Dr. Anthony Fauci, Director of the National Institute of Allergy and Infectious Disease discusses the public health and scientific challenges associated with COVID-19. He reviews history of pandemic coronaviruses, transmission of coronavirus, cell structure of the virus, and virology.
Twitter @PennMDForum I really appreciate the opportunity to be able to make this presentation to you today on the public health and scientific challenges. Associate ID with Kobe 19 eso I have no financial relationships with commercial interest. I want to show this slide. First. It's It's a a viewpoint that I wrote for Jammeh in January, literally at the first time, it became clear that we were dealing with a new infection here, and I entitled the viewpoint coronavirus infections more than just the common cold. I did not mean it all to be facetious, but I wanted to point out to the readers who may not appreciate that we have had decades and decades of experience with coronavirus is in fact, in this file, a genetic tree simplified somewhat of the human coronaviruses, which also, as you know, ah, very prevalent in bat species and other intermediate hosts. But the four coronaviruses that are highlighted in yellow all those viruses which cause the common cold about 15 to 30% of all the recurrent common coals that we generally experienced during the winter months are caused by coronaviruses and then in 2000 and two in 2000 and 12 we were confronted with two pandemic coronaviruses, the SARS, or severe acute respiratory syndrome, which is a pandemic outbreak originating in the Guangdong province of China at 8000 cases, and 785 deaths. And it burned itself out because of public health measures without the benefit of a vaccine. And then, in 2012, the Middle East respiratory syndrome again, a coronavirus that jumped species from a bath to a camel to human. It's still smoldering with new introductions in the Middle East, and these are the two pandemic, or pandemic potential. Coronavirus is they have been handled relatively well, all things considered. But now we have the third pandemic coronavirus, which was recognized in the Wuhan District of China in December of 2019, the end of the year and the virus identified, and the sequence put on the public database by the Chinese in the first week of January. This is now called SARS coronavirus, too, because of the follow genetic proximity to the original sauce coronavirus one. So, just to be clear, the disease we refer to as co vid 19 or coronavirus disease 19 There was a lot of thought and discussion put into what we would finally named this the virus itself. As I mentioned a moment ago. It's SARS coronavirus, too. So let's fast forward to where we are right now. The evolution and explosion of a pandemic of historic proportions, like nothing we have ever seen for respiratory outbreaks since the 1918 pandemic flu Ah, 102 years ago. The numbers are striking now, having reached the million deaths in 33 million cases, the United States being the hardest hit country in the world. Despite our designation as being the best prepared for a pandemic outbreak, the heat map here shows the relative prevalence incidents and now number of cases relatively speaking. Throughout the country, we've had seven million cases and we passed a mark just a couple of days ago of 200,000 deaths and essentially really no particular end inside. And I'll get into that in a moment. Although there are some areas of the country that are doing actually quite well, I want to talk a little bit about what happened in the European Union compared to the United States, because it may not explain the reason for, but it will highlight the differences between where we are and where the rest of the world is. If you look at this slide, the blue line being the peak of European Union, which peaked a little bit before we did. But then when it went down and got under control, it had a very low baseline, which actually did extremely well for several months until just recently, when several of the countries particularly Spain, France and to some extent the UK tried to open up the economy again. And we're really went to the point where they disregarded some of the classical public health measures and you see, they've rebounded now up to around 38 to 39,000 cases a day. But look at the United States. We peaked at the time shown on this slide, driven predominantly, but not exclusively by the dominating effect of the northeastern corridor with the New York City metropolitan area at one point accounting for about 40% of all the countries cases, hospitalizations and deaths. But something different happens and related to the degree of which we, as a country shut down. As you can see our baseline plateau owed at an unacceptably high level of 20,000 today. And when we tried to open up the economy according to the opening up America again that some of you may remember there was a great deal of variability as to the adherence of the prescribed guidelines, and over a period of a month or two, the baseline went up to 70,000 cases per day, and now we've leveled off at approximately 40,000 day for the last few weeks. Why did this happen? Multi factorial. But at least one of the examples are if you look at the degree to which we shut down compared to the European Union as represented by Italy and Spain, you can see that if you have various parameters that tell you how much you shut down, namely movement over time. If you look at the visiting of parks and out of spaces, look how much less we went down than Spain and Italy. If you look a mobility in the workplace is the same thing, much less than Italy in Splain. And if you look at other parameters such as visits to grocery and pharmacy stores again a big difference between the United States Spain and Italy. Quick, look at the virology. Rather simple. We've been studying coronaviruses for decades and decades. It's a beta coronavirus. It has a large genome and RNA virus, which means it will mutate. Whether those mutations will be FINA. Typically important, it remains to be seen. It has an important spike protein whose receptor binding domain binds to now the ace two receptor distributed throughout the body, including the upper and lower respiratory tract, the G I tract and certain heart muscles. This is a picture of the confirmation of structure of the spike protein, with the receptor binding domain colored in green. Reason, I show that is that this is the basis for most of the vaccine candidates that are now being pursued again. The receptor has been known since the days of SARS coronavirus one, and it is in fact, the receptor for SARS coronavirus, too. With regard to transmission, we all know that this is a respiratory born virus transmitting extraordinarily efficiently, particularly in close contact. There is a degree of aerosol we don't know to what extent that is, it's likely not the dominating mode of transmission, as opposed to the classic respiratory droplets the virus is found in multiple body fluids, but its role in transmission is unknown and animals both domesticated and zoo animals have been shown to be effective. We do not believe that this is a major factor in human infection. This is a light refraction shot of what happens when an individual coughs or sneezes. In fact, we know now what we did not know before. That speaking and even breathing lets out enough respiratory droplets for transmission of infection, and we'll get back to that in a moment. The risk of transmission varies between the type and duration of exposure. There are secondary infections are common in household contacts and in congregant settings such as close settings. Hence the cruise ship outbreaks. There have been clusters associated with social or work gatherings that are non household. Here are some examples the now very famous Skagit County Washington outbreak in a choir in which one individual was symptomatic in a closed space during choir practice and infected 87 individuals who were there with him. This is an example of a super spreader event, not necessarily a super spread, a person but an event. The right situation at the right time or the wrong situation at the wrong time. And here are some other reported examples of clusters family gatherings in Chicago, church gatherings in Arkansas. Now the CDC has recently come out with an analysis of what the risk the odds ratio of transmission in different settings and it's very clear, has shown to the right side of that dotted line that restaurants, bars, gyms and closed church gatherings high risk for community spread. One of the most extraordinary aspects of this particular virus that's very perplexing is that about 40 to 45% of infections are asymptomatic, not pre symptomatic, but asymptomatic, namely individuals who do not have symptoms during the course of the viral replication in their body and clearing the virus. The other thing that matches up with this that makes it difficult to do contact tracing is that a substantial proportion when you model it of cases of infection are caused by individuals who are without symptoms and transmit their infection in the a symptomatic period to an uninfected individual. And so with that, the fundamentals that we speak about every single day for the prevention of both acquisition and transmission are the following universal wearing of masks or cloth face coverings. Maintaining physical distance. The 6 ft rule. Avoiding crowds and congregate settings, particularly indoor settings like bars and not wearing masks outdoors. Always better than indoors. There have not been any reported super spreading events that have occurred outdoors. They have all been indoors and again, frequent washing of hands. The clinical manifestations are protean. The incubation period is now a solid median. Five days with a range excuse me of 2 to 14 days. Flu like syndrome really characterized. The early component of this disease has shown on this slide, with one exception. A curious among several individuals. Loss of smell and taste, which precedes the onset of respiratory symptoms. Again, A curious and perplexing part of this disease in convincing people of its seriousness is the fact that most of the disease is mild. About 80% of individuals have mild to moderate disease that doesn't require any specific medical intervention. About 15 to 20% developed severe disease, requiring in many cases hospitalization, intubation and even ventilation. The case fatality rate varies from a few percent to 20 to 25% in individuals who require assisted ventilation the manifestations of severe disease, air predominantly and acute respiratory distress syndrome. But as we learned Mawr and Mawr week by week and month by month, we see interesting manifestations such as cardiac injury manifested by a arrhythmias with sudden death. Cardio myopathy is with congestive heart failure. Also kidney injury, neurological diseases, curious hyper co arugula ability with micro thronged by in small vessels and acute stroke associated with rahmbo anabolic phenomenon. There is now well established multi system inflammatory syndrome and Children very reminiscent of Kawasaki syndrome. The other thing that's perplexing new and we're learning about is what some people call long haulers, namely people who clear the virus. So they are viral, logically quote cured of the disease. But for weeks and even months and maybe longer, they have lingering symptom. Atala Gee, that could be muscle aches, muscle pains, fever, what people refer to as brain fog or an inability to focus or concentrate. These are things that in some respects resemble my algae can cephalopod the or chronic fatigue syndrome, although it is clearly different from that now, as was just heard in a very elegant way from Dr Aga. Well, there are collateral negative effects of covert 19 another health issues. So I'll go quickly through these because it was so well presented a little while ago. If you look at the potential indirect effects of this pandemic on the use of emergency departments, 23% decrease in heart attack presentations, 20% decrease in stroke, 10% decrease in uncontrolled high blood sugar. In other words, people are staying away from emergency rooms because of the fear of co vid 19. Now we just heard about the cancer very well. The changes in the number of patients with newly identified cancer before and during coronavirus. Just take us an example breast on the left hand side with the baseline to the far left with the dark green, and look at the diminution as you go down, particularly through March. In other words, people are not being diagnosed. In addition, 17% of patients in active treatment have reported delays in their cancer therapy, and 67% of patients and survivors have expressed concern about health when you shelter in place. And my colleague at the N. I H. Ned Sharpless has written in science. A couple of months ago, Theis estimation that covert related reductions in cancer screening and treatment over the next 10 years could result in a many as 10,000 excess deaths from breast and colorectal cancer. So let's move on now to who's an increased risk for severe covert 19 illness. Again, this is not a uniformly serious and fatal disease. It varies greatly older adults if you look at the parameter of rate of hospitalization per 100,000 population, dramatic difference between Children on the left hand side of the slide and the elderly who have a dramatically MAWR increase in hospitalizations than those who were young and people of any age with underlying medical conditions. These are some of the ones that are strongly associate ID with an increased risk of severe disease. Paramount among these is obesity and chronic obstructive pulmonary disease as well a serious heart disease, kidney disease and others. There are other disease that have less of a strong association of an increased risk, and they include those shown on this slide. I won't go through all of them, but I want to point out two or three, which are prevalent, that is, hypertension, diabetes and other chronic lung disease. again the unusual and disturbing disparity of the risk of not only getting infected but of a serious outcome. If you do get infected among minorities. African Americans, Latino X and where we have enough data for Native Americans, Alaskan natives and Pacific Islanders. Look at this disparity again with the parameter of the rate of hospitalization for 100,000 and compare Hispanic and black at 3 59 and 3 57 with White at 78. Dramatic difference. Quickly moving on to therapeutics. You heard a little bit about this from Dr Aggarwal. The N I H has put together a treatment guidelines panel made up of experts from throughout the country in various aspects of the clinical care of covert patients. It's a living document that is upgraded and updated regularly providing clinical data from established published data as well as from expert opinion. It's easily accessible. There's the link covert 19 treatment guidelines dot N h dot gov. With regard to the treatment, two of them have already been recommended by the guideline. I'll get to that in a moment, but there are others that in various stages of clinical trial, direct anti virals, convalescent plasma that got an emergency use authorization. But we really need to wait for the results of the randomized, placebo controlled trials. There's hyper immune hyper immune globulin, which will go into clinical trial shortly within the next couple of weeks. Ah, lot of promise with monoclonal antibodies. And then there are immune modulators that inhibits side of kinds, as well as adjunct therapies such as anticoagulants. Let me take a look at two of these that have been reached the guideline panel for approval. One is from Death Severe, which was the first drug shown in a randomized, placebo controlled trial that had a positive effect of diminishing the time to recovery. In 1000 patient study in 10 countries, the UK did a very nice randomized controlled trial of over 6000 patients in individuals hospitalized requiring ventilation or oxygen, and a substantial significant difference in the 28 day mortality with Dex, a meth zone versus the placebo of note early patients not only did not benefit, they probably had a deleterious effect, which tells us something about we already know about the pathogenesis that early on you want to hit the virus and leave the immune response intact, whereas in later disease what you want to do is demand dramatically diminish the hyperactive inflammatory response. I want to talk a little bit about monoclonal antibodies because that really is important. We have studies that are ongoing now, as I speak in the outpatient inpatient family prophylaxis, when one member is infected and full prophylaxis in nursing homes. The data on these should be coming out within the next months and finally on vaccines. We've taken a strategic approach, namely, the federal government has made major investments in facilitating the development and try a little of six candidates. And we have harmonized the protocols toe have a common data and safety monitoring board, common primary and secondary endpoints and common immunological parameters for correlates of immunity. These are the three platforms that are being pursued. New click acid with messenger are in a viral vectors. Either chimp add no human. Add no VSV or measles and classical protein Sub unit. Five of these are in Phase three trial, two of which started at the end of July just a couple of months ago. We should have results of these sometime in November and December. There's never a guarantee you will have a safe and effective vaccine. But I am cautiously optimistic that we will looking at the preliminary data from Phase one trial, inducing robust levels of neutralizing anybody. But again, it remains to be seen. We need to wait for the results of the Phase three trials, which I believe will be available at the time we get 2 November or December could be earlier. I think that's unlikely, but that's not impossible. So the question I often get asked, even with the vaccine, when will we return to normal? Well, by the time we get people vaccinated, namely even those who are reluctant now but will hopefully change their mind, it's going to take several months. So what we foresee is where we are right now is we have non vaccine combination prevention that we have all to a greater or lesser degree been implementing. If you have a partially effective vaccine, namely 60% as opposed to 75 80 85% you're gonna have to continue to have the prevention modalities that we are dealing with right now complementing the vaccine. If we get a vaccine that's 90 plus percent effective there will be less dependency on the stringent public health measures. But I believe that at the end of the day, ah, vaccine will be available. But we will have to not abandon public health measures completely. So let me close with this last slide, which is the website for our prevention network. For anybody wants information about the trials. Or if even you wanna express an interest and perhaps volunteering for one of these studies, you can log on no commitment. You could just express an interest. And if there's a trial near where you are, you can enroll. So again, thank you for giving me the opportunity to make this presentation. Thank you very much.