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Feb
16

An illustration of the virus and summary of Research Priorities to Inform Public Health and Medical Practice for Domestic Zika Virus: A Workshop

Late last week I was contacted by John Liebler a science and medicine illustrator and he had seen the Zika glycoprotein E homology model and wanted to use it to produce an image of the virus.  After reading up on flaviviruses it appeared to me that the original model was of the trimer and not the dimer as it would appear on the surface. This pushed me to do another model and send that along to John. Here is his beautiful image and his blog. Also while at it check out his images – they are gorgeous. I spent a while last night comparing Zika to the one he did for dengue from the cryo EM data/ structure. There may be subtle differences such as Zika having bigger pimples on the surface. A huge thank you to John for enlightening me and pushing me to do another model.
Art-of-the-Cell---ZikaVirus
Today I was listening to a live stream of an Institute of Medicine meeting on Zika Virus. There were good points which I tweeted but it was also frustrating to not be there.  It was very sad that they had a twitter stream on the website but no one was apparently conveying questions to the speakers or moderators. Very sad. Anyway below is the full text from the website if anyone is interested if you have several hours to read it. IOM needs to work on social media for these kind of events and relay questions IMHO.
Event ID: 2858721
Event Started: 2/16/2016 8:19:21 AM ET


Please stand by for realtime captions.GOOD MORNING EVERYONE. I WILL GIVE YOU A MOMENT TO TAKE YOUR SEATS. I would like to welcome you to the national academies of sciences, engineering and medicine and today’s workshop on research priorities to for public health and medical practice for domestic Zika virus. I am for us, the executive officer of the National Academy of Sciences and research Council. I want to extend a very warm welcome on this cold day to all of you for attending this timely and momentous workshop. Today’s event is sponsored by the HHS assistant secretary for preparedness and response. We thank you very much for galvanizing the nation around this issue. It was two years ago that she came to the academies with a very core vision, she wanted to be able to draw on all of the strains of the members and the staff from across the academies to address emerging public health issues and disasters, and also to be able to respond to them in a very timely manner. In particular, she wanted us to develop a rapid response capability to do this in preparation for or immediately after a public health emergency. Today’s workshop is the second time we have exercises rapid response capability. The first time was after the ebola virus emerged in this country in 2014 and that identified public health practice. Today’s workshop was organized in less than three weeks, which is a tribute to our staff and to the cochairs. It draws on Academy members from our division of Earth and life studies as well as our health and medicine division. And want to thank the staff for their ability to organize the so quickly, and particularly thank Diane and Mary, the cochairs, for the ability to organize this workshop in such a quick and effective manner. Finally, I want to thank all of you for participating in the session today. We have a few people who will not be here with us because of the weather and the effect on travel. On behalf of the academies, I want to wish all of you a very productive and engaging workshop. Now it’s my great pleasure to Victor, introduce the president of the national Academy of medicine.


Thank you. Welcome. I am the president of the national Academy of medicine, formerly known as [ Indiscernible ] and I am pleased to see all of you here today despite the weather. It is a very important workshop, research priority to inform public health and medical practice for domestic Zika virus. I would like to begin also to thank the assistant secretary for preparing this response, [ Indiscernible ] for once again showing her leadership and putting this together quickly and timely on a very important topic. I would also like to thank the board on health sciences policy for organizing the event and particularly Jack, who put in a enormous hours and had to indoor all — Inderal the were and concern of those who couldn’t make it today. I think this is such an important topic. I wrote down Zika virus once again I’m prepared. My job is to frame the meeting today, but to also give you — give me the opportunity to tell you about the recent response report we have about what the world should do in preparing for future emergency responsiveness and prevention. Just as the Ebola pandemic is waiting and people are starting to forget it, now emerges the Zika virus, a new threat to global health. Many of you know that Zika in the Americas was first confirmed in February 2014 on Eastern Island chili. But if you watch CNN this morning, one of the American workers claimed that he also had it a few years ago in traveling back from overseas. But as you all know, it has been spreading. Since 2015 and 2016, it has been spreading very quickly. Many of you know that in late 2014 Brazil detected a cluster of febrile rash illness, and this link to Zika was confirmed in April 2015. By October, a single state in Northeast Brazil reported 56,000 suspected cases. You will here are — hear more about that, is spreading so quickly that right now Brazilian authorities estimate that between 497,000 and almost one point 5 million cases of Zika have occurred since the outbreak began. February 4, 2016 there were 26 countries and territories in the Americas that reported local transmission of the virus. As you can see in this slide. The biggest cause of concern, not only it is a very mild illness symptomatically, it is the link to microcephaly, a condition that is caused babies to be born with unusually small heads and sometimes with damage great. Also other neurological symptoms and autoimmune like illnesses. And commonly these are quite devastating. As of January 30, 2016, the Brazilian Ministry of health reported 4783 cases of microcephaly or central nervous system malformation including 76 of deaths. Many of you know, that in fact it is a virus of the [ Indiscernible ] family related to West Nile. It primarily is transmitted through mosquitoes which are prevalent everywhere and causes one in five people to become ill with the most common symptoms quite mild with fever, crash and joint pain. International organization responded and [ Indiscernible ] has issued at the day and homage — epidemiologic updates on Zika virus as well as neurological, autoimmune and congenital malformation associations. As you all know, and emergency committee was convened by Margaret Chan, [ Indiscernible ] under the [ Indiscernible ] regulations on February 1 of this year and formed the advice of the committee that [ Indiscernible ] announced the recent cluster of microcephaly and other neurological disorders reported to be a public health emergency of international concern. That is a very rapid and bold move for WHO and we feel that they have been quite responsive. On Monday, February 8, the CDC announced that its emergency operation center has put this on level I status. CDC only put level XIII times, in fact, — level I level CXLIII previous time in its history — level I three previous time in its history. Zika virus has spread explosively and it is alarming when you think about the side effects and complications. I think it is imperative that we mount an effective response to Zika is often also take steps to build a stronger global framework of preparedness and response that will protect us more effectively from all such threats. As you know, the Institute of medicine which is now the health and medicine division has been a strong voice in this area in emerging infections, actually back 22 years ago we released a landmark report called emergency affections [ Indiscernible ] to help and United States. This report gave recommendations on how to increase US preparedness and many of these recommendations have been put into action. A form grew out of this report and they convene regularly with experts around the world and since 2007 has prompted notable initiatives in areas of disaster crisis, standards of care, medical surge capacity, engaging public and critical disaster planning decision-making. Workshops. When you look at this whole situation, and with the WHO declaring the Zika virus is a global public health emergency, I think it’s really time also to take a look at the whole area of infectious disease outbreaks and pandemics. This is an article which I co-authored for the New England Journal of Medicine published 20 — just look at this 10 years, the number of pandemics and outbreaks and epidemics. Particularly, to me, you can see back even in 2007 Zika virus was in fact detected and had an outbreak at that time. But I think what is — drives home to me is that since 2013 or 2012 through 2015 we have a series of outbreaks. We could hardly celebrate that we are succeeding in any way, in fact, you can see that Zika is another wake-up call for which we must spring into action. In that context, I think it is very clear based on the pandemic — Ebola pandemic and recent meetings that everybody agrees we need to create a global health risk framework. A global architecture to reduce and mitigate the next global health crisis and certainly before the outbreak occurs, we need to identify leaders and roles and resources and appropriate times for responding. Successful containment of future outbreaks requires timeliness. And coordinated response informed by good planning and evidence, but not by fear or politics. As we have seen many responses to many of the pandemics. We need to avoid this trust, we need to avoid — missed trust the — mistrust or snake not — or state law or miseducation. — Or stigma or miseducation. We need to move urgently in this country and globally. Seven foundations, the Gates foundation, Rockefeller, Ford, [ Indiscernible ] ask the national Academy of medicine to lead and convene a commission to develop global health risk framework. Many of you might have read this report already which was posted on January 13. It is online on our site and you can see the entire report in the New England Journal of Medicine. This is a commission that is asking the question, what do we need to do in terms of creating a framework globally so that we are much better prepared and much better responsive to any of the outbreaks. The commission is run by an independent body of, as you can see, commissioners that come from five different continents, truly international with a broad range of expertise in health and also in financing, defense, and many other areas. There is oversight by an international oversight group. And partly, and the for work streams it ask the question of governments work stream, finance, how to strengthen health systems, and also are in the in the medical product work stream. — R&D In the medical product work stream. There were 11 days of workshops that had input from more than 250 different experts. This report was, and you can see the consultation we did, with three commission meetings and the report was released on January 13. The report name is neglected to mention of global security, a framework to counter infectious disease crisis. Look at this title because, this to me is the most powerful statement made to the global leaders, that this is not only a health issue, it is a global economic insecurity issue. And in fact, the key finding of the report is this. It poses threats to global security and economic stability. Lives lost, borders closed, and of course economic impact. This report went through an analysis to look at how many human lives were affected by pandemics and if you look at the past 100 years, nearly 100,000,000 deaths altogether. But if one were to look at the cost of the pandemics economically, we have Harvard scientists who analyzes, over the last 10 year period the average cost economically globally is $60 billion a year. That translates into 21st-century as much as $6 trillion a year. A huge impact, up to 6% of the GDP. So the economic impact is great as is the human and others, that is because of the connectedness we are seeing in this day and travel, access to communications, but it fuels the contagion, both of the virus but also tremendous fear of response. So our report emphasizes greatly to, not only ourselves because we all converted, but in fact to the global leaders, that they need to step up. They need to step up investment to actually have emergency response and also preparedness for pandemics and infectious outbreaks. The scale is huge and, therefore, it is important to make the commitment. When we open the meeting in New York a few weeks ago, Dr. Larry Summers, previous secretary of treasury open the meeting and pointed out that this issue has as big an impact as climate change, but is not getting the global attention. Importantly, if you look at the overall impact of investment in security, military or otherwise, it is a fraction of what we are doing because we are always arguing for budgets from health ministers versus seeing this as a global issue. So the commission said that the goal should be to commit for $.5 billion a year, a fraction, to make humanity much safer. Of that, three-point for is to strengthen public health systems and those should fundamentally come from the countries themselves. We are not asking for handouts. But importantly, but we also need to have an international center for emergency preparedness, response and also contingency funding and World Bank funding which amounts to $150 million, and finally, $1 billion for research and development which is a small fraction if you think about a small to medium-sized tech company. The ability to get people together to think about developing vaccines and drugs and other areas of clinical research. The framework has three major issues. One is national public health capabilities, infrastructure and processes to build on a common standard and regularly assess through objective and transparent processes fully consistent with legal obligation. Second is a more effective global and regional capabilities in terms of response. That we believe by a re-energized WHO with enough resources with a dedicated center for health emergency preparedness and response coordinated with the rest of the UN system supported by the World Bank and IMF. And third is the Excelerator program of R&D . We’re not asking — if one were to look at the current investment, one could imagine on an ongoing basis that the dollars needed for coordination of privatization etc. I don’t have time to go over the details of the recommendations. But each government and states of government should consider protection from infectious disease threat as part of the basic duty to protect their citizens. It is not really a health issue, it is a security and protection issue. The members agree on benchmarks on core capabilities for effective systems and that WHO should develop an external objective transparent and a mechanism to measure compliance. Importantly, donors should make support the country’s contingent on countries participating and complying with those metrics. Also, we have to have a global effort towards outbreak in preparedness and response. We should develop a watch list look at daily to look at what is going on with infections. A center for preparedness, and of course, being able to mobilize those funds which are needed for emergency, both the World Bank pandemics and the WHO contingency fund. Importantly, took celebrate R&D to create an independent committee to coordinate and prioritize our effort to mobilize $1 billion to maintain a portfolio of projects. And of course, importantly, as you discuss here, Vicki has helped us create another work stream to ask about standards for clinical trials. Ability to streamline decision-making so that we don’t have to rediscover it every time we have an infectious outbreak. This is all in the works. Let me sum up by saying, we need for Zika virus and of course all infectious outbreaks the importance of public health and health systems strengthening. Without that, we can do all we want and will not happen. I can also say that in fact this is still a long way to go and many, many many countries. Surveillance reporting. Vector control, education travel guidance and research and development. Finally, as this meeting is supposed to address the workshop to bring many of you together, the key stakeholders together to identify, discuss and explore key factors to reduce the likelihood of local transmission of Zika in the United States, areas of insufficient knowledge related to the key factors and prevention strategies, research questions a specific concern, and critical communication needs of evidence-based information for public health officials, providers and the general public. So thank you very much for being here. I want to thank the speakers and the organizers, and I look forward to a very exciting day. Thank you. [ applause ]


It is my pleasure to introduce the cochairs of this workshop you have done an enormous job in a very short time. First is Diane Griffin joining us from Hopkins. Despite the weather, she is here. She is a [ Indiscernible ] of the Department of molecular microbiology and immunology at Hopkins. She is not only a recognized leader on the pathogenic of viral infections, but I can tell you she is a great leader and contributor to academies. She is on the Council, my Council, she is also vice chair of national Academy of science, and she is been the president of American [ Indiscernible ] and so many others. So thank you for being here. And of course, it’s also my pleasure to introduce Mary Wilson, the other cochair of the workshop. She is adjunct Professor. of global health and population at the Harvard school of Public health, previously chief of infectious disease at Auburn Hospital and Harvard hospital for more than 20 years, served on the advisory committee of many committees but also CDC and also to the national Institute of Public health in Mexico. We are so glad she is here with us. Her interest clearly is [ Indiscernible ] infections and merging of microbial threats. Here is Mary Wilson.


Thank you. We are so pleased Victor that you were able to be with us today in person despite her when travel — difficult travel. As cochair of the planning committee for this workshop, I would like to welcome you to this workshop on research priorities to inform public health and medical practice for domestic Zika virus. It is being hosted by the national academies of sciences, engineering and medicine. In accordance with the national Academy procedures, and independent planning committee organized the meeting, and this just shows the members of the planning committee who we thank sincerely who have all spent many hours in recent weeks working to put this meeting together. The purpose of this workshop today is to bring together experts and stakeholders and discuss important research questions that would be most beneficial to pursue now to provide public health officials, healthcare providers and the general public with the most up-to-date information about Zika virus transmission , health risks and measures that should be taken to prevent the spread of Zika virus in the US. The presentations and the discussions will focus on these. You have seen these already. The first this key factors to reduce the likelihood of local transmission of Zika virus in the United States. And within this we will be focusing on for teams — themes, epidemiological characteristics, virus vectors and reservoirs, disease pathogenesis and consequences of infection, and clinical management of public health interventions and strategies. We will look at areas with insufficient knowledge related to the key factors and prevention strategies. We will look at research questions of specific concern and among these are, for example, what studies are needed to establish causality or the absence of causality between Zika virus and microcephaly. And finally, what are the critical communication needs of evidence-based information for public health officials, providers, and the general public regarding the level of risk and associated risk factors, transmissibility of the virus, associated health consequences, and the measures and strategies that should be taken to minimize the number of infections and prevent spread of Zika virus in the United States. This is a standalone workshop. It is not part of an ongoing study by the national research Council. I would also like to give you some sense of the format of today’s meeting. We will have an open plan to read this morning. We will have 10 speakers. Because of the weather, not all of them will be with us in person. But they will provide focused content in areas of expertise to really look at some of the research and initiatives already established, but to understand better the potential gaps that need to be addressed. The afternoon will consist of a working lunch and four separate breakout sessions with discussions exploring in more depth the four thematic areas, epidemiology, virus vectors and reservoirs, disease pathogenesis and consequences, and clinical management and public health interventions. After the breakout sessions and during those you will have a chance to really explore in depth some of these issues the facilitators will prepare and then will bring back when we reassemble in this room this afternoon the content of the individual sessions. During the final part of the afternoon, participants will have an opportunity to bring up other areas that have not been discussed and to bring up and much and other important Zika virus issues. There will be a publicly available summary of the presentations and discussions made during the workshop that will be prepared by [ Indiscernible ] and will reflect what has transpired during the workshop. Will be published by the national academies press. All of the views and ideas presented in the report will be those of workshop participants. There will be no formal consensus findings and recommendations coming from this activity, and it will not contain findings or recommendations by the planning committee. I would now like to turn over the podium to Nicole, assistant secretary for preparedness and response at the US Department of Health and Human Services, will deliver the charge to the workshop participants. Thank you.


[ applause ] good morning everybody and thanks for being here. I think you have heard the charge now. I just want to start by thanking all of you again for being here. Thank you Bruce and Victor and Mary and Diane and the whole planning committee, as well as Jack and folks on my staff for getting this organized. I have been in this position since 2009 cents H1 and one. One of the things that is been very clear to me is that with every emergency situation I have dealt with we have realized in retrospect that we have missed very very important scientific opportunities to advance knowledge. That is really what this is about. In some sense we have the saying never let a good disaster go to waste, but we also by the same token have obligations to be sure that the next time we confront the situation, we don’t find ourselves in the same situation that we are now. That’s really the motivation for this workshop, and the motivation for a broader initiative coming from my office. Which we call science preparedness and response. It is really to say just as we are prepared for disasters, we have to be prepared to do science when an emergency or disaster confronts us. The components of science preparedness are available, but they start with being able to figure out what are the important questions to ask and answer. How do we avoid a situation where we get to the end and say I really wish I had done this. We will always do that, but I think that we believe by bringing people together across a broad spectrum of disciplines and perspectives, to that we can at the beginning scope out a much broader array of important issues. And then be able to prioritize them. A second piece of our science preparedness initiative is to be able to get an infrastructure in place. Many of you know that during H1N1 we were really challenged by getting university [ Indiscernible ] to move quickly enough to do important work. There is now a public health emergency IRB. I think that will help a lot. Whether it’s moving IRB quickly, whether it is agreeing upon trial design so that people are not duking out what the optimal trial design is for a vaccine or a drug or therapy, in the middle of an epidemic, whether it is bio specimen collection or banking, whether it is development of research networks or research registries in a box that can stand up and people quickly, all of those things are part of what I view as science preparedness and response of things that I think we need to be able to talk about here. As I have been listening to the Zika conversation over the past several months, what I would say is, I feel as though it is characterized by things that characterizes in any emergency we deal with. Where you stand depends on where you sit. There is a fair amount of groupthink that always happens and people the — see things from their perspective. Whether you are a pediatrician or obstetrician, whether you are a mother or pregnant woman, whether you are a climate or environmental sciences or geneticist or engineer, social scientists, every single group of people you talk to has a really different perspective about what it is that is important, and it’s often the loudest voices that carry the day. So the purpose of this really is to get the broad array across the whole spectrum of science and good minds thinking about what really is the research agenda, how do these different disciplines interact, how can people work together. As you know, a first party doing this is to galvanize, get the research community together to identify what the important questions are. We now have a standing contract with the national academies. It is our expectation that when we are confronted by new challenges that within 2 to 3 weeks they are able to use stand up a workshop like the simple people together and make a set of findings available to the public. We hope those findings are really going to galvanize the research community to focus on important questions. We hope that they will galvanize funders, not just US government funders, but funders will be on the US government to support research in areas within their mission space. We hope it will galvanize industry partners. To help to develop vaccines, therapeutics, potentially new mechanisms of vector production, whatever it is, hopefully industry put — will help with this endeavor. [ Indiscernible ] are holding a countermeasure development workshop later in March to focus and drill down even more on the science related to countermeasure development. Frankly, to galvanize citizen scientists within this country, maybe around the world, and other kinds of interventionists to think about what they bring to this research agenda, what they bring to this fight. And to see how it is that we can address a critical infectious disease challenge going forward. We are not certain from scratch. There has already been a lot of good science and a lot of activity going on. There is a lot of infrastructure in place already from other infectious disease outbreaks, and I have high expectations that this workshop will move as well beyond that in setting a set of priorities. Understanding that as we learn more, the priorities can evolve and change. Thank you again for being here. Thanks to the academies and everybody else, and I look forward to today’s discussions. [ applause ]


We are going to be moving out to the first panel, and I would like to invite Dr. Ronald Rosenberg and Dr. Marco [ Indiscernible ] to the podium. We will be having four panels during the sessions of this morning. Each will have either two or three speakers. I will introduce the speakers at the outset, and they will give their brief remarks, and then assuming we have time, which we plan to, we will open up the session to questions. If you do have questions, we will ask you to go to the microphone located in the aisles of the auditorium and please give your name first. During the afternoon breakout sessions, there will be much more time to give in-depth comments and discussions, but what we would like this morning is for you, if you have questions, ask brief questions so we can accommodate any points that need to be clarified for the entire group. Our first speakers — I am going to provide only the title or position of the speakers. You have the more detailed biographical information about all of the speakers available to you. We want to leave the maximum time for the speakers to be able to provide their content. Our first speaker will be Dr. Ronald Rosenberg to is acting director division of vectorborne diseases national Center for emerging and [ Indiscernible ] infectious disease errs in the second speaker will be Dr. Marco [ Indiscernible ] director Department of communicable disease and help analysis Pan-American health organization. Please join me in welcoming Dr. Ronald Rosenberg.


[ applause ] in 2007 there was an outbreak of undifferentiated fever on the island of [ Indiscernible ]. That is in the Western specific. It is a little — Pacific Ocean. It is a little place in at the time there were fewer than 7500 people living there. It has had periodic dengue epidemics and it look like that, but it also didn’t quite look like it. For instance, there was a lot of conjunctivitis and also many of the people who were tested using dengue kids — kits were negative. The CDC came out and investigated and found that because of the epidemic was Zika virus, which is a big surprise. These are the characteristics of the epidemic. What I would especially call your attention to is that when a randomized household survey was done, of more than 550 people, the indications were that almost 75% of the population had been infected with Zika. However, fewer than 20% complained of any symptoms. Even subjective fever. There will be people much more expert than me who will be talking later this morning about the characteristics of the virus. But I do want to point out that Zika virus is a member of the [ Indiscernible ] and these viruses are almost exclusively vectorborne viruses. One third of all of the pathogenic arthropod borne viruses belong to this Jenness. — genus. Both takes the mosquitoes can transfer the virus, but usually not the same species. As pointed out earlier, generally, these infections can be quite mild. Even in some serious diseases like thinking do have a large proportion of people who have mild symptoms or maybe even subclinical symptoms. However, when you do have the spectrum moving toward severe disease, the viruses tend to fall into two general groups. One are those that are the hemorrhagic viruses that increased capillary permeability with examples of course yellow fever and thinking. The second — attendee. — dengue. And the second is a group characterized by West Nile virus. I also want to point out at the beginning, contrary to some of the press reports, Zika virus was not discovered as an incidental finding of the yellow fever study. It was discovered as a deliberate strategy by Rockefeller foundation scientists after the second world war that followed the yellow fever studies, ended in 1965 with the purpose of discovering previously unknown Arvo viruses. In Uganda alone they discovered nine pathogenic viruses, including West Nile [ Indiscernible ] and Zika. I would also like to point out that, by the way, the — this is the infamous Tower in the Zika forest. That is actually a very narrow band of forests between Lake Victoria and the Kampala highway. Just weeks before the epidemic in Yap, the full sequence of Zika virus have been published by two scientists from Fort Collins. I said that we were surprised by the epidemic on Yap, and if you follow the chronology of the disease, you will see why. Here is the discovery of the Zika virus on the shores of Lake Victoria in 1947. It was not until seven years later that the first human case in Nigeria in 1954. During the 60 years between the discovery in 1947 in the epidemic on Yap, there were a total of 14 people for whom there is publish evidence they had been affected with Zika virus. These were throughout Africa and also in Asia, but there were no epidemics. Then in 2007, we have the epidemic in Yap , and then we have a period of about six years when the virus essentially disappears in an epidemic form, although it was found here and there. It reemerge with a vengeance in 2013 in French Polynesia and very rapidly spread eastward all the way to Easter Island, and this process took less than two years. So it was no surprise I think to any of us that it turned up in South America. It essentially was following the same course as Chickamauga virus one year earlier. What we did not anticipate was the possible language with how the virus was manifesting itself. This is essentially what we knew from the specific — Pacific. Essentially it was the same as in Yap. The disease was quite minor. Most people were actually asymptomatic. But there were the first suspensions from French investigators that there was Guillan-Barre syndrome and there was also an indication that there might have been a spike in microcephaly cases in a major maternity hospital in French Polynesia in the year after the epidemic swept through. The epidemiology of Arvo viruses is inseparable from the ecology of the vector. In this case, it is the transects [ Indiscernible ]. — genus [ Indiscernible ]. It was first isolated in Uganda from [ Indiscernible ] in that tower and is been isolated from another of other and in the South Pacific may be transmitted by mosquitoes like [ Indiscernible ] which are native to the area. But this particular species is one that concerns us considerably. It is a highly habituated mosquito. Is one of those tests like cockroaches that have evolved over the last 15,000 years to exploits changes in human behavior and human habitation. So essentially it drives around where people live in very close proximity. This recently published map shows not just where it has been found, but also where regions are hospitable to its and so where we might be able to find it. There is a cognate species that actually extends considerably farther into the zones, especially in North America and Europe. This is a very personal list, and the whole purpose of this meeting is to expand and refine a list, about some of the things we need to know or tools that we need to explore the Zika virus. Some of these have already been touched on. First, we have — we know very little about the effective course of Zika virus. As you can see, know what was really even after the epidemics in the South Pacific terribly concerned until the problems emerged in Latin America. We don’t really know what the length of viremia is, we don’t know how infected asymptomatic patients are and don’t have a good antibody profile for it. Should it be the cause of birth defects really depends on having good incidents data and some very basic studies, which are underway in Latin America now. Until we have incidents and have baselines, we do not know what the risk factors are. So we would not know for instance if they are confounding or contributing factors, if it were causing GPS or — GBS or birth defects. We don’t know whether the virus has mutated, and that is a cause of this explosive epidemic potential. We of course have to be concerned about the transmission in blood products and in transplantation. We have done this quite successfully for other Arvo viruses like West Nile, but the issue of sexual transmission, especially if it is confirmed that exposure and pregnancy is a factor, is something we have never faced before with any of the Arvo viruses. Are diagnostics are really wanting for good serological diagnostics. We can easily diagnose the virus itself by amplifying the RNA but when people are living in an endemic area for other viruses, getting a positive I GM without doing a [ Indiscernible ] is extremely difficult, so this is an area on which all of epidemiology depends. We need to do a lot of work on animal reservoirs. It was first isolated from a subhuman primates. We don’t know if there are other vertebrates it can go into and whether or not it is even now in Latin America infecting possible reservoirs. We still have a lot of work to do on the vectors. We don’t really know the course of Zika in the mosquito, incubation for areas — periods or even the species transmitting. Finally, I want to point out that Zika and Chattanooga — Chickamauga did not come out of nowhere. There are about 200 identified Arvo viruses and another 200 that are possible. Only 90 of these have been incriminated as causes of human disease. And most of those 90 and I put Zika in this category until very recently, are so obscure that they have not really been studied. So regarding that last point about [ Indiscernible ] Arvo viruses that come from nowhere, I want to conclude with this photo. This artifact which is been abandoned in the Zika forest is one of the original mobile labs used by the Rockefeller foundation medical research Council and the East African virus research Institute during the time the Zika was discovered. While not terribly interested are moved by symbolism, I do want to say that looking at this photograph, I wonder whether our strategy of investigating these obscure viruses that can emerge suddenly and cause problems that we had never anticipated has over the years lost its wheels as well. Thank you.


[ applause ] thank you. Thank you for the invitation. I would like to give a brief overview of what is going on in Latin America and an account also of the [ Indiscernible ] putting together for 35 member states and several territories in the Americas. As you saw before, what we have here is the countries and territories of the Americas that have reported Zika virus infections since May May 2015. Officially confirmed laboratory started with Brazil. Just before, Easter Island reported the first couple of cases in 2014. It is traveling north. It is now almost everywhere, 26 countries and territories, and let me start with Brazil. This was the first country to report in May This was the first country to report in May 2015 confirmed the detection of Zika virus. Nonetheless, in February and January and January 2015, already the states of [ Indiscernible ] in the Northeast were seeing an increase of symptoms suggestive of Zika virus , signs and symptoms in people like conjunctivitis, rash, and fever. This is important for the correlation related to the potential link to microcephaly. Just in October, Columbia reported the first cases of Zika virus and Columbia has a very strong laboratory platform and is following several pregnant women, — with the Zika virus and that will tell us a lot. But at the same time Columbia reported , as you can see, Brazil was already reporting in October an increase in microcephaly. In children. Then as of today, we have 26 countries and territories, and they are all here. We are emphasizing that all the countries of Latin America and the Caribbean will be affected, lovably except Continental Chile and Canada because of the presence of the mosquito in all these countries and the lack of immunity of many of the population. Of course, we’re not saying these countries will have a massive outbreak. But there are reported cases and we don’t think it will be an outbreak in the United States, but none the less, precautions have to be taken an aggressive response has to be in place. The mosquito is present in the South in several areas. This is the weekly epidemiological — epidemiological curve in these 26 countries. There are the countries — countries only reporting if you cases, but the bottom line is we have not seen the peak of this outbreak in Latin America and the Caribbean. You see that 120,000 cases have been reported. But this has to be put in context because, as you know, laboratory diagnosis is not widely available. There is no commercially available test. The window of diagnosis is only probably five days. Many people reported be for — as reported before, one in four only develop symptoms, so people usually don’t go to health services. The difference between Chikungunya and dandy because they produce a strong pain in the bones in the joints, but think it is usually — Zika is usually very mild disease. At some point several of these countries, because it is also important to qualified that this was not a reportable disease and many of these countries, several countries actually when they confirmed the presence of Zika virus, they stop counting. Brazil was one of them because of the huge number of cases they saw and now they came with estimates between [ Indiscernible ] of Zika virus in the country. A few weeks ago. Columbia just recently said that they are expecting 500,000 cases. We cannot be surprised if we see 2 million or 3 million cases in the Americas. In 2015 there were over 2 million cases of Dengue reported and 6000 cases of Zika — Chikungunya favor. Suspected or confirmed. It is the same mosquito, lack of immunity. So we have not seen yet the peak of this. These are some of the symptoms and clinical cases. I can be easily confused with Chikungunya and also Dengue fever. I always advise clinicians, if you don’t know what it is, think of Dengue first because this is the one that has high mortality . Here is the — what you have here on the left side is the rates of microcephaly in Brazil between 2010 and 2014. Very small. On the right you can see the rates of microcephaly in Brazil in 2015 and 2016. Certainly an increase. You will note that Brazil started using different definitions and standards, but no matter what definition they use, the evidence suggests there is an increase in microcephaly. They are now reviewing all the records of the infected children and going back to the mother’s and they have confirmed several hundred cases of microcephaly and still 3000 or so are under investigation. There is a paper coming submitted by Brazil to the [ Indiscernible ] presenting the ecological analysis or the correlation between the Zika and microcephaly , and this is the state of [ Indiscernible ]. As you can see in blue and the red line, microcephaly reports, and nine months before outbreak of rash and fever detected by authorities, and increase that was mentioned. Then the first case of Zika confirmed in May in May 2015. So the analysis has been done, and we cannot talk about causality because we do not know the correlation — because correlation does not mean causality. Similar exercises have been done for other states. Brazil is now conducting a case-control study. It is expected that probably in April we will have some more data to tell us about what is going on. A couple of cohort studies, pregnant women and children with microcephaly. Columba late — Columbia is following about 2000 more women. Let me referred to [ Indiscernible ] syndrome. You see the yellow. In French Polynesia the report of Zika cases. There is a mistake because — in red we have the GBS in French Polynesia. The issue is, as per this, four weeks after the Zika epidemic started in French Polynesia, we started to see an increase in GBS syndrome. And later on newborn cases with neurological malformation. I think 17 reported. What we see here is the Columbia data showing that in blue the Zika cases, 25,000 , and what we see also is the Guillan-Barre syndrome or neurologic syndrome. It’s about four or five weeks also that we see that Guillan-Barre is showing up. We are now in the process of working with our colleagues at WHO modeling this epidemic, and if there is a link finally, cause-and-effect for Zika, microcephaly , we should be expecting to see microcephaly cases and Columbia around June. It is important to follow up these cases. We have put together a strategy that is based on three pillars. Detect, prevent and respond. Early detection of the virus, risk reduction, but we are recommending an aggressive insects vector control campaign which is the only present tool we have. Several head of states in Latin America have come forward and are on top of this. But of course, because we don’t want another several hundred cases the microcephaly, regardless of if it is the cause or not. We tell them don’t focus on the cause, let science run its course, and we will know at some point if it is the cause are not, but it will be the same response regardless with the mosquito. By targeting the mosquito, we are targeting Chikungunya, Dengue and Zika. We’re coordinating responders. In the Americas we have to laboratories at WHO collaborating centers, the CDC which we have a good relationship with, and we are conducting several workshops to train countries in terms of laboratory diagnoses. We have a lot of needs, and we have been discussing with agencies how to collaborate. As of today, there is a meeting in Puerto Rico of all WHO centers to discuss diagnostics and to try to come up with a strategy based on the Dengue strategy because at the end of the day more than 200 [ Indiscernible ] the key issues for our members is communication, to educate people, to pass information and facts to the people and two women of reproductive age, and to pregnant women. Several missions are on the way with partners through the global response network of WHO. The important thing to coordinate, we call it also an expert consultation on Zika research. In March it was announced that [ Indiscernible ] so a lot of going on about trying to find out what is going on with this because there are a lot of questions we don’t know we need to know. In the meantime, we need to strengthen surveillance of Zika, neurological malformations and birth defects, and we have a website available to everyone. I think you for your time. [ applause ]


Thank you very much. We’re not going to have time for questions right now for these panelists, but if we pick up time later in the morning, we will come back to any specific questions for these two. Thank you very much. We are now going to move on to the session on virus vectors and reservoirs. Scott Weaver will be holding down the fort as the one person here and present in the room. And one or both of the other speakers will be joining remotely. Scott Weaver is a university chair in human infections and immunity University of Texas medical branch. Tom [ Indiscernible ] is chief operating officer bio protection systems new link genetics Corporation, and Wayne is professor and founding director of signature research program in emerging infectious diseases do national University of Singapore, and please join me in welcoming Scott Weaver. [ applause ]


Thank you Mary and Diane and the Academy for the opportunity to participate today. And everyone for braving the weather to come out. I am going to begin by pointing out what an African virology friend told me a few weeks ago. Not only do we not know very much about Zika virus, but for the past half century, we have gotten the name wrong. The original spelling from Uganda has two I’s. it will be a bad idea to change it now. Dr. Ronald Rosenberg wants to through some of this information with the discovery in the 1940s when the Rockefeller foundation began yellow fever studies and also describing many viruses in that part of the world. The virus was isolated for the first time from a monkey waste it up into the canopy, and it became by REMIC — developed a fever. The following year the virus was isolated from mosquitoes collected up in the canopy, and later three human infections first detected in Nigeria. Then in 1956 there was an experimental infection done with a human volunteer that confirmed relatively mild flulike illness typically caused by Zika virus. In the first isolation in Asia came in 1966 collected in Malaysia. And then finally the first human affections in Asia in 1977 in Indonesia. What we know about the distribution of Zika virus over that long period of time is shown in this map. In red are the countries where there is evidence from surveys that people have antibodies against Zika virus, but I need to point out that many of these studies, especially the early ones, were done with nonspecific methods that may have cross-reacted with unknown viruses at that time. Ingold are the locations where the virus was detected either in human cases or mosquitoes or reservoirs — host such as monkeys. It was clear for many years the virus is present both in Africa and Asia. I am going to talk about the enzymatic cycle in the context of studies done. Since the 1970s in eastern Senegal were the Arvo viruses circulate in a virtual identical cycle and that part of West Africa. The studies in Senegal have shown that there are three mosquitoes that are important factors. That occupy for us. And there are three — they occupy forests and nonhuman identification — identified host. These viruses generally appear only Averell — every seven or eight years when samples of mosquitoes are collected but Zika virus occurs more frequently with adjuster may be other short-lived reservoir hosts with faster turnover rates in this part of Africa them for the other three viruses. Another factor could be [ Indiscernible ] transmission which has been documented by the isolation of Zika virus for male mosquitoes. We think the main mosquito that transports us to nearby villages is [ Indiscernible ] because our field studies have shown that it leaves the forest and enters a villages to buy people. But how the virus would move from a nearby village for people entering the forest to an urban habitat work and establish the urban cycle is not well understood at all. During the urban cycle, various mosquitoes apparently serve as vectors. I would also like to look a little bit at the history of this quartet of viruses. The history of emergence from the cycle into human transmission. Yellow fever virus we understand fairly well. We think it originated in Africa. Then during the age of sailing ships, especially during the slave trade, the ships would transport both domesticated [ Indiscernible ] as well as people who were susceptible to infection, and an onboard transmission cycle would carry the virus across oceans into the New World, and we had regular outbreaks in various tropical locations, even intemperate locations where the mosquitoes were introduced and could survive for the summer in the Northeastern US. As far as we know, this never happened in Asia, and it is not clear why. Dengue we think originated in Southeast Asia where the [ Indiscernible ] the first while they were in the prime might cycle then moved into transmission cycles for humans and transported around the world by sailing ships. We also know the Dengue subtype two apparently stole back from that transport into forests in West Africa where it circulates today. As far as we know, this is never happened in the Americas. There is no clear evidence of that transmission. Finally, Chikungunya virus also has a long history of emergence from Africa, probably aboard sailing ships during the 18th century to both Asia and to the Americas. The same kind of scenario as yellow fever and Dengue. But there is no evidence that [ Indiscernible ] transition — mission — transmission was established in the New World. So what is the risk for spill back of the go into a Enzootic cycle elsewhere in the world? If we look at that quartet of viruses, how often has is happen with these other viruses? Yellow fever, it has succeeded to establish Enzootic cycles in the Americas, but not in Asia. We’re not even sure it has ever been transported to Asia out, — Dengue virus, we know that it has pulled back into a Enzootic cycle in West Africa, but so far not in the Americas. Chikungunya has not established a Enzootic cycle anywhere outside of Africa. Than for Zika virus there is no direct evidence of Enzootic that — transmission out of Africa. There has been no research for some parts of Asia, so the information is very limited. The problem is that, defining or proving the existence of these cycles is logistically extremely challenging. In less you can find viruses that are genetically very distinct, coming from forest mosquitoes versus urban mosquitoes and people like we have done for Dengue, it’s very hard to tell whether there is a Enzootic cycle unless you detected by monkeys like we see in the New World with yellow fever for example or you work in very remote locations. So this is a phylogenetic tree. The most recent genomic strains of Zika available, and you can see that there are two main lineages of Zika virus. One found in Asia and recently in the Americas. And then a second one appears to be restricted to Africa. And here are some of the recent strains from Asia and the South Pacific and then the American strains appear. I want to point out here the main finding that, first of all, the closest relatives in the Genus our African sister viruses of Zika, suggesting that Zika probably did originate in Africa. The remainder of the conclusions I will show you in a map format showing the history of spread as far as we can deduce from the studies. We think that the virus may have been introduced into Asia a long time ago, as early as centuries ago. It is impossible to distinguish that scenario from just not having sampled another lineage in Africa that gave rise to the Asian strains that would be more closely related. So we don’t know for sure. Than in 2007 the virus was introduced into Yap, causing outbreak. The same year there was an outbreak and [ Indiscernible ] which was clearly transmitted by [ Indiscernible ] mosquitoes. Than the virus spread into French Polynesia and on to other areas of the South Pacific. And we think then that the next introduction into the Americas probably occurred from French Polynesia. But I also want to point out that the Yap and French Polynesia and introductions appear to be independent. And they probably came from some part of Southeast Asia where we simply are not doing the surveillance to find the progenitor strains. Then subsequent spread throughout Latin America and the Caribbean now. Then finally a recent outbreak in the Cape Verdean islands off the coast of Senegal. And I was told informally by an African virologist that they think that the strain originated directly from West Africa. And it appears to be transmitted by [ Indiscernible ]. So why did the sudden Zika emergence occurred during the past few years? I am going to present a few hypotheses that in my view are some of the leading ones. There’s certainly others. One is that Zika virus underwent some sort of adaptive evolution to enhance infectivity of these mosquitoes that are transmitting in all of these recent outbreaks. The precedent for this hypothesis comes from Chikungunya virus, which in a series of very detailed studies we now understand has between 2005 and 2009 underwent a series of adaptive mutations in its proteins that allowed it to infect much more efficiently and this allotted to expand his geographic region to places like Italy and France and many parts of Africa. The second hypothesis is that the adaptive evolution do not involve mosquito vectors but evolved the human host and increased efficiency of infection of humans and replication could lead to higher levels of human viremia, which would also facilitate more efficient circulation of the virus and spread, and also could explain the higher risk of trance — the central fetal infection. The remaining hypothesis is that nothing at all has changed with this virus. In fact, possibly all Zika strains from Africa or Asia have the same epidemic potential, up by chance the virus was introduced into naïve areas with the right numbers and populations of susceptible people and vectors to start the amplification, and especially in French Polynesia where the populations were large enough to reach the levels of tens of thousands of infected people. That may really have for the first time increase the risk of the virus dispersing around the world and affecting travelers in establishing itself in the most naïve population on the planet which is in the mind — Americas. Became very epidemic where it looks like we’re seeing the same kind of epidemic transmission support this hypothesis that maybe the African strains as well have this epidemic potential. So why do we not detect outbreaks before? I should you evidence that it has been in Asia and Africa for many centuries probably. Yet we have only detected 14 infections prior to 2007 it is possible that academics have occurred in those locations but remained undetected because of the difficulty because of the difficulty making a distinguish men from Dengue and yellow fever and the lack of diet mystics — diagnostics for Zika virus. Another hypothesis is that there is a relatively constant level of spillover from Enzootic cycles in Africa perhaps also in Asia that result in relatively constant levels of infection in people throughout their life so that there is a regular occurrence of Zika cases but we simply don’t know even notice them because this is in a background of malaria and Chikungunya and so many other infectious diseases in places like Africa and Southeast Asia that we don’t notice them as we specifically go looking for them. Under these circumstances the herd immunity and this is supported by some of the seroprevalence I mentioned earlier which can be as high as 75% in Asia and Africa, that herd immunity may even protect women by the time they reached childbearing age from the risk of microcephaly. So if there is a small number of constant infections going on. And a lower rate of microcephaly common microcephaly may occur at a frequency only slightly above the levels we see for other viral infections and never had anyone’s radar at all into we see a major epidemic. And so secret — Zika the virus strains in Africa and Asia perhaps did not need to undergo any kind of adaptive evolution, and may not have or may have low efficiency of transmission depending on which of these hypotheses you want to believe and test. Finally, I want to acknowledge the people who have done the Zika work in my lab group shown here. Our iron — parvovirus group in Galveston, the evolutionary studies, and this is the group that did the field studies in Senegal including from the Institute Pastore. And we have very important support from the NIH to allow this project to take place. Thank you for your attention. [ applause ]


We are hoping to go directly to the presentation by Dr. [ Indiscernible ]


Good morning everybody. Thank you for the invitation. I am so sorry I cannot be with you there. I was defeated by the weather yesterday. I was going to cover for Mac different topics listed here. Including — for different topics including climate change, covering slightly different aspects of the Enzootic cycle, the possible role of direct transmission of the virus from human to human without the agency of mosquito vectors. I think we have accepted climate change is happening. There is a predicted significant continuing increase in the global surface temperatures. This is data from the United States. You see almost a 4° increase compared to baseline values over the last decade or two decades. So what is the influence of temperature on transmission of Zika and other arthropod borne viruses? Temperature has been shown to be really the most important factor limiting or contributing to virus transmission. Because it prolongs mosquito survivorship and shortens the incubation period which is the time between taking a blood meal with the virus and the infectious salivary glands of the mosquitoes and the ability to transmit. That is a temperature dependent [ Indiscernible ] rainfall also contributes. And temperature and rainfall are linked to chime — climate change goes to the warming of the surface and also the extreme climatic events such as El Niño. And many times this is been linked to the emergence of parvovirus is including yellow fever and now these events in the Americas over the past two years are at least temporarily associated with one of the largest El Niño events on record. And we have seen an extension of the [ Indiscernible ] in Europe which seems to coincide with the period of increasing temperatures. Nevertheless, this linkage between climate change and parvovirus transmission is speculative at this point. We don’t have any really good research that shows empirically that there is a link an association. I think in, for the US the major result would be the longer transmission sees for both of these important factors in the United States with climate change. This map deals with temperature and particular and the transmission shows a temperature suitability index which is a measure of the influence of temperature with the position of the vectors, Tran 20, and — and the potential for transmission. If you look at the map of the United States, the southern Florida, southern Texas and California are areas of the higher color and these are the areas that have been affected by indigenous transmission from time to time of Dengue or Chikungunya. I think those are the areas of concern with changes due to climate change this could expand northward. Scott has mentioned the association with isolation of Zika virus from mosquitoes in Africa, and he mentioned the possibility that there is an indication that transmission cycles involving different host may have applied to Zika. The species listed here isolated from different countries in Africa are often those associated with Chikungunya and yellow fever transmission that suggests that they play a role in the transmission cycle with primates in the forest regions of Africa. This shows you the association of these species with Zika as well as yellow fever and Chikungunya. Zika is the isolated for many other species. Does not associated with the colored dots, and the species sometimes have general feeding habits not specific to nonhuman primates the suggests along with other factors that alternative transmission cycles may occur. That’s an area that needs to be studied. I will reemphasize the point earlier, we no longer have in place the ongoing field studies and research that occurred during the Rockefeller virus laboratory data, and continued by the Institute pastor but much of that infrastructure is now really gone. And we are at risk of not knowing what we don’t know. Scott Weaver suggested that there could be an established Enzootic cycle such as occurred with yellow fever when it was introduced over 400 years ago into the US. I am contrasting what we know on the left with yellow fever and on the right with Zika. [ Indiscernible ] was only introduced a year and a half ago in areas where there could be spillover into a reservoir. Obviously this happened with yellow fever on the left. At some point in time humans were the source of infection for mosquitoes at the canopy level and transmitted between human primates. A Genus [ Indiscernible ] are involved in that cycle. We know nothing of the potential for [ Indiscernible ] yellow fever vectors to transmit the Zika virus. They would be the leading candidates for establishing — establishing a Enzootic cycle. So we have no data. As Scott mentioned, the transmission occurs with Zika in African mosquitoes, it occurs with yellow fever [ Indiscernible ] and there are no studies of vertical transmission in [ Indiscernible ] and we actually don’t know much about the African species either. Monkeys in the New World develop often fatal infections with yellow fever. African muggings — monkeys have resistance that contribute to transmission. So we really need to know something about the susceptibility of New World primates to Zika virus to assess whether they can play a role in the Enzootic cycles. One point is that yellow fever today on the rights is confined to the Amazon and [ Indiscernible ] for us in South America. But that has not always been the case. In the early 1950s yellow fever spread of Central America all the way to the US border, and there are mosquitoes and plenty of nonhuman primates in Central America and Mexico and the Caribbean. So yellow fever demonstrated the potential to invade a part of the Americas all the way up to the United States and I think with regard to Zika we have to consider the entire region — tropical region as an area for potential Enzootic transmission of Zika virus. If that were to occur we would have the reservoir that would be potential for repeated inductions into the human population and no way to really control it without vaccination, recently in just the last few weeks there have been reports of a mysterious [ Indiscernible ] monkeys in Nicaragua and also in Ecuador in a few cases in Panama. Whenever this happens one suspects yellow fever because they are highly susceptible to lethal infection. These animals have hepatitis and renal failure and studies are in progress, but one of the issues is, primatologist working in — on the biology and ecology of primates, I can tell you that it is proving very difficult to work out the samples from Nicaragua because of restrictions on sample — getting samples out and into the United States or into any other country due to the requirement for [ Indiscernible ] permits, the convention on international endangered species. There are other permitting problems just getting out materials from a country and into the United States and the appropriate laboratory. I think we need to facilitate this process if we are going to have an appropriate surveillance system for Zika virus and Enzootic infection in human primates in the Americas. What is the potential for persistence of the Zika virus in the Americas? Obviously there’s plenty of human hosts infected by by remake hosts — the remake hosts and mosquitoes — viremic hosts. there is some evidence that the virus may persist in the human host or maybe animal host, and there is potential for direct transmission. So we have talked about the Enzootic cycle that could extend further than the [ Indiscernible ] fever cycle, probably not a direct threat to the continental US, we don’t have enough monkeys here. Vertical transmission, we know very little about that with Zika. And alternative vectors, other species we have seen in Africa other isolation of Zika for multiple species suggesting the possibility of other host being involved in the transmission cycle. Actually, there are similar findings with yellow fever and people have looked very hard [ Indiscernible ] although there is — there been isolations from takes and bats — ticks and bats and we simply don’t know the potential for alternative vectors or host. If there is a Enzootic cycle in the US, we should be especially wary that other species like marsupials and perhaps lost — sloth would be involved in transmission based on their first encounter with this virus. Finally, let me take up this issue of direct transmission. Central transmission will come up in discussions in this meeting. There is congenital transmission, contamination of the blood supply, but what about direct contact spread? So we really don’t know much about the viremia levels for Zika. It seems to be similar duration to other viruses being transmitted by human biting mosquitoes. But data is needed to assess the potential for vectorborne transmission and blood contamination transmission. There is a suggestion that the virus has adapted to human hosts, at least with respect to the code on usage of nonstructural genes which shows changes of adaptation to humans as we indicate humans are more affected by [ Indiscernible ] or spreading the virus and that is specific to the Asian type. What can the Zika virus — the Zika virus has been shown to be present on PCR in Europe lasting a lot longer than the viremia up to 10 days. There are individual patient profiles at the bottom of the slide showing the upper curve being detection of virus in Europe and the viremia appears to be quite short. Similarly, a study in Tahiti looking at 182 patients and days after onset and the virus present [ Indiscernible ] saliva lasting up to a week or so after onset. Actually more frequent than blood. So it seems like most of the viremia is probably in the incubation period with Zika. We need to understand that better to understand the transmission cycle, and there certainly appears to be potential for shutting some — shutting — shedding saliva and urine. Some of the critical gaps are we clearly need to understand the relative contribution of the two major species in transmission. What experimental studies are done, it is not often the design, but we need to understand the minimum dose to define and then to link those data with viremia patterns and humans. Will other mosquito vectors play a role in transmission, and particularly the susceptibility of [ Indiscernible ] is really important to understand. With respect to the Enzootic cycle. Cacique of apathy — good Zika habitation for more efficient transmission by [ Indiscernible ] or humans explain its recent emergence? And there seems to be some evidence for adaptation that may play a role in enhanced replication in humans. What is the magnitude of risk for mosquito borne transmission in different regions of the US? That may be true — temperature related or there may be other vectors that could play a role. And that could come out of experimental testing. Prospects for reducing transmission for vector control I think will be spoken of later. What is the role of the a symptomatically infected people in amplifying hosts? We don’t really have the profile of viremia and an understanding of the role of humans as hosts. Human to human transmission. We need to know more about shedding and made a qualitative — quantitative and epidemiologic studies to detect transmission. I think we covered the issue of the Enzootic cycle, but just to emphasize we need to make use of primatologist out there in the field. We know — we need to go back to principal of the Rockefeller foundation days and conduct appropriate field studies involving vertebrate by — biologists. We just don’t do that anymore. What are the interactions between Zika and other related viruses? It may be that the absence of microcephaly in Africa is in part due not only to immunity but cross protection immunity from related viruses that are very prevalent in Africa and Asia. And we need to understand the interactions of these viruses and vectors, as well as the role of immunity and cross protection. I will stop there and thank you very much for your attention. [ Captioners transitioning ]


We will move through the material fairly quickly because we are running behind. Viruses known to be transmitted by this particular subgenus. We keep referring to 80 Stoudamire. You, these except epidemic poly arthritis which is caused by Ross River virus in Australia and the South Pacific. These are some of the viruses that we may want to be paying attention to either based on historic information that you just heard about or what we suspected to be certain characteristics that may lend themselves to emergence. Going to mention a few of these. This produces essentially the same disease. Ross River and turn 26 but it is an awful is born. This is one of the closest relatives of Zika virus. We know very little about this virus at all. Other than it’s been associated with human disease. Japanese encephalitis, and other related lady virus, much better understood than Zika can cause severe disease and is very common in Southeast Asia. And then Rift Valley fever virus, this is a virus that occurs all over sub-Saharan Africa. It occasionally causes major outbreaks in a domesticated livestock and spill over to people. There’s reason to believe that this virus could establish local transmission here in the United States. We know that many of our mosquito vectors are competent to transmit this virus. And then a couple of others like Synvisc that produce — produce a mild form. This is an avian virus that could be spread to other parts of the world beyond Europe and Africa.


Back to these urban mosquito vectors. Why are they good vectors? We will talk about Aedes aegypti. There are certain properties of its ecology and behavior that make Aedes aegypti the perfect vector of these viruses. It tends to bite during the day but Morten portly, it preferentially bites people. Even when it has the opportunity to bite animals, it tends to bite people. It’s highly domesticated. The library are founded containers of various containers and people’s backyards and water storage containers in many parts of the world where there is no domestic water service. The adult females tend to enter homes and stay there for the duration of their life. They have extremely high levels of exposure to people in they also tend to bite more than once during April reproductive cycle. They might bite several in the same household, increasing their chance of infection and transmitting to multiple people. Another vector, it is behavior is not quite as conducive to transition. It is a day biting mosquito but it has a different preference for hosts. Also tends to be para domestic but also feral. You can find it both in natural and domestic water containers. These potential vectors or two of several others. Believed to be involved in some of the recent outbreaks. In the South Pacific, 80s polonaise ESS, also others listed on the screen. These have also been involved in different outbreaks on different islands. In the US if Zika virus here what other mosquitoes decide could be involved Aedes triseriatau is one well-known vector that transmits a virus called La Crosse virus which is a major cross the pediatric encephalitis here in the United States. What about other potential mosquito vectors well, as shown already, many species have been implicated as being infected in Africa but we don’t know which of these have the capability to transmit efficiently. They include different types.. Traditional methods have basically failed for Dengue. We recently, turn 26, and yellow fever, we had major urban epidemics in the Americas about a century ago and earlier. And, what you typically see in the United States is a truck driving up and down streets, spraying an aerosol out the back. That is very ineffective for controlling Aedes aegypti because as I mentioned, the adult females stay and fight it houses. The sprays do not penetrate very well into houses. . Vocal control around cases could work well for controlling the initiation of the cycle after importation if we could quickly diagnose and identify these people. We could do limited spraying in their house in nearby houses to control Aedes aegypti because it has a limited flight range. Only about 100 m over the course of its lifetime. Targeted source reduction if we eliminate the habitats of Aedes aegypti around houses, sometimes in sewers or other locations, we can have a major impact on reducing the populations and is suppressing transmission. And then integrated vector management involving not only source reduction but targeted control using different methods then we typically used to control vectors of West Nile for example which are outdoor, biting, nighttime biting mosquitoes. It is critical in these interventions that the community participate. Communities and individual homeowners must take personal responsibility for eliminating Aedes aegypti from the property. There are also some bio and genetic control approaches that I will mention any moment. This is how we control mosquitoes here in the US. For something like West Nile. Almost completely ineffective for Aedes aegypti control. What’s our history of controlling ? Especially in the Americas? , There have been some notable successes in the past including in Brazil and as part of a global malarial eradication campaign, there is renewed efforts to find better ways to control mosquitoes but for Aedes aegypti specifically, the was a hemispheric eradication program implemented for about 20 years, from the 1950s to the 1970s as part of a yellow fever eradication program. Aedes aegypti was eradicated from almost all the countries in the Western Hemisphere. You can see, in 1970, only three countries in South America, some of the Caribbean islands in the southern US still had Aedes aegypti present unfortunately, these efforts waned and Aedes aegypti has now returned to almost the identical distribution we saw in the 1930s. So why did this effort succeed for a couple of decades well? First of all, there was a top-down approach in many locations because there were paramilitary governments in place that could exert a strong arm and making sure there was very good compliance in communities. There were dedicated disciplined staff available to implement these programs. Our cities in the neo-tropics were smaller in those days and there was a lot of detailed mapping to identify the sources of the VAR Bay.


We had fewer automobile some not as many used tires. Far fewer plastic containers. I think this is a major factor in Latin America. When I started working there 30 years ago, all the beverages were sold in a reasonable containers with a deposit on them. Now everything is disposable plastic. Even a small bottle cap is enough for Aedes aegypti larvae to develop economic development has taken precedence over many of these activities. There hasn’t been adequate funding for these programs. Or rather, there was adequate funding earlier, not so much today for these programs. Another important factor, in those days we use residual insecticides like DDT in most places, that is not considered environmentally acceptable. Why do we feel after this program ended? Well, the major drivers were urban growth and — in a tropical locations, the lack of effective control and then globalization continues to move viruses, people and mosquitoes around the world. The outdoor space spring, our mainstay control method here in the US does not work. In the community-based programs on their own have not been effective in sustainable. The lessons we learn, we need vertically structured programs, top-down, they have to be more sustainable. We need to develop some use of better residual insecticides that can be applied into the walls inside houses to control Aedes aegypti for longer periods of time. We have to reinvest in infrastructure to do this kind of work. And we have to have triggers for emergency response. When we know a virus like a Zika or Chikungunya is arriving in a region, we have to be able to react quickly and we have to have sustainable government committee partnerships, and integrated approach going in both vertical directions in the control programs need to be regional and local. Some of the new techniques that have become available last couple decades are some very nice inexpensive though tech Ovitrape traps. They attract females. They land on a sticky surface and are exposed to a lethal insecticide. There are spatial repellents, even impregnated curtains, in places where people don’t want to screen their windows because it limits ventilation. These curtains can repel mosquitoes from entering homes . newer residual insecticides that can be applied inside homes . there are new methods to release sterile mosquitoes, developed by foxy tech in the UK. These sterile males go out and meet with wild females and essentially sterilize them at the larger — larval stage. A lethal gene will kill the larvae. The transgene does not persist in a location in the populations of mosquitoes on a small scale can be reduced by up to about 90%. Finally, Wolbachia has been adapted for use in Aedes aegypti. They are shown to spread naturally populations in several parts of the world and in the lab, those will suppress the replication of dengue and Aedes aegypti and likely Zika virus as well. We are entering a new era that will allow us new opportunities to use a variety of different tools that are moving to the pipeline for controlling these vectors. But, critical to this program will be community engagement, the coordination with product testing like vaccines and therapeutics in combinations with vector control could be very important. The international mobilization of resources is also going to be key in these efforts. That is the end of this material. I don’t think we have time to discuss all those questions. This afternoon, we will bring them back. [ Applause ]


Thank you, Scott and thank you to all the speakers. Because of time constraints we are going to bring all of the speakers back at the end of the presentations and open it up then for Q&A. I would encourage all speakers, as we go forward, to try to keep — I know it’s an impossible task but we still want you to try to keep within 10 digit to 12 minutes. NX panel will be on disease pathogenesis and consequences of infection. We have three speakers, one, who will deliver his remarks here and the other two remotely. The first speaker will be Doctor Richard Kuhn, professor and head department of biological sciences, director at Purdue Institute for inflammation, immunology, and infectious diseases. Purdue University. The second speaker will be Michael Diamond. Professor, department of medicine, molecular microbiology, pathology and immunology. Head of the division of infectious diseases and vaccine development, center for human immunology in immunotherapy programs. Washington University school of message and. The third speaker will be Doctor William Britt, the Charles A. Alford Professor of Pediatrics — pediatrics at the University of Alabama school of medicine.


Thank you, Mary. In my advancing these things? Next slide. So, Zika virus is the member of the plate a virus family and that is the good news because we know a lot about lady viruses. Its genome is a positive stranded RNA, about 10,600 nucleotides in length and as we part extensively, the virus is transmitted by mosquitoes. I will talk mostly about the structure of the virus. The structure is presumably going to be similar to all the other viruses we seen. The virus portable contains a lipid by leader may bring which come from the coast — host. Inside that membrane is a single genome RNA together with many copies of a protein. There are two other proteins found embedded on the outside, embedded in the lipid by leader and founder of the outside and that is the envelope protein and the membrane protein. This is a life cycle of Aedes aegypti virus. This is we expected Zika to be similar. The virus will bind to a respecter and be internalized and inside under the page conditions, it’s membrane will fuse with the host. It will release the genome RNA which is that infectious. It becomes translated. It makes viral proteins. As proteins establish replication factories for producing viral RNA. Subsequently, for producing the virus particles. This virus particles bud into the endoplasmic reticulum. Undergoes a maturation process in which this immature noninfectious virus becomes mature and finally it’s released from that infected cell. Over the last 15 years or so, there’s been a lot of work into the structure and function of Aegypti virus proteins. We have structures for many of the proteins of the virus. There are Street flexural that I — there are seven proteins involved in interacting with the host and making new copies of RNA and do virus particles. So, the major surface protein on the outside of the virus is the envelope protein. This protein has two major functions. The first, is to bind to a target receptor. This is how the virus homes to specific cells within the body. Once it is on to the receptor and is internalized under low pH conditions, the E protein rearranges itself and carries out fusion of the Bible membrane and the cellular membrane. This releases the genome RNA into the cell


That protein, that envelope protein is the major target for antibodies. However, we do know that in dengue virus infection, patients make antivirus against the N and. N protein. We believe this is important in virus biology. What is seen here are two molecules of this surface protein. This is E protein viral. Three domains of the protein are shown in red and in yellow and blue. This is the part that is on the outside of the virus. There’s actually another component to this protein that is embedded in the membrane and is not shown in the structure. That was the structure from dengue virus. We have a number of lady virus E protein structure spirit we do not have it for Zika virus yet. If we look at a schematic comparing Zika virus with the other viruses, we can note a number of similarities in terms of the organization and we expect the E protein to be very similar in its structure. But there are some notable differences also. There are some insertions and deletions relative to the other lady virus a proteins back is slightly different on Zika relative to the other Flavivirus. This is showing amino acid identity amongst the structural proteins. And some of the replication proteins, and S3 and and is five with the Zika virus. One thing that is perhaps striking is that there is fairly high conservation in the replication proteins, less conservation when we look at the structural proteins and in particular the PRM protein has the least identity among the different viruses and so although we know a lot about this lady viruses in particular we know a lot about dengue virus and West Nile virus, there are clearly significant amino acid differences that are going to suggest that Zika will behave differently under certain conditions. Many years ago, my colleague, Michael Rosman and myself and members of Abbott Laboratories determine the structure of dengue virus using a technique called crime electron microscopy. This is a surface shaded view of the virus and you’ll notice that the virus surface is extremely smooth. That you protein that I mentioned instead of standing up like we see with HIV or influenza, actually lies flat, it less parallel to the surface of the virus particle. This structure repeats this pattern of E protein over and over again in a very ordered array. And so we can place, or we can see the envelope protein in the structure and on the next slide we see the organization of that E protein that I showed a few slides ago. It’s a very ordered arrangement on the virus particle. We also know quite a bit from studies primarily of dengue virus of the maturation pathway of the Flavivirus. We expected Zika to be similar. We start off in the endoplasmic reticulum with an immature, not infectious virus particle. That virus particle undergoes a lot of significant translational and conformational movements as it moves into a low pH environment. In that environment, a host protease cleaves the precursor protein, PRM, resulting in a mature virus particle. One thing in particular is that we found with the dengue virus and to a lesser extent the other Flavivirus, that this host controlled proteolytic event is not very efficient. We believe that this inefficiency is actually important for the biology of the virus. In fact, and many preparation, coming out of both cell culture and from infected patients, we see a mixture of mature, fully infectious virus particles and what we call partially mature virus particles. This is the result of an inefficient cleavage. In fact, in patients who are experiencing dengue and severe dengue infection, there are quite a number of antibodies that are directed against this PRM, this immature component of the virus particle. This is work that has been ongoing at Purdue between my lab and in laboratory of Michael Rosman and what we see here are Zika virus that’s been highly purified and has been cry oh frozen in prepared for electron microscopy. I would just say now that you can see there are smooth particles in this preparation and there are particles that are bumpy and are presumably partially mature. Right now, we don’t know the breakdowns of those. We think the Zika virus is a little better at getting to be a mature virus then dengue virus but we don’t have completed data. I should say we have collected many thousands of particles and we are closing in on a structure for Zika virus. We should I think at that very shortly. So, this idea of maturity involves the amount of pRM and the hose cleavage of the smallest R that enhances the structure and — and other aspect I do not have time to talk about, the dynamics of the particle. These completely affect the ability of the in virus to infect cells. The influence the entry. They also influence the exit of a virus from cells. This repertoire, this diversity of virus particles has a huge impact on the immune response in also we predict, has an effect on the disease and pathogenesis of the virus. Here are unanswered questions on Zika virus structure. I just told you that the dengue virus population is pleomorphic, and states of dengue exist due to variable PrM content. Temperature also plays a role. What you may see any mosquito will be different than what you may see any feverish human. That influences the protein dynamics of the particle. How does the structural rigidity of Zika contrast with dengue and the other viruses? That’s .1. .2, are we going to see unforeseen surprises in the Zika structure? Or will it be similar to dengue and West Nile? I’ve already pointed out that we know there are a number of differences in the structural proteins. What unique features of these surface proteins are going to influence the antibody response? And if there is subtle or significant changes, how do they effect the ability to induce neutralizing antibodies and how do they affect receptors? Finally, how does the structure of Zika influence receptor interactions and govern virus tropism? I think this is a critical question in terms of Zika virus compared with the other Flaviviruses. Clearly, Zika is getting into different cellular compartments that the other viruses do not. Finally, how would the structure inform function of receptor usage, tropism and entry? On my last flight I want to point out that there is a resource that people can go to to look at genome sequences and sequences that are coming in from different Zika resources this is the virus pathogen resource this is supported by the national Institute for allergy and infectious disease. In here is the website that you can go. It is and informatics platform and I suggest that if you are interested, please go ahead and visit that. Thank you. [ Applause ]


Thank you very much. We will go on directly to the remote presentation by Doctor Diamond Thank you for the opportunity to talk and I apologize for not being able to get there . As alluded to, sometimes the airplane and Weathers do not cooperate. I will try to make some points which are important for understanding Zika virus disease pathogenesis. As mentioned by other speakers, Zika virus is a Flavivirus. And has the same Arnie structure with 10 genes three of which are structural and seven nonstructural. The Flaviviruses are related to other members of the same family practice includes hepatitis C virus. I will mention hepatitis C later. These are positive polarity Arnie viruses. Most of them are mosquito or take a translated. Some of the disease syndromes that they cause and where we think Zika fits into this. The Flaviviruses, the ones that cause epidemics in humans tend to cause either encephalitis, shock syndrome or liver failure. The five major ones that we think of really are Zika virus, dengue virus, that’s the one that cause most of the disease. 390 million infections per year. West Nile — West Nile virus is endemic in the United States. Japanese encephalitis virus and yellow fever virus.[ Indiscernible ] These are different in the context of what types of diseases may cause and the particular mosquitoes and the regions[ Indiscernible ] The globe. This is a diagram of where the Zika virus stands. This was alluded to earlier by Doctor Rosenberg. This is the relatedness. You can see Zika virus is very close to another virus we don’t know too much about as Richard alluded to, and has a significant amino acid similarity to dengue virus although it falls in its own virus enclave. Is more distantly related to the and syphilitic virus including West Nile, Jeff and I — Japanese and St. Louis. And also to tick borne viruses. One of the other interesting figures about Zika is at its mosquito transmitted.[ Indiscernible ] Old world evidence of nonhuman primates as being a somatic was of our.


One of the questions I wanted to address is is the pathogenesis of Zika it different, unique, how does it relate to other virus infections. I will review the four major viruses in terms of diseases they cause and where Zika stands. The and syphilitic Flaviviruses which includes West Nile, Japanese and tickborne, these viruses effectively replicate locally where the mosquito bites. They spread through the training lymph nodes. Ultimately they spread to the brain and spinal cord and infected neurons. At this direct infection of neurons which can lead to injury directly but also by bystander injury. This leads to cell death and the peripheral and central nervous system. This is a clinical outcome of encephalitis, meningitis, and also as we saw in the US during the hour — early outbreak of West Nile, and it should paralysis. These are what we call and syphilitic lady viruses that target neurons. Then there are competitive bid lady viruses, yellow fever is a primary example. It can infect liver cells and cause injury but can cause injuries to kidney. Taking it a renal syndrome. This can lead to acute liver and kidney failure and this can be very devastating although fortunately we’ve had a vaccine for yellow fever which has been used in many since the 1930s and 40s. Then there is the hemorrhagic fever and shock syndrome which includes the dengue virus which infects my light cells. And can produce high levels of pro-and amatory cytokines along with interesting factors about the virus biology, particular the NS1 protein can lead to a shock syndrome or hemodynamic instability as well as leading syndrome. Were Zika fits into this we still are not — we are at the beginning of understanding. Why is there microcephaly, what about Guillain Barré Syndrome. I went to briefly sum up the clinical scenarios that we see for the different viruses. This is West Nile. Its major effect is the mosquito unlikely the virus into the skin. Replicate locally and causes viremia. The key question is whether the virus is able to cross the blood brain area are cross into the spinal cord. If it doesn’t, it remains in acute illness in many people. Some people do not develop symptoms. Then it is cleared over time. And other individuals and for West Nile that is Perdomo people have covered that is, the virus can cross into the brain and infects the neurons. This is how it becomes an and syphilitic virus. In contrast, and gay has a unique pathogen. Mileage shells are the primary target in this leads to the clinical symptoms you see on the left including the severe vascular symptoms. Really it is due to the unique pirate — biology of dengue. There are four different types. Those occur not the first time you get it but potentially the second or third time. The reason is it is immune enhancement disease. Studies have led to a greater understanding and resolution of this clinical disease pathogenesis such that after the first infection develop antibodies to the original infection you had. If you had dengue 1, you develop antibodies to that. These antibodies can protect against dengue 1 for life although there are some questions for the. These antibodies on occasion can cross-reactive to dengue 2 and dengue three and thank you for. They cross-react with it or not neutralize. You get into buyer — virus complex, this can facilitate entry into a mileage cell which expresses[ Indiscernible ] Receptors and that leads to a higher levels of a production of virus which also leads to higher [ Indiscernible ] . It’s a combination of the cytokines and indigent email which we believe changes these the permeability which leads to a plasma leakage syndrome and this causes the unique dengue pathogenesis. The second infection is usually worse although this happens relatively infrequently. What about Zika virus? What do we know about it? I think Scott alluded to quite well in his talk — we’ve known about Zika for a long time but because it did not causes the symptoms we are aware of, [ Indiscernible ] . We have studied other Flaviviruses, there are number of questions. What we know about animal models? Scott alluded to the 1947 and 1950s and studies where was isolated. When Reese’s became febrile. A blood sample was taken and injected into mice into the brain. This led to a number of mice being sick and then the virus was [ Indiscernible ] In this generate the original Zika stock. That is still being used today. That virus was only found in the brain and spinal cord suggesting that Zika virus may have a propensity for Nora tropism however it would injected directly — it was directed in check led — into the brains. The other study was in 1976. That is when another investigator took Zika virus as part of a series of a larger panel of virus and was injecting it into mice. That showed[ Indiscernible ] In this case the mice got sick in the mice died. There was no pathologic description. We really had some studies on Zika virus and action and mice or monkeys to work with. This leads us to a number of unanswered questions that will need to be addressed. What are the urgent needs from the standpoint of understanding pathogenesis? We need animal models of infection and disease pathogenesis with circulating strains. Scott alluded to this earlier, there may have been changes in the amino acid and nucleotide sequences which can alter the potential for transmission in the mosquito population but also for pathogenicity[ Indiscernible ] . We need to understand that using reverse genetic analysis where we can make mutations into infectious viruses and test hypotheses about why the current outbreak seems to be worse. Then we need mouse models a nonhuman primate models. We are at the beginning because nothing has been done for many decades. We want to understand how the virus effects, disseminates, and how it does cause Guillain Barre. In humans. Outside of the animal model, we went to perform longitudinal study is to follow the virus goes and what is the nature of the injury, perform detailed pathologic analysis and answer the question why is it worse now and why is it — is it only in some people? Are there genetic factors that can lead to [ Indiscernible ] Disease. I want to review the two recent publications done on Zika virus. Microcephaly in the earlier talk that was alluded to that there is mounting evidence now that Zika virus is associated with microcephaly and two recent case reports, one in the New England Journal and the other[ Indiscernible ] Makes Zika the likely cause of microcephaly now. In the first paper, there were two new boards with — two miscarriages[ Indiscernible ] They were positive for Zika virus RNA and only the brains were positive. The genetic sequence of Zika virus was obtained in fragments and there was[ Indiscernible ] Seen. In the second paper which was due to a terminate a pregnancy associated with a very severe disease in the fetus, and that because there was[ Indiscernible ] Of the brain. There was viral RNA and he completed Zika genome was identified as well. This was virtually identical to the other strains that have been circulating in Brazil. There was also evidence of infection and injury in the neurons and tissue damage in the brain and spinal card. — Cord.


Let me review what I think are the main unanswered questions that we have? How does in utero transmission occur and why is Zika virus different event other Flaviviruses? Unlike Zika virus, we’ve not heard about microcephaly are other congenital malformations with dengue or West Nile even though we have hundreds of millions of infections per year. Why is Zika virus difference? I will remind you that there are other viruses that even as the [ Indiscernible ] Heaven shown to cause in utero infection. — Hepatitis B virus in approximately 4% to 5% of individuals can be shown to cause in utero infection. The risk factor for this was high viral load in the blood in the possibility is that Zika virus can infect cells in the layers between the mother and fetus which then would allow and facilitate transmission across into the fetus and then in fact the fetus, presumably[ Indiscernible ] Although we don’t know that either get in terms of where the virus actually goes and is it a muted response or the virus directly that’s causing the injury?


A second unanswered question and this was raised also before, does a pre-existing dengue immunity affected Zika virus disease in unity? We have no evidence at this time but this really has not been studied. Dengue virus as shown, has a significant[ Indiscernible ] It be protein level. We have antibodies are cross-reactive and the question is whether the dengue antibodies would cross-react with Zika and make things worse for Zika virus by allowing [ Indiscernible ] We don’t know this yet but it is conceivable. Certainly, Brazil has a pop elation of people who are think any. One idea is there are factors, the could be host factors assisted with dengue immunity that could Mexico worse and some individuals. Specifically, it is possible that Zika virus immunity could affect the dengue immunity down the road. These are two questions we will need to study that we have no answers for right now. The third major area is what is the basis for Guillain Barré Syndrome which seems to be assisted with Zika? Some studies in Micronesia and more recently from Brazil, this is to be a 20% to 25 fold decrease of risk for jamboree although the data is not totally clear. We do know that Guillain-Barré is a heterogeneous disease and it targets the she’s around nerves. It image though she’s. Damage — patients can do prelates, weakness or tingling in the arms and legs. What would be possible mechanisms, there could be in a pathology, the antibody or T cell response [ Indiscernible ] Could mimic a host protein. It could be that the virus has changed in sequence and now targets cells that are around neurons or near neurons or there could be some other association we don’t understand related to prior immunity to dengue. This is an area we need to study as well. This is my last slide. As a summary, on the left side in green, this is basically what we know which is that mosquitoes are the primary transition points picked the virus is introduced to this can. It probably infects skills in the sin. [ Indiscernible ] East on preliminary data that’s been published. This leads to the clinical syndrome which occurs probably in 1-5 based on numbers with the. Most people go on to protect with immunity. In the blue area on the right is the questions that are unanswered. How do we get transcendental transmission and how does this release — related to congenital affirmations? Sexual transformation was raised. Why is Zika unique among the Flaviviruses. This lease with persistent reservoir as we’ve seen with other viruses such as Ebola. What is the role of antibodies that are preexisted from dengue? What role the Zika have on dengue? Will this affect vaccine responses now that we are living into deployment of dengue vaccine in the field. And what is the effect on Guillain-Barré syndrome and what is that occur. Thank you very much for your time. Cement thank you very much. We will now have the final presentation in this panel by Doctor Britt Thank you for allowing me to give this presentation. Again, echo Mike’s comments. I tried to make it but the airlines were not cooperating pick — cooperating. I presume we are connected?


Yes, go ahead, Bill.


I’m sorry. I’m going to speak today about congenital viral infections and try to draw some parallels between rubella and CMBD. Not much discussion about Zika because little is known, if any of them. Congenital viral infections are relatively common. And they are defined as the trans placental acquisition of a virus in contrast to perennial infections which is the on the right-hand side. Which include some of the hepatitis viruses as well as some of the herpesviruses. Congenital infections are also seceded with central nervous system diseases in contrast to perinatal infections with the exception of herpes simplex virus. These are ranks of congenital infections and Brazil drawn from studies that have been published in studies that we carry out in Brazil and as you can see that ranges somewhere between 6 and 10 per thousand live births which in Brazil calculates to about 20,000 babies per year born with his congenital virus infection. With the frequency of these congenital infections and today’s technologies, why don’t we know more about the mechanisms of transmission and disease with these agents? Or merely because we are dealing with three systems simultaneously when we try to study congenital viral infections. We are dealing with the pregnant woman, the placenta and the fetus. Into the complex biological system. Each is development of a regulated during pregnancy and it’s difficult to study one system in isolation from the other three. I think this has led to a lot of the difficulties in understanding the pathogenesis of many congenital viral infections. There have been some a systems that are easier to understand, one was rubella. Rubella virus resulting congenital rubella syndrome and what we learned early on was adaptive energy blocked placental infection and blocked fetal infection shown in the third line. Thus, achieving adaptive immunity would prevent this syndrome and this was reflected early on in the UK when they studied the instance of rubella and all this is not a well-known slide you can see the red bars indicate the disease activity in rubella. When the disease activity fell, the instance of congenital rubella increased because of the increase in the number of young women who were susceptible to rubella infection. Were recently, studies in Asia have looked at the rates of congenital rubella syndrome versus a prevalence in the population. As you can see, when the prevalence reaches levels of about 80% or 85%, there is no congenital rubella syndrome. It is effectively emulating it as a congenital infection. Indeed, it 5%[ Indiscernible ] Vaccine uptake target in the early deployment of rubella vaccines. In contrast, cytomegalovirus has a much more complex epidemiology. Paternal immunity — maternal immunity is important. We know that in women who have depressed immune systems such as women with uncontrolled HIV infections, the instance of congenital infection in their offspring is higher. However, we don’t know how adaptive that immunity works. There have been reports of adaptive immunity interfering with viremia and with placental infection in with fetal infection however, none of these have been shown to completely block the transmission of this virus to the fetus. In addition, adaptive community — immunity in CMV show somewhat of a paradox,[ Indiscernible ] To this virus, the number of women with exposure to this virus increases with the increased rates of congenital CMV infection. This is in contrast to rubella which is shown in the inset on the lower right-hand corner. So the more women in a population who immune to CMV, the more likely it is to see congenital viral infections. Again, this is reflected in that we see a much higher yield of congenital infections from populations with non-primary, that is women with immunity than to those who acquire CMV as a primary infection during pregnancy. About a three or four fold increase. Why is this? Well, without going through details on the slide which are difficult to read I can see, we do see superinfection. Women with established immunity to CMV can be reinfected with new strains of CMV during pregnancy. This was first detected using an essay who defined serotypes of CMV. Marcy recently, — more recently, execution sequencing has been done on CMV isolates. We see they circulate as a quasi-speeches. Such as complex images of genetically diverse viruses in most individuals. Therefore, providing at least a reservoir virus — of viruses that could reinfected women. As you can see in the bottom panel, this diversity approaches that of dengue. The next step of detection is to cross the placenta. As eluded two, this is where the virus enters the fetal circulation per this is a very complex organ as most in the audience realize. It has a very unique structure in primates and some rodents. In that the structure sits any poll of maternal blood as illustrated in the light green circle. This enables any infectious agent that could be present in maternal blood, easy access to the fetal circulation. In some peers of gestation, they are represented maybe by a single cell layer thickness. This is illustrated by placental development that could facilitate virus transmission. Placental blood flow is incredible. By the mid-and second trimester, 3% of maternal blood flow passes through the placenta, therefore providing ample opportunity for any bloodborne pathogen to enter this space. As mentioned, during the second trimester,[ Indiscernible ] Such that the only thing to separate maternal blood from the fetal is the member [ Indiscernible ] . Again, and easy access to the fetal circulation. In addition, there are a variety of cells and[ Indiscernible ] That are in the stroma that could provide application and amplification for the fetus. In addition, we shouldn’t forget that the major [ Indiscernible ] In the placenta is to provide nutrients and oxygen to the developing fetus. Environments that in fact the placenta can certainly interrupt this function. The top panel shows that CMV can in fact have a blessed progenitor cells in the placenta limiting their self renewal capacity and therefore limiting the number of functional units available in that particular placenta. In addition, other investigators have shown that CMV can infect the placenta and result in a thrombotic basket left with the which decreases the function of these units of the placenta. Both cases, these interrupt nutrients and oxygen supply to the fetus it can result to damage in the central nervous system and other organs. That could contribute to some of the syndromes we see with congenital viral infections. What are the diseases once they develop and once the infection occurs in the fetus that we see? I will focus on the central nervous system because there are clearly other organ systems involved, most of these are self-limited and rarely have long-term consequences with the possible exception of the cardiac defects in rubella. The clinical findings we see our microcephaly, a logical deficits such as seasonals, deficits in perception such a sight and hearing. This is very important. Congenital — [ Indiscernible ] 25% of all the hearing loss in children in the United States. There are developmental delays. Laboratory in imaging findings show structural malformations, this is developed as a specific of the brain, when the[ Indiscernible ] A R classifications and vascular damage. Loss of neural mass and evidence of CNS inflammation. These are all relatively nonspecific responses to injury to the brain. This depends on the developmental stages of the brain. This is illustrated — this is a photograph provided by an investigator in Brazil showing an infant with microcephaly that was associated with maternal Zika infection. The CT scan on the right issues the calcifications in the brain. The large ventricles indicate loss of the cortex in this part of the brain. This is a total of congenital CMV. This child also has microcephaly and some of the same stigmata that the patient in Brazil had. There is a CT scan and you can see the calcifications to the large ventricles and the loss of the cortex. These are very nonspecific findings and provide us a little insight into the mechanisms of disease caused by the specific agents. What are the direct postulated mechanisms of disease, direct virus disease to the developing CNS? It could be loss of neural progenitor cells. These virus have been shown to infected neural progenitor cells and cause damage or loss. And portly, they can infect the supporting vasculature in CNS and as a result of any vasculature, they will lose the [ Indiscernible ] By the CNS. They can result in altered cellular positioning of the cells. Altered connectivity within the CNS, increasing a proptosis if these connections are not made . virus induced alterations in neurotransmitter response again leading to neural dysfunction. However, all of these may be operating simultaneously and they provide, often, a variable phenotype even under controlled experimental conditions. The bottom panel shows brains taken from rhesus macaques fetuses that were inoculated transfer essentially in the second trimester. They were not inoculated in the brain. They were inoculated in the peritoneum. The virus spread to the brain and caused these brain defects. You can see the brain from the control animal on the left has normal structure. The animal on the far right, number 1, has loss of all structures in the Cortes. The coronal section of the brain shows the ventricular Magaly and the loss of the cortex. In the middle, one of the fetus inoculated missing tradition shows and other pattern of pathology, a loss of certain areas of the brain, focal infections and focal loss of the cortex. Again, the pathology is probably dependent on the magnitude of each of these possible mechanisms of disease. Finally, as Mike alluded to, the possibility of host inflammation as a cause of some of the disease we see in infants with congenital CMV should not be overlooked. Mrs. data we generated using a newborn mouse model of congenital CMV infection and it which we use [ Indiscernible ] CMV to infected newborn animals peripherally, not Intracranial he. We know about eight days after infection we seem marked changes in their central nervous and brain development. On the right you can see the cerebellum from one of these infected animals. It’s much smaller than the controls. Defoliation, the complexity of the cerebellum is much reduced in this animal. This is not associated with widespread virus infection in the cerebellum but with widespread inflammation and induction of a variety of inflammatory genes. Below the panel on the left, you can see what happens when we treated these animals with steroids. That is shown on the right side of the panel. Those are virus-infected animals. The white histogram shows a vehicle — vehicle treated animals versus those treated with steroids. As you can see, we can normalize the cerebellum area of structure by treatment with steroids. On the right-hand side you can see that some of the genes in the cerebellum’s that are developing develop into regulated are also normalized by treatment with these steroids. Those are shown in the shaded bars on the right side of each of the columns. Host inflammation[ Indiscernible ] A significant role in the damage we see in congenital infections. Said the research priorities are really, and I think they echo what’s been noted in the earlier talks in the session and the earlier talks this morning. We really need to generate comprehensive and definitive natural history studies of congenital and perinatal Zika virus infections. These are likely require new diagnostics, perspective phase, newborn screening and long-term follow-up. I think this is important because we really don’t know the spectrum of disease with this virus. We see the cases of microcephaly but there could be other infections that end of contributing to long-term morbidity of these patients, be it loss of hearing or impairment in vision. These need to be well done and very comprehensive studies. Secondly, the studies will help us inform the development of informative animal models that recapitulate key aspects of human infection and allow us to define, design strategies and interventions to prevent these infections. Thank you.


Thank you. [ Applause ] Thanks so much. We will move now to the final panel on clinical management and public health interventions. I like to invite the speakers to come forward. Doctor Albert Ko U.S. Ted Epidemiology of Microbial Diseases at your University School of Public Health will go second. And Doctor Laura Elizabeth Riley, director of obstetrics and gynecology infectious disease at Massachusetts General Hospital in Boston.


Thank you very much. I will probably be the quickest person you’ve heard all morning. This is about perspective for me. So I will tell you a little bit about what I do every day. I am high-risk obstetrician and so what I’ve been dealing with the seeing women come in who have been exposed and now they want to know what should we do. That’s really my perspective. You seen this before. This is the New England Journal article that recently came out. I will describe quickly a little bit about that patient. This is a woman who had been in Brazil and at 13 weeks gestation she noted symptoms consistent with Zika virus. She actually went back to her home in had also had an ultrasound at 14 weeks and 20 weeks gestation which only showed a mild decrease in growth of the baby but no malformations at that point. When she returned home, she had another ultrasound at 29 weeks. On that ultrasound, this is what they found. You can see there are Intracranial calcifications on one panel and on the other panel, this is a cross-section of the placenta. There are Intracranial calcifications. You can see on the postmortem specimen, these are the areas where there are the calcifications as well. This is microscopic analysis of the brain tissue which showed there were virus throughout. Esau these panels earlier from Doctor diamond, I believe. And so when we start to think about how are we going to counsel these women who have been exposed and then they come back to the US in we need to decide what to do with them, this is the guidance of that came out recently. The most recent guidance that came out from the CDC about how to handle these patients. How we put this together, we take the guidance from the CDC and we — I apologize, I jumped ahead — this is from mmwrthe that was published from a few of the cases that were in Brazil any real dive down look at those pregnancies in the things that are important to us certainly is, at what point in pregnancy to the affection incur? And from this small group of studies, smoke but patients, most of the infection occurred in the first trimester. There was some in the second trimester and then 26%, there was no known time of exposure. That is an important point for us. The second piece of information I think you will see becomes important is that obviously, what we were looking for and what we’ve been focusing on is microcephaly I point to you at the bottom, you can see there are other issues including, other than calcifications, ventricular enlargement as well as[ Indiscernible ] Which is something that was mentioned in the last speakers presentation. There are a number of the potential neurological abnormalities to consider. Now we are going to those guidelines which I mentioned before. I put an arrow here because the number one first stop for someone who has traveled and been exposed, for pregnant women who have traveled and been exposed, the first step is to do a test for Zika virus infection. That test is the ITM test. We are putting a lot of stock into this test. A test we do not have a lot of information about. Another piece of the algorithm, this is for women who live in an area with ongoing infection, in addition to the information we will get it from the Zika test, there is also — there are three arrows pointing to the reliance upon ultrasound. We are putting a lot of energy into doing these ultrasounds and you will see that some of the ultrasounds are serial fetal scans. This brings up a set of other questions, including, at what point will you see those abnormalities of the microcephaly, of the listed separately, they Intracranial consultations how often do this ultrasounds need to be repeated. What information when you gain over time from this? Again, these are areas where we really don’t have information. Again, it’s about perspective my perspective as an OB provider, you can imagine I’m sitting in a small room with a couple that wants answers. What I am doing is taking the CDC guidance and I’m taking my own knowledge of CMV and rubella and I’m trying to put it together about Zika virus, of which I know very little. We don’t know what the infection rate is in more importantly, the incidence of maternal fetal transmission by trimester is particularly important. And, what are the factors that influence that transition? Is it the severity of maternal infection? Is it the maternal immune response? We don’t know. We had information that we can glean from other infections as the last speaker mentioned. Also because a relationship between Zika virus and other adverse pregnancy outcomes. I think we have probably pretty well-established the association with microcephaly. As I mentioned, there may be other neurologic abnormalities that we should be aware of and looking for that we don’t yet know about. And then, again, the full spectrum of phenotypes in affected fetuses. That is not completely numb. Our next speaker may mention some of those. In addition, the main response to Zika virus infection, I think that’s very clear — clearly a priority. The peak induration of that response, Odyssey the cross-reactivity of Zika with other related Flaviviruses needs to be consider. Again, the reason I put a focus on that is because that is the second step in our algorithm. Not having the answers to these makes it difficult to councilwomen. Obviously, the performance of serologic testing for its domestic paintings. The IGM. How well does that work. Once we get a negative result back is a really negative into what point can you tell a woman it is negative. Finishing up, the other questions that we have, I did not point them out on the algorithms but for women who then are found to have ITM positive or ultrasound abnormality the next step in the algorithm is to do in amnio — is to consider doing an amniocentesis for Zika . It is not known what this is a tizzy — sensitivity is in the amniotic fluid. The next question comes up as well, which is, what’s the optimal timing for amniocentesis based on our knowledge of fetal infection and the pedal response to infection? Those are a few of the questions that a high-risk obstetrician has in many general OB/GYN’s as well as we are trying to give women reasonable counseling. Thank you. [ Applause ]


Thank you very much. It’s great to be the last one because you can see your talk withering away with everyone’s points being made. [ Applause ] It also gives you the opportunity to get some perspectives and comments on previous speakers. Mine will be from our experience of the last year in Brazil. We’ve been working there for 20 years in — let’s see — does the pointer work? Okay. We work in the city of Salvador where that red dot is. That was the forefront of the epidemic of Zika virus. To give a quick run through of that timely. In March 2015, the first cases of Zika virus were detected in Brazil. In the city of Salvador as well as another region in northeastern Brazil. Rapidly, we had a large out broke — operate. It is important to know this is an it cute illness because if you look at the curve on the — I’m sorry — if you look at the curve on the white lines, there is the dengue surveillance system. And what cases they picked a. In the black, that was positive surveillance for Exanthematous illness. I will come back to this will we talk about the clinical presentation. Beginning in April through July, we had a cluster of cases of Guillain Barre. This is 50 cases in a city of 3 million cases. There were other atypical neurological manifestations that were noticed or admitted to the neural intensive care units. Then subsequently, starting in July, the obstetricians, when they were doing routine ultrasounds of pregnant women, were identifying increased congenital abnormalities such as the figure on the bottom right-hand side. That shows eight distances of corpus callosum. This was frequent numbers — on social media, the obstetricians were talking to each other but they never communicated that to the Brazilian Minister of health. And everyone knows as previous talks have said, the talk about the outbreak that occurred in October. I will drill down on several of these, particularly the acute infection by Zika virus, the Guillain Barre and about the clinical management. Lara give a nice presentation about the microcephaly and the potential association and then I will come back to the public health implications at the end. Acute Zika infection, the evidence we have this is our current knowledge gap, is really from a small case series in outbreak settings. The majority of these cases are asymmetric as discussed. The clinical attack rate is 18%. For the most part it is a self-limiting illness. This is from — the top panel is from a case series including the outbreak in 2007. The bottom is from a small case series during the initial identification or detection of Zika virus. The important finding is there is pretty much ration 1% of the cases but theater in 50% — fever and 50%. This goes back to what is happening in the pathogenesis during acute infection. What we do know about viremia is really from a very small K-series. This is from New Caledonia on the right-hand side. I believe a previous speaker showed this. After the onset of illness, the viremia is fairly short, less than five days perhaps three days. What has been coming out and published reports in the media is this issue of the prolonged shedding. This study from New Caledonia, there were shedding of 214 or 15 days. Were some studies presented and published in Emerging Infectious Disease is a couple days ago which detected virus in the semen, up to 62 days. This is all through — we do not know the survival viral particles. In terms of knowledge gaps, one is the duration, one is to inform our understanding about the transmission dynamics. Also, this issue of viral shedding in with the implications of that is on the clinical implications on viral shedding. Going down to the other potential sequela of Zika virus which is this association[ Indiscernible ] Sequela. The evidence is shown in the top of the slide. We do now is there was a cluster of 42 cases after the outbreak in French Polynesia. This is a population of 270,000 which estimated the majority, more than 50 or 60% were exposed. The second piece of evidence comes from the Brazil outbreak where we have identified roughly 100 to 200 Guillain Barre cases among 400,000 to 1 million cases. From all those cases to date, there is one confirmed case published and that was from the outbreak in French Polynesia. The major knowledge gaps — what is really the nature of this association. This goes back to some of the issues described before. Similar to microcephaly. The barrier is diagnosing this post a picture process and populations that have previously been exposed to Flaviviruses. These patients are coming in 8 to attendees after acute[ Indiscernible ] . How to make that diagnosis and actually test that association. At least and populations which have previously been exposed to Flaviviruses such as in Brazil. The second is the clinical presentation and the outcomes of these cases. Because of the difficulty in confirming them, we do not have a handle on how their presenting. Anecdotally, and this is just from pulmonary results we have done in our team has done, most of these patients are coming in with classic Guillain Barre . The response to intravenous immunoglobulin is good news but this could be a case of [ Indiscernible ] Buys. There’s an important caveat that needs to be brought in. Now with, as many this because of talked about, this culture — circulation of dengue, turn 26, and Zika, the important one is turn 26. There has been a report of Guillain Barre in we are now finding confounding. Within that cluster of Guillain Barre that we have been investigating in Salvador, we’ve identified patients who zero convert to turn 26. There is a couple listens and confounding due to this co-circulation of these two viruses. Lastly in a portly, along with that, Guillain Barre was a very obvious — to go to the intensive care unit in the half the patients are filled with patience with Guillain Barre. We also had patients who had to my when eating encephalomyelitis. We had patients with encephalitis that would fill the space. We also had patients with many — outpatient neurologist identified it strange isolated sensory disturbances. That Guillain Barre may be a part. If we go back to the figures — I think the important thing is risk after exposure. Weather is through symptomatic or a center medical infection, that risk is small. If you think a 42 cases among a population of 270,000 4/2 have been exposed, that brings you to 30 cases over 100,000 as the attack rate. The question goes back to, what are the host pathogen and an ocular factors, the mosquito factors that may influence this? I was skip the part about the complications. Congenital complications of the Zika virus but I want to talk about what we have now another we have 4000 cases a microcephaly? Some of those are cases of CMV or toxoplasmosis that have been picked up by surveillance. There are aspects of this case presentation that may be different than CMV. For example, we don’t find involvement of the hepatic system or the cardiac system or other extra CNS findings. I think the major issue is what do we do to take care of these patients? This is a current outbreak. We have no evidence or prognosis. There are warning signs for us. This is a study published by our group. You can see in the upper right-hand side — I’m sorry, the right upper side, you can see some of the lesions we’re finding in these cases a microcephaly. Cases of scarring. Model pigmentation, optic nerve involvement. These are older scars. Scars that are not fresh inflammatory scars. Theater — these are scars that give insights that this may be an old, burned-out infection that occurred early in pregnancy. We are seeing the scars or these lesions also in babies who do not have microcephaly. The knowledge gaps at this moment is, how do we screen these babies at birth? What is their prognosis in the future? How do we manage the severe manifestations? We were shown CT scans of the case of a typical case we are seeing throughout Brazil. You can see the CT scan at the bottom. You can see the linear calcifications. Were are having readmissions of our patients for hydrocephalus and seizures at a fairly rapid rate. That’s one of the major clinical concerns that we are having to deal with. And as Laura said, this is likely a fraction of the burden because the presidents with other congenital infections. Finally, a very important point and how is the family be infected. What are the interventions to provide supportive family and address stigma, especially with all the media and awareness about this condition? Let me just stop with a diagnosis but the important diagnosis — having gone through these sequential epidemics or clusters over the last year, we do need a test for acute infection. We need a test to identify intrauterine infections in fetuses and newborns. I would make the point that one of the most important diagnostic priorities is have a test that we use for taxable as Moses in rubella to screen women of childbearing age for risk purposes. The other important diagnostic, we need a tool to evaluate immunity. To understand projects whether this will come back. There are important issues that need to be dealt with in the short-term. One is by review is short-term acute infection. We don’t know what the persistence of the virus is in the fetus and newborns. We suspect it is actually quite short since many babies are PCR negative on birth. In current diagnostic test — this is a dilemma. We do not have an adequate PCR test at this point. I mentioned the importance of an antibody detection. Bells also discussed in the previous talks as well. I think those are some of the short-term and long-term challenges we had. Thank you very much.


[ Applause ] I’d like to invite all of the speakers to come up and we will have a few minutes for Q&A. I give enormous credit to our speakers in trying to cram a huge amount of material into very short presentations. Our speakers who spoke on mine are also still available. If you have questions, please go to one of the microphones in the aisle, introduce yourself. Tell to whom the question is directed and please keep your questions — and I’ll also ask the speakers to keep the answers, brief.


[ Indiscernible – low volume ]


My name is Bob and I’m a pediatrician at Johns Hopkins. I want to thank all the speakers for these wonderful presentations. My question has to do with the analogy between CMV and what you’re seeing. CMV, as you mentioned, you will see many other factors — some data loss, has that been seen in the Polynesian island outbreak? Is that also seen in the Brazil operate?


— Outbreak


To whom is the —


That is for Doctor Rosenberg — in the Polynesian operate, that they also see small gestational age babies. And[ Indiscernible ] What they know in the Brazil operate?


There were no detection of birth defects from[ Indiscernible ] . It was a relatively small population, probably 5000 people and we don’t know how many of those were pregnant.


[ Indiscernible – low volume ]


Notemac — no. I said it was on. I’m not sure how carefully it’s been study.


Let me add in French Polynesia, yes. Retrospectively there were 17 women identified, of which about 11 — three of them opted to continue the pregnancy. They were identified by ultrasound with classifications in microcephaly.


Let’s go to this cyber questions.


One of the things that we struggle with when dealing with the emergent news and science is how to counter actually risk from perceived risk and pseudoscience with actual signs. I gave you that introduction because there are two prevailing items that seem to be discussed and I haven’t really heard us as a scientist either from a public health or medical side, address how to counter the impact. One being the most recent conversations about larva side having some significant issue or potential or probable correlation to the microcephaly. The other one being other social media related science, pseudoscience around genetically modified mosquitoes being associated with this particular [ Indiscernible ] Can we from an applied science aspect quell or address those concerns so we know how to educate our public better?


I will start with the second question about the transgenic mosquitoes. There have been very small contained releases in Brazil. Again, these male mosquitoes made with wild females. They produce offspring that die 100% in the larval stage so the transgene does not persist in the population. So, between the very small-scale other releases and the lack of persistence, there’s no way that that could explain anything to do with the Zika outbreak. The first question about larva side use, and a country like Brazil and perhaps Albert can comment on this, I think there’s very limited application of larva side, especially the poor communities were a lot of these cases are occurring. This absolutely no mosquito control available to the majority of people in the cities.


I think the concern was with –[ Indiscernible ] I can’t pronounce the name of that but — the use of that in the Northeast, particularly where the Ametek — epidemic has started is very minimal. In other parts of the country but not in the Northeast. Is also more used in rural and for agricultural purposes then the urban. Many of these cases started in the urban centers.


May I remind you to give your name, please, before you ask a question.


Diane [ Indiscernible ] . I am a fellow at National Science Foundation in the ecology and evolution of infectious diseases. We just put out a dear colleague letter on the Zika virus for rapid funding. As a result of starting to look at the proposals that are coming in, what we would like to know is, what sort of data are or will be available? Last year, one of the big issues with people who wanted to do modeling was access to data. So, what is being collected? And what is being made publicly available?


Would you like to do


Actually, I know this is a difficult question if you could provide any information.


I would volunteer our colleague. [ laughter ]


We are working on it. Remember, this was not a reportable disease. Countries are now reporting. He saw a slide with an epi-curve. Data is flowing now but still, we have some challenges from some countries. Some countries need to set a system and improve this. I don’t see a major problem with the data being available. The issue is that countries own their data and they like to discuss the issue. As far as [ Indiscernible ] , It is always available to be brokered with the countries. But, the data that I presented is on the website. Now. Of course, there will be more data needs and so on but I think it’s a matter of — and I understand[ Indiscernible ] Going to Brazil because there has been concern and issues. But I understand also[ Indiscernible ] Is working with the CDC and case-control study with the CDC. While there are constraints, I don’t have a doubt that there will be data available regarding Zika, Guillain Barre, which is actually available and microcephaly which is only in Brazil.


Thank you.


Let’s go to decide.


I would like to comment.[ Indiscernible ] I just wanted to point out with regard to congenital anomalies that this is not entirely unique among the Flaviviruses. I want to point out I think it would be nice to have an animal model[ Indiscernible ] Ask important questions on pathogenesis in developmental embryo toxicity. There — Japanese and satellite is in pigs is a commonly — is commonly associate with congenital [ Indiscernible ] Leading to Sobrack also — often. A mosquito borne Flaviviruses in Africa called [ Indiscernible ] Is often associated with a similar findings in sheep.[ Indiscernible ] Stillbirth and births with neurological anomaly. And I think this is an area for research that should go on in parallel with Zika. We currently do not have animal models that could be studied in this way.


Thank you, Tom.


Hi, Nikki. Thank you to the panelists for terrific presentations. I have two very quick questions. The first I think is for [ Indiscernible ] It seems like there are a lot of people around the world now that are engaged in one way or another [ Indiscernible ] Or other more basic research studies. And yet I’m not sure that they all know that one another exist or how to find one another. Whether it’s him all gene vector side or whether it’s on the epi-side or whatever. I am wondering whether any of you may be aware of a central place where people who are doing work could declare that they are so we can start to develop a broader research network. The other question has to do with vector control and I’m just wondering whether there are any precedents for using crowd sourced information to identify reservoir vectors, stating whether, other sorts of things so that others involved in eradication could go there and do something? If I think about the analog and Deepwater where people reported oil birds and someone wash them off, I don’t know whether there is any experience with using that kind of information for vector control but if there is it would be great to hear. Thanks.


I will comment on the vector control. I do know some programs that are making use of smartphone technology for people to reports presence, densities of vectors in different parts of the world. And to have this trigger some kind of alert system or dengue in the past. Perhaps now for Zika. [ Indiscernible – low volume ] I don’t know the details but these are very simple, I’ve been bitten by a mosquito in my house, kind of reporting. Nothing very sophisticated. Probably soon it will be the opportunity to photograph a mosquito if there is one you can tell without mutilating it to the point beyond identification. Things like that are being developed that not ready yet. The question about information on expertise, resources — I want to point out that the global virus network and Doctor Esparza is here who is the president can comment about this, is working very hard to compile a database of expertise from around the world. Special resources, reagents, study populations, things like this to improve communication globally for Zika research.


Let me add to that. While I mentioned some of the studies that are running in Brazil and Colombia, it is a valid question but it’s not an easy one to deal with. We should understand that Brazil is a federal country with 5000 units a pallet he’s, a strong estimate — academia network that are collaborating with scientists around the United States and around the world. A lot of studies are going on. While at PAHO we try to broker this and to get information, we have Summit coming from the government but it will be difficult to have all the information. I think it’s a valid question. And we should try to get as much as possible. It is a huge issue now going on between the countries. Columbia is also doing a couple of studies but I don’t have a doubt that there are other research centers in Columbia, which is a very good national Institute of health, establishing bilateral collaborations with academics from the north and south.


Let’s go to decide.


Good morning. Executive director of Harris County public health. In Houston. Third most populous county in the US and operate the mosquito program for the entirety of Houston and Harris County. Thank you for your presentation today. All of them were spot on. For me public health practice standpoint we are obviously very, today as I was listening to the comments I went from oscillating between optimism and, oh my gosh. Really, my question is about the real vectors and the real[ Indiscernible ] And Culex. As you entered, the possibility that[ Indiscernible ] Mosquito might be able to transmit Zika virus while we have this mosquito in our population in Houston, we also have Aedes in our population in Houston. We have to continue with West Nile virus activities and a completely different strategy for Zika virus, Exeter. The question I have for you is twofold. One, which disease pattern should we be hopefully watching? Is it West Nile? Is it dengue, is it turned 26 to give us a little bit of a trajectory? And second, is there any real opportunity for delaying the onset of our mosquitoes contracting Zika virus?


I think the response of the first question would be, our recent experience with it dengue and Chikungunya is probably the best predictor we have at this point of what we may see in the US with Zika. As you know, we’ve had local transmission of dengue involving up to thousands of people in Florida and South Texas. Smaller numbers even in Houston. I think Chikungunya surprised many of us and that we only saw 14. I’m talking about cases in Florida in 2014 and zero last year even though we had thousands of imported cases diagnosed. I think Zika — were not expecting outbreaks of millions of people. We don’t have the same level of exposure to Aedes aegypti as people do in the Caribbean and Latin America. But I think that the other question about what other vectors can be involved and what can we do to limit transmission — there’s a certainly the possibility for any of these viruses to bury occasionally beat transmitted by different mosquito species. There are many mosquitoes out there that are susceptible to infection and can transmit in a laboratory experiment but they just don’t have the right level of contact with people.[ Indiscernible ] Is a great West Nile vector because it is a lot of birds. Occasionally feeds on people but I don’t think we will see efficient Zika virus transmission except by mosquitoes that focus a lot on humans as their hosts. The other question about what can we do? I think, ideally, if we were in a situation where we could very quickly diagnose imported cases and we had an efficient control program like Harris counties which is really one of the best in the country, they would be prepared to go to that person’s home, to some local treatment in their house and surrounding houses. That could reduce the chance of the cycle beginning in a place like used to. Unfortunately, we have all these a systematic cases that we will never identify. So that strategy is not going to have a very big impact. But, if we do enough surveillance that we detect circulation quickly in a place like Houston, then, again, I think we can intervene by doing a permit are based approach to try to contain that. If we can detected early.


I might just make a general if the Domino — epidemiological observation too. West Nile virus is a bird virus. If you are infected with West Nile, it’s because you’ve been bitten by a mosquito that had been a bird. There is no transmission from human to human of West Nile virus by mosquito. Which is a different case than Chikungunya, dengue and a Zika. Those provide two very different epidemiological pictures and in particular in the case of controlling an outbreak, we probably will have somewhat better luck with Zika then we will with West Nile where we have no control over the bird population.


Thank you.


I have a question about the ability —


Lynn Goldman.


About the ability to identify the Zika virus in mosquitoes and that is, we’ve heard a lot about the clinical tests in the sensitivity and specificity of those and there is an ability to distinguish it from dengue but not completely. What about in assessing levels of virus carriage in mosquitoes? Can we dissolution from dengue and Chikungunya or no?


There are tests available that are very specific and very sensitive that could be used to screen mosquito pools. In fact, again, back to Harris County, they are working toward implementing this in the next few weeks. They collect Aedes aegypti throughout the warm part of the season and in the past few years they’ve tested all their pools for Trent 26 virus. I suspect, soon, there will be a dip to — dipstick type essay which is now available for Trent 26. It works well for mosquito pools. It has limited sensitivity but the typical amount of virus any mosquito that’s capable of transmitting can be detected from that dipstick assay. Harris County has been using that for a couple years and then they can do confirmatory work through PCR if they detect a positive with that assay.


And that’s been for Zika as well? Or Trent? Two the PCR is available now for Zika and I suspect that the same company that developed of those, they are called back tests, they are working hard to develop a Zika test.


Thank you. I am from NICHD, NIH. Thank you for the presentations. I was reflecting on the neuropathology, two kinds of neuropathology spirit one is in the fetus you have microcephaly but as there’s no weight matter damage, [ Indiscernible ] Manifestation of these children. Where as in the Exanthematous two, it seems like a [ Indiscernible ] Condition. There may be some molecular clues about why these differences in these pathogenic mechanisms. One may be that early in the gestation, 12 or 13 weeks and beyond, there is hardly any [ Indiscernible ] Going on. Mostly there is gray matter neuron formation and migration from the neurons and — [ Indiscernible ] Into the brain. If I assume rightly, in turn 22, it is prime — primarily seen a much older people. If you can understand these differences and how there may be molecular targets to find out the pathogen mechanism and preventive. Has Guillain Barre in seen in children, in younger children are only older people?


The French Polynesia experience, I believe they were all adults. At least in the Brazilian cases, there is a bias toward elderly. Just like Guillain Barre in general. And going back to the question about the mechanism. It’s not clear if there’s a link between the two. We still need to know — just the autopsies were published last week. The one which was the most interesting one which was from the MMWR, there were two spontaneous abortions around 18 or 20 weeks. They did not really go into depth about the autopsy. They identified the virus in the brain PCR. They did not go into the histopathological findings. I think what we suspect is — and maybe to make a caveat in this was an earlier question — we don’t know what the distributed is. A lot of the findings in both the fetus and the newborn are actually things you see in a lot of infections. We see this in toxoplasmosis. With you sometimes and syphilis. Certainly in CMV and sometimes in Rebello. The ventricle Magaly. The difference in this — we can’t find virus outside of the brain. But that may be because we are not looking at the right time or were not taking snapshots. We have in Salvador, a number of stillbirths. This will come out in the next week. We have cases of hydrops was calls this into question. There’s a lot more we need to find out about this.


— It may be autumn these in disease it doesn’t usually happen to the fetus? Two I didn’t see anything like that in the fetus is.


I’m sorry. I regret that we have to cut off the questioning. There will be much more time for discussion during the breakout sessions this afternoon. I’d like to now thank the speakers and invite my cochair, Doctor Griffin to make some additional comments.


Thank you everybody for this morning session which I think has been fantastic. [ Applause ] And as a prelude and background for the breakout sessions that are going to be this afternoon. If you go to the next slide, this is the overview. First thing is lunch. Bunch for those of you who are able to register for a breakout session, you have a yellow ticket in your name badge which you can give to a staff person in the great Hall who will give you — you will also get a box lunch. We are hoping there will be some left over because not everyone may have any of two,. Then we may have some for this field were not able to register for a breakout. You will have to wait to see. If you’re not registered, you don’t have a lot to R there is also a cafeteria in the basement where you can get lunch. For the breakout sessions, go to your assigned room. There, we will continue the discussion with additional talks. The information identification of questions, et cetera, will be compiled. You will come back here and go over the outcomes from each of the breakout sessions. You will get more instructions at your breakout. Here are the rooms for the breakout sessions. See you back here in a little while.


[ Event is on a break until 12:30pm ET ] [ Captioners transitioning ]


[Captioner on stand by waiting for event to resume.]


George, this is what it will look like.. There is also a clicker


Can you hear me?


Loud and clear.


[Captioner standing by]


[Participants are in breakout sessions and will reconvene at 3:30 EST. Captioner on stand by.]


[Captioners transitioning]


[ Event is in breakout sessions. Captioner on stand by ]


I would like to invite all of you to come back into the auditorium so we can continue with our next plenary session. During this part of the program, we are going to here — to hear from each of the breakout groups. The sequence will be each of the facilitators will give a brief discussion, and then we will open it up to your comments on that particular topic. If you have additional comments to make, or additions they would like to make. After we have had a chance to go through all of the breakout groups, we will then have a more general discussion and really try to identify any topics or areas that were not covered in any of the four breakout groups. With that, let me call on Dr. Pavia to get the report from the first breakout group on epidemiological characteristics.


Thank you. First I want to thank the group that participated in my breakout session for a really thoughtful discussion. I probably can’t do justice to all of the contributions. There should be slides to summarize this. If not — I will talk us through it. The overwhelming sentiment was that the real reason the epidemiology needed to be understood was in the face of the question about congenital anomalies because that’s what is making the emergence — what is making this an emergency. Those were the most critical epidemiologic needs, really to understand — nail down whether there is a true causal association between Zika virus and microcephaly and other congenital anomalies. The risks to the pregnant woman, the risk to her fetus by trimester, cofactors and understanding what the true spectrum of congenital anomalies will be as it’s almost certain to be quite a bit broader than simply what we’ve recognized so far as microcephaly and failure of progression of neurodevelopment. All of this really is dependent on having more effective diagnostic tools. When we think about and jerk — when we think about an urgent need, diagnostic tools are necessary for doing the research as well as the restrict — the research to develop better diagnostic tools is critical. Clearly there’s a better — and need for better tools to look at lifetime — to ascertain the yes — the accuracy and make the sequence more effective so we don’t need to do PR NT assays. To understand whether there can be urinary or salivary testing, any testing strategy depends on having good quality control and there is an urgent need to develop standardized reagents that could be used to standardize the quality of testing that’s going on throughout the country and around the world as well as development of commercial assays. Whatever tests are developed need to be made available quickly, both for epidemiologic research and to answer the clinical urgent questions. We had a very robust discussion about risk communication in the setting of the epidemiology. This communication needs to use both traditional media to try to communicate risk once we understand it better but also should be a 21st-century strategy that uses new-media and also if — assesses the effectiveness of risk communication because as we’ve seen in all of our recent public health emergencies, what we think we are seeing is not always what people — what we think we are saying is not always what people here. There’s an urgent need to understand the other modes of transmission and to communicate effectively about them. Sexual transmission probably produces the greatest level of anxiety, but the other potential modes transition — transmission competent messaging and control efforts. We need to understand whether there is a risk in transfusion, transplantation and at the same time, we may be able to use transplantation screening as an epidemiologic tool to determine how much infection is out there that gets through voluntary deferral for travelers and looking for rash illness. Surveillance is a challenge for which we don’t have all of the answers. There’s a number of assets — aspects that are challenging. Clearly birth defect surveillance essential to understanding the response to Zika virus and birth defects are complicated enough where we have good networks but doing it in places where the birth defects will be seen first in a comprehensive way that accounts for background incidence and other causes is something that needs to be resolved. We need surveillance that is sensitive to new introductions of the virus. We don’t know how long the delay is between the first reported case in the actual introduction of the virus. If we are going to use prevention methods that are responsive and focused on areas, then we need a more timely method of detecting the introduction. We clearly need to understand the — the extent of infection and were there is a herd immunity. We had a robust discussion about alternative ways of doing surveillance for a challenging illness. One of the ideas brought forward as the idea of using crowdsourcing as a potential way of detecting signal for possible novel birth defects or introduction of illness understanding that of course the noise ratio is always a challenge. And lastly, but maybe most importantly, something that kept coming up in the discussion was the availability of the data for rapid decision-making and for people to understand what data other people were developing when answers were coming in. The challenge that we’ve seen in this outbreak is similar to what we’ve seen in multiple previous episodes, and that is that data sharing is difficult. Understanding what’s going on at any given time is challenging and we need new methods and perhaps to think about different ways of thinking about data sharing. We’ve already seen advances from our journals in terms of doing rapid publication, still protecting scholarship and prior application rights but there are other issues that need to be acknowledged, including acknowledging the role and importance of investigators in given countries and not having countries with more resources coming in and taking information away — there are intellectual property and the possibility of developing diagnostics or other interventions for which there’s a financial incentive. That needs to be respected. Asian privacy needs to be respected. But as these problems — patient privacy needs to be respected but as these problems come forth there needs to be a way to — bring this forth before it’s been totally peer-reviewed so people know what data are being collected, to prevent redundancy and allow multiple uses of the same data sources. I think I am going to stop there and try to leave time for discussion.


Do you want to take any questions now if there are any specific points? Or other comments from members of the group?


Or we can save this for the more general discussion after all four of you have presented. So breakout number two, virus was — reservoirs and vectors, doctor David Lakey.


Good afternoon and again I would like to thank my group for a very robust, thoughtful discussion today. Also Dr. Weaver, Dr. Scott, Dr. Higgins for the excellent advice as we went through this issue. I think I came to the realization that we don’t understand this virus to the level we need to. A lot of the discussion related to basic understanding of the biology of this virus. What are the potential vectors? What different types of mosquitoes could potentially carry the virus? And also an understanding of the potential reservoirs for this virus. The need to understand that both in what’s going on and — in Central America, South America but also what are the potential reservoirs here in the United States? There’s a lot of discussion about the role of asymptomatic infection. What world does that play to the spread of this virus — what role does that play to the spread of the virus? We also have discussion about the environment. The role of the environment both on the vector, but also the role that temperature has on the replication on the virus within a mosquito. That can play multiple roles in leading to a better understanding of that is important. We had significant discussion related to new technology and the need to look at the new technologies — and the technologies that look at different modes of action and these are being developed — but we really need to do that thoughtfully and make sure there’s a development part of this with an evaluation to make sure that we look at these new technologies the best way that we can. As was noted in the previous discussion, we believe we need to better understand the role of human sexual transmission, that obviously is a hot issue. There will be a lot of discussion related to that and we don’t understand that to the level we need to. One of the things we believe — and it’s a little bit in vector control but also public health in general, is that the need to get out in front of this as much as we can related to education of the general population really to do vector control, and the discussion of again — not necessarily in our area, but the issue that we need to discuss this with physicians and get that health information out as quickly as we can. We don’t understand the role of vertical transmission. It has spread from one mosquito to another mosquito. It was brought up that this is very important and mathematically — in mathematically monitoring this and we don’t understand that to the level we need to. There was discussion about some of the basic infrastructure we need in order to respond and for this evaluation — basic laboratory capacity. How are we going to detect it once it hits our southern border or other places? There’s a limited diagnostic capacity within the public health system right now for Zika virus and that will be a major challenge for us in the response. We need to train additional researchers to be able to be part of this ongoing analysis. Like the previous discussion that led to share data, so that we can work together on the response and in that overall response, how do we government and what is the — how do we govern it and what is the role to make sure we are moving forward? There’s a lot of discussion related to the potential for other viruses to be able to move into the urban cycle. The discussion earlier today about the 200 different auto — are both viruses and which could potentially — and what’s next on the horizon and the need for basic research to understand these viruses to the level we need to. That was the discussion. Thank you.


Thank you. Are there any point of clarification that anyone wants to make? Okay. Thank you very much. The next session was on disease genesis — pathogenesis and consequences of infection.


Our group had a great discussion with lots of good ideas. They really wanted to focus on the important issues with respect to both the virus and the pathogenesis of infection. The first order of business is to understand the virus. Understand both the structure and how it may be different form other flavivirus . So where it replicates — we don’t know this. Encouraging research on primary human cells rather than tissue culture cells to understand better what the tropism is and then what effect it has — whether they are killed and what type of effects there are. The next level once you understand better the virus itself is the pathogenesis of the virus. For this we are going to need both animal models, that’s the second point but we also need to study human disease in a much more depth than has been done yet. The order of the day right now is to try to develop for identify appropriate animal models. Models that are being used right now are mostly immunodeficient mice or nonhuman primates, both of which have problems associated with them. So are there possibilities of other species that may be important, and to recognize that different host may –s — hosts may be appropriate with respect to pathogenesis, so the discussion of the advantages of guinea pigs or rats or ferret. — Ferrets. A large number of animals were discussed. They may be different with respect to congenital infection, versus the basic pathogenesis of the infection. And so then once you have your great animal model, then the host response and the control and persistence is a major question, and where is the virus persistent? That will influence both persistence and clearance of the virus, which is the other side of persistence. What do we need to do to accomplish clearance, and if we don’t, where is persistence occurring? Protective immunity is a very important question. It will be relevant to vaccine development, which we really didn’t discuss, but you need to understand both what the role is in both antibody and analogic properties as well as the immune response to protective immunity and also to clearance of infection. And then because of what we know about other Flavia viruses, particularly dainty — Denge, and the potential of that cross-reactive immunity to enhance infection in the host. And then thirdly, understanding human disease. That’s the pathogenesis we really want to understand. And to do that, you are going to need to be studying people who were they are getting infected. So really promoting and accelerating the ability to do human research in the field, collect samples, distribute samples, share samples, etc., is a critical need that was identified. Once you have been able to do the research or initiate the research in the countries where the effect is occurring, the questions need to be asked, the timing and location of the virus infection, except now you know more specifically what the questions are that you are trying to answer in your animal models. And an additional question is the genetic susceptibility to different forms of virus, particularly with respect to neurologic disease, because again it is usually an autoimmune disease and so are Cephalo myelitis. So these may very well be certain people and genetic backgrounds that are particularly susceptible to those complications. And lastly, the relevance of persistence in particular sites, semen is one example for sexual transmission but also in blood or other tissues that may be relevant for transmission of the virus to other individuals. So that’s our summary and I would be glad to answer any questions or have that expanded on by people that were in our group.


Any comments? Thank you.


[Applause]


And the fourth breakout was on clinical management and public health interventions, Dr. Lynn R. Goldman will describe that group ‘s collaboration.



I should start by thinking Stephen Whitehead for giving us extremely thoughtful presentations that helped to kick this off. So in thinking about both clinical management and — did I go the wrong way?


Those were my slides from before.


Okay. I think that’s not my first slide. There we go. So there are several issues that we thought were important and I am going to go through them one at a time, and there’s a little overlap here because I think that when it comes to public health intervention but also clinical management, especially epidemiology starts to come into play but also some of the other things that you’ve already heard a little bit about. But we thought establishment of causality, particularly for maternal fetal transmission and causing microcephaly was extremely important. And that there are several issues that needed to be addressed. One being the biological plausibility for the relationship, the role of the placenta and is the virus to easily moving across the placental to cause the in utero infection but also the pathological evidence that the virus is actually causing CNS damage. We also felt there needed to be epidemiology studies to look at health outcomes in babies, whether cohort studies, or case-control studies that might look at either microcephaly Forkey hombre — or either Guillain Barre. They were designed to do that and they don’t control for potential confounders. As was said before, that we would need better molecular tools for examining Zika virus exposure Reppert — retrospectively especially for case-control studies and better definitions of the cases on the outcomes to look at full-spectrum of what the birth outcomes might be. Management of pregnancy was a concern in terms of the guidelines we heard about earlier today and evident Sherry basis for those guidelines. One question we thought needs to be addressed is whether there’s maternal fetal transmission in asymptomatic women who are pregnant, and given that some of the women who had children with microcephaly had not recalled that they had an infection, that might be a recall problem or it might be there is asymptomatic transmission. Research on risk communication and issue in the United States, certainly there’s a lot of concern for those who might become pregnant or who have traveled and have a sexual partner who has traveled to an area of transmission and how do we communicate the risks? What’s the information that should be communicated? How do we communicate that accurately? In terms of some of the elements of the pregnancy algorithm that has been recommended to practitioners, certainly the serum Sica — Zika virus results, that’s a test recommended to be used but what is the actual


Fertility — specifically and productivity value especially in a population that’s not very exposed? And as well, the ultrasounds — will they provide the information that people wish to have early enough — at an early enough stage to be informative? Its consideration about establishing a registry given there is some protocol, the algorithm — algorithm that’s been developed and people are testing women. Should those women be in some kind of registry and followed up over time, perhaps followed up with the outcomes of their pregnancy, given that it seems most of them are having the serology done at the CDC. And lastly the beliefs about the deed and other — DEET another insect repellents? Is that an alternative? [ Captioners transitioners ]


The fact everybody doesn’t have medical coverage for contraception. In the area of clinical assessment this overlaps with the last slide that the issue with the CPR test and the predicted value, how you interpret those results. The presence of Zika virus and bodily fluids that has effects for clinical management. And clinical management someone has to be worry about effected fluids. Is it is — in the semen but people ask how long they need to abstain from sexual intercourse which is a question clinicians need to be able to answer. The risk from blood transfusions and the possibility of Zika buyers persisting in breast milk and should there be advice given to lactating women about that. And also the fact that because there is a PCR test in use that the Zika detected may not be living there — viable Zika virus maybe Zika are in a — RNA causing concern among those who don’t need to be concerned. I think general agreement for every aspect of public health and clinical activity so — says that to be more accurate see, tests that can actually be applied in the field as well as in clinical settings.


Management of travel is often something that comes up in public health when we are doing with a communicable disease. What is the evidence base for providing advice to returning travelers and what advice should be providing to move inviting them to self monitor. If they are returning to an area that has Aedes mosquitoes like Southern California, should they be using DEET to prevent transition of potential Zika to the mosquitoes in that region whether they are symptomatic or not. Are the stigmas graded for help areas are being painted with the same brush as areas of Zika transmission? Which is a risk communication challenge. Is it possible to better define some national areas that are at risk for Zika transmission instead of whole regions being characterized as areas with transmission? And then the possibility in public health of some cohorts of people who travel frequently antimilitary and migrant workers that might be able to be recruited into surveillance or epidemiology studies to understand more about transition.


Vaccines and pharmaceuticals are of obvious interest for either public health overtreatment clinically. There are no current vaccine candidates seem to be in the pipeline although there are some research being done 25 essential targets — potential targets to — to identify potential targets in an effort requiring several months two years. It was noted by a few people in the group if one could develop a multitenant vaccine for several of these viruses that might be a more sustainable approach. In terms of therapeutics, there is press about an IV immunoglobulin been developed that could treat exposed pregnant women are people with Guillain-Barré. There are no known targets for firms edibles to prevent transmission or effects but it would be nice to identified those and several barriers were identified including time, bioethical considerations in bringing things to the market quickly, and resources to develop these things. In general, there were a number of issues that our group discussed that we thought needed to be brought to light that might help to facilitate research in public health practice. Some of these have been mentioned already. The capacity to ship samples across borders, the availability of PPE such as for health surveillance workers working in C, transmission areas. Improving — Zika transmission areas. Improving networks. Many issues around the area of pregnancy related research in terms of the need to incentivize industry participation in that, the bioethical issues that arise as well us some work that was mentioned that the national vaccine advisory committee is working on was looking at vaccines in pregnancy.


I think some of the other ideas such as prepositioning with standard study protocols and other disaster science resources of the more applicable to the next problem is not necessarily this one as well as an idea that under the affordable care act there could be some incentives to the research or that the federal government could work harder to improve our health so we can coordinate data even our data the United States between brothers and their infants is hard — mothers and their infants is hard to put together. And how we could improve the engagement of the health system as well as communities. So thank you.[ Applause ]


We would like to open this up now to the entire group for comments either specifically related to the presentation which were excellent summaries that you just heard. Or other specific comments that you have to make. Please introduce yourself first and make sure you go to one of the microphones.


Could you discussed the issue of the level for the virus because our experience with trying to do a DSl was much more difficult to the DSL 2.


This was a BSL 2 agent, so that issue is not a huge one. There was some data that was spoken about in our session on semen studies in mice showing that other fighting viruses can effect but those kinds of studies can be done, and I am sure are being done.


Hello. I am Diana Weber. I have ship samples across international lines many times and recently published a paper. So I would like to address the last breakout group. For endangered species in species that are in society issues you are not going to be able to circumvent societies or other international laws, especially US laws. So maybe the plant would be to expedite approval between countries because society, it has to do with approval between the exporting and importing countries. That you are not going to be able to circumvent it to export samples.


In defense of breakout group number four, I don’t think anybody was talking about circumvention. I think they were talking about visitation and perhaps prepositioning of such agreements. Because it takes a long enough to do them that it is very hard to them in the course of a crisis. And everybody is so busy with the crisis that we can’t really do it right then.


Right. I can appreciate that. You can look at expediting the process.


Dan Strickland, listening to all of the breakouts together and our old one on inspectors, — vectors, maybe this is the right or the wrong group to complete — contemplate a set of best this is for response. All of these things are bullets. Some of them are quite immediate. And very important. But to assemble those into a set of best practices for an entity for the US federal government or for foreign governments, it might be just a very small step.


It’s worth pointing out that some of the books were on our slides from the Ebola response workshop too.


I think that is an excellent idea to try to approach this as generically what’s the best response and then P position those things — preposition those things and be prepared.


Thank you. Excellent job summarizing. We somehow got into three of the for groups — four groups and you did a fantastic job. I wanted to add 2 points. One was around the real understanding about animal vectors — I should say animal reservoirs and potential for animal reservoirs as being a resource of transmission based on what we know or don’t know and companion animals and other animals that really come to mind and does that change when we have potential for bites you can start to go down a list. But are there some unknowns to be aware of? The second point is really more of applied research pieces, which is a real challenge in many mosquito control programs for the countries that they are very Culex and they are focused in that way with completely different strategies. Now you have additional strategy coming from daytime writers and potential Zika virus. So really, the question is about are there opportunities of looking at research on how again with the point that was just made about best practices about layering or searching on top of that baseline rather than having two separate programs operating individually but how can you have, mentoring programs — complementary programs. It would get be great to get some thoughts and research on that. Thank you.


Thank you Doctor Schall I think our group what agree with you related to the animal reservoirs. That is part of the first bullet we have that we need to understand the biology and the different factors and also the reservoirs and also understand that here in the United States and also in Central America. Are they different, are there animals here that could potentially play into that application? But that was our thoughts related to that first bullet point.


A point made in our group was the need to coordinate data with human epithelial sheet to vector epidemiology as well as was attended by any so we retooled for this.


The one area I hadn’t heard is the concept of health. As soon as is entomology human — it may be a way out. Thank you.


Peter from Mount Sinai New York. They were mentioning in the morning that he was proposing an RND program of $1 billion annually. Can we get some more sort of traction on that idea and be sure it is really — [ laughter ] — From portion of that money come? — From where showed that money come? I thought it would be interesting to hear.


[ laughter ]


It seems to me that that recommendation for $1 billion wasn’t just for Zika. It was for a much broader level of preparedness. When you look — with at the end of our session one of the people at the table said here is the important question. How do we know mixed one is next — which one is next? We don’t. This Zika situation policy importance of the recommendation in the global health security report in fact there is someone potential threats and have no way of knowing which one is the next one and that we are not doing the research to prepare for them.


Victor?


I think I can tell you that when they number was compiled, it is all based on several different sources that are leverage together for the report. Investing from from cyclicals [ Indiscernible — low volume ] there is a number of issues going out between Peter and Cheney and Jeremy about a vaccine development plan. I report talks about the initiative committee to bring together ideas. [ Indiscernible — low volume ] Some of the companies are putting things available to work together. So there are new initiatives. Peter, you may want to say would you have found.


Peter Hale with the foundation for vaccine research. We publish a paper in the new England journal of medicine last July about a $2 billion global vaccine development fund to speed the development of vaccines it — that we couldn’t get the money to get for the trials. We know that when the Ebola epidemic versed in west Africa, we have seven promising candidates for vaccines. All of them or stuck because the countries the money to go forward to human clinical trials. With the exception of one. And we know how much that cost us, and we are going to go to the same situation again and again. Right now — we have the West Nile vaccine. We are not getting much industry for major vaccine benefactors two them forward so they are stuck in so they go back into the freezer. So there is a need for new financial mechanisms to mobilize the assets needed to put these vaccine candidates into development.


Develop on the secure repertory environment and how it impacts research in response to things like Zika, it is a very significant major problem and research on all kinds of viruses and responses — I would like to give a couple of examples of how absurd the regulations can be. We learned with our campus being home to the world Center for emerging viruses. It is a collection of 6000 different viruses supported for many decades by the NIH and the DOD at one time. We learned last year most of our strains are passed in monkey kidney cells. We learned last year we needed a permit to send any virus strain out of the country and we confirmed this with the attorney here in Washington who interprets these regulations. It took us four months to get inside this permanent place. Virtually shut down during that time. How using self that were generated decades ago impacts the welfare of African green monkeys today, I have no answer for that. [ laughter ] Second example, Department of commerce expert permits. Zika partially is not regulated by the DOC but chicken is so every time we sent one of those viruses out we have to get a DOC permit even to send them to their country of origin in some cases where they were sampled years ago. That usually takes us to two to three minutes. Plus on top about our own university repertory system, we have to get MTAs for shipping almost any biological sample anywhere off of our campus. That often takes a couple of months to negotiate the wording if the MTA is acceptable to both parties. This inhibits the flow of virus strains in the progress of research. I think this is an area the national Academy by be able to address effectively. Thank you.


Does anyone here wants to make more comments on that topic?


I don’t want to comment on the issues around select agents and animals, but were this an outbreak in which we had the ability to do human studies rapidly, we would run up against those issues that we have talked about here and elsewhere for many years with the ability of rapid research in an emergency in people. And those problems have been solved yet whether it is the use of a single IRB or the rapid contracting with the fast flow of funds. There has been progress and this would be a good task. The bad news is we have no vaccine or truck to deploy in this outbreak at the moment, so we are not faced with those problems.


If I could ad, — add, I think those are very important points it helps to put some specificity to the issues we were discussing in our group. It is not a matter of needing to dispense with something like an MTA because you don’t want misunderstandings about who owns what material and where it came from and what its origin was. But that it has all of these issues becoming to — too entangled in legalisms that are not necessary in order to achieve those goals. So I think it is a good area for the national academies to look at, because one could standardize on some of these things. I personally have spent time going back and forth about language and MTAs and it is of the best use of anybody’s time even if it is not an emergency. And if it is an emergency then you are basically not saving lives and you could be. — When you could be.


We wanted to have time also to allow any participants including those who are sitting up here to bring up issues that were not included in the four sessions that we discussed. Things that were not on the radar screen that infect should be mentioned today.


George Sunday university of Texas. This morning at the plenary session I saw a map of the areas affected. There were quite a lot of countries where it said serologic evidence. For example, I saw India among many others. So my question is why are we focusing only on the few countries that we know there was microcephaly and are we doing anything with these other countries? How does that affect causality also?


I don’t have an answer to your question, but I have wondered the same thing myself. To put it another way, this is a virus that has been prevalent in many parts of the world and has infected many, many people and why haven’t we detected my conceptually before today? — Microcephaly before today? It could be evaluated other I think if there isn’t current infection that it would be very challenging to retrospectively determine if somebody had had that particular infection given the amount specificity of the symptoms, and it resembles other for barrel — flaviral illnesses. It would be very hard to go back and say if they were microcephaly cases in the 70s in Africa, that it was or was not caused by Zika. I also thought with somebody said earlier today was interesting. Perhaps there is some immunity conferred by having childhood infections as we used to see with LaBella — LaBella — rubella that one might have expected because people have childhood infections and have immunity from that. So it may be a different dynamic in a place where it has been endemic than in a place where it is spreading to an adult are getting infected for the first time in their lives. That is another possibility.


I think this is like lots of emerging infectious diseases that have been around for a long time and we don’t recognize them or recognize how serious they are or what the convocations are until a situation like this occurs. And that you study it and then you can also retrospectively be looking for it elsewhere. So there are numerous examples of diseases and publications that have been going on for a long time that we just didn’t recognize. There were enough of them that were happening.


On the other issue that has also been mentioned as whether there has been a change in fires. I think all of these are areas that serve further study.


Sir — sorry. Maybe I didn’t make myself clear. I realize these are reasons, but why added we also studying these other countries where we don’t see the microcephaly?


I am not sure that we are not seeing it also. It has to be looked for.


I think it probably also points out the difficulty of looking for congenital anomalies and doing research in areas with high levels of poverty and contamination and congenital infection. I don’t birth defects research rises to the top of the agenda — doubt birth defects research rises to the top of the agenda.


And also higher rates of infant mortality. Often there is a spectrum that involves infant mortality and fetal loss with spontaneous abortion. So where an at come is on a spectrum can involve a multitude of factors that impact the fetus. I do think there is probably people who have done studies in those countries that have banked serum and the might be the opportunity to go back and look at some of those. I just have a feeling that there are such resources available.


Are there any more issues? If not, I think it’s time to wrap up. This really terrific workshop — I would just point out first of all I think it has been great and I really appreciate all of the input from the speakers both this morning and in this afternoon’s breakout sessions and all the input that people gave. And just to know that this will be written up by repertoires who are writing of the workshop and the issues that were addressed. There will not be findings and recommendations as above explained before, but this is a fast track workshop report also. So it should be out in fairly short order and available to everyone.


I would again like to thank the speakers who on very short notice are willing to put together a presentation and the facilitators and all of the other people who were needed to make this meeting work here at the IOM particularly Jack Herman who helped in doing so much of the work in the organization. It really has taken a lots of people many, many hours to put this together and we appreciate all of the input and again, thank you all for your participation on a day that started out very nicely.[ Applause ]


[ Event concluded ]

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