the way you did this if you were successful is you didn't have resources to eliminate all malaria at once. Therefore, you used the resources you did have strategically with spatial and temporal consideration. So you did something one year, the next year that allowed you to do something different, the next year something different yet. You consolidated gains allowing you to move your resources. So you're not pounding your resources in the same location over and over again. You're bringing some sort of a durable solution to some of the areas so that those resources are then available to go do something similar elsewhere. The next thing you did if you did well in this exercise and this is perhaps controversial, you delayed implementation for some communities to achieve durable elimination for all of them. So this is very much a difficult decision you can imagine and often it's influenced by logistics, by political influence, by existing infrastructure and so on. So it's not simple. So what I'm working up to here is that much of the malaria activity that's being conducted today is useful in terms of suppressing transmission that it has no durable effect. And the way I formulated this proposition and asked my colleagues at CDC since Malarian issue, I asked them, I said if the malaria control program that you managed received only 5% of its current funds five years from now could you maintain the same level of control for five years? Everyone said no. If we removed 95% of the resources in two years we're back to the same level of control that we had before. So the point I'm making to you is that in terms of regional elimination within adequate resources we must think strategically temporally and spatially in order to distribute those resources in a way that can accomplish elimination. So the resources and these are kind of by take home points. They have to be focused initially, particularly on areas where durable elimination is possible. After that they must be shifted to remaining malaria areas in this situation. The strategy must be temporally and spatially structured and that is by and large what is totally missing from malaria control efforts today. No consideration of where they are used and when they will be used in terms of making resources available later on. The gains controlling malaria must be consolidated. You simply cannot continue spending at the existing levels indefinitely. That means you have to consolidate some gains or you're going to go back to it. Consolidation is one key factor. Many of the schemes that recognize consolidation is necessary kind of put it out this way. Look, let's just distribute that then we'll do IRS everywhere. We'll get as much suppression as we can and 30 years from now we'll worry about consolidation when the transmission level is low. I don't think that's necessary. I think considerations of consolidation and the implementation of it can be done from the very beginning of the programs. Now, how do you pull this off in a country like Africa that has 50 different countries that have malaria risk? That's a tough problem. Many of these countries aren't exactly the best of friends. I think it's going to best be accomplished where there's strong transboundary cooperation or within countries where you can do this kind of implementation with consolidation on a small basis. And the last point on these bullets I think is that even though many of the measurements of the effectiveness of malaria interventions now they'll say number of lives say, or number of dailies not lost to malaria. And it's usually put forward in that that kind of a metric but really we may need to be considering is what we're doing effective in terms of leading to elimination. And so I'm suggesting that it might be better to measure our success by the durable spatial and strategic accomplishments rather than simply the reduction in morbidity and mortality. And let's see if I can go to the next slide here. Maybe that's my last point. I think it is. So again, the take-home message is it's not just what you do and how much you do. It's temporally and spatially how you do it especially with a disease like malaria where it is so focused in certain areas and it's so well defined by the ecology, the population, the climate and so on of that area. So the key for your Nobel Prize then is to ensure that as you work for a disease elimination, whether it's malaria or another, if the resources are not available to do the whole job at once is to think strategically about how these resources can best be used for a long-term, durable solution to the disease problem. So thank you and I'll take some questions. We have a time for quick answer. Since the gates are a huge benefactor of this can you or do you have a slide on what they're thinking to be known of it? I don't have a good sense that they are thinking I mean on paper certainly they're thinking a long-term eradication but I'm not saying much evidence that there is a specific strategy about how the resources should be used up to that point to ensure that this happens. And I did have one other slide and I think it's maybe important that I show this one because it's not just me who thinks this and this is a quote by Tom McCutcheon and who I think is I'm not a malaria here's a guy who I think should demand some respect he says there's presently no agreement or even much discussion regarding the structure approach that would address the whole of Africa and he says success against malaria will however also involve the initiation and implementation of regional programs whose success can be monitored and a strategy to expand these programs into all endemic regions of Africa. So certainly there are people who recognize that a strategy is not merely how I'm going to get enough money for more red nets next year and how I'm going to deploy them. If we're talking about elimination there's got to be a strategic vision that says when and how those are going to be used with certain outcomes matching those with the resources available. So look I'm not a Gates recipient and I'm not privy to what they're thinking but I don't have a lot of confidence that there is a strong component of specific planning about using resources to accomplish these goals. My impression is they're much more oriented toward developing technology that someday might be capable of reaching these goals rather than the play out itself. So when are the countries that declare the unification as the goal? In 2009 today? In this country we have two resources here, the mine and the middle range of the Arctic Monument for tunnel systems. Now one of the major difficulties across the North the transmission is very low but in series of the process interactive it's a major issue so then this it's much bigger sphere and they must bring the process in this thing called local transmission. So I don't know this PMI program of all human beings but there's pretty much focus on the control of this transmission. Not much into the surveillance whether there will be any cost to change the resource of the region so surveillance becomes an issue. So the point is as in the illustration the exercise, did you notice that once you've gotten control in a certain area then you need the introductions become very important and that's definitely the case so for example in Zanzibar which is one of the PMI countries that is close to elimination this becomes very important identifying travelers identifying cases and the problem with malaria is that many people can have parasites and they're asymptomatic so it's very difficult to propose going around and covering the entire population and determine where they have parasites so you're depending on them developing clinical symptoms visiting a clinic and getting a proper diagnosis so there's a shift for example in Zanzibar from emphasis on bed nets and visual spraying although those aren't going to be dropped to diagnosis and treatment of the people who do have parasites so I think it's happening and I think it's more oops we're close to we're close to elimination what we do now in fact there's an article by Rick Stechiti where he suggested that exact proposition he said bed nets and IRS work we should know that and now what we do we've got transmission so low and we've got to change our strategy and that's the point and part of the exercise that I gave you and I think for the most part that shift has not happened as a consequence of foresight it's more a a consequence of good luck yeah so our question was if you're going to sustain elimination do you have to continually provide bed nets and it's a good question and I think it's really case by case I suspect there are many places where reintroduction rate is low enough that and the risk is low enough that if you just treat clinically ill people and maybe do some focal vector control and diagnosis around there the place where they live and so on that you could probably maintain elimination having said that a lot of people use bed nets not for enough please particularly which transmit malaria but for other pest biting species that just keep them from sleeping well so it's quite possible that even in places where nets are restricted for malaria people can continue to use them for these other species okay well thank you very much