An Update on Covid-19 Testing, Treatments, and Vaccines

good afternoon welcome back to ucsf medical grand rounds i'm bob wachter chair of the ucsf department of medicine uh welcome to our live audience here at ucsf and throughout the ucsf health network as is our habit we will post this video tonight on youtube usual time is about 7 30. i will tweet out the address and our previous grand rounds in this series have now been viewed uh 600 000 times a few quick ground rules for the audience uh same as usual put your zoom window in full screen if you have questions type them into the q a box you'll be on mute and my colleague quinny chang is monitoring the q a we'll send the most interesting questions that we will try to ask of our speakers next slide so i want to highlight this for you this is the ucsf magazine issue for summer uh 2020 and these grand rounds are really only one of the mechanisms that we're using to communicate with people about the pandemic this is just a spectacular issue that covers many of the facets of the pandemic from a ucs point of view including highlighting people who are doing extraordinary work in all kinds of ways including medical students and emergency medicine and stem cell biology and custodians uh people working in the navajo nation uh annie lukemire who you'll hear from in a second uh is talking about clinical trials uh the number of articles in the issue as well including one i wrote about uh about tweeting the pandemic so uh i recommend it to you and the address is up there at the top uh next uh please so um we hit another sobering milestone just yesterday with more than 150 000 deaths in the united states alone while we know that we can markedly decrease the spread by wearing mass by keeping our distance and by avoiding crowds ultimately the path to salvation will come through testing to identify cases and then the use of effective treatments and one or more effective vaccine in all of these areas testing treatments and vaccines we've learned that progress depends on the science but it also depends on logistics on funding on policy on politics and much more as with all things coveted it's extraordinarily complex and [Music] rapidly changing so uh if it's possible to have a classic session uh in this grand ranch grand round series and a disease that's only five or six months old i'd say this is it we've covered all sorts of topics in the last several months but really haven't come back to these three topics which seem like they are ultimately a core it seemed like a great time to revisit the three issues of testing treatments and vaccines because they're extraordinarily important and because there's plenty that's new exciting sobering and more than a little confusing so that's what we will do today and as i said ultimately uh if we're going to get back to something resembling normal in our lives it will be because we've made the progress that we need in uh in areas of testing treatments and ultimately vaccines so i'm grateful to our speakers for educating us on these topics since the very beginning of the pandemic and we brought them back again to uh to update us on where things are so the three speakers today uh the first is uh chas lang langelier who is assistant professor of medicine in our division division of infectious diseases at ucsf health uh chaz's research is on the biology infectious lung disease with a particular focus on what makes people susceptible to respiratory infections he's also become quite an expert in covid testing and has helped teach a lot of us about uh about the ins and outs of testing and that's what he'll talk about today after chas we'll hear from annie lukemire annie who's professor of medicine in the division of hiv infectious diseases and global health at zuckerberg san francisco general hospital her research interests include hiv and tuberculosis co-infection and the development of novel tuberculosis diagnose diagnostics but like many of us she's toggled her career to focus a lot of her energies on kovid and has become a leader both locally and nationally in clinical trials of various therapies for covid and she will give us an update on therapies and finally uh last we'll be joel ernst who is professor of medicine and chief of our division of experimental medicine also at zuckerberg san francisco general hospital joel's focus is on the mechanisms of protective and pathological immunity mostly focused on tuberculosis but he's also studied and worked with vaccines and has done a lot of work uh excuse me on virus hasn't done a lot of work on vaccines including working on a tuberculosis vaccine but he's become our go-to expert on the prospect for vaccines in covet so you will hear from him last the format today will be three individual talks first chaz then annie then joel uh each one lasting about 15 minutes i may have a question or two after the talk and then when they are done we'll have a panel with all four of us uh that should be from about 12 55 to around uh 115 or so so with that let us go ahead and get started and bring chas back to uh give us an update on what's happening with testing okay well thanks very much bob um i'm happy to uh give an update on testing today and just going to start with this slide that provides an overview of the cumulative test per state and despite the staggering um and dark statistics of coven 19 in the united states um one good thing is that california has responded well with testing you can see that we have had amongst the highest numbers of tests done of of any state next slide please let's just take a look for a second at ucsf statistics and what we're looking at is the test positive the number of cobia 19 positive tests over time and in the upper panel um we can see that um the increase across the us has been reflected here in san francisco red is icu patients uh on ventilators um yellow not on ventilators and then acute care patients in orange and um as many hospitals have done ucsf um is doing asymptomatic uh screening of patients before they enter the hospital and you can see the differences in case positivity rate based on test type about seven percent for uh symptomatic patients and um less than one percent for asymptomatic patients next slide please um so a number of things have happened in the uh past several months with respect to testing and at this point um 193 um sars covid ii sars coronavirus tests have received emergency use authorization from the fda 158 of these are molecular tests they include rt reverse transcriptase pcr essentially the gold standard isothermal nucleic acid amplification tests like the abbott id now they're much faster turnaround time there are two antigen based tests that have received eua you can see one here it's a sofia 2 antigen test and then there are 33 antibody detection platforms that have received fda authorization next slide please i want to take a moment and just focus in on nucleic acid and antigen tests and comment on their sensitivity so the limit of detection or their ability to detect amounts of coronavirus and genome copies per milliliter varies with pcr being the most sensitive 10 to the two genome copies per ml ranging to a group of tests all lumped together as laminar flow assays these essentially are strip based diagnostics that can detect antigens or nucleic acid using crispr cast technologies these laminar flow assays are really fast they can be done anywhere they don't require a complicated instrument their sensitivity in terms of comparison against the gold standard of pcr is not entirely determined but you can see the breakdown in terms of how things stack up against pcr next slide please so um i want to comment just for a second at home collected sars coronavirus tests so following uh the the breakthrough finding that in fact you don't need clinical training to stick a q-tip up your nose and uh put it in a tube of liquid uh the fda in early may uh authorized uh the first standalone at-home test kit most of these are pcr based and several companies now offer them they come in cute packaging with easy to read instructions that are accessible to a fifth grader you take your sample uh you put it in the package you send it out and then you get a result in a couple days or a week so this has been a significant change in uh the last couple of weeks that now at home testing is more readily available next slide please one key comment that i want to make relates to the timing of testing with respect to sensitivity now uh the true sensitivity of pcr assays is somewhat complicated to measure because if pcr is the gold standard against which other assays is compared one has to ask what is the best gold standard for a pcr assay but that notwithstanding i wanted to show these data from a study at mass general and the key point here is that sensitivity of pcr assays decrease over time and concomitantly you can appreciate that the sensitivity of serologic antibody based assays increases over time as a patient makes antibodies against the coronavirus next slide please so what is the reason why sensitivity of pcr assays decreases over time well it's because viral load decreases over time so this was a study of 129 patients that looked at the temporal dynamics of viral load and infectiousness infectiousness measured by positive culture for coronavirus and what you can appreciate is that most people if not all people in this study still had detectable virus more than four weeks out yet if you take a look at the black dots which represent culture positive cases you can see that after about 14 days or 10 to 14 days that very few people have a positive culture next slide please so while we're on the topic of viral load i think it's important to bring up um the concept of cycle threshold and this relates to pcr base assays so the reverse transcriptase pcr assay used to detect stars coronavirus uh depends on first uh reverse transcribing uh the viral rna to dna and then amplifying uh the amount of that dna using a polymerase chain reaction and the ct value or the cycle threshold refers to the number of pcr cycles needed to reach a detectable signal and that signal is above a given background and the key point is that the higher the viral load in the sample the more coronavirus rna the fewer cycles it actually takes uh to amplify that material to reach the threshold so in this case we're looking at a standard curve the red trace would represent a sample with much higher nucleic acid than let's say the green trace here um so the cycle threshold a good concept uh to understand to help interpret um some additional meaning from cyrus coronavirus pcr tests also potentially could be useful um on your next zoom family reunion if there's awkward silence on you know you can tell your cousin about the cycle threshold and that that might help break the ice next slide please um so why am i bringing up ct value uh well there's a growing amount of data that emphasizes and demonstrates that infectiousness correlates with ct value and viral load this was a study looking at 130 183 patients in france and they looked at the fraction of patients um with who had samples that were culture positive as a function of cycle threshold and what you can appreciate is that the samples that had a ct value of 13 according to very high amounts of virus nearly a hundred percent of those um were culture positive but um really what they saw is that as uh cycle threshold increased as viral load decreased um the fraction of samples that were culture positive dropped off and in fact beyond a ct value of 34 no positive cultures could be obtained from samples so that's an important concept to keep in mind and something to think about next slide please it's important to think about because several studies now conclude that viral load decreases over time and essentially ct value decreases over time and so this is a nice summary of that phenomenon it's a study that came out a couple of weeks ago in nature medicine and it looked at 77 pairs of individuals who were connected by transmission events so one person transmitted uh coronavirus to the second person and they tracked all of the dynamics of this process and what's seen in the figure here is the plot of ct values over time and you can see that after about seven days we're hitting a ct value greater than 35 representing low levels of virus and so one of the important findings uh in the study is that the authors were able to take into account this data they were able to take into account longitudinal data and build a model of infectiousness next slide please and what this model demonstrated is um that peak infectiousness and viral load actually happened before symptom onset this is something that we've observed in many contexts including in some of the cruise ship scenarios early during the pandemic um but a key thing that they observed is that after about seven or eight days the infectiousness of people in this study of transmission pairs essentially dropped off to a very low value and so these findings really raise the question of do we actually need a test sensitive enough to detect extremely low levels of coronavirus uh several days out from symptom onset when someone might not even be infectious next slide please so there's a growing contingency that argues that actually we don't really need tests that are that sensitive and in fact if really what might be most important is being able to detect the people who are infectious and perhaps if we use cheaper less sensitive tests but employ them more frequently um and with faster turnaround that this really might be what's needed to control the pandemic and so what i'm talking about here um are these uh rapid diagnostics these laminar flow assays that could be performed in someone's home or something like the id now or these antigen assays that'll give you an answer in 15 minutes now um we know that the sensitivity is roughly a hundred times less than that of uh pcr but the question is does this actually matter well in this paper the authors argue that no it actually doesn't matter for the purposes of surveillance screening so let's take a look at an example in this diagram and focus in on the green dot and so the green dot represents um a hypothetical patient who's tested six days after exposure and you can appreciate that at this time their viral load is so high that it doesn't matter um whether or not they have a very sensitive diagnostic test because it's going to be picked up one way or the other in fact that concept applies for several days during their disease course and so really what the authors argue here is that if you test frequently enough let's say people at home or prior to going to work got tested every day or every couple of days your chance of actually picking up a positive person during their high viral load infectiousness period would be very high and that would alleviate the need for a more sensitive test next slide please we can take this a step further and ask about the potential impact in terms of turnaround time um and this paper and others argue that in addition to frequency of testing to curb the pandemic turnaround time of testing is really important so let's extend that hypothetical example of the person represented by the green dot getting tested and let's say they have a 48-hour turnaround time for their test represented by the pink square so if we make a plot of um distribution of infectiousness of this person with covid19 during that 48 hours while they're waiting for their test results that 48 hours would be expected to represent 32 percent of their potential infectiousness and so um having to wait uh for the results of the test provides a significant opportunity to transmit to others now if instead the test result returned within 15 minutes then you would reduce 32 percent of the potential ability of that person to infect another individual next slide please so the authors modeled this by looking in the estimated potential reduction in r naught and they plotted both in terms of less sensitive diagnostics the gray bars or the current gold standard pcr diagnostics the pink bars what might be expected to happen in terms of reduction and are not and essentially what you see is that if testing was available daily it actually wouldn't matter whether or not somebody got pcr testing or a less sensitive rapid test because the chances are you would pick someone up during their infectious window you can see how things change if you look at the turnaround time extension to one day or two day you can see that the potential impact of testing gets reduced we can also see that if testing is extended to every three days or weekly there's a substantial drop-off in terms of the ability to reduce infectiousness in the population and if we move out to 14-day turnaround time which actually is something uh that is happening if uh for certain um uh commercial diagnostic companies where a test has to be sent out uh turnaround time is a week to 14 days in some cases that actually that isn't really doing a whole lot to help reduce infectiousness in the population so this is kind of a paradigm changing proposal that has been put forth and is really gaining traction and something to to think about next slide please i think it really raises the question though of when do we need a sensitive test and um well for community surveillance it might not matter that much um i think that really we do need to consider certain settings like for hospitalized patients with symptoms compatible with coven 19 or in high risk settings these are cases where we absolutely want to detect everybody who might be positive but if we're talking about potential impact on a broader scale in terms of reducing infection a less sensitive diagnostic test arguably could be more effective next slide please i wanted to briefly comment on pool testing as a strategy to increase compass capacity so concept here is simple um samples instead of being tested individually are mixed together and tested in a batch and if the batch is positive then you go back and retest each sample that approach is uh useful for surveillance in the context of low prevalence but really is not cost effective if the prevalence is higher than five or ten percent um this uh map of of the u.s is an estimate of the potential to improve testing capacity with pooling not very viable in areas with significant prevalence because you'd spend more time retesting samples than actually testing them individually in the first place i'm going to wrap up quickly here next slide please on a positive note um and i just want to give a brief update on the clia hub and so this is uh the clia lab for covid19 testing that's a partnership between ucsf and the chan zuckerberg biohub initiated on march 2nd during a task force meeting with the first test launched on march 20th and this is a volunteer-powered effort that has really made an impact on april 7th outreach to other bay area departments of public health was initiated and then by mid-april on many counties in california were being tested next slide please now over half of county uh half of california department of public health are sending their samples uh to ucsf and cz biohub um with a rapid turnaround of 24 hours um answers are are returned in time enough to make an impact and in terms of total tests there have been over 90 000 tests that have been done on the single day max over 2600 and testing has been done for san quentin and uh for many other key high-risk settings next slide please and so i'll wrap up there i'm giving a snapshot of updates and diagnostics and and turn things back to bob thank you chad that was that was terrific and i saw you added a little extra degree of difficulty by having the lights go out periodically and impressively you you pulled that off too let me throw a few questions at you i gather that that there now might be some correlation between what we call a false negative uh maybe those people are also not terribly infectious is that a reasonable extrapolation so you know we test people they're negative we know there's some possibility of a false negative but can we say that they're probably also not all that infectious if they come back negative even if though even though it's quote a false negative well i think in certain cases that certainly could be what's happening so if we're talking about a patient who's been in the hospital for several weeks and they're getting positive pcr results let's say their ct value is around 34 35 they may be positive then the next day if you test them they may be negative and then they may be positive again well they're really at that borderline of the limit of detection so in that case they're unlikely to be infectious and what you said is absolutely true you can also envision a scenario where a sample is just not obtained properly and for whatever reason there there isn't a viral nucleic acid on on that sample um in that case you know that would be a false negative but yeah that makes sense um the back to work standards still many of them say you should be in quarantine for 10 days or 14 days with an exposure uh why wouldn't it be that if you had one or two or three negative tests relatively early on after the exposure uh that you wouldn't be sort of clear with the probability that you have infection being close to zero well i think for many people um that scenario would probably work but um what we do our understanding of the actual incubation period you know is still being uh put together and for most people that's going to be five or six days and so by that time point you would expect someone who's been infected to have high viral loads because we're not absolutely sure yet exactly whether that applies to everybody i think being on the safe side that extended quarantine time is is what's recommended but i think we'll probably move to a shorter time frame soon um you sort of emphasize that how the testing is it's not just a yes or no there's a level beneath which you have less infectiousness is the level of uh the amount of virus or the cycle time is that telling us anything about anything about prognosis yeah that's a really good question um so thus far nobody is really identified a strong association between the amount of virus and someone's outcome or prognosis in fact um in surveillance studies people are identified who have incredibly high viral loads in in their nasopharynx uh ct cycles of 10 to the eighth and yet they're asymptomatic um we do know uh that some studies have identified a correlation with age but there doesn't seem to be a correlation with disease severity in fact by the time for people who do develop severe respiratory systems symptoms and ards by the time that happens by the time they require mechanical ventilation often their viral load is very low so it supports the argument that at some point it's the immune system kicking in that's doing most of the damage that it's the host yeah yeah all right uh great well we'll bring you back a little bit later i'm sure i'll have more questions for you but let's move on to the next topic thanks so much uh annie uh luke meyer will talk to us about uh about updates and treatments great thanks so much um so uh i wanna focus on um just some quick updates on what's been happening in treatment looking at both viral directed therapies which i've shown the life cycle here as well as immune based therapies and i think that the good news here is that our options are continuing to expand which i've highlighted in the pictures below starting with iv based therapies like rem death severe but now increasingly we may have options coming down the pike that are subcutaneous inhaled and obviously we would love to have lots of oral therapies particularly those that can be given outside of the hospital so i will talk a little bit about the outpatient uh therapeutic realm at the end next slide i'm going to start by talking about um uh rem death severe which we're i think familiar with uh as the rna dependent polymerase inhibitor was the first agent that was approved um for treatment of covid and we know that it shortens the course of illness for hospitalized patients i think the first update is that we have shortages which is not a surprise i think to anyone we know that hospitals around the country including in hot spots are running low on rem death severe and this includes bay area hospitals i'm not going to get into it today for those who are interested the california department of public health has a nice website which i've included here where you can track down to the hospital what the allocations are and those are based on reporting numbers from each of the hospitals and um each of the uh geographic districts for the uh their covet um prevalence and one of the challenges as we reviewed in an earlier grand rounds is that it's a pretty complicated process to make rem de severe so it's not easy to ramp up production even though there is a great deal of effort to do so so what does this mean then in terms of how we should be thinking about prescribing rem death severe well just a reminder that under the emergency youth officer use authorization which i have in the yellow box that use is recommended for hospitalized covert patients who have an oxygen saturation of 94 or less and need supplemental oxygenation and that's it they don't parse out amongst those individuals uh who should be given treatment or not however based on the limitations in supply the nih covid treatment guidelines um tried to provide some additional guidance this past week about how to think about um allocating rem disability supplies when they are limited and two of the main points that they make is that they suggest that rem deciber be prioritized for use in hospitalized patients who require supplemental oxygen but who are not on high flow oxygen or intubated and they also recommend that everyone gets five days only into or until hospital discharge and uh with the implication here that you would not extend if people aren't doing well which is what the package insert suggests that you can do and that for those who are on high flow or intubated that there's uncertainty as to whether this confers clinical benefit i wanted to talk a little bit more about this uncertainty about whether or not clinical benefit is conferred because i think i take a little bit of a different view on these treatment guidelines and i also just want to recognize that when you're running short of rem death severe it's incredibly stressful and that there's not an easy way to go forward for any of us who are in this position and trying to figure out how best to allocate a limited resource next slide so these data that the nih uh cova guidelines are referencing come from the act 1 study which as you all recall is still in preliminary form it was published in the new england journal but we're awaiting the final data report so just a reminder what the act 1 study was designed to do so it was designed to look at recovery recovery in patients who are followed through day 29 so that's not a tremendous amount of time for individuals to attain a clinical recovery and recovery was defined as being off of oxygen and being able to leave the hospital whether or not someone did indeed leave the hospital so how did people do and how did rem death of your look when you break this down by the base nine ordinal score so remember that those receiving oxygen which was ordinal score five in general showed um the the most robust benefit so clearly remdesavir looked better there in those not receiving oxygen and those in high flow oxygen there was a trend towards benefit but it was not statistically significant but you'll also notice that the numbers really go down there um there was not powered to look at these subgroup analyses and then lastly if you look at those who are receiving mechanical ventilation or ecmo um you could see that there was not a clear benefit between placebo versus rem de severe and this is where the nih guidelines really derive these recommendations to focus on those receiving oxygen as those most likely to receive a benefit and i think it is it is true that there is a clear signal uh that those on oxygen um who are not intubated did have a benefit in terms of the time to recovery but i want to give just a couple of caveats here so first of all these are subgroup analyses and that always gets a little bit tricky as the numbers get small if we look at the high flow oxygen patients first there is clearly a trend towards benefit in these individuals so i would not interpret these data to say that there's no benefit in those on high flow or non-invasive mechanical ventilation it was not statistically significant but clearly it was going in that direction so it certainly is a group in which if you have the rem deserver you'd want to consider giving it to them and it's further compounded by the fact that those on high flow nasal oxygen were concerned about them progressing they may have more severe disease second what about intubated patients this study was not conducted uh in the era of dexmethazone the vast majority of people did not receive um steroids so we have no idea what this would look like with dexmesozone being co-administered and we know that there is a marked benefit of dexmethazone which we'll talk about in a minute the other piece here is that the study really was designed to look at recovery within 29 days and that just really may be insufficient to assess for benefit in those who are critically ill so just as a snapshot from the appendix of this study for those who were intubated at baseline the complete only complete follow-up we have was at day 15 that was reported and at that point in time only 20 percent had recovered and only and 40 percent remained still intubated so uh you need time to get better when you're critically ill and you're intubated um and it just may be that we're not seeing the signal uh that may be there in intubated patients who may benefit particularly if they get dexmethazone on top of this now chas just made the point that later in disease when people are critically ill that the viral loads may come down and so it's unclear what the role of antiviral therapies are there but i think we were all also struck by a recent paper by jonathan lee and his group which showed that um that in critically ill patients in a subset there um many of them were still quite viremic um so i think we just don't know what the role is of rem death severe in icu patients and those are certainly people who are at high risk of complications and death and i think that i would not want these data to be interpreted to say that there is no benefit in the icu because i don't think we can say that from this paper it's not what it was designed to answer given the length of follow-up there okay next slide i want to move on then to talk briefly about dexmethazone sarah dornberg gave a really nice overview of the complicated recovery trial at last grand rounds where this was discussed and in the interim the preliminary report was published in the new england journal of medicine and i think we had some clarity from on this report both about the study design as well as the findings so just a reminder that this was a pragmatic uk study that randomized people to a number of different interventions but this intervention was randomizing to dexmethazone versus standard of care and you could see that there was a clear signal towards benefit in those who were in the icu with the reduction in mortality that was statistically significant so icu patients on dexamethasone had a 29 uh death rate versus a whopping 41 mortality which is really uh uh quite something um hypoxic patients who were outside of the icu had a much more modest benefit there was a 23 mortality rate in those who received dexamethasone versus 26 percent and those who did not receive dexmethazone and this was a statistically significant and there was not a benefit seen in those who were not hypoxic at the time of randomization and indeed there was a trend towards these patients getting worse um which was not statistically significant but does raise some questions about the possible harm for individuals if they don't require oxygen and may not have that inflammatory response so two clarifications and caveats that i would share here so first of all a clarification we know this is a bit of a complicated trial design and initially there were questions about uh additional therapies that people may have received so i think it's become clear that most of these patients did not receive convalescent plasma and very few received remder which was not widely available in the uk at that time in addition there's a second randomization that allows the use of an il-6 antagonist and very few of these patients were randomized to receive further il-6 so i think we really are looking at the effect of dexmethazone here and not these additional therapies what we don't have is additional information in this middle group who are hypoxic patients in whom i said there was a modest benefit now we know when people are on oxygen that can be two liters of oxygen and they can be relatively well versus high flow nasal cannula doing poorly and heading towards the unit and we just don't under have any granularity about what the impact was of dexamethasone spectrum of oxygen needs i think many programs have um like our own have interpreted this to to work out that if people have a high level of oxygen or look like they're otherwise doing um quite unwell those would be individuals in whom we would consider using dexmethazone whereas those who are really on a minimal amount of oxygen or look quite stable there may be less benefit but we really need data to inform us on that front and then lastly it's just important to recognize that because this was a large pragmatic study that was done basically as part of standard of care they had very little reporting particularly on the ad adverse events attributed to steroid use so we'll welcome more information about what the cost is of using dexmethazone in terms of things like infections but clearly you can't argue with the mortality that was seen particularly in the icu patients next slide as a result of these data both the nih and the idsa guidelines were updated and they say slightly different things so the nih treatment guidelines which are on top recommend using dexmethazone in those who are mechanically ventilated and gave that an a1 recommendation and in those who require supplemental oxygen they gave it a b1 recommendation so they do parse out the different level of support here and give the strongest recommendation to those who are in the icu the idsa does not parse this out and they simply say that for those with severe covid they suggest glucocorticoids rather than no glucocorticoids and do not recommend them for those who are not requiring oxygen next slide okay so moving on to interferon beta i don't have time to go through the background data but i will just point you in direction of a nice article and there are many others that are out there that have shown us that um covid may impact the innate immune system's ability to uh generate interferon and we know that interferon is part of the way the human body helps to control antiv uh helps to control viral infections so the fact that type one interferon activity is decreased has made providing interferons um a possible strategy uh to help mitigate uh the negative impact of covet in the body we saw a signal for this in the uh paper that was published in the lancet that looked at interferon beta 1b and this was given mostly in mild uh mild covid patients uh they did not appear to be much impact of the kalitra arm so when you look in detail into that study most of the benefit really did appear to be from individuals who got interferon beta 1b and they received it very early in disease so it was an intriguing signal but not one that appeared very generalizable to most of our hospitalized patients so building on this there was a press release this week from a company uh from the uk that looked at inhaled interferon beta this was a phase two study of about a hundred patients that gave 14 days of inhaled interferon beta versus placebo and they found a 79 reduction in the progression to intubation or death and found that these individuals were twice as likely to recover and you can see one of the individuals who gave their permission to the bbc to show them using this product i think this is intriguing and certainly an interesting area to pursue i think all of us in the hospital setting are worried about using inhaled agents and want to really be sure that this would not be an aerosolized generating procedure but nonetheless it is a very targeted way to provide therapy and certainly merits more exploration the next steps for this are a home trial of inhaled interferon beta to my knowledge this is only being conducted in the uk but i think we will all be very eager to see how this works you could imagine sending someone home at the time of diagnosis with an inhaler and then um i think as an additional important piece the act three study uh which is an nih randomized control trial uh that gives everyone rem death severe will now be giving subcutaneous interferon beta 1a for seven days to further explore whether providing interferon can really make a difference here so more data to come on interferon and we look forward to having that next slide il-6 antagonists i will keep this brief there are many observational and non-randomized studies of il-6 antagonists that show a variety of different uh results including some with a positive signal if we focus only though on studies that are randomized controlled studies the data have been much less rosy including a report yesterday of tocilizumab in a phase 3 rct of hospitalized patients it did not meet its primary endpoint no difference in clinical status ventilator-free day free days or death by week four there was one study that was leaked early that was showed intriguing results but still has not been published and that's over now two months ago since that was leaked um so i think many of us are beginning to be skeptical about where that study stands but certainly look forward to seeing it another il-6 antagonist has had a similar uh lack of promise in the randomized controlled trials this is cerulemab we know there was a negative phase two randomized control trial in severe and critically ill patients they tried increasing the dose and focusing only on critically ill patients but we heard earlier this month that there was the phase 3 randomized control trial with this increased dose and focusing only on mechanically ventilated patients also showed no difference in clinical status neither of the two guidelines recommends using il-6 antagonists outside of a clinical trial and i would say that given these data i think we really need to see a strong signal to move in the direction of supporting use for these agents next slide oh hydroxychloroquine um so this uh i thought this would be a grand rounds where i didn't have to talk about hydroxychloroquine and it's been quite a week um what i'm going to do is just focus on what we do know about hydroxychloroquine again focusing on randomized controlled trials which i think we all would agree are the gold standard data and this is by no means um fully comprehensive but i would stress that we have good data right now from randomized controlled trials um that by and large suggest that there has not been efficacy of hydroxychloroquine so we have four uh uh hospitalized trials that i summarize here which showed no difference in mortality uh two of them were stopped early due to lack of lack of benefit and there was no difference in the conversion to negative coveted pcr some of these studies did show a concerning safety signal as well in the outpatient setting we have at least two good randomized controls uh trials which did not show a difference in symptom severity or clinical status and we have at least two post-exposure prophylaxis studies that did not show a difference in the incidence of new illness nor pcr-positive covet infection using slightly different endpoints so i i think that we have to look at the data that we have these are well done studies and again the totality of these are are very clear that we do not see a strong signal that hydroxychloroquine helps and there's some data to suggest that certainly in some patients hydroxychloroquine can hurt next slide okay so i'm going to end by talking about outpatient treatment which really i think is the next frontier studies to date have been largely focused on hospitalized patients and i think there's going to be a real push to understanding what we can do to provide therapies for outpatients so that we can have them feel better sooner and reduce transmission to others and i just wanted to highlight four areas of interest recognizing that this is really a burgeoning field so one rem destivir which we talked about earlier unfortunately right now is only given as an iv medicine to hospitalized patients there's some discussion of giving it to outpatients who come into an infusion center but obviously it'd be a lot easier if we could give an inhaled formulation and studies are underway evaluating this with all the concerns i mentioned before about aerosolized generating procedures that we have to be careful about fava purivir is another oral rna polymer it's an uh rna polymerase inhibitor but it's oral it has a similar mechanism of action as rem death severe and it requires um intracellular phosphorylation one study was released again only as a press release it was a phase three rct of favipiravir versus standard therapy there was a trend towards um a faster time to negative pcr chas has told us that maybe that doesn't matter we don't know and there was a faster time to symptom resolution that was modest nonetheless um if we could have uh even a modest impact of a safe oral antiviral it would be very exciting to have this so i think we stay tuned for more information related to that another very promising agent is the eidd 2801 drug it's also an oral rna polymerase inhibitor with a slightly different mechanism of action it's a mutagen and it's a cytosine uh analog and this is exciting because it's possible that it could have an additive role with rim death severe given that it has a slightly different mechanism mechanism of action we need more data to help us understand if that really will be true and this is going to be explored in both inpatient and outpatient studies opening very soon and lastly there's been the launch of a large nih-funded adaptive pla platform trial that's exclusively looking at outpatient therapies this is called active two and it's being led by the actg and it should be opening we hope in the next week or so the first compound to be investigated as a lily monoclonal antibody but we believe that several oral agents will be included in short order and we will very much look forward to seeing what the treatment options are in the outpatient world which thus far we really have uh nothing good to offer our patients but we do very much need this um so that people can feel better and we can reduce transmission i will uh stop there and just want to thank you uh for your time and for including me in this grand round series thank you annie that was uh great you covered an amazing amount of material in a short time and i'm going to ask you to cover one more thing convalescent plasma which i understand here at ucsf health we are relatively routinely using uh although it doesn't seem like it's in the same evidence category as remnant severe and dexamethasone so where is that right now yeah so um we are running a study um san francisco general and at ucsf looking at patients who are hospitalized and hypoxic but not in the icu in a randomized controlled trial format because we want more robust data to really understand this a lot of convalescent plasma has been given around the united states as a matter of fact you can track it on the u.s covid website i looked this morning and over 50 000 patients have received convalescent plasma i think the challenge is is while we see early signals that this looks good we don't have randomized controlled data to really inform us about who benefits most we're giving it through compassionate use for more critically ill patients but many of the ucsf campuses but i think having randomized controlled trial data is going to be very important and there was a pre-print that came out just this morning that is a meta-analysis of many of the studies that are available and it did look like there was a mortality benefit but again this is some of them were randomized controlled and very small and some of these are just observational data or case controlled so i think the bottom line is stay tuned for more information but it certainly looks very promising if you had a patient who is a or a parent who is a 70 year old person at reasonably high risk of bad things who was diagnosed as having coveted and is still an outpatient maybe a little cough a little short of breath would you tell them to do anything other than take tylenol and stay hydrated well i think the challenge is that there's there's nothing that's approved for them to take right now um i would encourage them to be part of a study because i think that's one of the best ways that we can get um uh uh access to the agents that i just talked about maybe that's the uh downside of having a daughter who does clinical trials it says you call up and ask for advice and that's what your daughter tells you that's terrible news um but that really is the best advice that that that we have right now a lot of discussion about things like zinc and vitamins um but i don't think we have anything that's approved um and uh i think we really need something um but i think they need to have close monitoring and be careful we all know about people who can be more hypoxic than they are aware of it's certainly not the case in all patients but i think we all have seen some of those happy hypoxics so worth being aware of of that fact and uh we have a question maybe last one uh any adverse effects from steroids in terms of longer-term follow-up and the question of whether patients had pneumonia or secondary infections that of course were major cause of death in the flu pandemic and you know in 1918 yeah so we don't have that from the recovery study um and i don't know that we're gonna get it because it was um you know very pragmatic they got the information that they have we barely have we don't have any adverse event data during that time an interesting paper though did come out um reporting on uh the uh long-term sequelae of people who got steroids during the sars epidemic so sort of looking at the same question and and what they found is that there was a very small increased risk of a avascular necrosis which makes sense in general these are short courses of therapy and i think what we worry more about is again as you point out um short term complications with things like bacterial pneumonia or or viral infections getting reactivated but we don't have that from recovery i hope we will get it soon luckily we haven't seen a large number of bacterial pneumonias as a complication of the natural history of covid in the way that we do with influenza but one worries if you give steroids that that might change so i think we certainly need that data great uh okay thank you annie let's uh we'll bring you back a little bit later for uh for questions and discussion uh joel let's bring joel on so annie has given us some therapies that we know work but uh don't are not game changers yet so we're counting on you to tell us that there's going to be an effective vaccine that will bail us out so you're on okay thanks um so i'll talk about vaccine progress and challenges and the good news is there is progress and yet there are new challenges that we're confronting that are arising just now next slide please so first i just wanted to give a status rep in terms of covet 19 vaccines that are in human clinical trials and three of them actually have results reported from phase one and phase two studies the moderna the oxford astrazeneca and the third one the cancino vaccine all three of these have reported um that they have adverse effects that are tolerable and in all three cases there are measurable neutralizing bodies generated and since there's a reasonably widely held belief that neutralizing antibodies can provide protection and i'll show some evidence of that this seems to be good news with respect to having an armamentarium of vaccines available that may be safe enough for broad use and that may well generate protection now we don't have human data unprotected for any of these yet i'll just point out that there are really two and a third two major and a third format here we've talked before about the rna-based um vaccines the badarna in particular pfizer and bioentec have a variant of an rna based vaccine and there are some others that are earlier in development that show um interesting differences there are three there in the middle um pansy adenovirus from oxford and the the so-called oxford vaccine the adenovirus 5 from cancino and adenovirus 26 from harvard bi deaconess um just want to mention that adenovirus 5 which is a very well studied vaccine vector um in in a variety of contexts has a disadvantage in that this is a common pathogen in humans and it is very common for humans to have pre-formed antibodies to that adenovirus and so it's a bit questionable how important or how relevant pre-formed antibodies are but there is concern that they will eliminate the viral vector the vaccine vector early and there might be a less robust response as a consequence adeno 26 and the chimpanzee adenovirus basically are specifically chosen to get around that problem and i'll just mention that the the novavax vaccine there at the bottom is different in that it's a recombinant protein plus adjuvant vaccine now that's a very well studied format in other contexts and so there's every reason to think that we can predict what the results of that might look like but it's only recruiting phase one and phase two studies right now next slide please the question has come up about the role of t cells in providing protection and all three of the phase one two studies that have been published so far have reported on t cell responses the nature of the data shown is pretty simple in other words i think that we can conclude that the moderna vaccine generates cd4 t cells that have cytokines characteristic of so-called th1 responses it looks though from the original the initial studies as though there's very much of a cytolytic t cell response the way that each of these was done was to take peripheral blood cells from people who were vaccinated stimulate them with vaccine antigens and then measure a t cell response usually by cytokine protein so the moderna vaccine looks like it's got a a cd4 t cell response only a very small cd8 response the chadox or oxford vaccine and the cancino were acid in such a way that you can't differentiate cd4 and cd8 t cell responses but the good news is that each of these does seem to generate a t-cell response and the nature of that t-cell response needs to be studied more i wouldn't even attempt to try to compare across the board whether one of these is more robust than another because the assay conditions are very very different i think the main bottom line is yes there's a t cell response generated by these vaccines more data needed next slide please now this question has arisen are neutralizing antibodies generated and useful in culture dishes but do they actually provide protection the best evidence comes from experiments so far in mice and really the the the experiment that has to be done is the passive transfer of neutralizing antibodies alone to determine whether that improves the course of infection and there are two published studies so far using models of covid19 in which transfer of neutralizing antibodies was efficacious with respect to reducing the viral load the panel on the right there was published yesterday and this was for from a mouse vaccination study that showed that transfer of serum from mice vaccinated with a vaccine that contains the receptor binding domain of the viral spike protein protected by reducing the viral load transfer of t cells from those same vaccinated mice had no effect so this is an animal model system we don't know how it will translate to humans but at least the results are indicative that yes viral neutralizing antibodies actually are a mechanism of protection not just a phenomenon next slide please so this is just i'm going to describe this just briefly because this is also a recent report that shows that human sars kobe 2 infection induces functional antibody responses and what this figure shows is four columns and the columns differ in the kind of assay that was used to detect the antibodies the column on the right that shows all those numbers lists individual monoclonal antibodies that were isolated from individuals recovering from sars cov2 and what you see in the stripe that's furthest to the right that shows the most purple is antibodies that bind the receptor binding domain of sars kobe 2. the next one to the left is another construct of the spike protein and a few fewer of those antibodies bind that a smaller fraction yet block binding of the viral spike protein to the ace2 host protein receptor and a smaller fraction than that the leftmost column actually show neutralizing antibody activity so in a human that's infected or vaccinated there will be a mixture of antibodies and in this case they basically separated out individual clones and characterized their um functional capabilities and it shows that that at least some fraction of antibodies that are generated in response to infection actually have neutralizing activity next slide please now the question has arisen and some concerns have been risen from at least two publications one that was published a few weeks ago another more recently in a letter to the new england journal of medicine revealing evidence that immunity to sars kobe 2 after infection is transient and may be short-lived and so the panel on the left there shows really two time points since the recover since the onset of symptoms showing viral titers for binding the receptor binding domain of sars kobe 2 spike bracket protein and what you see there is that most of the curves go down this is a log scale so it's quantitatively a fairly substantial decrease now i wouldn't over interpret the results because this is really kind of back to immunology 101 and that's shown in the panel on the right it is absolutely normal after antigen exposure whether by infection or by vaccination for there to be an increase in antibody titers in the blood followed by a decrease and in many cases a decrease to fairly low levels yet what we have are memory b cells that can be recalled on re-exposure and what you see on the right word panel there is that the secondary immune response is even more robust the rate of waning of the antibody titers is a little bit slower but the main point is that what we're looking at right now at such early stage of study with waning antibody titers i think is not something that we should get excited about and i wouldn't absolutely would not use this data as a source of pessimism with respect to the value of vaccines most vaccines are aimed to generate a better antibody response or a better immune response than naturally infect natural infection alone so we need more data but i wouldn't be so pessimistic as some people have have been about these data next slide please so just a quick word about correlates of protection and and the reason to be interested in this is because these will be very very important in vaccine development so a correlated protection is an immune response that statistically correlates with protection from infection or disease and this could be antibody responses it could be antibodies just distinct antigens it could be antibody levels what's shown on the right side is a really good example of this and that's with influenza and and after influenza vaccination and then exposure to the hamal strain in the community and for influenza a an antibody titer of one to forty is successful at blocking infection in about 50 percent of individuals and what you see there is that the higher the concentration or the higher the tighter of antibody the greater the protection and in this case neutralizing antibodies are a coral at a protection and so by measuring these we may be able to compare the responses generated by distinct vaccines and in addition with the few caveats we may also then be able to extrapolate populations that are excluded from initial studies in other words if high-risk patients are excluded from the initial studies and we have a correlated protection from the initial studies and then you generate a rather vaccinate a a group of highest people let's say older adults and they generate similar responses that correlate with protection i think that that's at least some comfort that we're on the right track with a given vaccine next please next slide um so just a word then or a few words about testing vaccine efficacy we've talked about this a bit before the standard approach is a randomized trial in a community of people at risk and some people are randomized to control some people are randomized to the um vaccine itself and the rate of either infection or disease is compared to the two groups the first point here is that moderna and astrazeneca are both receiving a billion dollar each to support their cova 19 vaccine development and most of that one billion dollars is actually going to randomize trials because randomized trials are extremely expensive but the other thing that i didn't point out on that first summary slide but that i'll make the point here you might have noticed that the final results from the moderna study um are expected in october 22. the first three or the final results from the astrazeneca study in august 2021. now it's possible that there will be preliminary results earlier but the main point here is this may take a very long time before we know that we have efficacious vaccines and so i'll take a few minutes to just talk about an alternative and that is the alternative of controlled human infections or so-called human challenges these can have the benefit of smaller sample sizes all of the participants are exposed and exposed equally they can be much less costly they can be much more rapid but the drawback and i'll go into some detail about this is there is no precedent for doing human challenges or controlled human infection for infections that lack a reliable treatment in other words these are done for things like malaria where a human challenge can be done and as soon as somebody develops a fever after exposure to malaria-infected mosquitoes they get treated and the the challenge strain is drug susceptible so without reliable treatment there's a lot of hesitation about advancing into covid19 vaccine trials using controlled human infections next slide this is the source though of much thinking and discussion uh among several groups and i've just distilled down a lot of information here and listed some pros as i men controlled human infection can use a smaller sample size it can be less expensive complaint when compared with population trials the knowledge generation is much more rapid once the trials are initiated you can learn things from controlled human infections you can't learn from a community study because you can identify the precise timing and you can identify potentially identify predictive determinants of protective responses and finally controlled human trials if they're designed and set up may mitigate the risk if population trials take longer than expected for example if a population is vaccinated in a randomized controlled trial and then that population's frequency of covid19 decreases then there will be much less opportunity to determine the efficacy of that vaccine now the points against controlled human trials that there is there are disagreements about the upper limit of risk that is tolerable when there's reliable treatment as i've referred to there's also a risk to third parties in other words not only are the subjects in the trial exposed to infection but they can potentially transmit the infection including to the health care workers that are involved in the trial including potentially the family members and people in the community so this would largely require that people be sequestered and isolated during uh the period time after their experimental infection it's possible that the generalizability of the results could be limited because you would select people for human controlled human infections that are healthy and at low risk now it's possible that you could still generate knowledge particularly on correlates of of protection that could be generalizable but there is concern and this weighs in the decisions about the uh benefit ratio and i just summarized you there's still considerable planning and preparation still needed and i'll go into that in the next slide there are i think some pragmatic considerations you need appropriate facilities in other words you really need a bio safety level three biocontainment facility in order to essentially do experimental infections with a pathogen like this and so you need to minimize the risks to the participants but also to the staff and the surround communities in addition the point's been made that controlled human trials actually are resource intensive because you need a lot of ppe for example for all of the staff conducting the trial and in a local area where resources might be somewhat limited you don't want to compete for those limited resources likewise if you're challenging people and they're going to get sick and require hospitalization that can be a problem if there's a high prevalence of infection and disease at the time the next is the viral challenge stock ideally with attenuating mutations still needs to be produced generated assured to be stable and appropriate and safe for for this use um but the suggestion i think at right this point is that controlled human infection studies should and can land in parallel with clinical trials the who has commissioned a large committee of experts to discuss different features of this um and has put out a preliminary publication for public comment i've put the link there on the bottom of the slide next slide uh please so very quickly um there are also also ethical considerations for vaccine implementation in other words we're absolutely certain to have a limited number of vaccine doses particularly early so the question is what population what group gets prioritized to go first or second or beyond now there's a very safe statement from edc's advisory committee on immunization practices highest risk medical national security and other essential workers should be prioritized that's a pretty safe general statement but the devil's in the details um and i've listed some other considerations here there are others at disproportionate risk people with underlying medical conditions communities of color older adults residents of long-term care facilities the people who clean the hospital the complete people that serve food to hospital workers um teachers the national academies have commissioned a group to um consider all of these possibilities and pro work is sufficiently preliminary that there's not even a document generated but you can watch the proceedings of their meeting on youtube with the link shown there so the next slide is just a quick concern the recent case of estimated that only 50 percent of the u.s public um is willing to consider receiving or stated the other way 50 percent are considering declining over 19 vaccine there are some predictions that earliest vaccines might have only fifty percent efficacy so if only fifty percent of people are willing to take it that takes us down to a community protected uh only twenty five percent of the community that is protected so we need to assure that the vaccines are safe and i think parallel with all of these efforts we really need new approaches to um public outreach and explaining to people the benefits versus the risks of vaccines so that's what i have for today thank you great thank you joel um let me just bring on uh annie and jazz as well but i have a few questions for you to start with and we'll go over maybe to 125 if that's okay it's just too much information and uh it's two two wonderful opportunity to have three of you uh to discuss this to let it go uh and thank you all for such incredibly up-to-date talks there was a whole lot of information that was published yesterday or today in all of your talks uh so joel um about two and a half months ago or you told you told us that we would connect we were gonna have a vaccine on july 14 2021 uh i have not forgotten and uh i guess i was flabbergasted by those timelines for the vaccines that they think they may got not get done until the end of the summer or even a year after are those like wildly conservative estimates then if the vaccines really work we'll break the code and know much earlier yeah but they work first to correct the record i said july 1st 14th but i wouldn't state what year um i think i pushed so i think you know those are the end dates endpoints that are that are listed on clinicaltrials.gov and there is absolutely no doubt that there will be interim analyses so if something is really got a signal and is really you know the vaccinated group is doing much better then the results will be available much much much sooner is it real people talk about that you know we may know whether a vaccine works by the end of this year or early 21 is that a realistic number i hate to be too pessimistic i think that's pretty unrealistic they're just enrolling right now the moderna just started enrolling i think last week the oxford study is enrolling this week i mean so enrolling 30 000 people i mean they're gonna be a lot of sites but it's gonna take time okay um somebody asked if er if we did the challenge studies assume we would do them in relatively healthy young people does that give you a potential fake out in terms of whether the vaccine works in a 75 year old in a nursing home i think we can we know a lot about vaccine immunology and i think we know a lot about how to compare responses in different groups in other words let's just simplify it and say if one or more of the vaccines generates a neutralizing antibody response of greater at a tighter or greater than 1 to 40 and that seems to be protective and you vaccinate 75 year old people with diabetes and hypertension and they generate vaccine responses to a similar extent now it may be that they are less protected but i don't think you've learned nothing about what a 75 year old would do but i think it takes very careful analysis of immune responses so that you can potentially extrapolate to protect to a new group okay one um one bit of reassuring information has been the absence of well-documented re-infections there was a report this week and there seems these are these reports pop-up periodically that here's a case somebody who had coveted got better was all good and now is reinfected sort of what is your take on what we know about reinfection i might ask chas that as well uh from the testing standpoint what do you say um i'll let joe's comment on the testing aspect of it i think that first of all those seem to be uncommon um and second i think they could be better documented and i'll just punt the rest to jazz all right chess yeah i don't think at this point that we have clear evidence that the suspected re-infection cases are not simply people who were previously infected and have persistent detectable virus in their respiratory tract you know what we really need to do is do genome sequencing of the virus from these cases to figure out if they have a new infection or or the same one they had before but that's a hard thing to do you need to capture longitudinal samples so i don't think we completely know but it's looking like it's probably unlikely uh or at least very uncommon to have it's got to be i mean you think it'd be incredibly rare or we would hear about a lot of such cases so the point you're making is if i have coveted in march in new york and in may i have a viral infection and of course i think i have coveted again and i get tested positive there's a decent chance that's just my march infection still lingering it certainly could be possible you know especially if you had a very high ct value um it may just be the persistent viral shedding and it may not even have to be viral shedding viral rna shedding might be enough so i think you know that's another element of the documentation that i haven't seen yet yeah any um in terms of as we move toward oral therapies uh given the you know tremendous differences in risk in a 25 year old versus a 70 year old when they get this infection do you envision a world where the therapy is approved or prudent in a certain patient who's at a high risk group but in another position maybe you would say therapy is higher than the benefit and we won't give it to you i think it depends on what the type of therapy is in terms of the risks that we think of and we could use flu as sort of a paradigm there in that you know we we do have stronger recommendations for treating people with tamiflu if they're at higher risk but it's generally not a risky therapy so no one has an issue with giving it to everyone but you just may not get that much of a benefit if you're 25 maybe it shortens your course by a day um it might get a little trickier if you're giving iv you know infusions of monoclonal antibodies and that's difficult you have to bring people in and what what are the risks benefits um i think that we may really want to prioritize if it's a limited therapy like that also convalescent plasma is being explored for you know outpatients or people who are in the emergency room where it's just not feasible to bring in you know if we're having 60 000 cases a day in the united states conservatively you know that's just not going to happen um but but to really target the people who are at high risk for a bad outcome and are high risk for transmitting to to others but in a perfect world if we can get something oral that's an antiviral in general we have a very good track record of safe oral antivirals for a whole variety of other diseases the real kicker there i think is going to be getting it to people quickly enough i think we've really done a bad job with that with the flu we don't people we just don't get the medicines to them quickly enough we don't diagnose them um and so for much of this disease this chaz is beautifully shown when people are infectious um if we want treating them orally as outpatients have any impact on you know reduced forward transmission we have to get a hold of people very very quickly and it would stand to reason that the sooner we treated them would also make them feel better sooner from a personal gain point of view as well so to really you know mitigate this we we got to get these treatments to people quickly and that has to be directly tied to quick diagnosis for them uh i hate to do this too but one more hydroxychloroquine question first of all i assume this would be dead and gone had it not been uh politicized that the the evidence seems quite strong that you showed but there was one study that came out out of detroit yeah as an observational study and that's of course the one being touted as why you know we that all the experts don't have it right that hydroxycore couldn't really work can you say a word about that study uh and so it's it is as you said it was an observational retrospective study and there's a role for studies like that but i think we have randomized control trials as our gold standard for a reason it's not just in hydroxychloroquine i brought up with the il-6 antagonists there are many other agents that we've looked at where retrospective observational even case-controlled studies wow it really looks like it's good but we all know as providers that that we are imperfect and we get in the way here right we didn't give it to someone because we thought they didn't need it or we thought they were too sick to get this medicine we get in our own way there and there's a reason why studies are double-blinded because to take the provider out of the picture and to take the participant out of the picture um and so i think that all types of data are valuable but the preponderance of the randomized controlled trial data including in the inpatient outpatient and prophylactic settings are really telling us that there has not been a signal for efficacy i'm not really sure why that detroit study specifically was being so highly tatted there are other studies that are also observational and retrospective that have shown a signal and and then what you do is you follow up and do a randomized controlled trial and the conclusions from that study i would just want to point out our prospective trials are needed to confirm these findings so those investigators were in agreement that you need randomized control trial data great thank you uh chaz uh what happened to saliva well i know what happened to sly but we all have it but uh you know a couple of months ago everybody said we're just going to be spitting into a cup and we're not going to be sticking tubes up people's noses and yet we're still sticking a lot of swabs up people's noses so what happened to it well um i think more and more people are spitting to get their covet test um but um and and while it is increasing in terms of um how frequent saliva is being used uh as a diagnostic test you know it really hasn't gained widespread traction um you know i can say that uh using saliva uh to do uh screening on on their campus in part studies you know by and large show that it has comparable sensitivity to nasopharyngeal samples although you know you can find a study that shows it's less sensitive or more sensitive um i think part of the issue has been that we have more swabs available so there's no longer this significant concern of swab shortage that was there early during the pandemic and i and i think maybe some reluctance to revalidate tests uh to uh perform using a different type of sample so some inertia but saliva is still viable got it um does does testing tell us the level of positivity tell us anything about who's a super spreader and why um it's a good question we don't know that yet um i think you know there is suspicion that people who might have very high viral loads um in their upper respiratory tract would be more likely to transmit to others as far as i know there aren't compelling evidence yet to demonstrate that but um i i would say just extrapolating if you have you know 10 to the 12th copies of virus per ml in in your nasopharynx versus 10 to the third the chances are that you pass on a virus to another person are going to be higher so i think we'll probably have that answer in the upcoming months okay you didn't talk much about antibody testing it was really hot a couple of months ago who should have one now well you know antibody testing certainly um has it has a place and a role um it's not super useful for diagnosing acute infection um as as the sensitivity curve i showed demonstrated that it takes time for antibodies to to turn positive it's useful for doing serial prevalence studies to get an estimate of what fraction of the population has been exposed that's probably its main role and i think in select cases where somebody has had symptoms for um a significant amount of time their pcr test is negative and you still have strong suspicion and it could have important uh public health or infection control implications uh doing an antibody test might be able to provide an answer got it joel we're getting to the last question too um multiple different vaccines different mechanisms is is if three or four of them turn out to be useful is that just valuable in terms of the getting them out and getting them distributed and of course there may be some cross-country issues or is there a possibility that one kind of vaccine is going to be better for one kind of patient versus another that is a precedent for that for example with polio or is it just just it's better to have more choices i think it's a mixture of both of those um there are i think additional advantages so for example with the adenovirus vectored vaccines there's some reluctance to giving more than one dose because of the immune response to the vector you know the viral vector itself so one possibility is a so-called prime boost strategy where you would start with an antiviral vector based vaccine and maybe boost with an rna vaccine um and get you know sort of a multiplicative effect as a consequence i think the biggest soonest advantage is getting lots of doses out and available for for use it may very well be that we'll learn as you mentioned that one vaccine's better in this risk group or in that ethnic group um too early to tell about any of that yet okay last question for all of you this i did this to joel before i probably did to annie too uh date at let's assume game changing is a some combination of a fairly effective vaccine and fairly effective medicines that if i happen to get coveted i very unlikely to die that would be what takes us back to normal and we can go to baseball games in the theater again and get rid of our mass so when will that be and what will be the mechanism by which we reach that joel why don't you go first you have to give a date and a year who's going first i asked joel all right joel you did yeah um i'm sticking with july 15th and this time i'll tell you it is 2021. and you think it's going to be through a vaccine mostly i think it's gonna i i you know earlier i thought that that drug development was gonna outpace vaccine development now i think i've changed my mind i think vaccines are gonna be the first thing that i think so okay uh we'll go chas next you know i'll stick with the um a year from now i why not um and you know since i'm doing the testing section um it's going to be people having access to rapid at-home tests or tests uh available daily in the workplace uh or in the school and um that'll play a key role in helping to identify infected people before they pass uh coronavirus on to someone else interesting so you actually can see a world where it's the testing rapid testing i brush my teeth in the morning and i test myself and if i'm positive i stay home and so transmission goes out sufficiently that it's not based on a vaccine or treatments well i think it's going to require a multi-factorial approach like most things in life but i think testing you know really could play a key role in reducing transmission and you know really it's going to require a centralized effort from above instead of piecemeal efforts uh throughout our country but um that certainly isn't beyond the possibility where people have broad access to testing and it's done regularly great any last word i i have kids so i think in terms of school years so i'm going to say the end of the school year next year so june 2021 but i agree with chas i i ironically as the person doing therapeutics i don't think we're going to treat our way out of this and i don't think the vaccine timeline is going to get us there in time i want a vaccine it'll be terrific but let's not underestimate i think lots of testing and masks and changes in behavior around masks could really go an enormously long way i mean there are models saying if everybody wore a mask starting right now we could be done in three weeks i think that might be a little bit rosy but it does make the point that you know we we can stop this with i think even just behavior um i think we need those other things but behavior plus testing would go a long way great well thank you all incredibly instructive and up-to-date and uh and and interesting it's a little sad but real that the optimistic uh projections are a year from now that we may get there but that sounds sounds right uh thank you all really very helpful again this will be up on youtube tonight at about 7 30 or so let me thank our spectacular production team you see them listed there for putting these uh these things together which are not not easy and and having it come off flawlessly so thank you folks uh and uh look forward to seeing you all back again next week we will cover another topic in uh the coveted world we'll keep doing that until until we've gotten to that game changer thanks very much have a great week and stay safe

Channel: UCSF School of Medicine

Views: 119,779

Rating: 4.7442179 out of 5

Keywords: ucsf med school, ucsf medical school, university of california san francisco, med ed, ucsf medical student, uc san francisco school of medicine, doctors, physicians, ucsf, medical education channel

Id: kNADw5io9Ms

Length: 89min 31sec (5371 seconds)

Published: Thu Jul 30 2020

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In this UCSF Medical Grand Rounds (July 30, 2020), we get updates on three key issues in the Covid-19 pandemic. Chaz Langelier reviews testing, including test shortages, false positives and negatives, and the meaning of persistent PCR positivity.

Annie Luetkemeyer offers an update on treatments, including remdesivir, dexamethasone, convalescent plasma and antibodies, interferon, hydroxychloroquine, and the prospects for oral therapies.

Finally, Joel Ernst reviews the latest information about vaccines, including trials of the Moderna and Oxford vaccines, our growing understanding of Covid-19 immunity, the ethics of challenge trials, and determination of priority groups once a vaccine is approved. The session is hosted by UCSF Department of Medicine chair Bob Wachter.