In this Grand Rounds, Abinash Virk, M.D. , and Gregory A. Poland, M.D., speak on the COVID-19 pandemic and immunocompromised people and what has been learned.
So I'd like to welcome everybody to our CV grand rounds and thank dr Charney taught away for organizing this outstanding session. Today's title of our presentation will be the COVID-19 pandemic and vaccinations. What have we learned? What a terribly important topic to discuss. And I do want to just briefly introduce our colleagues who are from a different department and many of us know we have two speakers. Dr Avinash vert is a professor of medicine Uh in Mayo Clinic and she is the co chair of the COVID-19 vaccine allocation and distribution work group here. She has served as acting chair of the I. D. Division and is the founder of our Travel and Tropical Medicine clinic. And we're also joined by Dr Greg Poland who is a physician scientist, founding and current director of our vaccine research group and that and his lab has developed the field of viral vaccine. Um you know genetics. He is a distinguished investigator of the Mayo clinic and he has chaired or been a member of every federal committee that's been involved in vaccine decision making. Has received the NIH merit award granted to less than 5% of NIH funded investigators has served as president of the Defense Health Board appointed by George Bush and has served as the secretary and has received the Secretary of Defense Medal for outstanding public servants. So truly we have two experts in this space around which there's been so much discussion and I think we're going to start with Dr Poland. So Greg thank you for joining us. You bet. And they're good to be with you colleagues. Uh let me get my my slide first. A shout out to some of the cardiologist I've most worked with guy reader, rick, nishamura, rob McCully, paul. You and sam serve athm. Uh you guys are really just world leaders and what you do. And uh it's it's an honor to work with you. So Avinash and I are going to talk about COVID-19. I'm briefly gonna address breakthrough disease uh and boosters. Mhm. We've already done the disclosures. It's worth thinking about the fact that as of yesterday there were 775,000 COVID deaths in the us. So one out of every 423 Americans is now dead of Covid. That's the equivalent of 24 airplanes. Each one carrying 400 people, each one crashing and killing everybody aboard every week for 80 weeks straight. If that were to happen out of us skies, I think we'd see a very different response than the lackadaisical one. We have. As a result, us males in particular have lost two years of life expectancy for black males. It's three years more than since World War two. And of course we call that a world war. We've now exceeded the number of deaths in the us that occurred due to the 1918 influenza pandemic. We only have about 70% of eligible Americans who have taken advantage of getting a vaccine And surprising to me. Minnesota ranks 17th. I would have thought we'd be higher than that. Well, when we talk about how vaccines work and particularly covid vaccine, we're asking fundamentally, what is the vaccine efficacy or effectiveness? And it's worth thinking that this is a gradient of protection Does exceptionally well against preventing death. And then we get to lower and lower numbers as we get to mild disease, asymptomatic infection transmission. Those are numbers more around 60-plus% or so. And so when we look at efficacy, we're talking about this gradient. We're recognizing that this vaccine, like all of our vaccines, are much better at disease blocking than infection blocking. I'll come back to that in a minute. It of course, depends on the health of the underlying host immune system. And remember while we're talking about antibody, because we can measure antibody that's only one arm of the three important arms that determine our uh protection against disease efficacy depends on what the circulating variant or variants are, the community burden of disease and then individual genetic factors. So, if you look at the top of this drawing a disease that let me get rid of this bar here, vaccine that prevents disease, but not infection basically results in more asymptomatic or mild disease and much less disease that's characterized by high severity on the bottom a vaccine that prevents disease and infection and we're somewhere between the two against significantly decreases the chance that one dies, gets hospitalist or has severe disease but does much less against asymptomatic disease. So as I've mentioned host characteristics, pathogen characteristics, even which type of vaccine you get time since vaccination, all of these form a complex interplay that predetermine whether you're likely to get infected and if you get infected, what your body's response to that infection is likely to be. So, breakthrough cases occur because of this collision of waning immunity, newer variants, hi community burdens of transmission host factors and one that I've written quite a bit about, which we call the apparent paradox of increasing cases among the immunized as more and more people are immunized. So the idea what's the idea is once everybody's immunized, then 100% of the cases that you see are in immunized people though the number of cases is dramatically reduced Compared to a scenario where 10% of the people are immunized. Other reasons. This is, this occurs. And this is a chart from a paper in the Journal of american Medical Association. If you look at this orange line here, you see a uh not quite but linear Decorah mint in antibody response by age. So age alone is one of those host factors that predetermine antibody levels after vaccination. Now, what they've done is they've superimposed looking at antibody response to the original Washington or Wuhan ancestral strain in green and the p one or Brazilian variant in orange and you see that both age and variant type dec criminal the antibody response. So here's what I was mentioning about measles. So let's just take measles is of course the most contagious disease we know of other than ignorance and fear. And I say that only partly in jest If we take a school, for example, this is a paper I published almost 30 years ago. Uh, that is exposed where nobody is immunized against measles, then virtually 100% of people get measles, but none of the cases occur and immunized students. If you immunize everybody, Then you have about 100 who don't respond well. So 1900 of them are immune. The 100 that get exposed, we'll get disease. So all of the cases will be in people that were immunized. But if you look at who's susceptible when they're exposed, it's 2000 students among the unimmunized cohort. It's only 100 among the fully immunized cohort. But the media portrays it as oh my gosh, look, we have this increasing number of breakthrough cases. The other problem, of course is that headlines obscure. I'm taking you into a little deeper dive into the moderna data. You saw the headlines, 95% efficacy and that's as far as most people's thinking went, Well, let's just take individuals in my age group, those who are over age, 65. The point estimate of efficacy was actually 86 And the truth lies somewhere between 61 and 95. But the point estimate is the more likely. So here you have opportunity immediately for about 15% of this cohort to develop infection upon exposure. That's not really breakthrough. That's primary vaccine failure. Now, I also mentioned that vaccine type enters into this. So we'll look at the 122 28 days after full vaccination and look at vaccine efficacy in this case effectiveness against hospitalization. Well, for Moderna, the point estimate was 92% after 100 and 20 days For fighter, 77 For J&J 68%. Another study that just came out last week in the Journal of the American Medical Association using what's called a test negative design of about 4500 hospitalized patients across 18 states and they're looking at people who are hospitalized for covid like symptoms testing who actually had Covid who didn't, who was immunized, who wasn't When they do that. They're able to determine a ve against hospitalization of about 85%. If you look in the immuno compromised, it was about 51%. You look at people who were vaccinated 120 or more days ago For moderna, it was 85 for fighter, But vaccinated subjects were 50% less likely to die or need intensive care or require mechanical ventilation. Yet another study from something called Covid net. This is lab confirmed. Covid 19 hospitalizations in 99 counties in 14 US states. So about 10% of the population. They looked from january to july. So they were just sort of starting to get into the delta surge. Among those who are fully vaccinated. About one out of 13,000 were hospitalized. Only 20% of those went to the I. c. u. 70% of the hospitalized cases though immunized were in people over the age of 65, 87% of the deaths and people over the age of 65. And here's this paradox, Fully vaccinated cases who were hospitalized increased from .101% per month to 16 waning also obviously enters into that. But overall when we look at the breakthrough cases, they're older and they generally had three or more comorbidities. So overall, what could we conclude from this study? Hospitalization rates Were 17 fold higher in the unvaccinated than in the vaccinated. Another study from the Lancet that came out just last week, you all know the old adage when you're getting ready to give a talk. You're so busy. You don't read the literature that week. And one of my mentors taught me always look at the literature because everybody else will have and you'll look like a fool. So I went back and looked this past week and wow, there were several major articles. So this is a vaccine effectiveness against infection by age starting at one month from the time they were fully vaccinated out to five or more and you see that that drops quite a bit less. So for the 12-15 year olds by three months. But you look at the rest of us And you've gone from 90% down into the 40 and 50%. Now that's against infection. Remember the gradient we talked about now let's look at vaccine effectiveness against hospitalization, some minor wiggle in that. The point is, these are great disease blocking vaccines. We see that here they are much less good at infection blocking. In fact, if we now go and we look at uh effectiveness by variant, So the purple line is delta, the red is other variants and the blue line are those that failed sequencing. We couldn't tell what they are. Well, let's just look at delta this purplish line and you see from one month To greater than four months after being fully vaccinated, you go from 90-plus% vaccine efficacy down to about 60%. So time is the enemy here as well as variant type. In terms of booster vaccinations as vaccine. Ologists, we proceed from two. if you will theoretical constructs the first is in the context of an epidemic or pandemic is build immunity quickly by immunizing as many people as you can. We failed at that in the US then immunity always wanes. This is nothing new. And when you get to a certain point Israel got their first us last as you rebuild immunity now with a booster and you keep doing that until such time as you have viral variants sufficiently genetically distant enough from the ancestral strain that you have to refocus immunity by using a variant vaccine. We're not there yet, but there's a lot of work going in there. The other idea theoretically is that wild type and variant antibody responses are likely to be different. So this illustrates two theoretical constructs. One is that we do less well against variant types than we do against wild type and vaccination is superior to quote natural infection. That's been shown now multiple times. So what does it, what does the vaccine boost look like after infection? This happens to be with Pfizer vaccine. And whether you look at the original virus, the alpha, the beta or the gamma, you see that a booster dose provides Superior immunity. I mean you go from original immunity of a neutralizing antibody, this is on the log scale of about 456 To just over 9000 with your boosters. So even if waning occurs here, the slope and the duration of that to get back down to susceptibility is very long and that was true for all of the variants they looked at Similarly, if you look on the left hand side, this is participants 18-55 and on the right hand side this is a small study, as many of them are 65- 85. Didn't really matter by age, people responded exceedingly well when they looked a month after the third dose Going one month after the second dose from less than 200 to about 15, in antibody tighter. Now another study that came out was looking at hospitalization at a two dose fighter versus a three dose. So this is an argument for a booster dose of an MRNA vaccine. So if we look at covid related admission to the hospital, that line over time continues to climb in those that had two doses. That's the waning phenomena, barely a change among those that had three doses. This is for hospitalization and this is for severe disease. Same phenomena, tiny little bump here out at about 50 ish days or so. But a continued climb In those that only got two doses. What about death? Same phenomenon. Now you do start to see uh some change here. These are primarily people who have underlying host factors and don't respond as well as otherwise healthy people. The point is you begin to see uh very significant differences over time and people who got no doses versus two doses versus three doses of an M. R. N. A. Vaccine. So what does that look like? This? Is a third study from Israel. Uh as you may know, uh they've got just superior systems for detecting this and they've um they've devoted much more in the way of resources to these sorts of studies. But if we looked at confirmed infection and severe illness in the non booster and the booster group, the adjusted rate ratio, in other words, What does a booster do for you? Well it increases your protection if you will against confirmed infection by 11-fold versus 20 fold against severe illness. Again that gradient of protection. So booster doses are for those who are 18 and over whose primary series was MRNA vaccine six or months, six or more months ago. Or if you got J and J two or more months ago, They are generally divided into we should recommend this and we may recommend it should is for all of those of us who are over the age of 65, those who live in long-term care or who are 50-64 and have underlying medical conditions. The may we may offer it is 18 to 49 year olds with underlying medical conditions, 18-64 years old who are at increased risk for COVID because of their occupation or the institutional setting. More or less. You began to see this is some 90 Or so of the population that is over the age of 18. The bottom line here is that vaccinated adults Are about 2/3 less likely to get COVID infected. They're about 2/3 less likely to have a symptomatic infection. If they are infected, their viral loads decline rapidly and the virus is less likely to be cultural, There's 63% less likely as a result to transmit the virus to others like family. And if you look at age adjusted rates. So this is the newest data. The age adjusted rate of hospitalization and the vaccinated is about 4.5 100,000 verses. Almost 84 900,000 in the unvaccinated. And with that I will stop and a bone ash. The show is yours. I will talk about vaccinations and immuno compromised individuals. What's new about adverse effects with these vaccines? And just to give you a little snapshot of where we are with the 5 to 11 year olds and the vaccination rollout at mail and touch a little bit about the vaccination requirement policy here at mail. So, you know, so Greg just talked about boosters because of waning immunity or emerging variants. What I'm going to talk about is the additional does, which is really helpful in terms of improving the primary series immune response. And this is particularly important in immuno compromised individuals. And you know, this, you know, from other vaccinations like hepatitis B or meningococcal vaccine where we give us slightly different as scheduled to immuno compromised individuals. It's just to get them above that arbitrary threshold of protection for whichever disease that you're trying to immunize against. So in terms of immuno compromised individuals, we know we have about three million individuals who are immune to compromise uh seven million. But 3% of the population, these individuals are at higher risk of severe covid prolonged infection. The immune response is lower than immuno competent individuals. And unfortunately these individuals also tend to have prolonged shedding which is associated with higher likelihood of transmission uh to others within their sphere. And numerous studies have shown that immune responses among immuno compromised individuals are significantly lower than the vaccine effectiveness in the immuno competent individuals. And as Greg has just shown that they are higher likelihood of having breakthrough infections, hospitalizations and poor outcomes despite vaccination. So based on all of these issues and based on the fact that a number of studies have shown that giving an additional dose will increase antibody responses in immuno compromised individuals. Although not robust but good Up to about 50% increase. About 50% of the individual will have an increase in antibodies. The A. C. I. P. And FDA back in august recommended that moderately or severely immuno compromised individuals should receive an additional dose of mmr and a covid 19 vaccine does at least a month after they finished their primary series. And this is for the fights the vaccine for all the Children, about 12 Children and adults about 12 years of age And Madonna over 18 years of age back in august. They really did not give any guidance about the patients who received the johnson vaccine. But more recently in october we have new guidance that all individuals including immuno compromised individuals. So this is a notable point that all individuals who received the johnson vaccine, including the immuno compromised individuals should receive a second dose of the johnson vaccine. And this is also based on studies that were done that showed that johnson vaccine booster uh two months after the does was received had a very robust increase in antibody responses and was safe in terms of the side effects. So when we look at what compromises the moderately and severely immuno compromised individuals and this is exactly what you would be thinking is patients on active chemotherapy for solid and human geologic malignancies. The transplant patients, Bone Marrow transplant patients got two patients primary immunodeficiency ease And also patients who are on immunosuppressive agents for various conditions, including high dose prentiss on iE about 20 mg per day for many weeks. Um In addition, the Crp gave additional guidance and leave a two clinicians in terms of deciding whether their patients should receive additional recommendation. So if you have a patient who you feel doesn't really meet those criteria that I just mentioned but they do are but they are immune compromise, then you would be the best judge for that patient. The other guidance that came through was for patients who are going to be an impending immuno suppression. So if you have a patient who is going to go through transplantation or some other immune suppressive condition, then they should also receive the three does primary series as opposed to the two doses and hopefully complete that about a couple of weeks before immunosuppressive therapy is started. More recent guidance which just came out a couple of weeks ago is that patients who received the three doses the additional does for prime boosting should now receive a six month booster six months after the third additional dose has been provided to these immune compromised individuals. But there's been a lot of talk and a lot of discussion about the role of antibodies in deciding whether or not these patients should have these testing done to decide whether or not they get the vaccine really. We still don't have a proper correlate of protection in regards to antibody testing. There is a lot of data that shows that antibodies do correlate with immune protection but we don't know exactly what level and what type of antibody we should be doing to decide practice uh measures and so currently we're not recommending doing psychologies for deciding whether somebody needs a vaccine does or not. I was switching over to adverse effects uh what I want to just highlight is that they are amazingly robust US systems to monitor for adverse effects that cannot be detected in clinical trials even as huge clinical trials as these were. And so you can see on the slide the various numerous systems that are currently monitoring for adverse effects. Post authorization. We all know about the general kind of reactor Jenna city, some of the symptoms like uh you know, body aches, headaches, chills, et cetera. These are more common in women, younger patients and more common after second doses, Anaphylaxis is in the range of about 2-5 persons per million. And then I'll just talk a little bit more about these serious side effects. As we've gotten to know over the last few months. The first one uh, that I will talk about is mike arthritis. But I just want to give you a gender based kind of snapshot of these uh serious side effects. So the johnson vaccine is associated with thrombosis with from beside a pina syndrome as well as the Gonna barre syndrome. However, the TTS is more common in women. Where is the Goya? Barre syndrome is more common in men with the johnson vaccine and the M. RNA vaccines. As you are all probably very well aware associated with myocarditis and pericarditis and occurs more commonly in men than with women. So most. So this was data presented at the a crp meeting last week. So I want to share with you what the kind of, the summary data is. The highest risk group for mike arthritis and pericarditis is people between the ages of 16 and 20 for more common in men than women. More common after second dose than the first dose. And the rates are really equivalent between fighter and moderna. Although there have been more cases with the fighter but that's because more vaccines have been given that a Fighter uh, biontech vaccine Thus far, the vaccine adverse effect reporting system has had 3,336 reports of myocarditis pericarditis. Among the more than 400 million doses that have been administered, most of these have been the myo pericarditis and only a small smaller number have had pericarditis alone. And looking at the data that was just recently presented. The median age after those one is about 18, median age is about 20 after those two, Median time to symptom answered is essentially within the first week. Uh, and very soon after the vaccination within the 2-3 days More commonly in men. As you can see 67% after those one and 81% after those two. But not to say that women cannot get myocarditis or pericarditis. Although the numbers are much smaller. Here's another set of data that I just wanted to share with you. These are cases four million. Also data that was presented last week With the background rate of myocarditis, pericarditis is expected to be 1-10 for 100,000. These cases that I'm showing you up a million. And based on age and gender. So what you see here is the rates of myocarditis and pericarditis. Uh, in overall all the vaccines m RNA vaccines received and the highlighted underlined after those two of the Fighter and Madonna and right at the bottom of the colors for ages. So 12 to 15 is the aqua 16 to 17 is the darker blue green is 18 to 24 the purple is 25 to 29. And the rest of the ages listed here. What I want to highlight here is that very clearly you see that the younger ages and after those two is where you have a higher rate of uh my code, itis and pericarditis. When you look at males only, it's very clearly much higher than the overall weights, again being the highest with the 16-17 year age group, four million doses. And then when you look at females alone, you see that the rate is much lower. So this is the data that was just recently presented. Uh the S. E. R. T. Uh thus far of the 1600s or so preliminary reports, uh 877 met the CDC criteria for myocarditis. Of those, 95% were hospitalized and 77 recovered uneventfully. Some of the patients were still reported to be hospitalized. A few deaths were reported that there was no specific number that was reported yet. Uh Some of these people presented in the outpatient setting um and recovered very quickly switching over to the johnson vaccine, The thrombosis from the side of Pena syndrome. The Tts uh thus far, out of 15 million doses, about 47 cases have been reported and the highest age group is between 30 to 49 with the highest being between 30 to 39 years of age. And in terms of where these thrombosis have occurred. It's essentially any arterial or venous system that can help the thrombosis. But with the cerebral rail system being the most serious one and associated with a higher mortality. Uh recently there have also been new cases that new adverse facts, serious adverse effects reported with the johnson vaccine. One of them is the Gullion barre syndrome. Uh Thus 430 reports of G. B. S. Have been reported. Most of these were in males occurred about two weeks within the vaccination but can occur up to six weeks after vaccination and based on the background rate, this seems to be slightly higher than a background rate of G. B. S. More recently. Also, there have been new reports about myocarditis pericarditis with the johnson vaccine, although much smaller in number compared to the M. RNA vaccines. And they have been from the symbolic events like D. V. T. And P. E. Uh immune from Beside a pina syndrome. And these are all felt to be potentially related with the johnson vaccine and should be reported to the vaccine adverse effect reporting system. What about those three as uh Great just talked about the boosters. Whether it's additional does are the boosters. Most of the data shows that the adverse effects are similar to those two in terms of what type they are but they may be slightly higher than the does too and lymph. And nobody was more common after those three than it was after those two. But in terms of serious side effects that's why we don't have a signal for that. What about Children? I'm just finishing up here. Um The the FDA approved Pfizer's Covid 19 vaccine for Children 5 to 11 years of fade which showed 90% vaccine effectiveness In preventing symptomatic disease. And the side effects these Children had was very similar to Children between 12 to 17 years of age and very similar to what the adults had. In terms of the more common side effects like fatigue, body aches and chills. Um The A. C. I. P. Also recommended that we should go ahead with this vaccine for Children 5 to 11 years of age. Currently many compromise. Children between 5-11 years of age do not have a recommendation for additional does as we don't have enough data in this age group. So in case you're interested you can uh for your Children of your for your patients. Children. Uh The appointments can be made through the patient online services and they don't have an account. They can call and make an account with with the customer assistance people or you can directly call the Mayor clinic Rochester appointment office as listed below this has the vaccine. Uh Practice has become extremely complex. Uh And it's uh many doses there are age restrictions. There are restrictions in terms of what kind of booster to who can who can be provided that we're trying to keep this very straight as patients go through the lines for the vaccination. And then finally I just wanted to touch a little bit about the COVID-19 required participation. The exemption forms were available On October 25 submission deadline is today. In fact the submissions are essentially religious and medical. We have two separate groups that review the religious or medical exemptions. From a medical perspective, it's really only two exemptions that meet criteria which is severe or immediate reaction to a prior does or a vaccine component or a pre existing clinically diagnosed fear of needles. And there are a few of those patients On December three, those who have not done either will receive a final written warning. And on January 3, 2022, if people are still unvaccinated, they will be terminated. So in conclusion, uh in regards to immune compromised individuals. Additional M RNA does is recommended 28 days after primary series And and Mrna Booster, six months after additional does. There are numerous uh side effects serious side effects. Although rare with these vaccines that we have to continue to keep vigilant about and report to the vaccine adverse effect reporting system. And we have a required vaccination program in at mail bombs are due today And appointments are available for Children who can be vaccinated with the Pfiser COVID-19 vaccine as of last Friday. Thank you And we will take questions. Thank you first of all. Thank you both. Outstanding talks really adding a lot of clarity to an area in which has been sort of a maelstrom of information and confusion. So wonderful to have you here with us. Um and we have a lot of questions. The first one I'll just start with Lawrence Summers asked this question given that vaccine protects mainly against death and hospitalization, less against infection. That protection wanes over time that the new fighter drug appears to prevent 89% of death and hospitalization. Is there an expectation that mandates may wane. That is we now have pills do need the vaccination. I'll be very interest maybe I'll direct this one to Greg. And then I have another question for a Vonage. Good question. Who knows we uh we know top level results from a press release in regards to the to antivirals. Remember that with mark, it was about 50% with fighter about 89%. But we have not seen peer reviewed published data yet. And like louis lasagna, the pharmacologist always used to say use the new drug quickly because over time it's not as good. So I think I think that strategy remains to be seen. Generally speaking, we would still always push vaccination. Prevention is usually better than therapeutics And if you get infected you get antivirals, you don't necessarily develop protective immunity. So you finish that course of drugs, you're now susceptible again and you go through the same cycle over and over again with the Merck drug. There is concern about muda genesis that in fact it could provide a mutation pressure for the development of ever worsening if you will variants that might not have arisen naturally. No, thank you. And I have to say I I was just reflecting on the very nature of the question and it strikes me as if someone came to preventive cardiology clinic, would you say we've got great treatments for your heart attack? Go and have it rather than giving another buys a drug like before to lower your cholesterol. So it philosophically there's just some fundamental parallels that I find intriguing. A bonus. The question for you is you you mentioned the risk of myocarditis with vaccination. But what's the risk of myocarditis with covid infection? And how do they compare? Because that's really the question in my mind. Yeah, the risk of microbes itis with COVID infection is much higher than it is with the vaccine alone. I mean, the vaccine risk is pretty rare overall if you look at it, but the risk of my colitis is higher with COVID-19 infection. In fact, I've seen estimates of about 11-fold higher. Thank you know that I think it's important for all of us as cardiologist who are often asked these questions about my card itis in particular to be aware of that. I'm going to take 11 liberties host. Before I go back to my colleague's questions and ask a very pragmatic question, What's the risk of going out to dinner with my family in Rochester? If I've had a full series of vaccinations, including a booster, well, I don't know your family to know the risk paul. All right, I just need you to dinner with. My family always has a personal list for me, but over infections, you know, paul that your risk is a little lower in new york city going to a restaurant than it is in Rochester because new york city has a mandate that every employee in the restaurant and every customer in the restaurant has to be vaccinated, which is not the case in Rochester. So unfortunately, I think the risk is a little higher in Rochester. I, I personally, and I think that there's no way to quantitative. I personally wouldn't go to an indoor restaurant at this point, Minnesota ranks 17th in the nation in terms of people immunized. I'm shocked that even in a medical town like Rochester when I'm there, the number of people that don't wear masks that haven't gotten vaccinated. Um, so I'd be, I'd the air on the side of caution with that one. Thank you Kyle Cleric asks If one of 423 us citizens are dead due to COVID, what do we know about other countries and worldwide. Yeah, it does vary. It varies by state and that is a reflection of underlying immunization and it varies by country as you're pointing out it's a little bit apples and oranges. You know the death rate fortunately in the U. S. Has declined with time related to this soup period care that people now receive unless they're in a surge you know demand type capacity whereas in less developed countries that same death rate could be many fold higher. Thank you. And chat recall. Um I want to acknowledge the great overview and is wondering about the mechanisms of immunity that is antibodies versus cell mediated immunity. And if antibodies are the major factor and this was touched on a little bit. Should we be measuring tigers? Will there be a point where that makes sense to do at some point? Yes but right now we still don't have the absolute correlate of protection in terms of what level of antibody and what what type of antibody should be done. And T cell immunity is a lot harder to measure because that's just very labor intensive and very complex. And so it's not something that we can just do right now. So um you know it hopefully will be in the near future. But we still don't have anything. Nobody nobody agree with one other complication is a correlate of protection against what death severe disease moderate disease asymptomatic disease complications over what time period. So we have a sense of what that correlate protection is at the population level. But like Avinash said, really no idea yet at the individual level, maybe in a somewhat related question, Francisco. Lopez Jimenez, uh in addition to again, thank you for the talk says, what about a single dose scheme for people with prior infection? Can you consider the infection essentially analogous to the first dose and then give a single vaccine? Um would they have maybe um Uh similar protection to two dose 1 and Francisco? I hope I didn't put your question too much. Uh That's a great question. I will say that it is one area under active investigation. What we can say is that people who had prior covid and then get at least one dose have superior immunity. I mean, really superior immunity. I don't think the recommendations are there yet to say, well, just one dose I suspect that's where we're going to head. But right now that recommendation is two doses after Covid. I've been asked you feel the same way? I totally agree. Most of the data shows that even after the first does the antibody response is equivalent to two doses in the people who didn't previously at COVID-19. But there's more recent data that has shown that vaccinated individuals who previously had uh you know, uh covid 19 have a much lower risk of reinfection than those that have not been vaccinated and that's based on two does. And so right now we really can't say if you can just do one does or we should stick with the two doses. And I think that's something we'll have to see in the future. So suppose you've had covid and you've had two doses. Should you get a booster right now? You know what I see what silence both of you with that question Because that was that was Omar Abu. Is that he was asking that question. So hopefully we'll find out in the future and maybe I want to be sensitive to time. Um, but just wanted to ask you both one more question which has come up several times and that is you've had your primary series and you're going to get a booster. Which one do you get meaning? Do you stick with the same one or do you mix and match and and maybe I'll have you answered the same order that you spoke just for some order here? So Greg and then I've been executed please. So, you know, you're likely to get maybe different opinions as you look across the spectrum. But for this vaccine, Ologists, the data to me suggests that a mix and match strategy is superior. Um, So if you've got primary Moderna, get a fighter booster. If you got primary fighter get a Moderna booster um that's playing small differences. I think the main point is get a booster of either one. But the mix and match data shows subtle improvements with changing vaccine dr burke. So, um I agree with Greg and I would I would say that the biggest advantage is for people who got the johnson single does that. They should get they should that getting an M. R. N. A boosters actually really advantageous in that situation. Um, but how does that, how does that compare? Somebody got two doses of johnson? We don't know that because those studies have not yet been done between the M. RNA vaccines. Um, I think there's a bigger advantage from uh in the fighter people who get the Madonna booster. I'm not sure vice a versa. If there's a there's a huge advantage if somebody got Madonna as the primary and go get the fighter because again, those two vaccines are so similar, but I think it's mostly a dozing difference in those two vaccines. Well, thank you both very much. It's been a fascinating morning. I've learned a lot, really appreciate your time and your expertise. Thanks for joining us and have a great day. Everyone
