Dr. PAUL FRIEDMAN: So I'd like to welcome everybody to our CV Grand Rounds and thank Dr. Panithaya Chareonthaitawee 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. Abinash Virk is a professor of Medicine 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 ID 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 and founding and current director of our Vaccine Research Group. And his lab has developed the field of viral vaccine immunogenetics. 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 received the Secretary of Defense medal for Outstanding Public Service.

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.

GREG POLAND: You bet. And good to be with you colleagues. There's my slide.

First, a shout-out to some of the cardiologists I've most worked with, Guy Reeder, Rick Nishimura, Rob McCulley, Paul, you, and Sam Asirvatham. You guys are really just world leaders in what you do, and it's an honor to work with you.

So Abinash and I are going to talk about COVID-19. I'm briefly going to address breakthrough disease and boosters.

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 II, and of course, we called 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. It 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 percent 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's 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 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. A 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-- again, significantly decreases the chance that one dies, gets hospitalized, 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, high 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. 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 occurs-- and this is a chart from a paper in the Journal of the American Medical Association. If you look at this orange line here you see a not quite, but linear decrement 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.1, or Brazilian variant, in orange, and you see that both age and variant type decrement the antibody response.

So here's what I was mentioning about measles. 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-- where nobody is immunized against measles, then virtually 100% of people get measles, but none of the cases occur in immunized students.

If you immunize everybody, then you have about 100 who don't respond well. So 1,900 of them are immune. The 100 that get exposed will 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 120 to 28 days after full vaccination and look at vaccine efficacy, or in this case, effectiveness against hospitalization. Well, for Moderna the point estimate was 92% after 120 days; for Pfizer, 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 4,500 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 immunocompromised, it was about 51%. If you look at people who were vaccinated 120 or more days ago, for Moderna, it was 85%; for Pfizer, 64%. 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 starting to get into the Delta surge.

Among those who were fully vaccinated, about one out of 13,000 were hospitalized. Only 20% of those went to the ICU. 70% of the hospitalized cases, though immunized, were in people over the age of 65; 87% of the deaths in people over the age of 65. And here's this paradox. Fully vaccinated cases who were hospitalized increased from 0.101% 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 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 to 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 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. But 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 percent vaccine efficacy down to about 60%. So time is the enemy here, as well as variant type.

In terms of booster vaccinations, as vaccinologists, 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 there first, us last-- is 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 is it what is a 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 9,000 with your booster. 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 to 55. And on the right-hand side-- this is a small study, as many of them are, 65 to 85. It 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 1,500, 1,600 in antibody titer.

Now, another study that came out was looking at hospitalization at a two-dose Pfizer 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 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 very significant differences over time in people who got no doses versus two doses versus three doses of an mRNA vaccine.

So what does that look like? This is a third study from Israel. As you may know, they've got just superior systems for detecting this, and 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 more months ago, or, if you got J&J, two or more months ago. They're 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 to 64 and have underlying medical conditions. The "may," we may offer it, is 18 to 49-year-olds with underlying medical conditions, 18 to 64 years old who are at increased risk for COVID because of their occupation or the institutional setting.

More or less, you begin to see this is some 90% or so of the population that's over the age of 18. The bottom line here is that vaccinated adults are about two thirds less likely to get COVID infected. There they're about two thirds less likely to have asymptomatic infection. If they're infected, their viral loads decline rapidly, and the virus is less likely to be culturable 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 in the vaccinated is about 4.5 per 100,000 versus almost 84 per 100,000 in the unvaccinated.

And with that, I will stop, and Abinash, the show is yours.

ABINASH VIRK: I will talk about vaccinations in immunocompromised individuals, what's new about adverse effects related with these vaccines, and just to give you a little snapshot of where we are with the 5 to 11-year-olds and their vaccination rollout at Mayo, and touch a little bit about the vaccination requirement policy here at Mayo.

So Greg just talked about boosters because of waning immunity or emerging variants. What I'm going to talk about is the additional dose, which is really helpful in terms of improving the primary series immune response. And this is particularly important in immunocompromised individuals and you know this from other vaccinations, like hepatitis B or meningococcal vaccine, where we give a slightly different schedule to immunocompromised 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 immunocompromised individuals, we know we have about three million individuals who are immunocompromised-- seven million, but 3% of the population. These individuals are at higher risk of severe COVID prolonged infection. The immune responses are lower than immunocompetent individuals. And unfortunately, these individuals also tend to have prolonged shedding, which is associated with higher likelihood of transmission to others within their sphere.

And numerous studies have shown that immune responses among immunocompromised individuals are significantly lower than the vaccine effectiveness in the immunocompetent individuals and, as Greg has just shown-- that they're at 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 immunocompromised individuals, although not robust but good, up to about 50% increase-- about 50% of the individuals will have an increase in antibodies, the ACIP and FDA, back in August, recommended that moderately or severely immunocompromised individuals should receive an additional dose of mRNA COVID-19 vaccine dose, at least a month after they finish their primary series. And this is for the Pfizer vaccine for all the children and adults about 12 years of age and Moderna 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 immunocompromised individuals-- so this is a notable point, that all individuals who received the Johnson vaccine, including the immunocompromised 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, two months after the dose 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 immunocompromised individuals-- and this is exactly what you would be thinking-- is patients on active chemotherapy for solid and hematologic malignancies, the transplant patients, bone marrow transplant patients, CAR-T patients, primary immunodeficiencies, and also patients who are on immunosuppressive agents for various conditions, including high-dose prednisone i.e. about 20 milligrams per day for many weeks.

In addition, the ACIP gave additional guidance and leeway to 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 are immune compromised, then you would be the best judge for that patient.

The other guidance that came through was for patients who are going to be on impending immunosuppression. 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-dose 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 dose 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 this testing done to decide whether or not to 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 measures. And so currently, we're not recommending doing serologies for deciding whether somebody needs a vaccine dose or not.

Switching over to adverse effects, what I want to just highlight is that there 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 this slide the various numerous systems that are currently monitoring for adverse effects post-authorization.

We all know about the general reactogenicity symptoms, like 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 two to five 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 that I will talk about is myocarditis. But I just want to give you a gender-based snapshot of these serious side effects. So the Johnson vaccine is associated with thrombosis, with thrombocytopenia syndrome, as well as the syndrome. However, the TTS is more common in women, whereas the Guillain-Barré syndrome is more common in men with the Johnson vaccine. And the mRNA vaccines, as you are all probably very well aware, associated with myocarditis and pericarditis and occurs more commonly in men than with women.

So this was data presented at the ACIP meeting last week. So I want to share with you what the summary data is. The highest risk group for myocarditis and pericarditis is people between the ages of 16 and 24, more common in men than women, more common after second dose than the first dose. And the rates are really equivalent between Pfizer and Moderna, although there have been more cases with the Pfizer, but that's because more vaccines have been given [INAUDIBLE] Pfizer BioNTech vaccine.

Thus far, the Vaccine Adverse Event 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 myocarditis, and only a smaller number have had pericarditis alone.

And looking at the data that was just recently presented, the median age after does one is about 18; median age is about 20 after does two. Median time to symptom onset is essentially within the first week and very soon after the vaccination, within the two to three days. More commonly in men-- as you can see, 67% after does one and 81% after does 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 per million, also data that was presented last week, where the background rate of myocarditis, pericarditis is expected to be one to 10 per 100,000. These cases that I'm showing you are per million and based on age and gender.

So what you see here is the rates of myocarditis and pericarditis in, overall, all the mRNA vaccines received. And the highlighted, underlying after does two of the Pfizer and Moderna-- and right at the bottom are the colors for ages. So 12 to 15 is the aqua; 16 to 17 is the darker blue; green is 18 to 24; and 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 dose two is where you have a higher rate of myocarditis and pericarditis. When you look at males only, it's very clearly much higher than the overall rates-- again, being the highest with the 16 to 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 at the ACIP.

Thus far, of the 1,600 or so preliminary reports, 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, but there was no specific number that was reported yet. Some of these people presented in the outpatient setting and recovered pretty quickly.

Switching over to the Johnson vaccine, the thrombosis, thrombocytopenia syndrome, the TTS-- 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 have thrombosis but with the cerebral venous system being the most serious one and associated with a higher mortality.

Recently, there have also been new cases that new adverse effects, serious adverse effects reported with the Johnson vaccine. One of them is the Guillain-Barré syndrome. Thus far, 130 reports of GBS 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 GBS.

More recently also, there have been new reports about myocarditis, pericarditis with the Johnson vaccine, although much smaller in number compared to the mRNA vaccines. And there have been thromboembolic events, like DVT and PE and immune thrombocytopenia 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 does three? As Greg just talked about, the boosters-- whether it's additional dose or the boosters-- most of the data shows that the adverse effects are similar to does two in terms of what type they are, but they may be slightly higher than the dose two, and lymphadenopathy was more common after dose three than it was after dose two. But in terms of serious side effects, thus far, we don't have a signal for that.

What about children? I'm just finishing up here. The FDA approved Pfizer COVID-19 vaccine for children 5 to 11 years of age, 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.

The ACIP also recommended that we should go ahead with this vaccine for children 5 to 11 years of age. Currently, immunocompromised children between 5 to 11 years of age do not have a recommendation for additional dose as we don't have enough data in this age group.

So in case you're interested for your own children or for your patients' children, the appointments can be made through the Patient Online Services. If they don't have an account, they can call and make an account with the customer assistance people, or you can directly call the Mayo Clinic Rochester appointment office as listed below.

The vaccine practice has become extremely complex. And many doses-- there are age restrictions. There are restrictions in terms of what kind of booster, who can be provided, but we're trying to keep this very straight as patients go through the lines for their 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 dose or a vaccine component, or a pre-existing clinically diagnosed fear of needles, and there are a few of those patients. On December 3, 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, in regards to immune-compromised individuals, additional mRNA dose is recommended 28 days after primary series, and an RNA booster six months after additional dose. There are numerous 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 at Mayo. Forms are due today. And appointments are available for children who can be vaccinated with the Pfizer COVID-19 vaccine as of last Friday.

Thank you. And we will take questions.

Dr. PAUL FRIEDMAN: First of all, thank you both. Outstanding talks, really adding a lot of clarity to an area in which there's been a maelstrom of information and confusion, so wonderful to have you here with us.

And we have a lot of questions. The first one I'll just start with from Virend Smers asks this question-- "Given that vaccine protects mainly against death and hospitalization, less so against infection, that protection wanes over time and that the new Pfizer drug appears to prevent 89% of death and hospitalization, is there an expectation that mandates may wane? That is, we now have pills. Do you need the vaccination?"

Maybe I'll direct this one to Greg, and then I have another question for Abinash.

GREG POLAND: Good question. Who knows? We know top-level results from a press release in regard to the two antivirals. Remember that, with Merck, it was about 50%; with Pfizer, about 89%. But we have not seen peer-reviewed, published data yet. And like Louis Lasagna, the pharmacologist, always used to say, use a new drug quickly because over time, it's not as good.

Dr. PAUL FRIEDMAN: [LAUGHING]

GREG POLAND: So 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 mutagenesis, that, in fact, it could provide a mutational pressure for the development of ever-worsening, if you will, variants that might not have arisen naturally.

Dr. PAUL FRIEDMAN: No. Thank you. And I have to say 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 ahead and have it. Rather than giving another Pfizer drug, like Lipitor to lower your cholesterol. So philosophically, there's just some fundamental parallels that I find intriguing.

Abinash, the question for you is-- 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.

ABINASH VIRK: Yeah, the risk of myocarditis 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 myocarditis is higher with COVID-19 infection.

GREG POLAND: In fact, I've seen estimates of about 11-fold higher.

Dr. PAUL FRIEDMAN: Thank you. No, I think it's important for all of us, as cardiologists, who are often asked these questions about myocarditis in particular to be aware of that.

I'm going to take one liberty as host before I go back to my colleagues' 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?

GREG POLAND: Well, I don't know your family to know the risk, Paul.

Dr. PAUL FRIEDMAN: All right, how about just me?

GREG POLAND: I'm kidding. [LAUGHING]

Dr. PAUL FRIEDMAN: Going out to dinner with my family always has a personal risk for me, but not talking about COVID infection.

ABINASH VIRK: I'll say, 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 your risk is a little higher in Rochester.

GREG POLAND: Yeah. There's no way to quantitate it. 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-- so I'd err on the side of caution with that one.

Dr. PAUL FRIEDMAN: Thank you. Kyle Klarich asks, if one of 423 US citizens are dead due to COVID, what do we know about other countries and worldwide?

GREG POLAND: 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. The death rate, fortunately, in the US has declined with time related to the superior care that people now receive, unless they're in a surge, demand type capacity, whereas in less developed countries, that same death rate could be many fold higher.

Dr. PAUL FRIEDMAN: Thank you. And Chet Rihal wants 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 titers? Will there be a point where that makes sense to do?

ABINASH VIRK: At some point, yes. But right now, we still don't have the absolute correlative protection in terms of what level of antibody and 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 it hopefully will be in the near future, but we still don't have anything.

GREG POLAND: I would agree with Abinash. 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 of protection is at the population level, but, like Abinash said, really no idea yet at the individual level.

Dr. PAUL FRIEDMAN: Maybe in a somewhat related question, Francisco Lopez-Jimenez, in addition to, again, thanking 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? Would they have maybe similar protection to the two-dose one? And Francisco, I hope I didn't butcher your question too much.

GREG POLAND: 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. Abinash, do you feel the same way?

ABINASH VIRK: I totally agree. Most of the data shows that, even after the first dose, the antibody response is equivalent to two doses in the people who did previously have COVID-19. But there's more recent data that has shown that vaccinated individuals who previously had COVID-19 have a much lower risk of reinfection than those that have not been vaccinated. And that's based on two doses. So right now we really can't say if you can just do one dose or we should stick with the two doses, and I think that's something we'll have to see in the future.

Dr. PAUL FRIEDMAN: So suppose you've had COVID and you've had two doses. Should you get a booster?

ABINASH VIRK: Right now, yes.

Dr. PAUL FRIEDMAN: I see we silenced both of you with that question, because that was-- Omar Abou Ezzeddine was asking that question. So hopefully, we'll find that out in the future.

I want to be sensitive to time, 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, you stick with the same one, or do you mix and match? And maybe I'll have you answer in the same order that you spoke, just for some order here. So Greg and then Abinash, if you would please.

GREG POLAND: Yeah, so you're likely to get maybe different opinions as you look across the spectrum. But for this vaccinologist, the data, to me, suggests that a mix and match strategy is superior. So if you got primary Moderna, get a Pfizer booster. If you got primary Pfizer, get a Moderna booster. That's playing small differences. I think the main point is get a booster of either one, but the mix and match data show Subtle improvements with changing vaccine.

Dr. PAUL FRIEDMAN: Dr. Virk?

ABINASH VIRK: So I agree with Greg, and I would say that the biggest advantage is for people who got the Johnson single dose-- that getting an mRNA booster is actually really advantageous in that situation. But how does that compare if somebody got two doses of Johnson? We don't know that because those studies have not yet been done.

Between the mRNA vaccines, I think there's a bigger advantage in the Pfizer people who get the Moderna booster. I'm not sure, vise versa, if there's a huge advantage if somebody got Moderna as the primary and go get the Pfizer, because, again, those two vaccines are so similar, but I think it's mostly a dosing difference in those two vaccines.

Dr. PAUL FRIEDMAN: 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,

ABINASH VIRK: Thank you.

GREG POLAND: OK, be safe, everyone.