Zika Virus Research - with Dr. Michael Callahan | The Empowering Neurologist EP. 27

Hello everyone, I'm Dr. David Perlmutter and welcome to The Empowering Neurologist. We have a very important program today. Our guest is Dr. Michael Callahan. He is the founder of the Zika Foundation. We'll learn all about that. He's what we call a physician scientist. He's board certified in internal medicine, infectious disease, tropical medicine, and mass casualty care. And he's both on the clinical and research faculty at the Massachusetts General Hospital, Harvard School of Medicine. He has clinical appointments in a variety of places, including Bangkok, Indonesia, Panama and Nigeria. And between 2005 to 2012, he established PROPHECY, which is the first rapid deployment clinical research capability for catastrophic infectious disease outbreaks in the world. And his work did include significant work in relation to Ebola. He has served as a special advisor to on the topic of infectious disease to various presidents, secretaries of defense and health and human services, and also to the Office of the Commissioner of the Food and Drug Administration. Dr. Callahan has himself deployed to 7 mass casualty disease outbreaks, including things like Ebola, Marburg, H5N1, H7N9, bird flu, and MERS. And he used his experience with dengue fever to launch the Zika Foundation, where he is accelerating sustainable and low-cost interventions to protect women and men from the Aedes mosquito, which actually transmit dengue fever as well as Zika virus. His mission is really quite compelling, and that is to ensure that the 64 million pregnancies per year in the tropical Americas are kept safe from Zika and to prevent the epidemic of what is called paralytic Guillain-Barré syndrome that may very well occur in southern nations over the next several years. Very exciting information that we're going to learn today, so looking forward to this interview quite a bit. Well, good afternoon, Dr. Callahan. Thank you for joining us today.

It's good to be here, Dave. Thanks for the invitation.

So we're going to just jump right in, and, you know, for all of our viewers out there, I have a special interest in this living in South Florida. You know, we are sort of under the gun. It's certainly in the news right across the way in Miami and Miami Beach. It's been called sort of the epicenter of the Zika virus here in the States. But Dr. Callahan, you've been looking at Zika virus for a number of years, and how did that all get started? I mean, what was your morphing from what you were doing into the Zika virus?

Thanks, Dave. Originally, my focus area was large-scale disease outbreaks, and a cousin of Zika, a related disease known as dengue, really a much more severe disease in many ways than Zika, was our big study project. And we'd worked for years with the Department of Defense, the WHO, and foreign nations to control dengue populations. So I spent a lot of time with dengue in Asia and with Africa, and because of the similarities of dengue and Zika and the symptoms that they present to people, we would oftentimes enroll Zika patients. About 2,000 of them were enrolled in my dengue studies over a period of about 12 or 14 years.

So you're not new on the scene as far as Zika virus goes. I mean, all of us have been just sort of trying to catch up with this, but here, 10 to 14 years you've been watching this happen. But I think in some of the information you had sent me that I reviewed earlier today, You made it very clear that we underestimated and we were humbled by what Zika virus seems to be doing now. Tell us about that.

Oh, thank you. So I have a lot of humility about this disease, and this is common with infectious disease outbreaks, is the rules can change as these diseases move from one type of patient population to another. And Zika was originally described in Africa, actually in 1949, and it moved with its transmission vehicle, a type of mosquito that we'll talk about a little bit later, from first Africa to Asia and then Asia to the tropical Americas, and Zika came behind it. Somewhere along its journey, it changed in a way that made it much more neurodestructive, where it would actually target rapidly dividing nerve cells. We see our first real evidence of this in the island of Yap in Polynesia in the middle of the Pacific. Prior to that, With those 2,000 patients that I'd seen with Zika, which absolutely includes about 113 pregnant women, we saw no congenital birth defects at any time. None of these small heads that you see, which we refer to as microcephaly, and the other events as well.

Do you think that your sample size was large enough and it was— it could have happened, but you just didn't see enough patients?

Well, we are spending a lot of time going back to those patients and And seeing how those children who are now adults or teenagers are doing. But historically, in Africa and Asia, this disease has not been associated with these congenital birth defects that were first really reported in Brazil. This is a key point. In Asia and Africa, Zika is a disease of children. So it is true that we never saw large numbers of women of childbearing age getting infected. As we did when this virus exploded onto the landscape in Central and South America. So we might have missed it because— but it's unlikely. And those agencies and groups that we work with, which have amassed thousands and thousands of Zika patients in Thailand and Cambodia and Indonesia and India, we don't have the numbers to demonstrate any significant changes in intrauterine growth or birth defects.

But yet we are now seeing that. So what has changed?

We anticipate that there were several amino acid changes in the virus. These amino acid changes, we normally would— these would fall under what you would call mutations, were selected for a much more efficient pathogen that could be more invasive in humans and go to protected sites. And that would include the unborn child to go into these protected neurologic tissues to traverse the placenta and go down the umbilical cord and infect these children. That's what we've seen with, unfortunately, the children that have died intrauterine, okay, as well as with several of our adults. We're looking very carefully at this new capacity for neuroinvasiveness. We had not seen that before 2013.

We're definitely going to jump all over that because I want our viewers to know you and I have had some conversations about this, and there are some You know, this is a moving target and very much a developing story, but I would like everyone to know that, Dr. Callahan, your team has the largest clinical experience with Zika virus on the planet. That's fair to say?

Yes, but we acknowledge the extraordinary contribution of our international clinical colleagues. So there are teams and teams of physicians that have given us that well-controlled experience, but I'm personally at 1,700 Zika patients and well over 10,000 dengue patients. We feel clinically pretty comfortable with this disease and understanding it. So yes, Dave, that's true.

Last week in Science magazine, there was an interesting article describing the challenges that may be faced in attempting to develop a vaccine. I mean, whenever there is something like this, an infectious disease outbreak, everybody's jumping on, you know, wanting to have immediately a vaccine that people can get. And that doesn't seem like a very viable approach to dealing with Zika virus right now, does it?

Well, no. The FDA's owned— we have a history of making accelerated vaccines under the emergency health response capacities of the US government, a story for another day. But we made ZMapp, which is the monoclonal for Ebola. We did that quite briskly and quickly. And we've made multiple emergency influenza vaccines for international partners. And vaccines Are my first go-to therapy for large-scale disease outbreaks. However, with the viruses that are in the Zika family, we call them flaviviruses, they are very protean or diverse. We do not have one type of virus typically in one patient. It is a cloud of similar viruses that deviate from each other, and that produces a large, broad antibody response. Those proteins that we make in our body that are elicited or brought out when we're exposed to these viruses, and those antibodies are overwhelmingly good and lead to the cure. However, with flaviviruses, it's well recorded by our group and others that the antibody against one of these viruses, if it goes against the other virus, can make the disease worse. It does this by grabbing that virus and moving it into a protected site in your body and hiding it effectively from the immune system. This is a catastrophe from an infectious disease standpoint. Mm-hmm. Your point about vaccines is important. If the vaccine mimics those misbehaving antibodies and actually puts those viruses into a protected site away from normal Yeah. A normal convalescence, that could be a tragedy. There's evidence, Dave, this happens in certain vaccines. We've seen it with a number of the candidate dengue vaccines that were produced in China and Taiwan that were more dangerous than the wild-type dengue infection. This is a big controversy, and we personally would tell you that those people, clinicians, that deal with large numbers of these patients We are very concerned about a poorly coordinated vaccine effort. We have humility about this disease, and we need to work very carefully and very slowly to make sure we do no harm.

Does it seem to you that the misplaced emphasis on hoping for a vaccine may be taking people away from the tried and true ideas in dealing with infectious disease outbreak, like looking at what What are the vectors, and how do— for example, in this case, how does the mosquito replicate, and where— what is its environment?

Yes. I'm an infectious disease doctor, so I believe in therapies, and I make drugs, many that are in the market and are very successful as antimicrobials. But in this case, rather unmagnificently, we are compelled ethically and to meet the needs of the burden of this disease by focusing on prevention. And while vaccine strategies are underway and while we look for antivirals, a drug that will help to prevent Zika, we really are doing a disservice if we don't stop infections. So again, we focus on the mosquito and the mosquito-human contact.

And in, in a moment, I think we'll talk about what it looks like when a person has Zika virus, but fair to say that people may often not think they have it and it's confused with with other types of illnesses?

Yes. I used to call Zika dengue light because they would come in with the symptoms that were reminiscent, similar to dengue, but nowhere near as severe. For example, when they were symptomatic, they would have the headache, the headache particularly behind the eyes. They would have stiff neck and muscle aches. They would have a dengue rash, and they would absolutely have fever. Zika patients, oftentimes, as many as 3 out of 4 patients have no symptoms. We have cases in our study where we know our researchers were infected with Zika, and we know when it happened to the tenths of a minute because they were in the wrong exposure zone in Southeast Asia and got infected. Yet, all of them have Zika, but about 3 out of 4 foreign-born people would not demonstrate any infection. And we would find the virus in their bloodstream. So you are correct. You

know, I just want to hold on that thought because I think it's really important. You know, we need to know who has gotten the Zika virus for a number of reasons. We know, for example, it has been sexually transmitted, it has survivability in semen, that the individual who is infected proves to be part of the vector for future mosquito infection, Therefore, other humans. But you're saying that 75% of people with Zika basically don't have symptoms and therefore wouldn't even know.

Yes, and I am one of those people. I am Zika immune, and I do not recall when I got my Zika— when I was infected with Zika, which was in Nigeria sometime in the late '90s, and it showed up on serology. And the reason why is I was being used as a control. As a Zika-negative Anglo—

Manifestor.

Yeah, and what happened is that I turned up Zika-positive, and I cannot recall an illness during those years at all.

The big thing people are talking about, of course, is the risk during pregnancy of contracting this virus and then having a baby with microcephaly who is basically going to require full-time care moving forward. That's been the big There's been some discussion of the increased risk of what is called Guillain-Barré syndrome, or post-infectious ascending polyradiculoneuropathy, if you will, meaning you get weak in your arms and legs and it can even compromise your breathing. But there does seem to be new data suggesting that getting Zika virus as an adult may be an issue as well, and specifically that it may relate to neurological issues. Can you tell us about that?

Yes, and the data is new, but our rate of change on the global knowledge base of Zika is 6% every 45 days. So we know 6% more about this disease that we frankly ignored for the first 60 years every month and a half. So at the end of a year, we're going to literally triple our fund of knowledge of Zika. And with that comes our experience with these patients. So to your question, in a study that we've been running in 3 nations in Central and Northern South America, we look at the convalescence, the cures of Zika. They get their infection. The viral load will go up, peak, and then come down between 5 and 9 days. They will or will not experience those symptoms, but afterwards, starting around 6 weeks, we reassess them, and we found some things that we cannot explain. We found persistent fatigue syndromes. We've found chronic headaches, which are sort of like a— almost have a meningitis-like component, a stiffness of the neck. They are not the retroorbital headache that we originally complained of. We have tingling and numbness of the fingers, and we have short-term memory loss, word-finding difficulty. In the case of several executives in the business sector, they complain that they've had trouble managing their people, or they've had trouble coming to a rapid decision, which previously was trivial for them. Wow. So we're tracking this. The numbers right now are 69 individuals greater than 65 years of age who are PCR confirmed. That means there's no doubt about it. They were Zika patients. Starting at 6 months, we reassess them clinically, do pretty comprehensive neurologic evaluations, not a spinal tap, but we do image them, and then we find these problems. So we're following these— them very closely.

Let me take a step back here again for our viewers. What we're hearing right now from arguably the most knowledgeable researcher and clinician on the planet in dealing with Zika virus is that it is an issue potentially for adults as well and that, fair to say, it does have an effect upon the brain. I mean, that's what you just described to us. Yeah. About 3 or 4 weeks ago there was a publication I think put out by Florida State University in the rodent model demonstrating that Zika virus had a predisposition to going to and involving the hippocampus, the brain's memory center, at least in the rodent model. And I'm wondering then, could what you're now telling us be the human manifestation of Zika virus involving the brain?

It's a critical question. I think this is a— the phenomenon is driven by the fact that we just have so many patients now And we— they are well scrutinized by our colleagues both in Central and South America and our overseas colleagues in Southeast Asia, as well as our own American workers and collaborators who are down there at bedside. There's no ambiguity about the presentation of these patients. If there is a dissenter in this opinion, they need to come with us and forego further studies in the mouse and see this disease in people. This is a big problem for us, is watching laboratory-based research, which I support completely here at Massachusetts General Hospital in Boston and funded hundreds of millions of dollars in federal research for these diseases, but you must validate the disease in people. You have to go and get on an airplane, embed yourself in these clinical trial units, and get a— become clinically experienced with these diseases before you can— Yeah. Boldly assert that it is a disease restricted to the unborn child is Gillian Beret.

Boots on the ground. Let us, if we can, then move on a little bit and get back to the Zika mosquito itself, because I think there is, you know, at least here in Florida, a bit of a misunderstanding, a big misunderstanding, especially when we look at the efforts that are being made to get rid of the It seems to me these are the efforts that were used, that have been implemented here for 5 decades in spraying the swamps at night, etc. Why is the mosquito— what is this mosquito and why is it different?

Okay. So this is an amazing, horrific little animal. I've been working with mosquitoes for malaria. That's a wilderness mosquito that does not tolerate urban settings. We've been working with culex, the mosquito of West Nile virus. It's a mosquito that It prefers to feed on birds, so it's quite adapted to fly high in the trees. Somewhere around 200,000 years ago, one type of mosquito called Aedes, specifically Aedes aegypti, found it more convenient to feed on people, to feed on hairless, slow-moving food sources that would cluster together. At the beginning, really, of human civilization, when agricultural systems were born, people would cluster together, and this mosquito no longer had to chase fast-moving furry animals out on the savanna, but could co-locate with people and adapt to intensely— what would become later urban environments. This mosquito is human-trophic. It prefers humans at about a 6 to 1. If I put all of our animals in the cages in our insectary and I put one of my graduate students in there too, it's the graduate student that gets bitten at that—

Always.

Always. Further, it's amazingly adapted to avoid detection. It is known for its silent flight. It is known for being morophilic. It actually watches you watch it. One of the fastest ways that we find this mosquito and tell it from a malaria mosquito or a West Nile mosquito is when it's on our hand as you look at it, and if it jumps off, Chances are it's Aedes aegypti or its close cousin, Aedes albopictus. We'll call these mosquitoes for the main one the yellow fever mosquito, Aedes aegypti, and the Southeast Asian tiger mosquito. That's Aedes albopictus. We'll use the common names moving forward to complete this thought. So when World War I happened and soldiers were sent all around the world. So too did the ships that carry them carry the water in their ballast, and in that water, this mosquito from North Africa moved very successfully to China, onto Taiwan, southern Japan, and then to the Americas. So what we're seeing here is the distribution system for diseases in Africa and Asia was prearranged in the tropical Americas. This mosquito adapted beautifully to life in the American tropics: Panama, Brazil, Colombia, Ecuador. Mexico, St. Louis, Houston, Texas, and Miami, and other cities. And then right behind it came all the diseases it carried back in its original home range. So how is this mosquito different? 5 ways. It feeds on people preferentially. It enjoys city living. It is an urbanite. It is tolerant of the pollutants of diesel fuel and can find humans against the background of all the heat signatures and the carbon monoxide and the carbon dioxide. It can breed in very stagnant water. Rather diabolically, it knows that if it lays its eggs in a pond, minnows might eat it, eat those eggs, and then terminate the cycle. So the females seek out temporary water, small water collections that could be in a drainpipe, a bottle cap that's left upturned, or particularly an old tire that's left in the backyard. So by avoiding predation, it intensifies the number of mosquitoes. Next point, it's a weak flyer. I told you that way back we believe, and the medical entomologists believe, that the mosquito found it convenient to feed on people, and the people were indoors, so the mosquito went indoors. It really lost its capacity for heavy-powered flight. This mosquito is a hopping flyer. Its total life is spent with linear flight ranges of 150 to 200 miles. 50 to 300 feet. And this poses a huge upside for public health measures in that we now know the ranges that we need to control with either our directed pesticide use or biological control or others. So my last point of all this is that the mosquito also tries to avoid you in the final seconds of the bite by going to areas where you're less likely to pay attention, like your feet, and also to the backside of your head. It sees you looking at it, and it does what's known as kettling. It circles nearby and goes to the backside of your head and avoids being heard by the ears or goes down low where about 65% of all of our laboratory bites in our mosquito rooms are below the knees. We'll come back—

We're going to put up a graphic right now that'll show really the percentage of where these bites occur. You brought to our attention You mentioned the fact that there's a cousin or a close relative of the Aedes aegypti that we're all talking about, and that is this Asian tiger mosquito. And, you know, the concern about that is that the range is different. You know, we normally associate mosquitoes with the warm tropics, but it looks like there is a bigger threat even for more northern latitudes based upon this other carrier.

Yes, that's true. We don't want to create hysteria about that, but I have big problems with the second mosquito. The colder-tolerant cousin of Aedes aegypti, what we call the yellow fever mosquito, is the Southeast Asian tiger mosquito. It is found in Connecticut. It is found in Worcester, Mass. It's found in Gary, Indiana. It is found in Pueblo, Colorado, and throughout the irrigation ditches of Central California. It, in other parts of the world, is a phenomenal transmitter of dengue. It lacks just a couple efficiency points compared to the yellow fever mosquito, but is in many ways much more significant because now more of the global world population is at risk, particularly Middle Europe up to around Lille, France, for example, and drawing a line into the former Soviet Union, the southern Caucasus, and then into central India. So places that get snow in the winter. tolerate the Southeast Asian tiger mosquito. And I'll tell you, from my time in Washington, D.C., it basically was 100% of all mosquitoes captured in our traps were the Southeast Asian tiger mosquito.

People are told when you go outside you need to put on insect repellent, but I think you're building a picture here, painting a picture that this is not an outside threat as much as an inside threat.

Right, and you probably have the graphics from our website, from the Zika Foundation. We have very good close-ups of this mosquito so that in about 1 minute, an unfamiliar— a person unfamiliar with biology can learn our little rhyme for identifying this class of mosquito. So you can look at it on the web or on our website or through your web link, and it's a black and white mosquito, a black mosquito with bright white It's an indoor mosquito, as we mentioned. It's a daytime biter, and it has silent flight. What we teach to our schoolchildren in Brazil and Panama and now Houston is black and white, indoor bite, silent flight, and you're safe at night.

Yeah.

Those sort of helpful cues allow Those that are taking care of their children or taking care of vulnerable populations to look at the mosquitoes that are around them, either caught in traps or landing on themselves, and to figure out whether or not there's Aedes aegypti in the area. Look for those signatures when you see this mosquito on the web or on our website.

Here in Florida, not a day goes by that we don't see—

There's about $60 million of Department of Defense funding that we published For the first time in the foundation's website. The important point here is that not all repellents are the same, and there's a lot of upselling of repellents. We will tell you categorically that almost every single nutraceutical repellent does not work for greater than tens of minutes, but 3 classics— well, 2 classics and 1 new agent are phenomenal. Okay. They are, in order of relative efficiency, DEET, diethyl enyl toluamide, which was your grandmother's repellent. It was invented in 1959. It is safe in pregnancy, but alas, it does smell like a chemical. That will give you reliably about 6 hours of protection. Choose a manufacturer that uses microzonal DEET. The second one is a surprise to us, but did stunningly well in our deterrent studies where we put people with different repellents on it with a female mosquito ratio of 2,000 to 1. We find one of the most successful new repellents is made of lemon of eucalyptus. Lemon of eucalyptus will run about 6 to 6.5 hours of deterrence against intense transmission frequencies. The next one is our best in our studies against Aedes aegypti and Aedes albopictus from both Asia and the American strain. We test against Mosquitoes taken from different parts of the world, and that's Picaridin. Picaridin is a plant-based phenol compound that was just discovered really about 7 or 8 years ago and is one of the backbones of the U.S. Department of Defense ways in which we protect our soldiers from multiple pathogens. Each of these repellents not only protects you from the Zika, Dengue, Chikungunya mosquito, but also works against the Malaria and West Nile mosquito, as well as fleas and ticks. So you get a lot of bang for your buck there.

But on the other hand, there are some things we can do that actually attract mosquitoes. Are you hearing me?

I am hearing you now. Yes, sorry, David.

There are some things that we can do like perfumes and even floral clothing that can attract mosquitoes.

Yes, in fact, what's sometimes missed in the narrative is that mosquitoes don't feed on blood. They feed on sweet carbohydrate sources. They're nectar feeders, and in some parts of the world, they're critical for pollination. There are parts of the world that absolutely need mosquitoes. The mosquito only feeds on nectar until the female mates. Once she mates with the male, she adopts a different seeking behavior. She needs protein, not carbohydrate. She needs protein, and she gets that as blood. In about 20 to 40 minutes after mating, she It changes their whole questing behavior from nectar-seeking to finding humans to feed on for Aedes aegypti. When that happens, that's when our problem starts.

It sounds like a horror story.

Yeah, it is.

Let me, if I can— we watch the evening news here in Florida, and we're, I think, led to believe that there are great strides being made in eradication of the mosquito as they show video clips of airplanes flying over and spraying. But from what you said about this mosquito, it doesn't seem like aerial spraying of this Naled and all the other things that may be being used is really the right approach.

Well, we can tell you what hasn't worked in the past with aerial spraying for this mosquito. There's been a lot of money spent in Singapore Taiwan, and Japan, and several Central American countries trying to control Aedes aegypti with aerial spraying. It does not work. The reasons go back to the behaviors of this mosquito. These mosquitoes are very different from each other. This is an indoor resident. About 60% to 70% of our total community population is indoors. It is not flying around at night when aerial spraying happens. And it is a weak flyer. It does not fly up high in the air column like the Culex mosquito. What you saw in Florida was the adapted mosquito control plan for West Nile control, which involves a very powerful flying mosquito that flies at night. And that was the one— Culex— we mentioned before. It feeds on birds, needs to get high up into the trees to find that sleeping crow or blue jay to feed on. So aerial spraying with Nalad or many of the other Air insecticides have been proven systematically to be less effective.

I'm not asking that.

For C. diff, you need to be on the ground, spray houses and yards, and absolutely control breeding sites by getting rid of that standing water we talked about.

Then why are we seeing this happening here in Florida that they're doing this aerial spraying at night, I might add, later now than 10 o'clock at night because Apparently they were spraying children at football games. Why is this happening, and why are we being told that this is to keep Zika from happening?

You know, I cannot comment on the decision, but it is a highly visible public health intervention. It helps to promote, you know, a lot of trust that things are being done. But I will again be— I am emphatic about this, because the mosquito control global community has seen the success and failures of different control measures. For this mosquito and for this problem, you need yard-to-yard control with backpack-mounted sprayers, and you need to work on your biologic controls. That aerial spraying does a disservice by wiping out mosquito-eating insects, the dragonflies, the robber flies. In some parts of the world, they account for 20% of the predation of the Aedes mosquito. Other cultures and other systems have fought aggressively to preserve the biological control, the things that eat Aedes aegypti, while making judicious use of pesticides by putting the pesticides only where the mosquitoes are.

Now, the infectivity of human semen of an individual who's been infected with Zika virus to a sexual partner. I believe you're involved now in some clinical trials of already existing drugs to see if you can eradicate that or at least limit the lifespan.

So it broke up just a little bit. You were talking about male long-term carriers in the semen?

Yeah, and the fact that you're involved in some clinical trials to help to reduce the viability of the organism.

Right, thank you. So we're now following 196 males who are greater than 80 days this past weekend, greater than 80 days, who are persistently positive with RNA from Zika. Now, it's an important— that sounds obviously terrible. It is terrible news because those males involve a large number of asymptomatic males. And we have confirmed, of course, that a growing percentage of northern infections in Europe and North America are due to sexually transmitted Zika from male to female contact or male to male contact. But when we look at the semen and we look very closely, we actually find it's pieces of RNA. It's not intact viruses. So we think the virus tends to fall apart somewhere around 40 or 50 or 60 days. We just frankly don't know. We need more males to study, and then we need well-designed clinical trials to test our antivirals, not against just the male themselves to eradicate the disease, but to get into the semen. testes into the seminal vesicles and to wipe out this disease where it has a protected haven. Those studies are just being designed right now, and the lead candidates are just going through what we call an institutional review for safety.

You're also involved in a genetically modified male mosquito that— can you tell us about that?

I'm sorry, repeat your question, Dave.

The genetically modified male mosquito that you're— Talking about introducing.

Right. This is a real, real use of science. There are lethal genes that are in the mosquito population which actually result in the destruction of all the larvae. A company that was born out of Oxford University is called Oxitec, has commandeered and introduced this lethal gene persistently in the male Aedes mosquito. They grow up the male mosquito, which has this lethal gene in them, and that male will not ever bite a person because it's the females that bite. They grow up these male mosquitoes and release them into the community. By doing that, the females are overwhelmed with these lethal males that are laboratory bred in these very sophisticated, clean, pathogen-free laboratory settings. They're released into the cities and the suburbs. Those female mosquitoes The females. The females. The females are overwhelmed only by these males, mate with them, continue in their own life cycle to lay eggs, and when those eggs hatch, those larvae that live in the water, as they grow up, accumulate this lethal toxin. It's actually a protein, and that results in 100% demise. In our studies where we're watching this work being done in Panama, we are seeing 80 to 90% reduction in female mosquitoes after about 3 or 4 weeks. In other studies, they're having even better success. What this does, Dave, which is really the— really a paradigm shift, is it preserves the other parts of mosquito control. Biological controls, we have not wiped out predatory insects that eat Aedes aegypti. We have not added pesticides to the environment. We have not wiped out honeybees, for example, which are critical for our crop pollination. So it really is a clever play, and we're watching this group with keen interest. I'm reasonably hopeful for it.

Dr. Kellner, I'd like to just take a look at this next graphic which talks about what the symptoms of Zika will look like. And, you know, again, reiterating the fact that you told us that 75% of people who are infected—

I lost you, Dave.

I'm going to go to What does the Zika virus look like in terms of clinical presentation? How does a person know? But again, keeping in mind the fact that only 25% of people who are infected are even going to know that they have the virus. So what does it look like?

Okay, so I'll do it in the chronology of the symptoms. And we've had multiple opportunities to look at household members where the one member of the household gets Right. We identify it in the laboratory, and then we go and do daily visits of the rest of the household members, and we see the chronology or the sequence with which fever— with which the symptoms come on. For patients that are symptomatic, that is the 25 to 30% that have symptoms, the first finding is a feeling of unwellness, typically a chill or just a touch of fever. This is followed by real fever that is not— that can sometimes be not insignificant Followed next by a headache, which is kind of distinctive. It is not like your tired migraine, busy at the end of the day headache. It is a retroorbital headache. It involves the upper frontal area of the skull, and the patients typically— in Thailand, the term was arupa, which means the frontal headache, which is seen and is similar with dengue as well. Headache is number 2. Number 3 is myalgia, a fancy word for muscle aches, typically of the shoulder and the lower back first. But some people come in with a limp because their muscles are hurt in their upper thighs. The next, the 4th symptom that we find with significant reliability is conjunctivitis, a fancy word for redness of the lining of the eye, followed often by a redness of the white part of the eye as well. That typically comes on about 36 to 70 hours after the onset of fever. And last in sequence, Yes. Is a rash. And in lighter-skinned or hypopigmented people, we see that rash a lot less than was previously reported. We see it at about 24% to 28% of the time. And the rash is typically on the trunk first, sometimes on flexor— what we call flexor surfaces. That's the inside of the arm, not the outside of the arm. And it can spread centripetally and get darker red. It usually disappears in about 3 days. And that's pretty much it. That's it for acute Zika for symptoms. Yes?

Now, you— a person has these symptoms. What should they do if they suspect that they have Zika virus?

That's important, not just what they do, but what they don't do. The first thing to do is to protect yourself paradoxically from mosquitoes because now you can infect and accelerate the disease in your own environment. So strangely, for the first time, we are trying to protect American Aedes mosquitoes from travelers returning from down south. So we were asking them to wear repellent so that they don't transmit the Zika virus or dengue or chikungunya to Miami Aedes aegypti and potentiate the infection. So repellent. Other deterrent mechanisms which are on the website involve the clothing color and, as you mentioned, avoiding the perfumes and the deodorants that That mimic flower scents and bring in both males and female mosquitoes. Next on that list is a story for the men, is they must protect their partners, male or female. They need barrier contraception or abstinence. They need barrier contraception just like we do for all STDs, sexually transmitted diseases, which is universal use of condoms in particular and other barrier controls, but condoms. This is to prevent the infection during intercourse or other sexual contact and protect their partners.

And how long would they need to do that?

Our recommendations are remarkably conservative and are now being followed by the WHO and the CDC. Originally, we were calling it only 60 days because that's how long we were finding Zika in the semen of males. Now we are compelled to push that number out to 3 months, 90 days. You might find me talking next month that it's now 120 days if we continue to recover active infectious virus from the semen of males that are over their disease.

Now, your foundation website is updated quite frequently. What is the address for that?

Oh, our website The website for the late breakers is www.zikafoundation.org, and you can navigate through all the approved repellents. There is— we don't care which manufacturer you use. We just give you the ingredients for you to find, and there are examples of the types of good manufacturers on there. There's also how to apply repellents and sunscreen because they can antagonize each other. The use of clothing that you wear during your travel or when you're going out for lunch on a sunny day in Miami. There are clothing alone because of the patterns and the shades can deter mosquito bites from this species from 40 to 60%. So there's a lot of passive behaviors that will not be intrusive and are very easy to adopt. And we use them globally and we use them in the U.S. Department of Defense to protect our soldiers.

Well, Dr. Callahan, several things I want to say. First of all, and I know I'm speaking for our whole audience, we're grateful for the work that you're doing. And I know that this is a very much— Don't thank me, Dave.

I think so, but I'm glad to help.

And, you know, clearly this is a moving target, and it's an evolving threat, and it looks like you're doing your darndest to stay ahead of it. And we're, again, very appreciative of that. I'm going to, in closing, invite our viewers to visit your website frequently, zikafoundation.org, to stay on top of these things. Again, we're all grateful for the work that you're doing, so thanks for spending some time with us today.

Thanks, Dave, and to the listeners, get educated because the interventions that are on that website will protect you against 4 diseases. And dengue and chikungunya and yellow fever, these are not trivial diseases either, but they're all protected by the same deterrent measures. So best of luck, and do contact us and criticize us and help us do a better job. Thank you.

Great. Thank you, Dr. Callahan.

Thanks.

Well, again, a lot of thanks to Dr. Michael Callahan, probably the world's leading researcher in the Zika virus, based at The Massachusetts General Hospital, Harvard School of Medicine. This is interesting information for sure. We underestimated the Zika virus, and truth be known, we have not really been given the whole story. Now we know a lot more. We understand that this virus does seem to be affecting adults and does have some lingering issues with reference to the adult brain. We learned that it is a mosquito vector that is mostly active during the day and mostly indoors, and that these issues of spraying, aerial spraying in Miami and across South Florida, may be not much more than window dressing, having very little effect upon the actual Aedes aegypti mosquito, that what really needs to happen are more on-the-ground efforts to reduce the availability of standing water and take care of it in that way. So a lot of great information. I am hopeful that you will visit his website, which is zikafoundation.org. I think what we're going to see is an evolving story here. We're going to learn more and more over the next months, especially as we get to the warmer months in Florida and in the southern part of the United States. But what also was very intriguing was this tiger mosquito that seems to like colder climates. So there's a lot more to keep on top of, and I'm hoping that you'll visit his site and stay tuned. Thanks for joining me. I'm Dr. David Perlmutter. Bye-bye.