麻豆传媒

News Live Expert Panel discussion of unique angles to the COVID-19 pandemic and the effects on all aspects of daily life around the world. 

Topic: Drug trials and the latest on remdesivir and hydroxychloroquine studies, reports of possible vaccine progress, treating COVID in the ICU, public health policy and research on how the pandemic is progressing, can we safely “re-open,” what interventions have worked, which have not, and what still needs to be done 

Who: 

• - Chief, Division of Health System Innovation and Research - University of Utah Health. Hess is co-leading an outpatient clinical trial. They are examining how long patients with COVID-19 shed the virus, an indication of the length of time they’re contagious, and whether hydroxychloroquine reduces shedding.
• - Assistant Professor - Virginia Tech. Duggal is working to develop a reverse genetics system to study COVID-19 vaccines and treatments.
• - Professor of Medicine and Global Health -  Duke University. Denny is chief operating office of the Duke Human Vaccine Institute.
• - Associate Professor, Medicine -  UCSD Health. Martin is now leading the UC San Diego Return to Learn Program -- an effort to potentially test all students, faculty and staff for COVID-19 monthly.
• .- Director of Global Health and Emerging Pathogens Institute, Professor -  Mount Sinai.

When: May 14th, 2020 at 2:00 PM EDT  

Where: 麻豆传媒 Live event space on Zoom - 

This live event will also be recorded and transcribed for use by media and communicators after it is concluded.

Thom Canalichio: Okay, welcome to this 麻豆传媒 live expert panel. We’ll go ahead and get started, we have today with us five panellists from different universities and organisations to talk about the current Covid pandemic and different aspects of that, that are effecting everyday life around the world, with a particular emphasis today on drug trials and progress in developing vaccines, as well as the latest on the spread of the pandemic and the disease modelling.

I want to introduce our panellists briefly here for you.

We have Rachel Hess; she's the chief of the division of health system innovation and research at university of Utah Health. 

We also have Nisha Duggal, she's an assistant professor at Virginia Tech. 

We have Thomas Denny, professor of medicine and global health at Duke University.

We have Natasha Martin, associate professor of medicine at UCST Health and we Adolfo Garcia Sastre from Mount Sinai, he's the director of global health and emerging pathogens institute and a professor there at Mt. Sinai. 

Thank you to all the panellists for joining, for the media who are in today’s call. Without further ado I want to go ahead and get started, and starting with Professor Garcia Sastre, can you explain for us the work that you're doing on researching some drug targets that are potential for treating the corona virus and explain to us what the different targets are. Transitional factors and sigma receptors are what you’ve been studying. What are those exactly and how would targeting those things help to fight Covid?

Adolfo Garcia-Sastre: Yeah, so there is a great interest in finding drugs that will inhibit the virus, that will hopefully make an impact on the disease. Our lab has adopted an approach to look for these drugs, that is a rational approach in which the factors, the drugs that we are testing, they are based on evidence, hypothesis that they are likely to have an impact on viral replication, for that we have developed a medium throughput assay, meaning we can do perhaps 50 assays’, 50 drugs per week. Not a large amount, but these are drugs that are predicted to make an impact on viral replications, so we have set up a replication assay where there is a culture, drugs inhibit viral replication and the drugs that we are choosing are based on collaborators that we have that make predictions about what drugs are going to be most likely inhibited. And these predictions, the first ones that we have been testing, they have been based on an interactive map – what is that? Finding what host proteins interact with viral proteins incurred by the virus, with the hypothesis that this host proteins that now have been identified, that interact with viral proteins are going to be used by the virus to promote replication and that’s why the virus is talking – is contacting these proteins and based on these proteins that were identified by our collaborators at UCSF, there was also prediction about what tracks we know that they are already being used in humans that are inhibiting some of the factors that are now known to interact with these viral proteins. And these are the factors that we have been looking at, these are the drugs that we have been looking at and as part of these studies we are continuing more studies but the first conclusion that we have is that we came out with two classes of inhibitors. One class is inhibiting factors that are involved in protein synthesis that are likely more used by the virus to produce viral proteins. That’s one set of drugs, and the other are drugs that are targeting what is called sigma receptors, which is one of the host proteins that is interacting with viral proteins. And there is many drugs that they are targeting sigma receptors. The interesting this is that most of the ones that we have tested, they are inhibiting viral replication and we are trying now to identify the one that is more potent and the one that is more specific for these sigma receptors and more drugs that are already being used in humans. 

Thom Canalichio: Great thank you and so people can understand further about this, are there – what are the kind of common drugs that you're studying that are already in use that people would be able to understand what some of these drugs are and how does the action they have compared to what's being studied with hydroxychloroquine and remdesivir.

Adolfo Garcia-Sastre: Yeah so for example hydroxychloroquine is one drug that actually is predicted and is known to bind and inhibit sigma receptors and that’s probably one of the reasons why it has anti-viral activity. The interesting thing is that many drugs in addition to bind one particular host protein, they can also bind others that are similar to – so they have multiple proteins they can inhibit. Hydroxychloroquine in addition to inhibiting sigma receptors, is also able to inhibit the receptor that is found in cardiomyocytes. In cells from the heart and this is probably the reason why it has some problems and gives cardio vascular problems and some adverse event for which it may not be the best drug that we can use right now to inhibit viral replication in people because of this adverse events.

Now the interesting thing is that, of the sigma receptor binders, there are some that bind even better than hydroxychloroquine to sigma receptors and they have more potency, anti-viral potency and they don’t bind any more to these receptors that are found in the heart cells. So, we think that there could be better alternatives to hydroxychloroquine that will inhibit better the virus without having the adverse events that hydroxychloroquine has. So that’s some of the studies that they came out from this initial set of inhibitors that we look at.

Thom Canalichio: Great, thank you Dr. Garcia Sastre. Since we brought up hydrochloroquine I want to go next to Professor Hess there, university of Utah. Rachel you are doing a clinical trial currently about hydroxychloroquine and especially the effect on decreasing viral shedding in newly infected patients. So, what can you tell us about that study that you're conducting and how does hydroxychloroquine impact newly infected patients versus patients who have more severe progression of the Covid infection?

Dr. Rachel Hess: Thank you very much for that question, I think that the last answer was a nice Segway into this. We’ve been asking the question whether or not hydroxychloroquine versus placebo in outpatients newly diagnosed with covid-19 can decrease viral replication as measured by oropharyngeal, meaning throat swabs daily in people infected covid-19 and then also surveying their household contacts with daily viral swabs as well to see if it decreases household transmission and the question that we’re asking is, can hydroxychloroquine be effective earlier in the infection to decrease that viral shedding and decrease household contact acquisition.

I think we’ve seen a relatively high rate of recovery from covid-19 but given the prevalence, also a very high rate of hospitalisations, a high number of hospitalisations although a low rate compared to the number of people infected. So, decreasing that acquisition decreases people’s risk and that’s the question that we’ve been asking as well as some secondary questions around immune development etc.

Thom Canalichio: So, conducting this clinical trial there at university of Utah health, to get test subjects, it requires having somebody newly tested and diagnosed with the infection. Can you tell us about the progress of the pandemic and how its deferred in Utah currently compared to some of the more densely populated areas of the country and why?

Dr. Rachel Hess: Yeah, I think that in Utah we were lucky to be able to see the leading edge of this virus infecting our colleagues and our fellow members of our country and the world, both first in Washington and then in New York state. So, we moved very quickly to encourage social distancing, encourage work from home policies and encourage school closures to decrease the density of people that we have, not only in the state but also in individual areas. And by doing that we have been able to decrease the predicted rate of infection in the state of Utah, which has been wonderful. We haven’t seen the same overwhelmness in our health system. 

We’ve also had a really amazing response from our governor and our state epidemiologist as well and members of our state health department in order to encourage social distancing, encourage masking, encourage good handwashing and both health systems in our state, both the university of Utah Health and Intermountain Healthcare have really come together to staff co-testing tents. Tents that are providing testing to both Intermountain patients and University of Utah patients as well as just the population in general. We’ve also benefitted from the ARUP laboratory which has been amazing in allowing us to spin up very quickly, high numbers of testing capacity.

Thom Canalichio: Great, thank you Professor Hess. Since we brought up now the disease progression, I want to go next to Professor Martin at UC, San Diego. Natasha as an infectious disease modelling expert, what do you have to say building on what Rachel talked about in terms of social distancing being employed to flatten the curve and what does the current modelling that you're looking at suggest about the reproductive number, both before and after social distancing and how we’ve seen that be affective?

Natasha Martin: Yeah thanks, I think what Dr. Hess said in terms of places getting a bit of a heads up and being able to act quickly in terms of implementing social distancing interventions and the substantial effects that that likely has had on reducing transmission is really important. If you look comparing what happened in New York City to what happened in the state of California who implemented social distancing in the state home orders earlier comparatively in their epidemic, you see a dramatic difference in the trajectory and we just don’t see in California what you saw in New York City and that’s promising.

When we talk about social distancing and its effect in flattening the curves and reducing transmission, often we turn to what I do – and that’s infectious disease modellers to try to help us understand that impact. So what the modelling has done is been able to try to understand how social distancing has effected what we call this reproduction number that you ask about and the reproduction number is the average number of infections that an infected individual will transmit to you through the course of their infection and many people now will have heard about the basic reproduction number r -0 [noughts], and that is the average number of infections that a single infected individual infects at the start of an outbreak when there is no immunity and there's no social distancing. And our estimates – that number for R-0 [nought] is going to vary by setting, but our estimates for example here in San Diego indicate that before social distancing that could have been as high as 4.7. somewhere between 3 and 6 so each infected individual was on average infecting 4 to 5 other individuals with their infection. 

With our models now we’re seeing that with social distancing interventions, its reduced that transmission rate, reduced that likelihood of transmission to somewhere between 0.6 and 1. So now each infected individual is infecting less than one new person. Which means that eventually you're breaking that transmission, you're reducing that epidemic. And that’s been really useful information both in San Diego, but many other teams are doing these analysis nationally and in other countries to try to help us understand the impact of social distancing interventions on reducing transmissions and sort of preventing the acceleration of the epidemic moving forward.

Thom Canalichio: So, tell us what is being done there at UC San Diego with your return to learn program and the strategy for implementing testing and contact tracing so that you could develop a strategy to relax social distancing, return to campus while still monitoring these infection rates for any changes?

Natasha Martin: So, if we’re able to resume some amount of in person instruction at UC San Diego in the fall and that is still a big IF – we may not be in the position to resume on campus instructions and in person learning, but if we are in the position in the fall to have some amount of instruction and reopening of campus activities, the goal of return to learn is to provide sufficient testing for active infection for all students faculty and staff on campus, so that we can detect outbreaks at the earliest stage. Now there are a number of other policies that we’re looking at in terms of how we can mitigate the risk of transmission, reduce the risk of transmission on campus, through reducing classroom sizes and other interventions but the point of the testing initiative itself is to improve our ability to detect outbreaks at the earliest possible stage. We know from clinical evidence that individuals who become symptomatic are likely infectious several days, up to 2 or 3 days prior to their developing of symptoms, if they develop symptoms at all. So, there's a really critical period of time where people are transmissible and they can be spreading the infection but they aren’t aware of that and they wouldn’t normally be caught by our standard passive screening walking into the health centre if they don’t feel well and they ask for a test.

 And so the return to learning program is an effort to increase that active testing, active monitoring so that we can detect outbreaks at the earliest stages and so that the public health researchers and the clinical staff on campus can adequately do case identification, contact tracing and appropriate isolation of contacts in order to prevent those outbreaks from occurring that would overwhelm our campus. 

I think the underlying idea is that we realise that university campuses are not islands. That we will very likely see viral introductions from off campus. Either through our off-campus students or faculty and staff – and the idea is that we want to be able to put in testing programs that we can detect these outbreaks early and act accordingly.

Thom Canalichio: Great, thank you Professor Martin for shedding some light on that, and as we talk about what we need to do to reopen with testing and contact tracing as well as the research into drugs that might be able to help treat the virus, obviously in the background this whole time we’re holding out the hope that a vaccine could be developed as soon as possible. So on that note I want to turn to Professor Denny there at Duke University and ask Professor Denny could you tell us a little bit about the work being done at your human vaccine institute there and especially explaining the messenger RNA type of vaccine that you're focusing on and how that works?

Thomas Denny: We’re pursuing a number of approaches as Duke currently, but for a vaccine to be successful one has to discover or develop an appropriate immunogen that is what's going to drive the immune response in the host. Traditional vaccines require that you develop that immunogen you get that growing in a cell culture in a laboratory and grow it in very large numbers and then have to purify it and then get that to the point of what we call phase I material to try it in the human clinical trial. 

That process can take a very long time. That can take 9 – 10 – 12 months’ time and getting cells to produce that immunogen at a high batch rate is challenging. Just think of scaling up a recipe that you may have in your house and now all of a sudden, you’ve to to take it from a family of five to a thousand people and you’ve got to do that overnight. It’s a challenge. 

Messenger RNA vaccines approach a little bit differently. They use the individual, the host if you will – as the bio reactor. So, you identify a genetic sequence, a messenger RNA that will be able to get into the individual and into their cells and reproduce and produce that immunogen that will confer immunity. So, traditionally MRNA vaccines are one of – a bit of faster track to get into clinical trials, they typically require less amount of material than batching up the so-called traditional vaccines and bio reactors. One challenging part of a messenger RNA vaccine is how you get it into the host and into the individual. You typically have to package it in some sort of lipid or nano particle approach to protect it and help to get incorporated into the cell. So that has a little bit of technical challenge but the thoughts are that messenger RNA vaccines can be brought to the clinic and brought to scale up in a faster period than a traditional approach. In Duke we’re pursuing that, we’re also pursuing some traditional approaches of vaccines, for development of corona virus.

Thom Canalichio: One thing I understand that is meant to be avoided in developing a vaccine is creating and enhancing antibody response. This I think will help people to understand why it takes a significant amount of time to develop and deploy a vaccine. Could you explain what that is and the concerns detecting and preventing something like that.

Thomas Denny: Yeah, not talked about a lot but most of us who develop vaccines – we like vaccines and we think they're good, but there can be some negative effects of vaccines and one of them is what's called an enhancing antibody and an enhancing antibody is an antibody that when you give it immunogens, somebody develops an antibody profile that actually doesn't work in protection for them, but it works in a way that it actually enhances or enables them to become infected at a higher rate than they normally would if they didn't receive that vaccine. And one of the probably hallmark trials that this played out in was probably 7-8 years ago, there was an HIV vaccine trial and there was a placebo type trial where folks got vaccinated in a high prevalence area and some did not get vaccinated and the cohort of people who were vaccinated ended up being infected, that is the transmission rate was much higher in them than it was in a placebo group. That trial was abruptly stopped, there was years spent at mining the data from that, looking at immunologic profiles to understand what could happen. So the concerns of rushing too fast into large number of people with vaccines for Covid is that if you have a vaccine that helps to develop that unfavourable antibody response, then we will be putting many, many people at risk of being infected with the vaccine that as you heard earlier, already has a very high transmission rate to people.

Thom Canalichio: Thank you Professor Denny, I think that really helps to understand a little bit more about why it takes as long as it takes to develop a vaccine and on that note I want to Segway to Professor Duggal, Nisha Duggal at Virginia Tech. Nisha can you tell us about what you and your collaborators are doing to develop reverse genetics to test the efficacy of vaccines and how that works and is this the kind of thing that you're looking for or what exactly do those kind of tests achieve?

Nisha Duggal: Yeah so, my colleagues and I are working with animal models of SARS – CoV-2 infections and reverse genetic systems in order to identify viral genetic determinants of disease as well as host determinants of disease. So, for example factors such as age, sex, obesity that might influence disease progression and yes, I think these are perfect systems for assessing vaccine efficacy and whether there is enhancement of disease. I think we all certainly hope that's not going to be the case but I think it’s definitely incredibly valuable to do those experiments in animals to determine what kinds of effects there are.

Thom Canalichio: Great thank you for clarifying that for us and I understand you're also studying the viral shedding of the corona virus during pregnancy and the potential transmission of antibodies from mother to foetus. What can you tell us about that – the significance of pregnancy in corona virus infections and does this have to with gender differences between men and women or why else is it important to study and understand?

Nisha Duggal: Yeah, I think you’ve listed a few important reasons – so one – a number of hospitals have reported that there is a slight skewing to more individuals being male who are hospitalised with covid-19 – around 60% and also for other respiratory infections, pregnancy is a risk factor for severe disease, though I do not believe, according to the most recent reports that's been seen for SARS –CoV-2, however pregnant women are always a high risk population and need to be monitored, I saw a study recently in New York that’s decided to screen all pregnant women in the hospital for SARS-Covid II and identified 15% of their women were infected and most of them were asymptomatic, so just as the regular population, there's going to be a lot of asymptomatic cases for pregnant women, that would be the case too and we’re hoping to understand how infection either before or during pregnancy can effect infants so we’re hoping that exposure of pregnant women will allow for the transfer of maternal antibodies to infants and will protect them against subsequent infection, however certainly we need to perform those studies first before we can say.

Thom Canalichio:  Thank you Nisha, I want to turn to questions from our audience, thank you so much for submitting those and we’ll get through to those for each panellist as we go along. I want to invite other media who have participated in today’s event to please chat us your questions. First, I’d like to go ahead to Dan Keller of Keller broadcasting.

Dan Keller: The quick questions would be to Dr. Denny – how long would it be advisable to do phase I?

Thomas Denny: Well typically safety testing is a combination – I mean it’s never over but its typically a phase I – phase II. So, phase I – 30 – 40 patients, dosing and looking for some early signals. Phase II then you're refining your dosing and going at dosing administration schedule again and continuing to look at safety signals. So you would hope that if you were starting to see some of these things, you would see them – it would be between the phase I and phase II period but you know, there's examples out there where it’s not a perfect scenario and sometimes some of these things don’t show up until you get into the large number of the people which is typically in the efficacy trials when you get into thousands. So, you hope that you find safety signals early on, but some complications in both the drug field and the vaccine field sometimes do not appear until you're into much larger number.

Thom Canalichio: Thank you Professor Denny. Dan what was your next question?

Dan Keller: Things are being kind of rushed in the vaccine development that's why I asked – another one is or Dr. Martin, how often would it take testing faculty staff and students essentially for finding corona virus infection. It seems like with such a population the interval infections would be – there's a big interval between testing, how would you make this really work?

Natasha Martin: So, yes thanks. So the testing rates that we are proposing for UC San Diego is that we want to test ideally a 100% but at least 75% of the population a month and that number came from some mathematical modelling that I did where we looked at what would happen if you seeded an infection in a population and you had different testing numbers that were tested per day and at each day we would calculate the probability that an infection had been detected on that day. So, what our aim was to have a sufficiently high testing rate, such that when we were sufficiently sure that we would have detected an infection on that day, there were less than 10 infections detectable walking on campus. So, in terms of your testing interval question –absolutely if you test once a month, then you're going to be missing some infections. The aim of the testing rates that we propose is not to be able to detect the first infection as its introduced on campus. The aim is that we want to be able to detect an outbreak before there are 10 detectable infections wandering around on campus so that we can do appropriate case notification, contact tracing and isolation based on those. Because if you think about it, for every 10 cases, they may have up to 9 contacts that each need isolation and they may need isolation housing for two weeks. So, it quickly escalates. So that was the thinking that under pinner our desire to test at that frequency. Of course, if you are able to test more frequently and more than once per month, then you’ve reduced that testing interval and increased your ability to both detect outbreaks early as well as detecting infected individuals before they're able to transmit to others. But even at the rate of testing the population a month UC San Diego has 65,000 individuals on campus. It’s a huge volume and that’s kind of what we’re trying to understand with the return to learn program in terms of can we actually scale up testing easily, conveniently and get it processed in the lab at that scale.

Thom Canalichio: Thank you Professor Martin, Dan you also had a question for Dr. Hess?

Dan Keller: Actually, how about Dr. Garcia Sastre or Duggal? I assume Dr. Martin is sitting in front of a picture of some library, the trees don’t seem to be moving. 

The question is – have there been thoughts about using spike protein or isolated ACE2 domain binding sites as a decoy to keep corona virus from binding to ACE2 in early infection, as well as just for a vaccine and would there be a danger of inhibiting ACE2 and that you would not be breaking down angiotensin II - and it might get hypertensive? Also, are there complement components to come into play in the lung destruction and would monoclonal against complement be useful or tried?

Adolfo Garcia-Sastre: Okay, I take a first shot to this question – so in terms of using the receptor binding the main or as a decoy, yes there are some thoughts like that but its perhaps difficult to produce in the levels that are required to be used as an anti-viral, so the approach that most people are using is trying to bind small molecules that will prevent binding of the spike to the ACE2 receptor and if this have been identified, hopefully they can be manufactured to higher level that will be required for the receptor binding the main.

However, the other use of the receptor binding the main is an antigen, as in the vaccine. So in this respect Dr. Denny was talking about the antigens that people are using for vaccine, most of them they are based on spike because you will like mainly for a vaccine to induce antibodies that will bind to the spike and will prevent binding of the spike to the receptors, so will prevent infection. As the spike region that binds to the receptor is the receptor binding the main of the spike, one consideration to use as an antigen which probably is more easy to produce. If one is not producing it as messenger RNA but as protein, receptor binding the main could be a good alternative to be produced to high amount as a protein and to be used as a vaccine. But for that one needs to compare how good of an immune response receptor binding the main alone is able to versus the full spike. I know that there are experiments that are being conducted in this – in order to find out this particular answer.

Thom Canalichio: Did any of the other panellists want to respond to that question for Dan. 

Adolfo Garcia-Sastre: And there was another one about complement, maybe someone else wants to answer.

Thom Canalichio: Dan if you could repeat that part of the question that Dr. Garcia Sastre is unable to adjust. 

Dan Keller: They’ve been looking at some monoclonal against [inaudible 31:04] lung to treat the cytokine storm, I'm just wondering does complement come into play in terms of lung damage. There are antibodies against complement components. 

Thom Canalichio: Thank you Dan, any other panellists have thoughts about that area? Dan it looks like you may have stumped our panel on that one – 

Adolfo Garcia-Sastre: No, no I can answer that, I thought maybe someone else wants to address it. 

So, there are two approaches how to treat people with a drug for that infected. 1] Is using an anti-viral that could be targeting the host or targeting to the virus, but what's an anti-viral? Something that inhibits viral replication. The less viral replication you get, it is likely you haven’t damage. However, once you get into severe disease, perhaps it’s not so much important to inhibit viral replication because there must be already not so many virus around, while the important thing is to eliminate the next [inaudible 32:00] response, that may be causing the damage more than active viral replication at this stage. And that is when there comes the possibility of treating people with immune [inaudible 32:14] with things that will prevent cytokine storms, or like I just said, for example – things that will inhibit complement. I'm not familiar if there is anybody following the inhibition of complement, but that will be similar to other approaches that are used in mono [inaudible 32:28] they have a potential to work, but is always a problem is very tough to find the balance between the good things that these things do, the cytokines that complement, taking away and killing viruses, versus the accessible response that is responsible of disease. And that's where the problems come in order to find what is the best way how to treat this cytokine storm or this damage that is due to – they don’t respond to the virus. That is no good animal models at this moment for very severe disease, that means that we are a little bit blind about how to deal with this type of inhibitors. However there are some inhibitors like inhibitors [inaudible 33:14] six or the cytokines that have been tested because certainly they have some potential to work, but I'm not familiar and that could be my ignorance if there is also anything going on with inhibiting complement for preventing complement mediary damage. 

Thom Canalichio: Thank you doctor and Dan, thank you so much for those questions. I want to go next to – 

Dan Keller: Can I get one last one in?

Thom Canalichio: Go ahead Dan.

Dan Keller: Okay thanks. Has anyone considered as an antiviral using siRNA – not as the vaccine using mRNA, but using siRNA?

Thom Canalichio: Professor Denny, that sounds like that’s in your ballpark, is anyone working on that there at Duke?

Thomas Denny: No, I think he means that not as a vaccine approach but as a treatment approach. Is that correct Dan?

Dan Keller: Yes.

Thomas Denny: That’s not in our wheelhouse.

Adolfo Garcia-Sastre: But there is some thoughts, we are not using this RNA here but that’s also a very interesting approach. One of this is with the use of siRNA is the delivery, you need to have the siRNA to be delivered in enough amount to the cells where the virus replicates, but certainly it’s an approach that has potential. I'm sure there will be some groups that are working on that.

Thom Canalichio: Great, thank you Dan for those questions. I want to go next to Barbara Fraser – Barbara I'm enabling your audio. Barbara is a freelancer from Peru, Barbara go ahead with your question, I think this is best addressed to Professor Martin. 

Barbara Fraser: Thank you so much, I'm a freelancer in this space, from Lima, Peru. Not a specialist in health reporting but I'm curious about whether it’s possible to trace backwards through models or to figure out backwards through models from the time the first case was detected, how long it might have been circulating in that locality, either in the country or in the locality. Peru detected its first case in a person who had imported it, but there are several parts of the country that have really, really strong outbreaks and I'm wondering if it might have been circulating in those places even before that first case was detected. Can models tell that?

Natasha Martin: That’s a great question. So, there are a few different ways that we can try to understand that question. The first is to use molecular epidemiology. So viral sequence analysis and reconstruction of evolutionary tress using the molecular sequence data can help us understand how long a virus has been circulating in a given area, so for example – some teams at University of Washington did that and found that at least in Washington in the United States, the virus was likely circulating many weeks – many, many weeks prior to detection of the first case. The other piece of information that can help us in addition to the molecular sequencing is also just a basic understanding of what the characteristics of that first detected case are. So if you first detected case is a death, then it’s much more likely that you have a lot of virus that has been circulating, because obviously only a small proportion of individual that obtain the infection actually die from the disease, so if the first time you see it – it’s a death, then it’s a good indicator that there was quite a lot of transmission occurring prior to that point that just was undetected. 

So, I think the sequence analysis is the best way to understanding that in terms of the timing of viral introductions, but we can also use understanding in terms of the aspects of the case to help us give us clues in that area as well.

Barbara Fraser: Thank you.

Thom Canalichio: thank you for that question Barbara, I want to go next to another journalist with questions, we have Suzanne Toro, she's from KLBP public radio in Long Beach. Suzanne go ahead with your question; I believe this one will be – well I'm not sure which panellist this will be best for.

Suzanne Toro: Okay great. I was curious – you know I've been tracking this history of vaccine of virus and the series of patents, have any of you  been in contact with Inovio and their patent that they designed in three hours, on January 10th 2020 – its INO 4800 and if you have I’d be curious what you think about DNA vaccination. In addition, why – do any of you know why there was such delay when this information was shared from China, this sequencing back in 12/31/19 and the first lockdown didn't happen until the end of January, seems really unusual to me.

Thom Canalichio: Thank you Suzanne, any of our panellists have knowledge about the Inovio vaccine and Suzanne’s question?

Thomas Denny: Not to specifics, I know there is DNA approaches right now, in fact there’s over 100 approaches right now for different kind of vaccines. Candidates are being pursued, but I have not looked at the Inovio patent. 

Adolfo Garcia-Sastre: Yeah so the Inovio approach – although I have not completely knowledge about the specific sequences that are used in it, it’s an approach that they have been using – it’s a company that is trying to use DNA vaccines, so these are a little bit step behind the RNA vaccines, they use DNA also to be introduced into the cells, making the cells factories to produce antigens. So, they are also trying to get these vaccines in a spike mainly into clinical trials and see what is the impact. 

Now the question comes with why they went so fast in making the prototype which is very easy once you know the sequence, they have to basically design the VNA that will be able to produce the spike, which is what you want to produce in order to – as an antigen for a vaccine. Why they went so fast since the moment that the sequence was published? Well that’s a question I guess is for the world. Also, in my lab, as soon as the sequence was published, we started to work with the virus and my collaborators started to make proteins to find this protein – protein track - that I mentioned before, and that takes time. But they started right away, why? Because I think to me it was quite clear that this – and to many scientists, that this virus has a very high potential to be able to start a pandemic, how things were evolving in China. 

Now, one may think well but if the information is not there, perhaps it’s not going to make a pandemic, perhaps it’s going to be like SAR Corona Virus I, perhaps it’s going to be mitigated, perhaps nothing is going to happen, but there is also a good possibility that what is happening now, was going to be happening and many of us started to work with this virus since the first moment that the sequence was found.

Thomas Denny: Yeah, I’d say one of the benefits of probably Inovio is they had capital sitting there waiting that they could just deploy on this problem. Most of us in the academic world as we started getting active in this area in January had to remobilise funding that we had for different types of things or required funding to do work in this area. But industry, it’s a little bit easier for them to bring up a program and jump start it. 

The other thing keep in mind, both DNA and RNA based vaccines, best to my knowledge there have been none that are licensed today.

Thom Canalichio: Thank you, we’ll come back to you Professor Denny. I want to go ahead to Charlotte Libov - freelancer. You a have a question Charlotte I think that will be best for Professor Martin, go ahead with your question.

Charlotte Libov: Thanks so much and thanks for organising this Thom.

My question is – cities and states are obviously reopening very, very fast and a lot of them before the CTC guidelines about a drop in cases for 14 days. So, my question is- for somebody like me that's going to be watching the numbers, how can you discern whether there is a spike in cases due to something like says bars and restaurants opening, especially when cases fluctuate. I mean I can drill down to zip codes but I still don’t know what I would be looking for – when I should start looking for it? 

Natasha Martin: That’s a great question. So one of the challenges with trying to understand cases is that it’s obviously so dependent on the testing volumes, the more you test the more you're going to find and especially we’re encouraging states to increase and ramp up testing and they're doing that, then we’ll see more cases which is I think one of the reasons why the metric of proportion of tests that are positive has been proposed that sort of helps us disentangle that influence of the testing frequencies. 

But regardless, I totally agree with you – that using testing metrics is very difficult to understand because of the variations in testing between settings and between local regions as you mentioned, sort of sub-regions. In that sense what I think is helpful to look at are really the hospitalisation rates. so, the state of California for example is publishing county level hospitalisation rates in terms of new hospitalisations and new intensive care, current census counts of hospitalisations and intensive care beds. And that – although there's a little bit of lag between a new case and when that case may result in a hospitalisation, I think it’s a harder metric something that we can track with more reliability because it’s less reliant, this testing variability. So, tracking hospitalisation counts I think is a good way of looking at that question.

Now as you mentioned, if you're looking at a very fine detail where some zip codes may have no hospital or they may be referring to other areas – it’s hard to see that. This is also where I think it’s critical that we have really good contact tracing going on, because at the moment we’re hampered by our inability in many places to actually appropriately do case identification in contact tracing, but interviewing people and understanding where they are, who they have come into contact with, where this is happening, will help us understand a little bit better in terms of that fine detail which may be very important. In San Diego we have promising metrics overall in our county, but very worrying metrics in the South border and the border of Mexico and Tijuana which has an overwhelming outbreak right now and more deaths in Tijuana than we have seen in San Diego. So, these local concerns are very real and very important to monitor as best as we can – both your hospitalisations and also mortality data, although obviously there's a lags. I'm looking at deaths.

Thom Canalichio: Thank you for your question, I want to go next to Tina from Science 麻豆传媒 and Tina I believe you had a question that one or more panellists might be able to answer. Tina, go ahead with your question.

Tina: My first question I think maybe either Dr. Martin or somebody else could answer, I want to know how much a treatment is going to be necessary to help in the pandemic? Can you do it just with testing contact tracing and isolation alone or do you actually need a treatment and/or a vaccine?

Natasha Martin: So, I think we’ve seen from countries that have been much more successful than the United States in terms of their testing, contact tracing efforts – those public health interventions can be very helpful in reducing transmission and flattening the curve but they are insufficient in ending the epidemic. Even in places that have had very good testing and contact tracing programs, they have also – many of them have seen increases in cases and because we have been effective in reducing transmission and the proportion of the population who have had Covid and are likely immune to it, although we don’t know the truth in terms of immunity, but the likely proportion is very small, the truth is that we will only be able to end this epidemic when we have an effective vaccine. Treatments will help in terms of reducing mortality, but it’s the vaccine that we need in order to generate the kind of herd immunity that we need to actually prevent outbreaks and continue transmission of this epidemic. 

Thom Canalichio: Thank you – Tina did you have another question?

Tina: Yeah, I did, I wanted to ask about progesterone, Dr. Garcia Sastre, I think you showed in your recent study that progesterone may help slowdown the virus and I was wondering if doctor Duggal could maybe address whether that’s being looked at in animal studies.

Thom Canalichio: Dr. Garcia Sastre, go ahead and tell us about – 

Adolfo Garcia-Sastre: So maybe I start – so progesterone is actually one of the predicted sigma receptor inhibitors and that’s the reason why we tested in our antiviral assay, but only as per also our collaborators in Paris. We were doing antiviral assays at the same time. Without sharing the data – then this data gets shared, it’s amazing how good they feed the data in Paris from the data in New York in terms of antiviral activity, it gives us good confidence that actually this is the case and progesterone is an inhibitor like many other sigma receptor inhibitors, it’s an inhibitor viral replication, but we don’t know at this moment whether the levels of progesterone that there is in people, especially women are responsible for having a more antiviral activity and therefore that could be a reason why there is more men than women that have the disease. We don’t know about it and we have not yet been able to do an animal model to test this particular hypothesis. Maybe Dr. Duggal will be – 

Thom Canalichio: Yeah, Professor Duggal, tell us your thoughts about that.

Nisha Duggal: Yeah, I mean that’s one of the first things we plan on testing. Certainly the lack on an animal model is slowing down that – pretty good question but for starters 1] that’s been shown to be effective in mice and I think the only – there is a trend towards men having more severe disease, however that’s also – that gets exacerbated with age, so that could be that there are obviously more components than just hormone levels that are going to be at play here, so I think – yeah that’s a fantastic question and definitely needs to be tested.

Thom Canalichio: Great, thank you for those questions Tina, I’d like to go next to Leslie Mertz, she's a freelancer and Leslie has a question that I think Dr. Denny could best respond to. I'm looking for Leslie in the meeting so I can enable your audio. Leslie if you're there go ahead –

Leslie Mertz: Okay, yeah my question was about what your opinion is about the potential for pan corona vaccine maybe via a shared membrane structure or maybe some other that was mentioned and whether you think there are some certain research groups that are doing especially interesting work in that area?

Thomas Denny: A great question, happened to be a bit of a by side area- that's one area that we’re pursuing, so if one goes back and looks and talks to the evolutionary biologists, you'll find out that there are a lot of corona viruses out there in bats and animals that can hop to humans. So one of the approaches that we’re pursuing is actually to develop a pan corona type vaccine and if you think of a tree and the branches and the leaves, if you're making a vaccine to the novel corona virus that we’re dealing with now, you add on a branch or few leaves, but if you can make a vaccine that takes care of the trunk if you will – the gene - whole family of corona viruses there then one would prevent these types of pandemics at least from a corona virus in the future. So, we’re pursuing that. It’s complicated, it takes a lot of work but we do have an ambitious approach at this and we hope within about 12 months we would be to a point where we would be doing what we call phase I type clinical trials and this work we’re using a number of computational biologists to help us if you will – mimic if you will, or identify what would be the unique set of immunogens that would give that type of protection. 

Thom Canalichio: Thank you Professor Denny.

Adolfo Garcia-Sastre: Perhaps I would want to add something – I think it’s great trying to come out with a pan corona virus vaccine or at least a SARS – pan SARS vaccine but there is also another thing that we can think of. If a vaccine that is based on the – whatever antigen we have against the spike of SARS CoV-2 finally is being found to be successful. It will not be very complicated to add to this vaccine a second antigen that is based on the same antigen. Now for example for MERS, which is a problem - but not as much problems as SARS, perhaps MERS will again ramp up at one moment, maybe 10 or 20 years from now, and it’s very difficult to test a MERS vaccine because there are very little amount of cases for MERS. But it should be possible to add a second antigen that is MERS and have a bivalent vaccine that will not only work against SARS, but will also prevent MERS from jumping. So, I think some good things can actually come up at the end coming with a vaccine against SARS.

Thomas Denny: Excellent comment.

Thom Canalichio: Thank you for that Dr. Garcia Sastre. I want to go next to Felicia Wu [inaudible 51:45] who had a question I think for Professor Martin, go ahead Felicia. 

Felicia Wu: Thank you, my name if Felicia Wu and I am a professor at Michigan State University. First a quick hello to Dr. Hess because we used to be professors at the same university and now, we’ve got to different universities. Dr. Martin – like you, at Michigan state I'm involved with a team that's trying to understand if we open up in the fall the types of issues that we would be dealing with and how we could open up safely. If you would please answer a few short questions that I have regarding the logistics of the testing that we were mentioning if UCSD should open in the fall, I would appreciate it. 

Have you decided which test kits you would be using? My understanding is that FDA has come out with three types of emergency test kits right now, using for example the antigen or the antibody or viral RNA, how long would it take to get the results from those different types of tests? How likely do you think I is to get 75% compliance within a months’ time and would you prioritise particular people who ought to get tested before others? Thank you.

Natasha Martin: Thank you for these great questions and letting me clarify. So, the repeat testing that we’re proposing is a viral nucleic acid test, it is being done in an in-house laboratory that’s CLIA certified and EUA compliant so these are medical grade tests that can be immediately released to the student so that they're aware of their status. The sample collection is through a nasal swab, so the students are self-collecting. They will come to a nearby collection point at campus, they wab their own nose, drop it into a collection container and then its brought to the lab and we aim to get the test results within 24 hours. We have started the pilot on Monday and that’s what we’re achieving in terms of the 24 hours turn around. 

At the same time however, because cost is still limiting factor, even though we have – because we’re doing it in-house, have aggressively been given aggressively discounted cost, cost is still going to be a factor using the nucleic acid test and so we’re examining innovative platforms in terms of sample collections and methodologies and trying to bring it in within the CLIA lab so that we can get that certified and expanded, because as you point out, doing this at the scale of several thousand tests a day will be challenging, both in terms of the turnover of the lab but also in terms of getting uptake. In particular, although the nasal swabs have been acceptable to the students, we are exploring the possibilities of saliva which appears to be similarly sensitive to the nasal swabs but we need to work on that and obviously try to bring it under the CLIA umbrella, but when we’re talking about testing several thousand people a day, I think it needs to be as simple, as easy as possible in order to ensure we have high take up.

Thomas Denny: Could I have a question – 

Thom Canalichio: Go ahead Professor Denny, yeah absolutely. 

Thomas Denny: Natasha have you considered – for example for approach for triaging, have you considered pooling samples at all for the PCR testing and then breaking a pool and doing individual testing if positive lights up as a way of faster throughput and lower costs

Natasha Martin: Yeah, we are looking at those methodologies and things like tagging so that they can be immediately pooled together and then disaggregated if a positive is found and then rerun so that we can go and sample them. We are examining those. for the purposes of the pilot we’re not doing pooling just because we want to be able to have a rapid turnaround but yeah that's absolutely a way to do it in terms of reducing costs. I mean there are a lot of other institutions that are looking at innovative platforms in terms of testing with crisper technology and I think those are things that we want to look at as well because we want to be bringing the cost down from 30$ a test to 1$ or 3$ a test, to really be able to do that so yeah – we’re looking at that.

I'm sorry I didn't answer the question about priority populations. At the moment we’re not – the testing will be available to everybody although we are in discussions in terms of thinking about whether there are populations on campus that have special risks that may need additional testing in addition to what we’re proposing and that’s just something that we’re exploring right now, nothing firm.

Thom Canalichio: thank you for those questions there Professor Wu, I want to ask – since we’re on the subject of testing I want to ask Dr. Hess because your study really does rely on testing to identify test subjects for your clinical trial, because your goal is to target people as soon as they’ve been diagnosed. How do you feel we’re doing with the current capacity of testing and what more needs to be done and how else does that factor into your clinical trial and the timeline for that?

Dr. Rachel Hess: Yeah thank you for that question Thom. As I mentioned previously, at Utah we’ve benefited significantly from having a reference lab directly affiliated with our university so ARUP Laboratory has been able to spin up capacity to initially 5000 tests a day and now significantly more than that as well as equivalent antibody testing, so in our state we’re actually testing under the capacity that we have to test and we’re testing somewhere between 2500 to 4000 people a day. I think that when you start to ramp up to the levels that Dr. Martin is alluding to for campus wide screening, that level of capacity becomes one that needs to be scaled much more greatly and will likely be necessary to think about reopening safely.

Thom Canalichio: Dr. Garcia Sastre mentioned earlier the potential harmful effects of hydroxychloroquine on heart tissue, so I wanted to ask – how is your study screening or factoring for those risk factors and try to avoid them.

Dr. Rachel Hess: Yeah that's a really great question, we have been ensuring that no participant is taking another medication that can also prolong the QT interval which is the risk in the heart. It basically is the way that the heart conducts electricity through itself and when that is delayed it can cause the heart to beat wrong. So, we’re screening to make sure that there are no other medications. We’re screening out anyone that has a high risk for a prolongation of their QT and in those individuals for whom we have a history of prior electrocardiogram or heart tracing, we’re eliminating anybody who has had prolongation of their QT. one other things that I think we’re seeing in Utah that we’re seeing in other places is a very high prevalence of this disease among a population that has not necessarily been accessing healthcare previously, for various socio economic reasons and I think that as Dr. Martin mentioned, with the increased prevalence down at their Southern border we are seeing higher prevalence’s in our lower socio economic neighbourhoods as well, which is of course concerning not just to see how we take care of those in our community that have access to healthcare but those in our community who have not traditionally had access to healthcare.

Thom Canalichio: Thank you Dr. Hess. I want to ask another couple of questions quickly to Professor Duggal – Professor Duggal, I understand that you're trying to identify or get more information at least bout the mode of transmission as part of your study and I also want to ask you about the antibodies. So why is the mode of transmission so important when looking for a target for a vaccine and also what do we understand about antibodies and why can some antibodies maybe help you fight the disease but not necessarily protect you from contracting it?

Nisha Duggal: So, different transmission modes can require different therapeutics or different vaccine strategies or even just basically different recommendations for prevention, so my lab previously has studied Zika virus which can be transmitted by both mosquitoes and via sexual transmission so those are going to require different types of vaccination strategies and recommendations to prevent different types of transmission. So there have been some conflicting reports on the detection of SARS-CoV-2 in semen suggesting that it could be sexually transmitted, though we’re hoping to confirm that in an animal model and also looking at in-utero transmission. I think there's been conflicting reports there as well. so those can have different effects on disease outcomes and can require different treatment strategies. So, I think it’s important to assess whether these other alternative routes are important and then your second question –

Thom Canalichio: On the antibodies yeah – we develop antibodies or may have them, but they may not protect from infection.

Nisha Duggal: Yeah right, so antibody level can be very important for having a protective effect and having the in the right place is also really important so if you're looking at mucosal surfaces, different types, sub types of antibodies need to be present there in order to protect against infection, so just kind of links in with the route of transmission, just making sure that we have the right kinds of antibodies that are being produced.

Thom Canalichio: Great, thank you Professor Duggal – 

Adolfo Garcia-Sastre: Maybe I could add something there – with influenza – and that’s probably also happening with covid-19, we know that the majority of the transmission comes from viruses that replicate in the upper respiratory tract. But the severe cases are related to the replication of the virus in the lower respiratory tract, in the lungs, where you can get the pneumonia, the problems that they give you at the end with the severe disease. So, in order to prevent disease by vaccination, by antibodies, you need antibodies in the lower respiratory tract, which they have access through blood. You can get anti bodies in the lower respiratory tract, so antibodies in the blood may be able also to be correlated with protection. But the upper respiratory tract there is very little contribution to create antibodies. So, the antibodies that you find in the upper respiratory tract, these are mainly mucosal surfaces. So, you may require two different things in order to protect from infection, but to protect from disease and that's something that will play into equation in terms of the vaccines that will come.

Thom Canalichio: thank you so much, we’re just about out of time and I want to give each of our panellists a moment to just tell the media who are here how they can find more information about these ongoing efforts, so- Dr. Garcia Sastre, what kind of timeline are you looking at for your study and how could media connect with you and your institution to find out more?

Adolfo Garcia-Sastre: Well we are conducting – we have ongoing studies. We will start testing some of our antivirals in animal models very soon and then we are continuing testing some other antivirals. So, anybody that is interested they can contact me – sometimes I take a little bit longer to – depending on when it comes, because of the number of emails I receive, but I try to address the questions, especially if they are from the press – send an email.

Thom Canalichio: And we also have the communications office at Mt. Sinai listed on the video and the transcript. So, any media who are interested you can reach out to Dr. Garcia Sastre through those folks there at Mt. Sinai. 

Dr. Hess, what's your timeline for your clinical trial and what can media expect looking at if they're interested in seeing those results?

Dr. Rachel Hess: Yeah thank you very much for that question. We’ve been lucky in Utah that our cases have not been increasing at the predicted rate. That’s not great news for doing a clinical trial of enrolling covid-19 positive patients but good for our society. So, we are expecting results in the next 6 to 7 months. So, towards the end of this calendar year into the beginning of 2022 for publication. We looked at this yesterday and it looks like we should be complete by the end of December if enrolment continues, although it has been picking up slightly.

Thom Canalichio: Did you mean the beginning of 2021?

Dr. Rachel Hess: Oh, I'm sorry yes, I actually don’t know what year it is anymore. It’s all Covid time. 2021, I apologise.

Thom Canalichio: No that’s completely understandable, and as I said for Dr. Garcia Sastre, we’ll make sure to have the PIO available at University of Utah who can help to connect with Dr. Hess. 

Professor Denny, tell us about your progress on your trial and what can media look forward to seeing results about that.

Thomas Denny: The best way to get us is through the Duke’s communication office. That works best. We have the number studies under way at Duke. We have prospective cohort studies, we’re looking at natural history of infection and household settings also, looking at a lot of different issues around testing, different testing platforms, vaccine development side we currently are in a non-human primate model right now with a mRNA vaccine, looking to see if we can show protection in that and if we do get protection in that then we would translate that into making GMP material and going for phase I. We have an ambitious program looking at an mRNA antibody delivery mechanism, that we’ve learnt from studying people that have been infected and going to resolving their infection through the convalescent phase. 

We are hoping that we would have a product in a clinical trial by the end of this year, early January and then we’re probably 12 – 18 months out, looking more at a pan corona virus type of vaccine platform. That's a little bit more further for us.

Thom Canalichio: Great, thank you Professor Denny. Professor Duggal, tell us about the progress with your study and what media can expect to learn about results as they're available?

Nisha Duggal: Sure, so we have work ongoing here at Virginia Tech. My collaborator James Weger is actively making an improved reverse genetic system which should be released relatively soon. We’re also working on improved animal models, so we hope to have in the next few months and we’re definitely happy to answer any questions.

Thom Canalichio: Great, thank you Nisha. Professor Martin, I have a question for you, kind of related to what we talked a little bit with Dr. Hess about with enrolling people in her clinical trial with the need of testing and the rate of infection. The comparison between rural, less densely populated areas with the more densely populated areas that have already been peaking. Does this give us a false sense of security for those other parts of the country and should we not assume that those places are somehow safe just because it’s happening more slowly there?

Natasha Martin: Yeah, it’s a great question – if you look at the data, although at a national level it may look like things are improving. A lot of that has been driven by places that were hit hard and hit early like in New York city. And actually if you take out the major metropolitan areas that have been hard hit, the rest of the United States is getting worse and the cases are going up and the deaths are going up, so I think that speaks to the fact that the United States is large, its geographically disbursed, it’s not one connected place, it’s going to be a bunch of micro epidemics. So when we think about policies, it really needs to be locally driven in terms of what is going on locally and whether that makes the best sense and I think that it can be informed by monitoring good epidemiological monitoring as well as modelling to try to understand the trajectory as we go forward.

We’re doing that at UCSD and that’s part of the reason why we’re doing the return to learn program, to both new testing but also gather data as we go and try to adjust our policies in real time and also adapt our testing strategies. One of the things we’re looking at is waste water detection. Maybe we don’t need to test as much if we can detect things early in the waste water. So, we’re looking a lot of different public health surveillance strategies that could be helpful both here and on campuses but also in other areas to track locally what's going on and to respond accordingly.

Thom Canalichio: Great, thank you Professor Martin and I think we’d be very interested to have you back to talk more about the progress with your return to learn program as that takes shape and we see what the picture is going to look like more for the end of summer and the fall semester. We do have one more question, I hope that Professor Duggal maybe can answer this – is the corona virus prevalence among post-menopausal women the same as for similarly aged men? Is that something that you're familiar with at all and can you answer that?

Nisha Duggal: Sure, so I think just to clarify I should also say that it’s been not thought that infection rates differ between men and women but perhaps severe disease is more common with men and it appears that even in older populations where hormone levels are more similar between men and women, there is still a difference between men and women, with men experiencing – more likely to experience severe disease so yes –

Thom Canalichio: Okay great, thank you so much for clarifying that for us Professor Duggal. That was from Dan Keller with Keller Broadcasting, thank you for your questions all of the media who have been part of today. We have gone just a few minutes over an hour and I hope that’s okay. We’ve had some people drop out as we’ve gone a little bit long, but thank you so much to all of our panellists and thank you to the PIO’s at your various universities that helped to facilitate this. A special shout-out to Pascal at PharmaMar who helped us connect with Dr. Garcia Sastre. They’ve worked with him on some of his previous studies. Thank you so much to Natasha Martin at UC San Diego, Nisha Duggal at Virginia Tech, Dr. Rachel Hess at University of Utah, Thomas Denny at Duke University and Adolfo Garcia Sastre at Mt. Sinai. Thank you all so much for joining, media we’ll make sure to get you the video and transcript of today’s event. With that we’ll close. Thank you all very much. stay safe, stay healthy and good luck.