STHUTHI: Great. Well, welcome, everyone to medical grand rounds, both in person and via the Zoom-iverse. We are thrilled to have Dr. Petri here to give us an amazing-- give us an overview of the COVID-19 vaccine and the amazing science behind its development. It's also a timely talk as several frontline workers have begun to be vaccinated this week. So a little bit about Dr. Petri, he joined the infectious disease faculty at UVA in 1988 after completing a fellowship here. He's held professorial positions in the Department of Microbiology, Pathology, and Infectious Disease. 

I would describe Dr. Petri's illustrious career as "academic medicine goals," quote unquote. He served as chair of the Division of Infectious Disease and International Health until 2018. Throughout his career he has won innumerable awards, such as Virginia's Outstanding Scientist in 2017, and the Outstanding Faculty Award, which is the Commonwealth's highest award for faculty, presented by Governor McAuliffe. He has authored more than 150 publications. 

During the COVID pandemic he's undertaken the Herculean task to better understand the type 2 immune response in COVID-19, which leads to the devastating respiratory complications we see in the hospital. If that wasn't enough, he has volunteered to attend on the SPU floor units and relearned how to place orders. I can't think of a better person to take us through the development and implementation of the COVID-19 vaccine. So without further ado, here is Dr. William Petri. 

WILLIAM PETRI: Sthuthi, thanks. Thanks so much. It's been really wonderful working with you this year as chief. And thanks for the opportunity to talk about the exciting things that are going on with the COVID vaccine, and I'll jump right in. These are my disclosures, and-- start with, you know, traditionally grand rounds was with a patient presents something that-- Doug and I admitted on Monday evening a 71-year-old male who's got a past medical history of interstitial lung disease and he had tested positive for COVID five days previously, presumably acquired from his wife, and since that time had continued to get worse. 

And he had a pulse ox monitor at home and so he was desatting. And he actually put himself on home O2 to maintain his pulse ox. And so he came in to the ED and of course, there wasn't much of a question by Doug and I about that he needed to be admitted, and unfortunately his course has been progressively downhill despite the fact that he's on the two medicines that we know have some effectiveness for this disease. Remdesivir and dexamethasone were both started the night of admission by Doug, but you can see that the progressive deterioration. 

And so actually this morning at 4:30, Jeff Sturek from Pulmonology intubated him and now unfortunately he's on norepinephrine. And so I present this as illustrative. We can see these numbers and the terrible problem with the third wave, and we can see the excess mortality with a-- Red Cross's there from COVID-19. But it all comes down to individuals involved that we're-- each of us are caring for. And so thank goodness for a vaccine, and that we do see a way out of the terrible situation that we're in right now where patients are deteriorating despite our best efforts to care for them. 

And this is the virus that's responsible. I'm just showing you what's called a negative stain electron micrograph there, so you can begin to appreciate these little white projections that are coming out from that white sphere. Those are the spike glycoproteins and that's what the Pfizer and the Moderna vaccines are using to make an antibody response, because we know that antibody against that spike glycoprotein protects. We know that from the Regeneron studies, the antibodies that President Trump received. We know that just administering antibodies against a spike glycoprotein provides protection. The vaccine is designed to induce those. 

I think it's important to just take a step back for a second and understand how this infection works. I'll probably just try to explain this rather than point to it. And so if you can follow with me as you're looking at the screen on your left is a SARS coronavirus, and those green things pointing out are meant to depict the spike glycoprotein. That attaches to the epithelial cells in the airway, and then the virus uncoats, and it introduces its RNA into the cytoplasm. So this virus never gets into the nucleus of a cell. 

And in the cytoplasm it makes its proteins, including the spike glycoprotein, and replicates. And then on your right as you're looking at this diagram, those proteins are produced in the endoplasmic reticulum. The virus actually assembles from the cytoplasm, butting into the endoplasmic reticulum, and then is released to cause new infectious viruses. And so what I want to talk about just in brief is a little focus on what's going on on the left, that viral entry process, because that's how the vaccine is working, is by preventing that viral entry. 

And so again, the green things sticking out of the sphere are the spike glycoprotein. The rectangle is showing you the coding sequence. And so there's two pieces to this spike glycoprotein, S1, which is on your left and that's the N-terminus, then S2 on your right. And these are-- both of these are really, really important for the virus. S1 has a receptor-binding domain that attaches the virus to two receptors, something called neuropilin, which is NRP1 on that diagram there in the epithelial cell membrane, and then ACE2, the angiotensin-converting enzyme number two. 

And so after attachment then the virus then undergoes a huge conformational change that exposes the fusion peptide on S2, and this fuses the virus membrane with the plasma membrane of the host, allows the virus to get inside. And so everything with vaccines is how do we prevent this interaction of the virus with ACE2 and NRP1, because if you do that then there is no infection. This just shows you in the airway epithelium of a patient with COVID-19. On your left is a control where you don't see any coronavirus, which is stained in brown. Then in the middle and on the right are two biopsies from patients just showing you the colocalization of the virus, stained in brown with antibody against the spike and NRP1 which is this neuropilin, which is a co-receptor that's stained in purple. 

So this is what we're trying to prevent happening. This is what is called the prefusion conformation of the spike glycoprotein, and this was determined by what's called cryo-electron microscopy. And so it's a much faster way of determining protein structure than having to grow crystals. Crystallography was the traditional way but this allowed rapid determination of the structure. And the purple is the receptor-binding domain, which we want to direct antibodies against. The fusion domains are in green there at the S1/S2 boundary. 

You'll hear when the vaccine is described, they'll say it's in the locked conformation. And so what was done by Barney Graham at NIH was to put two proline mutations into this protein so that it cannot undergo the conformational change to allow it to fuse. And so you're not going to get-- an antibody response is going to block fusion because that part of the protein is never exposed with this locked conformation. What you do generate is a very, very effective antibody response against the receptor-binding domain. 

So, the advantage of teaching something is you learn it much better than the audience. I didn't know that about the locked conformation, what people meant by that, until I prepared for this grand rounds. But this is just to show you what's happening with this huge conformational change. There's nothing that changes its structure more than viral glycoprotein, so they're really notorious for this. And so on your far left is the prefusion state. Again the purple's the receptor-binding domain. 

You can see, then you have viral attachment. They're showing you ACE2, this cartoon was made before neuropilin was understood to be a co-receptor. But upon binding to ACE2 and neuropilin, the virus goes in this crazy conformational transition that you can see is the fusion intermediate. And so the top membrane is the airway epithelium, the bottom membrane is the virus membrane. And you can see those little blue things are the fusion peptide, FP, and the fusion peptide precursor region, which is in dark blue. And you can see that those are hidden in the spike glycoprotein in the middle cartoon. 

And so upon that, this forming of the fusion or [INAUDIBLE] the fusion of the virus membrane with the host cell membrane, and then the infection starts. So again, the vaccine is really designed to inhibit the viral attachment stage and not the fusion. So again, just one last look at this beautiful and terrible creation of the spike-like approach of this virus. 

So the other thing that's important to understand is the difference between nucleic acid vaccines. Because as everyone in this room knows, we have a wonderfully effective vaccine that is not going to work at all if people don't take it. And so understanding how the viral vaccine works is important to understanding how safe it is. And so then I think it's important on all of our part to be able to communicate that to friends and people that ask, whoa, they rushed this through, is it really safe? 

Well, DNA vaccines have to actually get into the nucleus of a cell in order so that, for example, a spike glycoprotein could be expressed. And so on the far left is showing you a DNA vaccine getting taken up into a cell going into the nucleus, and then you make mRNA. And so there's a slight potential whenever you put something in the nucleus that something bad could happen, right, that you could cause a mutation. 

RNA vaccines never ever see the nucleus. There's no way for an RNA to go backwards from the cytoplasm into the nucleus. And so the RNA vaccine, which you can see on your right there, is shown to be in a liposome or a lipid vesicle, is injected into the arm, and then that lipid vesicle and the messenger RNA is taken into the cytoplasm of human cells. And then you make the spike glycoprotein, you don't make the rest of the virus. And so it's no chance of getting an infection from this. 

And then with that protein being made, then there's a possibility making an immune response against it. And this has worked amazingly well and under this crazily-accelerated development of a vaccine. So that-- again, as we all know we're 12 months into the pandemic and to have a vaccine is just astonishing. And people are concerned like, well, gee, what got sacrificed to do things so quickly? And I think what has not been sacrificed is safety. 

And so if you look at this SARS-CoV-2 vaccine development on the bottom of this slide, it took literally just days to weeks when the viral sequence was released for both BioNTech, that's collaborating with Pfizer and Moderna, to know the sequence of the mRNA. And we knew from the original SARS and then MERS, that an antibody response against that spike glycoprotein would be protective. And so within weeks they were able to start assembling an mRNA vaccine, whereas ordinarily one could spend years trying to express that spike glycoprotein, get it properly-- properly folded so that it looks like the one in the virus. 

So all that was eliminated, so that was a huge time-saver. The other thing was-- is that the federal government worked with the companies to have a common clinical protocol for Phase 1, Phase 2, Phase 3. So the companies were all working towards the same endpoints for the FDA. And another thing that of course compressed the clinical trials is a terrible thing, is it was that the third wave of the pandemic coincided with the Pfizer and the Moderna clinical trials having 30,000 vaccinated, 30,000 placebos. So unfortunately it didn't take very long for there to be enough cases acquired that you can see that these vaccines were 95% effective. 

What has not been sacrificed is safety. And so again, Phase 1, Phase 2 were to show that it's safe, Phase 3 is to show it's effective. So we now have upwards of 30,000 people that have received the Pfizer vaccine, 30,000 received the Moderna vaccine, and at least half of those individuals had to be followed for two months after the second vaccination to look for any kind of long-term safety issues, which none showed up. But they basically added a month's delay, with 3,000 people dying every day, to be assured that you have this two-month window for safety monitoring. And the FDA is going to, of course, then require that the Phase 3 studies be completed, and so these individuals be followed out for one year. 

So really I think it is remarkable. So what has not been sacrificed with this speed is safety. So this is-- there's actually two Pfizer vaccines, a little bit confusing. You have to look for the b2 on the-- because that's the one that uses the full-length spike glycoprotein. And that's what's being released, that's what people are getting vaccinated with now. There's another one called b1 that just had the receptor-binding domain. On-- so you had to had to pay little bit of attention when you're looking at the literature. 

But it's the mRNA and it's in lipid nanoparticles, and it's given intramuscularly. And you get two doses, so one this week if you're in the first wave, and then one three weeks later. When the Moderna vaccine is approved, it may have already been approved this morning by the FDA because the only difference is that it's four weeks between the two doses. So the goal vaccination was to neutralize the spike glycoprotein. 

And so what we're looking at here on the y-axis is titer of antibody that it takes to prevent the virus from infecting a cell in a laboratory cell culture. And then we're looking on the x-axis is days after vaccination. And then the different colors green, as it gets darker and darker green, they're using more and more of the vaccine to immunize individuals. So this is the Phase 1, Phase 2 study where they're figuring out what is the right dose of the vaccine to give. And you can see that if you look at 30 micrograms versus 50 micrograms, they look essentially equivalent, that you're getting very high titers of antibody that neutralize the virus. 

And so this is how the amount that you get injected with was determined, and just demonstration that it's making the antibody response that we think should be associated with protection. So that's the antibody part of this. So there's also the issue of the virus, does it mutate? And it doesn't mutate like the way that influenza does, it actually has a proofreader. 

So it's almost like when you're typing on Microsoft Word, you have spell-check. This virus actually has a protein that checks the RNA polymerase and corrects errors. And so it's a much more stable target, but there are some mutations. 

And this is showing you that the vaccine is effective at neutralizing multiple variants in sequence in the receptor-binding domain. And if you just saw this, D614G mutation was just in Science Today. That's the predominant strain in the US right now because it's more transmissible than the original one. But you can see that we're still getting over 10 to the third neutralizing antibody titer against that variant. So that's also a good piece of news. Although there is some genetic drift in the virus, this vaccine is covering the waterfront. 

Well, there's not just antibodies but there's T cell mediate immunity as well. And so if you look at the bottom of this diagram, we're seeing proteins, in this case, the viral proteins being produced in the cytoplasm. Those are processed and they're presented on MHC class I, or class II to the immune system. So this is this beautiful system. So you see what's the light blue thing on the top is a CD8 T cell. And its T cell receptor is recognizing that blue MHC class I and is presenting a piece of the viral protein or peptide. 

And so that's the way that T cells can know whether a cell is infected or not. And so Polly Matzinger at NIH described this once, it's like that every cell in your body has a zipper on it, and the immune system can unzip it, look inside, and see is there a virus infection there or not. If there's not, it just zips it back up. And so T cell mediated immunity is really important to cure an infection once it's already started, so the extent to which the antibody doesn't completely prevent infection, a CD8 T cell response is really important. 

And this vaccine makes very robust CD8 and CD4 T cell immune responses. And so you've got a kind of coming and going, both an antibody response and a cell-mediated immune response. And then of course the vaccine works extraordinarily well. So this is this week's New England Journal. And the big graph is showing you the protection from everybody that got two doses of the vaccine, so three weeks apart, and the blue is the placebo group, and then the red is the vaccinated group. 

And so if you go-- in the first 14 days is when the groups begin to separate after the first vaccination. And you can see in the inset, that they looked just after dose one, so how protective is that? So if you got dose one this week, so you can see that by about 12 days from now or a little bit after Christmas, you'll have about 50% protection from infection. And then when you get that second dose is when you achieve 95% protection. 

So, when Tony Fauci was here speaking, or not here, he was zoomed here to talk a few weeks ago, I had a chance to meet with him afterwards. And he was saying that when the president of Pfizer called him up on Sunday evening to tell him the results of the Pfizer vaccine, that Fauci was astounded. He expected that the vaccine would be 50% effective, he hoped it would be 70% effective. And so to have a 95% effective vaccine was just, just extraordinary. So that's the efficacy. 

Let's talk about side effects. And so, pain at the injection site like most vaccines, you can see it was higher. 66% of people that got the vaccine versus 8% with placebo, some redness, and then swelling, much less common. This is after dose two, usually the side effects are a little bit more substantial after dose two. And then the systemic side effects, we can go through it. 

And actually, Sthuthi, if you can get Jen Sasson, Jen is one of our infectious disease fellows, former house officer here, and just received the vaccine yesterday. And so I don't know, Jen, if you can speak for a second to the side effects that you've anticipated or the whole process of getting vaccinated. 

JEN SASSON: Yeah, absolutely. It was a-- the process was very smooth and efficient, and I'm sure that's a lot of work on behalf of a lot of administrative staff and pharmacy staff and nursing staff. So seriously appreciate that, it was a very smooth experience, very quick, in and out. You sit for 15 minutes to observe for any reactions, which I didn't have. Everything went smoothly. And I got it yesterday afternoon and no issues yesterday evening, a little bit of a sore arm today, but otherwise no issues. So overall it was-- it went well. 

WILLIAM PETRI: Oh great, hey Jen, thanks. Thanks so much. Nothing like getting it from the horse's mouth, what it's like. And I imagine several people in the room have had the vaccine by now as well. So, there is a system for-- again this is really important I think, that each of us be like a spokesperson to the public about how seriously safety is taken with this. 

And so there's a whole network that the CDC runs, which is the Vaccine Adverse Event Reporting System. And so we as physicians, we administer a vaccine and the patient calls us the next day with a side effect. This is the system by which those are reported. So it's more than just following the Phase 3 study out for a year, it says we go from tens of thousands to tens of millions of people vaccinated. This Vaccine Adverse Event Reporting System will be very important to pick up rare side effects associated with vaccination. 

So who gets it? And so there is an independent advisory committee for the CDC, you can see the membership there on, under the title. And so their recommendations sort of actually follow-- the National Academies of Medicine, Science, and Engineering actually came out with recommendations for how to distribute the vaccine. It's actually-- that was someone from UVA that had a big role in that is Jim Childress, who's retired now, but was a professor of religious studies. Those of you-- undergrads at UVA may have crossed paths with Jim. 

But Jim was important in the ethical underpinning of who gets the vaccine first, was hugely controversial. And so number one was health care personnel, and this is-- I think the thought process there is that you don't want to have the healthcare system disrupted with people having to go into quarantine or isolation. It's very, very few deaths fortunately of health care workers because we're for the most part young, healthy people. 

And then the second tier, which this committee recommended was residents of long-term care facilities. And then you sort of see much different-- way fewer people, but probably a fourth of all deaths are in residence of long-term care facilities. And so if you want to make an impact on mortality, then that's the group that you're going to get the most bang for your buck so to speak. So that's how that was happening. 

Slightly different [INAUDIBLE] and this is vaccine allocation across the US from the New York Times yesterday. And so you can't probably read this, but it is 72,000 doses of the Pfizer vaccine have been distributed to the US out of the first 2.9 million doses being shipped. And so this is what's getting divided up not only at UVA but across the state. Virginia has taken a slightly-nuanced view of this, and so long-term care residents are getting vaccinated at the same time in Virginia as healthcare workers. So they're both in Phase 1a. 

And again I think it's this trade-off between having an impact on mortality and protecting the people that are delivering care, and then essential workers, and then Phase 1c, high-risk adults. And so 70,000 doses have been delivered and that should be greater than a half million later this month. So that's the prioritization in Virginia. And then Costi Sifri has shared this with me, so what's going to happen like for Phase 2, or group two at UVA. 

And so what's going to happen is if you're like me, and you didn't-- you were not part of Phase 1, when more vaccine is arriving, which should be happening really soon with Moderna getting approved, likely today, you'll be able to actually evaluate your own risk and things, and so you're at risk for-- you have workplace exposure. Number one, then your risk for complications, and so do you have a serious underlying illness, are you elderly? Someone who's 80 is 20 times more likely to die than someone who's 50. 

And so you'll actually put that-- you'll input that information yourself, and then you'll be advised to schedule early. And if you don't have a risk of exposure that's extraordinary or personal risk for complications, then they'll ask you if you could wait for a few weeks, but the decision will ultimately be made by you. And as Jen Sasson was saying, they're doing things tremendously effectively and efficiently. And so I'm sure that they're going to be able to ramp up vaccination rapidly enough, that it's not going to be a huge issue for those of us that didn't get the first wave of vaccinations. 

And here's the Moderna data. So this is out of the information that was in the briefing document that the advisory committee reviewed yesterday. Again, the blue is the placebo group and the red is the vaccinated, so again, extraordinarily effective vaccine. 95% effective in all comers. In those over age 65, it was slightly less effective, 86%, too. I think this is another one of the surprises about both of these vaccines is how effective they are in the elderly, because we've had a terrible time immunizing the elderly. The people that need to get vaccinated against flu or those that are over age 65, and they are the ones that respond the worst to the flu vaccine. 

So maybe these mRNA vaccines are going to have a much broader impact than even COVID-19, that maybe we'll have a better flu vaccine next year, or other viral diseases like respiratory syncytial virus, for which we have no vaccine at all. But again, the Moderna vaccine, also amazingly effective. And then this is unpublished data. Moderna was really pretty clever. So when they brought people back in for dose number two, which is again is 4 weeks for Moderna, three weeks for Pfizer, they did those nasopharyngeal swabs, and they found that the people who four weeks ago had gotten the vaccine had 2/3 less asymptomatic COVID-19 compared to the placebo. 

And that's just after one dose, so presumably after two doses the Moderna and I guess the Pfizer as well is probably going to have that 95% effectiveness, both as symptomatic and asymptomatic. It'll just totally break the back of the pandemic because it has been the whole problem with asymptomatic infection. So I don't know about you guys, everybody I know who traveled over Thanksgiving had a family member infected with COVID-19, including my brother's family, where one of his sons traveled from California and was asymptomatic, and in fact and gave the entire family COVID-19. 

And fortunately everyone is doing OK with it, but it is-- having protection against asymptomatic infection that I think is going to be just super. So now just to get a little bit of like the nitty-gritty of how this works, and those of you that got vaccinated probably saw this, is that the vaccine is thawed. And that is, you add 1.8 mls of normal saline, and so it gives you five to six doses then per vial, because 0.3 mls of the diluted vaccine is administered intramuscularly. 

Pfizer studied age 16 and up, Moderna studied age 18 and up, so a little slight difference. Then the second dose three weeks later, there's a little bit of wiggle room there as far as when the second dose occurs. And this is recommendation from the CDC on Monday, so things could change. But [INAUDIBLE] they are saying if you miss a second dose, get it when you can. Don't repeat the whole thing all over again. And you won't have a 14-day interval from receiving other vaccines for I don't think any especially good reason, but just that-- just for what is done with vaccines. 

It's probably not a good idea if you got the first dose with the Pfizer vaccine to get the second dose with the Moderna, because nobody knows, that hasn't been studied. Presumably, it would work fine but we don't know that. Even if you've had prior COVID-19, you should get vaccinated. So that's not an indication not to. 

The one thing is if you were in a study where, like the study that we're running at UVA, where we're trying to prevent household transmission of COVID-19 by giving antibodies against a spike glycoprotein, so the people that are enrolled in my study, we're letting them know you need to wait 90 days for those antibodies to clear your system to get vaccinated. Otherwise there's the possibility it's going to blunt the immune response against the vaccine. 

So that's maybe the only reason not to immediately get vaccinated except for the allergy, which I'll get to in a second. Actually I think Mike Nelson is going be able to say a word about allergy, but first, pregnancy. So you think about what we're trying to protect health care workers, so 3/4 of healthcare workers are women. And so the whole issue of pregnancy and vaccination is absolutely enormous. 

And the studies of course were designed not to include pregnant women because whenever you're trying out something new, you're going to want to give it in adults that can consent to whatever risk that they could have from the vaccination. So children, pregnant women are excluded. However, there's no reason that this vaccine should be unsafe in pregnancy. It's an inactivated mRNA, it's not-- there's nothing infectious about it. And so we're left with well, what do you do? 

And fortunately, the American College of OB-GYN came out with a position statement that these vaccines should not be withheld from pregnant individuals, which I think is really important. I think one thing to remember that if you do get a febrile illness from the vaccine, it's important to take Tylenol to suppress fever during pregnancy. That's probably the only thing to add to that statement. 

And for lactating women, again, there's no reason not to be vaccinated. Actually my nephew's wife just asked me that question because she has a six-month-old, and whether she should get vaccinated or not. You're probably going to protect your baby by being vaccinated because you're secreting IgA antibodies in breast milk against the spike glycoprotein. So really, really important that the-- again, it's going to be in-- the ACOG recommends this be an individual decision, so a woman who's pregnant look at the information, can talk with her physician, and decide. But no reason to exclude these groups from vaccination. 

So immunocompromise, yes, give the vaccine. We don't know if someone who's on mycophenolate or something, is that going to impact the degree to which you get a neutralizing antibody response? So a little bit of an unknown, but no reason not to give the vaccine. And again, these are not live virus vaccines so there's no contraindication to that vaccination. 

Again, prior COVID-19, go ahead and immunize. And what we know right now is if you've had COVID-19, you're probably immune for about three months. We don't know after that because it hasn't been enough time. And so the recommendation is to immunize even if you've had the infection. And then maybe-- this is what is in the CDC guidance. And I don't-- if you, Sthuthi, if you get Mike Nelson. Those of you who have not met Mike, Mike is our new head of the allergy division and everything. And I asked if he could just say a word about what to do about allergic reactions. 

MIKE NELSON: Hey Bill, thanks. And thanks to this elegant discussion of vaccine immunology of the COVID-19 vaccines. [INAUDIBLE] a couple of decades ago and I continue to do so. Thanks also for mentioning VAERS and the reporting of adverse events. [INAUDIBLE] absolutely critical for the emergence of these two vaccines using new technology that we report any adverse events that are [INAUDIBLE]. 

So as an army guy, I'm kind of the bottom line upfront, let me give you a few of my take-home points regarding this issue of hypersensitivity or immediate hypersensitivity to vaccines, so immediate-type hypersensitivity is a risk for all [INAUDIBLE]. I'll give you a little bit of data that in a second. A history of severe allergies and/or anaphylaxis is considered a precaution, not a contraindication advisory [INAUDIBLE]. 

I'll say it again, considered a precaution not a contraindication to these vaccines. The only contraindication of these vaccines at present is known allergy to the components of the vaccines, which are going to be either PEG, polyethylene glycol, or the lipid nanoparticles [INAUDIBLE] part of the development of these vaccines. And there are very few around that have that known type of allergies, so if you find them, please make sure you refer them to us so we can study them appropriately. 

In general, the benefits far outweigh the risks. And even those with severe allergies, including a history of anaphylaxis, should indeed receive the vaccine under appropriate conditions. So as you see here on the side and as has been mentioned, the 30-minute wait period is recommended for these high-risk patients, and certainly consultation with our service for some of the more anxious in that regard is open to you and your patients. 

I haven't seen the site yet but I'm sure that there are trained personnel, equipment, and medications for the treatment of allergic reactions to these vaccines, as well as all [INAUDIBLE]. The other piece to remember is that outcomes are good. All the reported reactions to date, they are [INAUDIBLE] appropriately. There are no residual effects. And then finally, we state the term anaphylaxis for the four cases that have been publicized in the media, but we don't know for sure what the mechanism of these reactions are, the details and the risk factors that underlie them, have yet to been clearly studied or demonstrated. 

So the background is yes, there are allergies to all the vaccines and anaphylaxis is a risk. In fact, I had a chance to go back and look at what that risk is, so 1.3 per million vaccine doses, all vaccines combined, has been reported in a study by Mike McNeil, and similar numbers from others who have looked at databases with large health systems. So it does happen, and you have to be ready to treat them as we are [INAUDIBLE]. 

The rate for individual vaccines is all over the place, 1.8 to 12.5 per million for MMR, or 3.6 per million for DTaP. It is a risk for all of them, so it's not a surprise that we see some immediate hypersensitivity reactions to these two vaccines. So as I said, the only immunogenic pieces of the vaccines are the polyethylene glycol, and these lipid nanoparticles. A pre-existing allergy is exceedingly rare. 

So for the four cases that are out there in media and various reports, include the two in the UK reported by the National Health system, they're all with the first dose and they all occurred within the first 10 minutes or so, past history of anaphylaxis including one with a possible food allergy. We know the least about what occurred in the UK, but the CDC and FDA are working to identify the details and risk behind those reactions. 

There's a little bit more transparency with the two cases reported out of Alaska this week, they're both public healthcare workers, reactions occurred within 10 minutes, they both were referred to the emergency room. One was classified as serious and not life-threatening, had flushing in the face and torso at 10 minutes, followed by shortness of breath and tachycardia, sounds very much like anaphylaxis, is treated appropriately with antihistamines, corticosteroids, and injectable epinephrine. Symptoms recurred, so instead of giving a second dose of epi, which is what I would have done. They initiated an epi drip on [INAUDIBLE]. And again, I think that patient was discharged with 48 hours. 

The other was much less convincing for anaphylaxis, eye puffiness, lightheadedness, scratchy throat, treated with antihistamines and a dose of epi, was asymptomatic within an hour. That's all we have. So we don't know the immunologic mechanism behind these four cases. When you start to think about 1.3 per million doses is a general risk for anaphylaxis and these vaccines, I think we're going to see whether or not this is a true signal over the next week or so. 

If you go back and look at the studies for the EUA applications for the two vaccines, Pfizer none in their entire study of over 40,000 patients. For the Moderna vaccine, they had two anaphylactic events, but they weren't temporarily associated. One occurred 10 days after placebo, the other 63 days after the second dose of the vaccine. So really zero cases of immediate site hypersensitivity in the two vaccines. 

WILLIAM PETRI: Great, well, Mike, thank you so much for taking us through that, and I find that very reassuring. I'm going to start asking about polyethylene glycol allergies now, that's a new twist. But welcome to UVA, we're really looking forward to your leadership in allergy and immunology at UVA. Just a few more things to touch on-- I think the vaccine, those of us that become vaccinated, you still need to maintain vigilance. The vaccine is only 95% effective if you're vaccinated, you want to be setting a good example for everyone else. 

And so this-- all the usual things still apply. And then I'll just close, I'm almost done. Always give your audience hope that it's almost over, and it's almost over. I just want to tell you what we're doing at UVA, because they say, well gosh, how can you possibly contribute at all? We've got a vaccine that's 95% effective. Well, the ways that we may be able to help with this is by having an intranasal vaccine and by using adjuvants, which are things you add to a vaccine that give a prolonged antibody response. 

And so the approach that we're taking is also to use lipid nanoparticles which is that circle in the middle, the spike glycoprotein which you'll recognize, and then we're mixing them with two, what are called toll-like receptor agonists, to generate an immune response which can then be delivered intranasally. Those of you don't know this story, Hoffmann got the Nobel Prize, I guess about five years ago. And he's a Drosophila biologist, so he's making mutations of fruit flies. And he had fruit flies that died of infectious diseases. 

And you can actually sort of see. You see those little filaments that are coming out from the fruit fly, the fruit flies don't look like that normally. That's Aspergillus that's growing out of the fruit fly. And so he thought, well, gee, these things are dying of pneumococcal infection Aspergillus, I must have mutated something that has something to do with the immune system in Drosophila. And this was Toll, that's T-O-L-L. And then Bruce Beutler shared the Nobel Prize because he found toll-like receptors. And so when we have a patient in the unit with sepsis, that's because the bacterial endotoxin has activated toll-like receptor 4. 

So these things have proven to be very important. But we can use those for vaccine designs, now we know what turns on the immune system is these toll-like receptors. And so-- and it turns out that the yellow fever vaccine, yellow fever has long been known to activate toll-like receptors to engender a long immune response. And basically what happens is that if you look and see those little black dots, almost look like a virus, those are plasmablasts. Those are the cells that make your antibody response. 

And so, one to two weeks after you've gotten the vaccine, plasmablasts are in your circulation. But they only stay in this regulation for a short period of time. In the case of yellow fever, they home back and they go back to the bone marrow where they came from. That's what's shown in D. And then they can stay in the bone marrow for the rest of your life. And so if you've had the yellow fever vaccine, which you need if you go to the southern hemisphere, your antibody levels in your bloodstream are just as high today as when you got that vaccine, in my case, 20 years ago. 

And that's because of the ability of the plasmablast to go back into the bone marrow. This doesn't always happen but if you use a toll-like receptor 7 agonist, it does. And so that's one thing that we have to add maybe to the vaccine world is this ability to get a long antibody response, and then intranasal so there's no need for needles. And it's heat-stable at room temperature, so perhaps little nuances that'll have a role. 

And this is the last data set I'll show you. This is work of Mayuresh Abhyankar and Barbara Mann in infectious disease, and it's looking in the mouse model of COVID-19 in our biosafety level three lab. And it's looking on the y-axis, survival versus days after infection with SARS-CoV-2, just showing that the immunized animals are completely protected, and nine out of 10 of the control animals succumb to the infection. So that's what UVA has going on as far as the vaccines. 

Just to close a little bit, like maybe a sort of a historical perspective, I love the history of medicine, and the NIH exists today because of the polio epidemic. And it was the work of Jonas Salk, who over six years, which was light speed then for making a vaccine, was able to take polio virus grown in laboratory culture inactivated, vaccinate a million children, and show that he can prevent paralysis. Will this really convince people of the value of biomedical science, that their children were no longer at risk of polio? 

And I remember my late mother relating stories as a child in Rhode Island or something, how the movie theater was closed in the summertime, the swimming pool was closed, because everyone was scared to death that their children were going to get this paralytic disease. And I remember as a child listening to those stories, oh, that will never happen again, what an amazing story, like that they had to close the swimming pool. But huge and this is really what convinced the public of the importance of science. Today's Science Magazine, the breakthrough of the year is the coronavirus vaccine. 

And I think that the picture on the right should have been on the cover, the very touching-- the way that the elderly have been so isolated for the last year because of this infection. And that's the impact that vaccination is going to have. And so, I think we'd all like to say good riddance to 2020. This is my last slide. But I think instead, I think we'll look back and we'll see that this is a year where science and medicine have really stood up. 

And all of us in this room have been providing care to patients with this infection at some personal risk before the vaccine comes out, and to see this rapid advance of science due to the public investment over the last 20 years in understanding immunity, infection, and how vaccines work. So I think we'll look back and say, wow, this is a really remarkable year. So I left some time for questions, I hope, and Sthuthi, you'll help me with this, with Zoom and stuff. Great, but thanks everyone, for your attention. 

STHUTHI: Great, so if anybody has any questions in the room, if you don't mind using the microphone in the center, so the Zoom-iverse can hear. In the meantime, I do have a bunch of questions that came through our chat. So, Dr. Petri, is there any data to suggest need for repeat vaccinations, say, next season, or an annual vaccination with COVID-19? 

WILLIAM PETRI: I'm-- it's hard to understand with the mask on. I'm sorry, Sthuthi, is it whether you needed one, so-- 

STHUTHI: Yeah, if you need a repeat vaccination, say, next season or an annual vaccination. 

WILLIAM PETRI: Right, and so, well, I guess the only thing that we know is that the virus doesn't mutate the way that flu does, and so that would not be the reason to have to re-vaccinate every year. I think we're just not going to know how durable the immune response is, and it's not just antibody, but cell mediated immunity. So again, having the Phase 3 studies, the FDA requiring the companies to take those patients out one year, we'll see with the-- how long lasting immunity is. So I think that right now I'm cautiously optimistic that this is not going to be an annual vaccination. 

STHUTHI: And as far as you know, are there any differences between the Moderna and Pfizer vaccine? Should we choose one over the other? 

WILLIAM PETRI: Well, I think the only difference between the Pfizer and the Moderna vaccines is probably that one is four weeks apart, so Moderna you get your shot at time 0, and in four weeks with Pfizer it's 0 and three weeks. So no, I think as an individual it makes zero difference. They're both wonderful vaccines, the side effect profiles are very, very similar. Because as we've all heard, the Moderna vaccine is easier to distribute because it doesn't require the dry ice or the minus 60 centigrade freezers. 

STHUTHI: Great. And do you know of any studies that are existing right now or in the pipeline to understand how the vaccines may affect initial infection and transmission as opposed to clinical symptoms alone? 

WILLIAM PETRI: Oh, thanks for that question. And so the only thing we know is what was presented by Moderna to FDA. And that was that study where they did nasal swabs when people came in for their second vaccine, and they saw that people in the vaccine group had 2/3 less asymptomatic infection than the placebo group. And so that makes me very hopeful that both of these vaccines are going to be effective against asymptomatic infection. And Pfizer is studying this right now. And of course, the data I'm presenting to you is unpublished but presented to the FDA by Moderna. 

STHUTHI: Great, and are there any suggestions that special populations such as people with obesity or people who are greater than 65 may require different or higher dose of the vaccine? 

WILLIAM PETRI: Right, that's a great question. Like with influenza, for example, if you go to CVS now, they're going to ask you how old you are because there's a higher-dose influenza vaccine that's more effective if you're over age 65. For the Pfizer vaccine, there wasn't any difference in efficacy for people over age 65. For the Moderna, slightly less effective, 86% effective versus 95% for all comers. But probably too soon to know if that's a significant enough difference to try to change the amount of the vaccine, for examples being given, so an important and unanswered question. 

But so far these look awfully good. And the companies were both, I thought, really ethical about the way that they enrolled subjects. And so they have a broad distribution of ages from 16 to over 80 in the Pfizer and from 18 and older in the Moderna. And big representation of the racial ethnic groups that are suffering disproportionately, so African-Americans, and Latinx were very well-represented in both of those studies which is reassuring. 

STHUTHI: And Dr. Petri, do you by any chance know what the likelihood of a vaccine being approved for children in 2021? 

WILLIAM PETRI: Yes, so as far as vaccinating children-- so the studies are ongoing right now to vaccinate adolescents. And so Pfizer has already started, Moderna is starting. UVA may actually be part of a study in January of immunizing adolescents. And those will go fast, so you don't need 30,000 people. Now you're just trying to show that it's immunogenic and safe so you get an antibody response, and there's not some side effect in adolescents that you're not seeing in adults. 

So those have to happen first, and those probably-- I imagine that the vaccines will be approved for 12 and up in the spring. And then the studies will follow with infants, two years of age to 12. So long-winded answer, but I think it's probably not going to be until next summer that we'll be immunizing children, but adolescents probably sooner than that. 

STHUTHI: Great, a couple more questions. What do we know or anticipate about response to these vaccine in patients with underlying hematologic malignancies and other cancers? 

WILLIAM PETRI: Thanks, so we don't know very much of anything right now about the immune response, people with a malignancy or patients that are immunosuppressed. And someone could anticipate that they might be the less effective. I think it's going to be-- time will tell. Certainly there's not a contraindication to immunizing. 

Back when our zoster vaccine was alive attenuated varicella virus that we couldn't give that to our patients with HIV, because there was a live virus. There's no safety issues with immunizing a patient with a hematologic malignancy or a transplantation, so no safety issues. But we are going to have to wait to see how effective it is. 

STHUTHI: And this is from Dr. Borish. Do you know if there are any adjuvants in the mRNA vaccine, including whether they manipulated the mRNA, either with uncapped RNA or modified ug content to make it more likely to engage TLR or RIG-1 MDA5 receptors? 

WILLIAM PETRI: Now I'm glad I'm not a student in one of Larry's classes. Larry has asked the most demanding questions. I know that the RNA was modified in a way to make it more stable so that it wouldn't be degraded. Because that's the big problem with RNA, our hands are just covered with RNA so-- But I would imagine that the goal was not to activate toll-like receptors with the mRNA vaccine because you really want the protein to be produced and then recognized by the immune system. But I-- not a good answer, I don't know the answer to Larry's question. 

STHUTHI: Great, and one last question. Thank you for answering all these questions. Multiple papers present the vaccine particles with the RNA inside. However, when they cite how they are made, they reference older papers where traditional lipofection particles are not coating RNA, it is attached to the outside. It was called spaghetti and meatballs in the 1990s. Do you know which mechanism it is? 

WILLIAM PETRI: I don't know. So the question is how did they actually make these vaccines? And my impression is the Moderna must have made it differently than Pfizer, and that's why the Moderna one is more stable at the higher temperatures. But the possibilities are that they're in liposomes just like we give liposomal amphotericin B, and I suspect that the Pfizer is in liposomes because those are very unstable. 

But there's also all these Lipofectamine reagents we use in the lab to get RNA DNA into a cell, and those don't require that you have a lipid vesicle. It's just mixing the RNA with these compounds and presumably along with something that's going to protect it from the RNA, so whether that's the polyethylene glycol or some of the other lipids. What is clear, like as Mike Nelson was alluding to, with the FDA documents you know every single component. And it's-- the amount of it in the vaccine. And so the Pfizer vaccine is basically mRNA and lipids. So yeah, I'm just a big cheerleader for these vaccines, I think it's just so amazing. 

STHUTHI: Great, thank you so much, Dr. Petri. 

WILLIAM PETRI: Thank you, Sthuthi. Thanks, everyone.