Mayo Clinic experts discuss the latest information on the SARS-CoV-2 variants, including how they evolve and evade the immune system, as well as the implications for both the health of affected individuals and the state of the pandemic.
Zelalem Temesgen, M.D., consultant, Division of Infectious Diseases; professor of medicine Featured expert:
Gregory A. Poland, M.D., emeritus consultant, Division of General Internal Medicine; Mary Lowell Leary Emeritus Professor of Medicine; director, Mayo Vaccine Research Group Featured expert:
Abinash Virk, M.D., consultant, Division of Infectious Diseases; professor of medicine
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The views and perspectives shared in these resources are presented based on information available at the time of recording.
Welcome everyone. Thank you for joining. I'm Teresa malin. I'm a program manager and on behalf of the Mayo clinic School of continuous professional development. I'd like to welcome you to the Mayo Clinic Covid 19 webinar series. Today's webinar is on stars Kobe two variants. This webinar is accredited by the MA. For one credit. You're the relevant financial disclosures before we get started. Like to cover a few points. The first isn't how you can claim credit. If you'd like to claim credit after the webinar, please visit ce dot mail dot e d u slash covid 0818. You'll need to log into the site. If it's your first time visiting, you may need to create an account after you've done this and logged in. You'll see an access code box showing here in the middle of the screen. You want to type in today's code which is case sensitive. So in all caps you'll type Covid C O V i D 0818. This will allow you to access the course, complete a short evaluation and then you'll have the ability to download and save your certificate this link and the code will be dropped into the chat box throughout today's webinar. The second item is how will facilitate questions as you say on the bottom of your screen there's a chat and a Q and a function. If you have any questions during the webinar for today's panel. It's important that you place them in the Q and a box rather than in the chat box. This will ensure that the panel can see your question. If you're experiencing any technical issues during the webinar please use the chat feature so a support team can assist you Upon completion of today's webinar learners should be able to discuss the latest information on stars Kobe two variants and discuss how the variants evolve and evade the immune system. I'd like to introduce today's panel moderator. Dr to Meskin. He's a consultant for the division of infectious diseases. A professor professor of medicine, he's also the director of the Mayo Clinic center of tuberculosis and director of the HIV program. And with that I'd like to turn things over to doctor to Meskin. Thank you Teresa greetings to all from the Mayo clinic for a brief period and not too long ago we were beginning to think that the end of the covid pandemic was palpably insight. Unfortunately this stand out to be not the case. We are in the midst of yet another search with increasing numbers of cases, hospitalizations and deaths. This in the United States as well as globally much of this current surges blamed on what is known as the delta variant of the SARS-COv-2, the virus that causes covid 19. What are variants in particular? What is the delta variant? What are their implications for the health of individuals as well as the state of the pandemic. How can we combat these new variants and end the pandemic. To discuss these issues and more I have with me to colleagues from the Mayo clinic dr Gregory Poland and dr Avinash work, Dr Poland is the mary Lowell, leary America's professor of medicine, director of the Mayor vaccine research group, Distinguished investigator of the Mayo clinic and editor and chief of the general vaccine. Dr Avinash Berg is consultant in the division of infectious diseases, is professor of medicine. She is a member of the COVID-19 vaccine allocation and distribution group and chairs the Mayo Clinic Enterprise Antimicrobial stewardship. We will begin with a brief presentation from both of our guest speakers and we will then transition to responding to questions and two questions from from you the audience. I will start with dr burke Avinash greetings everyone. I'm honored to be here to discuss covid vaccine, Covid 19 variants globally. Um and thank you for that introduction. Doctor Damascus next slide. Mhm. So as we uh you know are moving into the next phase of covid 19 epidemic and pandemic. You can see this is the most recent data from uh W. H. O. In terms of the number of cases and obviously we can't keep up with this on a on these numbers because they change on a daily basis. So the numbers you see in front of you are really from August 9, 2021 with more than 204 million people who have had COVID-19 as far as we know uh and more than 4.3 million people who have died. And as doctor to Meskin mentioned, there has been an increase in the number of cases primarily related to the delta variants. And I will go into more details about this next slide. So, you know, how do we define variants? You know? So the question uh we all hear about variants every day. And so the question is, how are these defined? These are really defined based on the mutations uh compared to the original state as train and then they are named according to a specific uh methodology and I will go over that shortly. However, there are many variants but some are actually make a major difference in terms of transmissibility, severity of disease detect ability and based on all of these factors. These variants are either named as variants of interest or variants under investigation variants of concern or variants of high consequence. Next slide So, I just want to talk a little bit about the path of physiology of SARS COV two because I think this is really important to understand when we understand the variants. So, I have a schematic of the SARS-COV-2 virus on the left and you can see that it has a number of proteins. It has a membrane envelope uh and within the cell itself it has the SARS COV gene which encodes the gene for the s protein and the receptor binding domain. So the s protein is this crown shaped spike uh that protein that is found on the surface of the SARS-COV-2 and very similar to other corona viruses as well. And this spike protein has uh if you delve deeper down into the structure of the spike protein, you look on the right, it has a more complex structure and it's divided into the S. One and S. Two regions. And the S. One region is really important because that's where the receptor binding domain is. And this is the part of the spike protein that attach is to the end angiotensin converting enzyme to to enter the human respiratory cells and then to cause its pathogenesis. City. It is it is really mutations within this spike protein at various levels of the spike protein, but particularly mutations within the receptor binding domain that are really Germane to the issue of transmissibility, detect ability and severity of these uh of the COVID-19 infection. Next slide. So uh so what happens is that uh the spike protein gene is depicted in in yellow. This is just dramatically shown for the discussion. Uh So the spike protein gene may have multiple mutations as a function of its replication and there are many mutations that are actually not meaningful at all in regards to the transmission or change in the path of physiology of the disease itself. And and some uh mutations are so significant that the virus is actually uh not ah functional thereafter and those disappear. But there are mutations that result in transmission increased transmissibility or increased uh severity of disease or allow the virus to escape the effects of monoclonal antibodies, the treatments or the vaccine and some of these are have have a more local or focal kind of impact uh and they may be emerging but haven't reached a level where they're going to cause mass degree of infection uh either in a country or uh on a global scale. So those are called variants of interest and those that have a significant change in their spike proteins such that they increased transmit miss ability. They have spread into many countries and they potentially have escaped or decreased susceptibilities to monoclonal antibodies or vaccines, alcohol, the variants of concern and those are depicted schematically on the right. It's next next slide. So this is just another kind of example of the mutations in the spike protein. And there are so many uh that are being characterized and and also defined for the emerging uh variants. So what I want to show you is that if you look at the second row, that's the wild strain or the type A the lineage type A which is the original Wuhan strain and there are this is the original one without any known mutations uh in that genome of the spike protein. But when you look at the second, the third row which shows the mutation called the D 614 G, which is a single minor acid uh mutation leading to change from expert to glisten this small, even though it's a small little mutation will change actually resulted in increased transmissibility and was the variant that actually caused the largest Output in the early part of the 2020 pandemic. And uh was initially detected uh a large part of it was detected in Europe and was related to the Italian outbreak. And since then, as you know, there have been numerous other variants that have been identified. And and as we have gone further and further into these variants, they have accumulated additional uh mutations. Uh as you can see in this schematic here, uh the alpha variant has a number of mutations uh the gamma which is more common in the south south american region? And then lambda have numerous different uh mutations. You can see that the D six months four G is common to almost all of the variants. Uh And and similarly there is another mutation that was seen in the alpha variant, the N 51 Y which was also seen in a number of these variants. So they really do very based on the type of mutation that they have. Uh the E for 80 for is another mutation that has been of significance because of the decrease in vaccine responsiveness in some of those uh that have had this mutation. Next slide. So the question comes up is, how are these named, who decides? And how is it named? So initially, as you heard, you know, there wasn't a specific name for the strain that came out of Wuhan and then it became the alpha variant before it was named the alpha Very and it was uh in general lay press, it was called the UK variant or the South african variant etcetera. It kind of became difficult to continue to follow these variants and thus for public health naming reasons. W H O uh in March also recommended that uh these variants being named based on greek alphabet and so that it makes it easier for the lay public as well as for public health and countries, et cetera to follow these naming uh nomenclature. However, from a scientific perspective, there are certain guidelines in regards to how these variants are named. Some of them are named based on the mutation, some are named based on the on kind of the evolution the filo genetic evolution of these uh these viruses. And this is similar to um many other uh viral uh naming uh conventions. So early on last year, sometime in 2020 from UK, there was a naming suggestion which was named as follow genetic assignment of named global outbreak Pango lineage and this really kind of the name Pango was to suggest the kind of uh origen of Sars-Cov-2 from the pangolins but also to help with kind of aligning that naming a convention there. So in this uh particular follow genetic assignment A was the original Wuhan's train and subsequently as more and more variants emerged, we are currently seeing a number of them uh in the b lineage. And I'll show you examples of that. And this really goes all the way from B 1.17, which is the alpha, the UK strain Down to currently ay.12. And so, you know, there are potentially going to be a number of other ones that we might see in the near future. Another way of identifying these and currently being used very commonly uh in the world has been uh from next train dot org which has been collaborating, which was basically developed through collaboration uh from researchers in the U. S. As well as Switzerland. And this is an open source tool for visualizing the genetics of the outbreaks. And numerous Countries have been able to submit isolates and genetic structures such that these can be uh named according to the next train uh naming uh convention, which they started from 1980, which was the original Wuhan strain. And these naming structure continues as more variants emerged. Next line, next slide. So just to kind of show you that, you know, when you look at a uh father genetic tree, it's not a dissimilar to how a family tree would be, you know, uh your great grandfather and your great grandmother, they had three Children and those three Children married somebody else and then they had, you know, each of those family members had three Children and two Children, et cetera. This is very similar to that in terms of uh the variations from the original strain and then the similarities between the variance within a particular grouping of viral mutations and hence uh named as lineage a lineage be and and so on within a group of variants that are similar and it may emerge from one particular mutation. Uh the similar variants within that group called Plaids. Next slide. So when we look at SARS cov two and see where we are, you can see that uh you know 19 A is uh in the left bottom. You can see that there's 19 A. Uh if you hit the next like um yeah thank you and then hit the next one again. So 19 A is sorry go back so 19 eighties and the left bottom and over the time which is on the X axis at the bottom. You can see that there were a number of additional viruses that were identified along the way that had mutations and that were different from the original strain. But as we have gone further and further into the pandemic, they have emerged significant uh variants that have caused a lot more disease. For example, the 21 A which is delta which is the current one highlighted in this greenish color. And you can see the large blue uh follow genetic tree was related to the uh the UK the alpha variant. Uh and you can see that the volume of uh the number of these variants kind of correlates with which variant has become the predominant variant next slide. And uh just talking a little bit about delta uh based on the pangolin lineage, it's B 1617.2. And then there are a similar related uh delta variants that have different uh mutations that are named as a Y 0.1 A 1.2 and 0.3. Uh The B 16127.2 and A Y three do not have a mutation called K. 417. And whereas all three of them share something called L 4 52 R. And have an impact on transmissibility. Uh This particular strain form next train dot com dot org is called 21 A. Um And based on the mutation that you see out there, what we do know is that it originally this delta variant originated initially from India and also from B 1617.1. Which is the coppa strain which was initially only considered um a variant of interest but this later changed and had a mutation to become the delta strain and became more transmissible. What we do know about the delta delta strain is that it is two times more transmissible than the alpha strain and has decreased uh neutralization with monoclonal antibodies. And also potentially some decrees with post vaccination antibodies as well. Next slide. So when we look at uh current W. H. O variants of concern. They are listed on uh of interest listed on the left. These are more focal or local uh infections with some degree of change and transmissibility but have not become significant enough for global concern. And those are listed on the left. Where is the variance of concern are as listed um on the right under the orange bar. And currently we're dealing mostly with the delta strain. Next slide. So mm uh the C. D. C. Has another nomenclature which is not used so much by the W. H. O. N. That is variant variant of high consequence. This is a variant that is basically a variant of concern but at the same time it has become significant such that it's escaping detect ability, it is escaping treatment, it's escaping vaccine effectiveness or it's even escaping a treatment or public health measures. And when it becomes a significant consequence in terms of the health care system not being able to take care of patients who have this variant then it becomes a variant of high consequence. Unfortunately currently we do not have a variant of high consequence globally. Next slide. So when we look at uh you know how does the W. H. O. Or C. D. C. How how is this monitoring happening? This is really happening on a global and national level in terms of submission of uh viruses from uh when they are detected for genetic identification identification of mutations. This is done at the state local levels, commercial academic and federal levels. There are a number of consortiums that are looking at uh at identifying these various uh mutations and strains next slide. So what's the current epidemiology of SARS cov two variants? Next slide. So as I showed you the previous uh you know, follow genetic tree. This is just another way of looking at it. And you can see that the original strains that we were seeing initially are not so commonly seen and have fewer mutations. Um and I'll show you more in terms of what if we are seeing currently. Next slide. Mm So this is just a schematic of uh the delta transmission across the world. Obviously a large uh you know travel associated illness. And you can see that uh when it first started in India very soon by uh by March of 2021 number of countries already had it on the right panel, you can see by june and august almost all of the countries have a scene delta and its sub variants. Next slide. And this is a kind of the geographic uh not the geographic but the kind of the transition of these variants. You can see that the initial kind of strains have essentially decreased uh in quantity. Whereas uh and if you look at the lower panel, you can see that the alpha has also decreased significantly globally. And delta has really kind of taken that space where uh with the transmission and the same thing has happened with with the beta and the gamma strains as well. Next slide a couple of uh kind of variants that I just wanted to highlight. One is the lambdas train Landis train originated from south american countries. Ah It uh was shown to have higher infectivity compared to alpha and gamma and had in vitro been shown to have decreased neutralization. Uh 34 decreased neutralization compared to the wild strain. But based on the data shown on the right from uh from G's Aid, you can see that the the amount detected has gone down and the amount detected in other parts of the world is much lower. Next slide, there is also another variant that has been uh important for people to know. That is the epsilon variant. Uh It is notable for its mutations for 27 4 29 and essentially was in first identified in California uh was shown to have maybe some increase in transmissibility and uh impact with monoclonal antibodies and and also potential decrease in vaccine effectiveness. However, the amount of excellent uh in the U. S. Has decreased substantially. Next slide. So when you look at what's happening in the U. S. Uh you know, since the napier back in mid june of about 8000 cases a day. From a high of 300,000 back in early january, we have gone up back to about 100 and 50,000 or more cases um a day and uh looking at this is data from the CDC as of last week, you can see that delta which is in the orange and the dark orange has essentially taken over as the predominant variant. Up to about 94% of all the cases currently are the delta variant, including the A. Y three. The epsilon as I mentioned earlier has gone down and so has the alpha been essentially pushed out in regards to the prevalence the next slide. So in conclusion the pandemic is obviously ongoing. New variants are emerging. Uh We just heard today that there's another variant emerging from Belgium uh that could potentially be of significance. Uh The global variants of concern currently is the delta variant but based on what we have seen now historically there could be a new variant emerging that could have additional impact on the pandemic and we will need to be vigilant uh to make sure that we are ready for this. Over to dr Poland. Dr burke, thank you for an excellent background. After Poland. You're you're muted. Doctor Poland. Okay, you hear me Okay now? All right, well I'm gonna, I was asked to address a few questions. I'll try to get through them quickly. So we have some time uh leftover uh to answer questions and I'm calling this now the most dangerous phase of the pandemic thus far. Next slide. Next slide, one thing I want to point out just so that people understand reality is that there is no one modality than in that in and of itself is sufficient to end the pandemic. Rather much like tires, brakes, seatbelts, airbags, collision warning, etcetera. It takes layers of mitigation and it starts with everybody being vaccinated, everybody wearing mass and everybody responsibly distancing Absent that we will continue as we have watched over the last 18 months. The evolution of viral variants, Avinash just mentioned one That's recently been identified called the B1621 variant which was first isolated in Colombia. Um, and now in fact is responsible for about nine of all the cases in Miami some of these variants as we've seen with delta are going to develop the ability to evade and whole or in part both vaccine induced and convalescent immunity. Next slide uh we've already talked a bit about the delta variant maybe just to put it into perspective. Whereas with the ancestral Wuhan strain we saw Our knots or transmission rates where one person might spread it 1.5-2 people. The estimate now for the are not with the delta variant is about 5-9. This place is it as one of the most transmissible viruses among humans that we know of shy of something like measles. It's accompanied by significantly higher viral loads on the order of magnitude of 1000 to 1200 times higher than what we saw with the original strain. And again allows for some mild to moderate evasion of vaccine induced in convalescent immunity. Next slide, just a simple graphic to show you the spread of delta and what exponential transmission looks like. If I could go back even a little further, which I can't on this slide. You see a few red dots that corresponded with us nationally pretending that the pandemic was over and eliminating mask and other mandates. And you see that uh coronavirus as it always will rapidly exploited that. And inside of a month basically the nation became a delta hotbed next slide. So when it comes to vaccines, I like to make it clear to people you have to choose which risk you want. And there are only three choices available. You can do nothing which is a choice to get COVID-19 infected and I'm among those who believe that if you don't get vaccinated, it is essentially inevitable that you will get infected unless you decide to go into complete isolation which carries its own risk of being almost howard Hughes like. And the Middle one which I think is the wisest ground ground to get COVID-19 vaccinated and wear a mask. Next slide. Well in regards to the questions I often get about vaccines, I want to make it clear, I've been a vaccine. Ologists for four decades. No vaccine has ever been studied to this degree and with this degree of scrutiny prior to release. And yet it's true as it always is in science that we never know as much as we wish we could know. We've been using influenza vaccines for some 70 years and as we're talking, clinical trials are going on on yet another next generation influenza vaccine. And that's because the science continues to evolve. Therefore, decisions about vaccines and about public health policy must necessarily involve a careful consideration of the known data based risks and benefits at the time that you're making decisions and policy. Next slide, I was asked to address how these vaccines work well. They all have a common final pathway and that is to develop anti spike antibody. Why that single pathway. Because the spike protein with its tip, which is the receptor binding domain interacts with the trans membrane ace two receptor and that is how the virus gets into host cells and causes the damage that it does. So if you can bind that spike protein with anti spike antibody then the virus becomes harmless. It cannot enter cells and cause infection. Next slide. So three types of vaccines are going to be used here in the United States others elsewhere. One is protein based characterized by the nova vax uh inactivated whole s protein. The second is viral vectored usually adenovirus characteristic by the J and J. And Astrazeneca vaccines as well as the Sputnik V. And then thirdly the MRNA vaccines, the Pfizer and Moderna vaccines again, all of them use the same final common pathway which is to produce spike protein antibody is raised against that protein and prevents or aggregates infection. Next slide. So we'll start with the MRNA vaccines. These are very simple in concept M. Ra vaccine started to be developed in 1960. So when you hear misinformation about how these are new and rushed, that person is telling you, they don't really know the scientific literature. These were developed as vaccines in earnest, starting 31 years ago in 1990. And the concept is simple. You simply make the synthetic genetic blueprint for the single covid 19 or SARS cov two structural protein called the spike or S. Protein that's injected gets into muscle cells. Is translated by ribosomes in the cellular cytoplasm and produces despite protein, it cannot get into the cell nucleus. Therefore it cannot integrate into DNA. It cannot persist in many ways. We wish those three factors were not true because then it could be exploited particularly for treatment of genetic diseases but they just don't operate that way. Next slide. So the fighters study if we look at the bottom look at the size of this phase three clinical trial, one of the largest vaccine. Phase three trials ever done with just shy of 44,000 people. Next slide. And we'll cut to the bottom line here which is the efficacy endpoints. So if you look at the orange line on the bottom, that's the vaccine recipients and you see that after about 14 days they no longer acquired infection. Whereas the placebo group continued to acquire uh infections. Now note a key point. All of these phase three trials were done before delta before alpha. These were done against the ancestral Wuhan and Washington Strains. So if you look at overall vaccine efficacy, it was right at about 95% against symptomatic disease. Next slide Moderna much the same way. About 30,000 participants in this case, not three weeks apart, but four weeks apart. Next slide. And we see basically the same thing. Within a week or two of receiving vaccine, you don't see further acquisition of infections. Whereas in the placebo group, you continue to see infections with an overall vaccine efficacy against symptomatic disease of about 94%. Next slide but those are the headlines and you have to recognize if you do, but you have to recognize as a scientist that those vaccine efficacy headlines are point estimates Look down a few rows to the over 65 age group. The point estimate was in the was 86.4% efficacy against symptomatic disease. But the true answer Lies between 61.4 and 95.2 and you see that to be true across each age group, sex risk factor etc. So while you hear the headline, the headline is an incomplete story. Have published about 5 600 scientific papers on these issues. And the problem is that particularly once you move into the population, The Phase three trials do not reflect the general population, the general population has people who are immunocompromised, people who are genetically predisposed to not respond to vaccine and people who are elderly, frail and with with multiple comorbidities. Next slide, the adenovirus vectored vaccines again, the same common pathway. The differences instead of MRNA, the gene encoding the spike protein is inserted into the adenoviruses genome. Next slide. So as I mentioned, that's J and J and astrazeneca would be the ones that you're most familiar with. Next slide And you see that the Phase three trial data were very good. So if you look at efficacy against um severe to critical disease, you see in the us, it was about 86%. Again, that was before alpha or delta. If you look at South Africa where the beta variant was circulating, it had decreased to 82%. Another fine point here when we talk about vaccine efficacy, we have to be careful to specify efficacy against what because there's always a gradient vaccines are very good at preventing severe and critical disease. But look at moderate to severe disease. The second blue bullet We've dropped from 86% to 72%. A symptomatic infection about 74 and yet vaccine efficacy against hospitalization was 85%. And the chat box is covering up my slide. I can't see vaccine efficacy against death remained essentially 100%. Next slide. So if you look overall at vaccine efficacy against variants and I've put this in qualitative terms, you see that when we're looking at the alpha or the beta or the gamma variant, delta variant hadn't been studied at this point yet, you see in general reduced efficacy, which I would say is even a little more pronounced against delta. About 40 minutes ago I received the White House briefing packet. Uh much of this information I think will be released and available to you tonight or tomorrow But just hit the highlight. One of the studies done in New York showed that efficacy against new infections had dropped from 92% to 80%. Even though vaccine efficacy, efficacy against hospitalization remained at about 92%. If you look at nursing home patients, efficacy against the Delta strain has dropped to about 53%. So that's why you're hearing talk about boosters after 24 weeks next slide. So the theoretical construct here, as is true in all of vaccine ology, is if you look on the far left side, we build a vaccine against whatever variant is circulating at the time introducing high antibody levels which are protected, they wayne with time. We often give a booster. You see the middle part of the curve there boosting immunity, which may wane with time and then refocusing immunity based on any new viral variants you're familiar with this. Only the timeline is expanded with influenza vaccine. We change one or more of the four antigens annually and have to refocus immunity with a vaccine against the new viral variants. Next slide. So I will end there and uh we'll take questions. Thank you. Thank you Greg. Uh Again, a very nice uh background to set the stage for the many questions and answers that we have. And and some if not many of the questions have been noted in your presentations but they probably would benefit from from some clarification. Um ab manage. Uh Can you clarify for us again, when does a mutant become a variant mutant becomes variant when it has a clinical significance in terms of infectivity and also transmissibility. Okay. And as you can imagine, there is a there are many questions both within this webinar and outside the webinar on boosters. So there is the recent recommendation for a third uh immunization. A third shot for patients with moderate to severe uh immune compromise. Can you elaborate on this a little bit of Greg? Yeah, sure. You know this first came out and we became aware of it as we looked at um uh antibody levels to vaccine in patients who had solid organ transplants and found that uh only a minority of them had developed antibody levels that we thought might be protective. Those data have been confirmed at Mayo clinic uh and at multiple other centers that expanded into further studies. Looking at people who had cancer on chemotherapy on disease modifying agents for auto immune diseases? A whole variety of things that we would call quote moderately to severely immuno compromised. And those data and I think appropriately so raised concern that for immuno compromised individuals, a three dose series not a two dose series was going to become necessary. And last friday you saw movement on that both at the FDA and the A. C. I. P. So that is now a recommendation. Thank you. So there is an expectation of an announcement perhaps even today about the so called booster shots. And there is a rumor in the media about recommendation of a third shot after eight months from the second vaccine uh administration there is a question about how this eight months is determined and what is the trajectory of uh waning immunity after vaccination. So this is a this is actually a very complex and nuanced question. All vaccines that we give have a by phase IQ immune response and others we give the vaccine nice high antibody levels with which always wane over time. Different for each vaccine. But particularly for protein based vaccines, they tend to wane uh more quickly. So then what you're doing is you're saying are we seeing breakthrough disease. And if so what kind is it severe? Is it death? Is it hospitalization? Is it moderate mild? Is it a symptomatic and it's really the far end of the spectrum that you're concerned about. We're less concerned in some ways about a symptomatic infection. Although when it's accompanied by transmission that that's a little different story, then we are, for example, about severe disease, death or hospitalization and what we've seen is that both over time and trying to separate the effect of new variants on top of that. We're seeing a deck rem intent in the protection against severe disease. Still pretty good. But small deck rem ints and then across that spectrum all the way to a symptomatic disease. So somewhere in that probably more like eight month time period I suspect we'll see a recommendation for a booster. Thank you Greg. We have learned about the higher transmissibility of the delta virus, the delta variant and perhaps other variants. What do we know about the violence of the newer variants? Is there any information on that? It doesn't seem to be a significant difference in terms of the severity of the disease as opposed to the transmissibility. Uh You know, as there are more cases, there is equivalent number of patients who are getting hospitals or dying from it very similar to what we saw with the original um you know Wuhan strain, what we do know is that delta variant does have higher viral loads. Uh and and also has a shorter incubation periods as opposed to uh the alpha or the Wuhan? Very and so you know, it's it's slightly different in terms of clinical disease but overall fairly similar to alpha or the Wuhan. Strange. Yeah, I would just maybe add to that. There have been four pre print. So take it as that pre print. They haven't been peer reviewed yet that do suggest some increased uh severity. But but here's the difficult part when we're comparing it to alpha or the ancestral Wuhan strain, we've learned a tremendous amount about how to treat it prone ventilation, Tosi antivirals, um uh how to ventilate better uh monoclonal antibodies, et cetera. So if you look in countries that don't have those modalities and you look at Delta versus ancestral or alpha strain, you do begin to see this differential severity, which fits with the idea that viral loads are so much higher in those individuals would be hard to imagine viral loads and delta, it's about 1000 to 1200 times higher. Hard to imagine viral loads that wouldn't cause more in the way of disease. But I think as a bone ashes pointing out treatment has become so relatively good that if you don't have surged demand on the system, you don't see the sort of elevated death rates, we would have expected to see Excellent point. Yeah. Thank you. So how does a vaccinated person, a covid vaccinated person compared to the unvaccinated person as a carrier. This has again been some controversial data because the first study out suggested identical viral loads that has not held up in other studies. So we don't know for sure. We need more studies what we can say. And this is this is really important. If you look at the Singapore multi center study that was done. What you saw was that uh, at the time of diagnosis, viral loads appeared to be the same and infected non vaccinated and infected vaccinated. The key difference was that viral loads fell very quickly in the vaccinated people and much more slowly in the unvaccinated which then correlated with mortality. Uh intensive care, admission, need for supplemental oxygen and the development of pneumonia. Thank you. The undisputed point might be that vaccinated people can transmit. They can, yes, they can, but they do much better. Very good. Uh there is a question and it's been an interesting question through the through recent months about mixing and matching vaccines. So can you get a the first dose of a particular vaccine and then use a different vaccine for your second shot. And what are the implications of that? Um, we'll take a first stab at it and I'm an ashcan can add to it. Both of us are very familiar with these data. Um uh we might have slightly different takes. But what the data suggests is that mixing and matching is not detrimental and may in fact be beneficial. Having said that there are sparse data on safety, there are some and there is no recommendation to do that. The practicality of it is if I had gotten one dose of vaccine a and that was not available, I would have no problem getting second dose of vaccine be that's not what's preferred. But early data suggests uh equal if not better immunogenicity. Arvin ash, would you agree with? I absolutely agree. And actually uh the study from um, UK where they had Astrazeneca patients getting Pfizer vaccine. Um, she seemed to have shown better immune responses. Um, but they did have higher react to jena city. Those people they paid the price of a little more reactive genesis city. Um, and you know the question about is there a difference between Pfizer biontech and Madonna? They're basically essentially the same because it's the spike protein M R N A. But the the amount in fighter is 30 micrograms whereas the mountain Madonna is 100. Does it make a difference? We don't really know, you know, we we don't know that information yet agree. Is it fair to say that the data as far south as it is on mixing and matching is really around the RNA vaccines and the Astrazeneca vaccines. So there is no statement that we can make about the JNJ vaccine as it is a single shot vaccine? Because there is a question about what do we tell about our patients who had received the J and J vaccine about it. Yeah, this is a real issue for him. I get I get messages every day about that. And unfortunately we don't have any data to really guide us with any you know policy statement at this point now there is a two dose J and J study going on. Those data are expected uh in the august early september timeframe. So we may we may have a better answer for that in a few weeks. Very good. Uh If so there's a there's a question about uh if an unvaccinated patient acquires covid. So if a patient is infected with covid, when does that person be vaccinated? I guess the first question to clarify for everybody is that Even if somebody had uh experienced a COVID-19 infection, that person should be vaccinated as well. The second question to this is then, when should that vaccination be done? Um a couple of comments on that. First of all, I often hear people say, oh I had covid, you know, last year I I'm protected. And the answer is every study shows you are not protected. In fact, if you look at the Kentucky study your risk of reinfection is about 2.3 fold higher Than people who were infected and got vaccinated. When should that vaccine occur sometime after 90 days. What's interesting is that you start seeing infections being acquired in that 100 16, day time period after infection that they're actually acquired some of them pretty early. I was surprised by those data. So so immunization is definitely recommended. I would say in scientific communities The controversy has been one dose or two doses Because one does data looked really very good. But the policy recommendations two doses when you're using Mrna. And for the same reason people who have had covid 19 before when they get the first does they seem to have a higher reactor jena city compared to the second dose as opposed to people who didn't have covid before they have higher reactor jena city after the second does. And also the antibody levels after the first dose. In people who had covid 19 before after the first dose have Pretty really high substantial increase in antibody levels equal to what they are in somebody who didn't have COVID after the second. Does. Yeah. Just to put some numbers on that because it's really astounding if you look at somebody who's naive after the first dose, the average antibody levels about 1800. You take somebody who is co previously covid infected, Give them one dose, their antibody levels average 30,000. Yeah. So as we approach the end of the allocated time for our webinar, how do you see the end game playing out given the delta variant and The other emerging variants? Are we going to have a seasonal COVID-19 or what's going to happen? I'm going to go first. I'm going to just say that at this point we're in it for a long haul without global vaccination. Um and then yes the long haul would potentially include um annual vaccinations like the flu vaccine. I'm going to my crystal ball is always hazardous. I think this virus has a lot left to teach us. I think there's the very real potential that this will get much worse before it gets better because of both viral behavior and human behavior which has distorted our response globally and nationally. And I think the long game is that this will likely devolve into something more akin to influenza and probably require regular boosters. Indeed. So the virus is one variable and our response to the virus is also another variable. So I thank you very much for your really wonderful presentations and the very informative responses to the questions that have been posed to us. I will then ah transition to Theresa Thank you everyone for joining us today to discuss SARS cov two variants. If you enjoyed today's discussion, please be sure to check out and register for upcoming webinars including one on september 9th. If you'd like to claim credit for today's webinar, please visit ce dot mayo dot e d u slash covid 0818. You'll need to log into the site if it's your first time visiting, you may need to create a compound. If you've done this and logged in, you'll see this access code box appear, you'll want to type in today's code which is case sensitive. So in all capital letters, Covid C o V i D 0818 will allow you to access the course. You have to complete a short evaluation and then you'll be able to access and download your certificate once again, thank you for joining us today and we look forward to seeing you at the next session. Thank you. Thank you everyone. Mhm.