COVID-19 Vaccines: Questions Answered

Paul Anderson: Welcome to Smart Healthcare Safety from ECRI, the most trusted voice in healthcare. Committed to advancing effective evidence- based care. I'm your host, Paul Anderson, and over the past 12 years, I've overseen our Patient Safety, Risk& Quality membership programs here at ECRI. Tens of thousands of healthcare leaders rely on us as an independent, trusted authority to improve the safety quality and cost- effectiveness of care across all healthcare settings worldwide. You can learn more about our unique capabilities to improve outcomes at www. ecri.org. We are recording this podcast from our respective home offices as we practice, and certainly encourage all of you to practice good social distancing, to help limit the spread of COVID. Today's episode is part of ECRI's ongoing response to the COVID 19 pandemic. In fact, it's a little bit of a special episode, just before the end of 2020, we held a remote meeting for ECRI staff to talk about the COVID vaccines and answer some questions from our staff. Why? Well, our staff are people seeking information and making decisions about the vaccine for themselves and for their family members. And we wanted to make sure that they went into the holidays with the best information they could from their colleagues who have been following the developments most closely. Now in late January 2021, we're tapping into some of those same colleagues to answer questions that came from our staff, and we thought it'd be a great opportunity to share that follow- up with the Smart Healthcare Safety audience as well. So to get us started, I'll ask our two guests to introduce themselves.

Marcus Lynch: Hi Paul. My name is Marcus Lynch. I'm the Assistant Manager of Horizon Scanning at ECRI.

Alfredo Penzo Mendes: Good morning. My name is Alfredo Penzo Mendez, and I am Senior Research Analyst with our Clinical Evidence Assessment team.

Paul Anderson: So welcome to you both. Marcus, I think this first question, we're going to start with you. As of right now, we've got two vaccines given Emergency Use Authorization here in the U. S. they are from Pfizer and Moderna. And they both require two shots, and that second shot is required to come three or four weeks after the first one, depending on the vaccine. So the question we got from a few different staff members is why do we need that second shot?

Marcus Lynch: Well, that's a good question, Paul. Basically the first time that your body sees any type of thing that would make you sick, like a virus or a bacteria, your body responds with what's called the innate immune response with cells and different proteins. And then eventually over a few days, like in about a week, your body makes antibodies against that virus, like SARS- CoV-2 the virus that causes COVID. So it usually makes two types of antibodies, IgM, and IgG. And what happens is, is the second time that your body sees that again, it makes a much stronger, like an exponentially stronger immune response of I only IgG antibodies. And so what happens is, is that allows your body to very clearly clear something like it says, Oh, I really need to remember this now. And it makes a much stronger response. So you want to do that in the context of vaccination, you're trying to expose your body to it, not once, but twice so that you have a really strong immune response set up to SARS- CoV- 2 when your body might be exposed to it in nature. And so yeah, through that process of seeing it twice, you get educated memory B cells in place. So that's why a lot of vaccines need two doses obviously some many vaccines that are in current clinical practice even require three because to keep it strong and high enough to protect people over time. And this is the phenomenon, maybe people have heard that statement that you don't catch the same cold twice. It's like, because you catch it and you start to make the response the second time you see it, your body jumps into place quicker. So you're trying to get it up and running by the time you actually see it.

Paul Anderson: Do we know what the consequences are if that second shot isn't received either on time or maybe not even at all?

Alfredo Penzo Mendes: Yes. Well, the consequence would be that you may not be immunized, you may not be protected with the virus. The booster has two roles first to strengthen the immune response, to make the vaccine more effective, but also to, as you just said Marcus, to help differentiate those memory cells so that the response is durable. That doesn't mean that single shot may not work in some people, but there is also the broader consideration of is this number going to be high enough so that the vaccine helps provide effective epidemiologic control? The FDA and the World Health Organization, both agree that a vaccine should be at least 50% effective to help us get the epidemic under control. And the preliminary numbers from the Moderna and Pfizer trials showed that a single shot can provide immunity for up to two months to 50 to 80% of people. The great unknown though, is how long that immunity is going to last. So a single shot may not provide immunity that lasts as long as the complete course. So if that number dips is the 50% for Moderna, for example, dips further because people got only one shot. Then the vaccine may not be useful over the long- term to help reduce COVID- 19 cases since insignificant numbers and to reduce transmission enough so that we can one day go back to normal.

Marcus Lynch: Right. And we're seeing preliminary evidence that suggests that the vaccines are maybe... Like if you only get one dose, there may be between 33 to 52% effective. So that's still an evolving story, but that's what we're starting to see.

Paul Anderson: And if those numbers are the numbers, that's not enough is sort of the short way of saying that, I think.

Marcus Lynch: Right. Yeah. It's definitely could fall below the 50% effectiveness and also there're questions about how long even that effectiveness is going to last, which it's going to take a little while for us to figure out if, to follow maybe people who never get a second dose, how that's holding up six months or a year from now is another concern. But yet it's definitely supporting the fact that everyone should be getting two doses and it's not a moot point or being over concerned.

Paul Anderson: Okay. We had a lot of questions from our staff about allergies and whether they are a contraindication to vaccination. So first, can we clarify what kind of allergies we're talking about in the context of the vaccination. I get personally your classic, like itchy eyes and congestion when there's a lot of pollen, is that what we're talking about here?

Marcus Lynch: No. Yeah, I guess really to get into maybe the really short answer of the vaccines essentially, CDC recommends that everyone get vaccinated unless they have a specific allergy to the vaccine or the vaccines components. So that's the bottom line is if you didn't have a bad response to that specific vaccine or a component such as what's called polyethylene glycol is a component of the vaccines that's been implicated in causing allergies then you should get vaccinated. What the CDC has recommended is the normal observation time for people to see if they get an allergic response is about 15 minutes in a lot of people who fall into those high risk groups of maybe having an allergy to other vaccinations, having serious immune responses, people have been hospitalized due to allergic reactions. Then the recommendation is generally that those people be watched for 30 minutes. But they're not discouraging anyone from being vaccinated unless they've specifically had a response to polyethylene glycol or the vaccines and actually your hay fever type of... To get a little bit more now into the science, people who are really interested in the science, there's another antibody type called IgE, right? So we talked about IgM, which is the first time you see something IgM and IgG are made. And when you get a vaccine, you want to make more IgG, but then there's another thing in this process called class switching that you make IgE, and that's typically involved in your classical allergies, like allergies to cat hair, asthma, the itchy eye kind of thing. And so that's not really implicated what people think these vaccines or the allergies to the current vaccines for COVID, it's an IgM mediated response to the polyethylene glycol, which then trips off a protein cascade called complement. And so it's a whole different pathway. And that's the science of why CDC is not saying typical allergies are not a concern. With that being said people who... They did ask if I'm taking allergy shots, should I wait? Waiting type of concerns. You should definitely be in contact with your physician and your allergist to see if you should wait after a specific allergy regimen that you're on and just see if after a certain treatment, should you wait before you get a COVID vaccine, but in general, people who have allergies shouldn't be concerned at this point that they might get an allergic response to the vaccine. It's actually a different mechanism they believe.

Paul Anderson: What do we know so far about the frequency, the severity of those severe allergic reactions to the vaccine, whether it's in the initial studies that led to the Emergency Use Authorization, or whether it's during the early days of the rollout so far?

Alfredo Penzo Mendes: Well, there is two aspects to that question. First of all, did they look? Well, of course they tracked adverse events, including allergic reactions, however, people who had a history of severe allergic reactions. And by that, I mean, people who need to carry an EpiPen because of a severe peanut allergy or allergy to bee stings, the reaction that can kill you essentially, those people were not included in the studies. So it's hard to get an accurate estimate taking that into account, however, among people who are in the trials and some of them may have underlying allergies that they were not aware of. The overall number was very, very, very low. There were a few cases that were reported and very prominent in the media when the vaccines were initially rolled out in the UK, however, people need to take into account that what the denominator to calculate a risk was during those first days of the rollout. So it's a few cases, but out of 50 or 60,000 people that received the shot during the first few days, so on the whole, the risk is not zero, but it's very, very, very low.

Paul Anderson: I think we'll say this a few times throughout the course of today's recording. All of this is very much in motion, right? So I mentioned, right, we're recording this in late January 21. It's very much in motion. Where can we send people? Where can we direct people to be able to say, if you want to keep up to date about what we know about the vaccine rollout, for instance, or about what are the current country indications and so on from a trusted source, where can we send people?

Alfredo Penzo Mendes: Well, the FDA and the CDC websites are a great place to start. They have information that is laid out for lay people. They have also links to deeper resources and our own ECRI website is also a good place to look at.

Paul Anderson: So I think what we'll do is in the notes for the recording here, we'll make sure that we include a link to at least the high level FDA and CDC pages. So that folks who want to click through can have a starting point and then they can explore on their own from there.

Alfredo Penzo Mendes: Yes. One more suggestion it's also to check with your state health departments, because vaccine roll- outs, prioritization dates are being determined at the state level. And our own website here in Philadelphia has great information.

Paul Anderson: So, there's been some discussion about unblinding the participants in those studies, the initial studies for the vaccines, that were used again to obtain the initial authorizations, the Emergency Use Authorizations for the vaccines. So let's start with can you define what unblinding means? And what are the conversations either for, or against doing that? And if we know it, what's the current status, whether a decision's been made and acted on yet?

Alfredo Penzo Mendes: Well the gold standard for approving drugs and vaccines also is a randomized controlled trial. And these are blinded, meaning that people don't know what they got, if they got a placebo shot or the real vaccine. And this is very important because knowing what treatment you got may change your behavior. People, for example, if they get the vaccine, they might feel protected and more likely to expose themselves to risks, for example, and that can change the results. It can introduce bias. It's relatively common in trials though that once a statistically significant effect has been shown that we have certainty that there is an effect that the trial is unblinded, that patients are revealed what they got and that they are allowed to... Those who were in the placebo arm are allowed to go and get the active treatment. This is called crossover, and it's often done out of an ethic concern knowing that, especially for long trials, knowingly keeping people with a placebo treatment, it's not always considered ethical, especially if we have enough data to reach a conclusion for the trial. On the other hand the downside of doing this is that you lose one of the study arms. And a major issue with the COVID vaccine trials is that we have good quality data, blinded trial data at up to two months follow- up average. So people got the two shots and then they were followed for two months to see if they got COVID or not. But that time is actually quite short considering also that immunity can decrease over time. So having a six month data, for example with blinded data, would really be ideal. So there are voices some have argued that to get that high quality data, we should continue the trial as the sign, as a blinded trial for up to six months. So those are the two conflicting visions as of right now, Moderna and Pfizer have both submitted drafted, sorry plans for unblinding and crossover that they intend to submit to FDA. They require FDA authorization to do the unblinding and they crossover, if they don't get that authorization, then they might endanger full approval of the vaccines. Right now, the vaccines are rolled out under a provisional authorization, emergency authorization, sorry, Emergency Use Authorization the EUA, but to get the full approval for years and years to come the Biologic License Application, they need to submit full data under a protocol approved by FDA. And of course, all modifications to the original protocol, they need to be approved by FDA as well.

Paul Anderson: Gotcha.

Marcus Lynch: Yeah. So, I think tagging onto that. So, basically when these trials were set up, they're set up to run for, I believe about two years. And so we were looking at we're gonna stop this... Not stop the study, but at certain time points, look at the efficacy. And again, for instance, set about two months, they looked at the study and said, does this work enough for EUA authorization so that we can start to get this out to at least priority populations? But again, like Alfredo said, the full BLA, which your typical vaccine is used for approval or your typical drug biologic, they get a BLA when you're not in times of emergency. Originally it was at the end of those trials, maybe these two year trials was the BLA. And now with these issues with the crossover and unblinding and saying, will people continue to really run this trial as it was designated? Now it's really, the issue is at six months, is that enough to actually get this full BLA? So that's again, is how quickly this issue is evolving. Some of it's a function of the fact that these vaccines are so effective, right now, the mRNA vaccines are so effective that people are saying, " Look, I really want that." You're right. A lot of people enroll in the trials for one of two reasons, right? They want really early access, they want to try to get protection and some people just want to contribute to science. Right. But there's a lot of people who said, " I'd like to have a first shot at that." It's really hard for that group definitely to continue to go for a long time, especially when they find out they might have placebo to just keep going right there. They were obviously the people who said, I'll sign up for a trial because I'm hoping to get an early shot at that vaccine and that protection, because maybe they're a high risk population. Right. So, those are the issues with crossover, the six month, BLA, EUA issues.

Paul Anderson: Just real briefly, you mentioned BLA, could you just define what BLA is real quickly?

Marcus Lynch: That's a Biologics License Application. So again, that's considered a full approval. If you were a pharmaceutical, you get an NDA, a New Drug Application.

Paul Anderson: Okay.

Marcus Lynch: So, yeah. So again, typically there's something called an EUA Emergency Use Authorization in times where you really need a treatment. That's like, let's just take a shot at it. So, usually a lot of drugs that have been coming out for COVID have come under the EUA, but again, typically it's like, we don't have any drugs. This person is in the hospital. Right. They-

Paul Anderson: Right.

Marcus Lynch: This is our best shot. We should give them a try, even if it hasn't been fully vetted, but there's a preponderance of evidence that it could help. Right. So we're not totally sure that it works, but it could help. So EUA is that level of evidence. So, right now the current vaccines are under that level of evidence, but they have the full approval that says that this definitely works has substantial benefit and doesn't have harms, you would require a BLA.

Paul Anderson: Gotcha. Okay. Thanks. Then Alfredo, you were going to say something there as well.

Alfredo Penzo Mendes: Yeah, it's just as a wrap up comment to this question. Time keeps moving in favor the trial. It's still blinded and we are now close to four months after its initial enrollment. So two more months, even though there are plans to unblind, it seems very likely that we are going to get the data and the issue will become essentially moot. Although I don't imagine that by the summer the trial will still continue as blinded.

Paul Anderson: Right. So, our staff asked a lot of questions about the accelerated timeline for the development of these two and some of the other COVID vaccines that are still going through their first round of trials before the EUA. And it is really astounding that these vaccines were developed in less than a year in most cases or in all the cases, I guess, when previous vaccines have taken years and more than a decade to get to this point. So, should we be concerned about how quickly these vaccines were developed with regard to either safety or effectiveness?

Marcus Lynch: Some of the concerns are again, because it's been so quick there's definitely been a Herculean effort by Operation Warp Speed to bring these drugs to market or the vaccines to market. There's a number of reasons to believe that, there weren't safety and efficacy shortcuts. Typically, so Johns Hopkins refers to the fact that, it would maybe be a legitimate timeline would be five to 10 years in the old way of doing trials. But what Operation Warp Speed did was they overlapped a number of trials. So usually you have to run a phase one, that's just a safety. And then a phase two is more safety in some efficacy on the second half of that. And then phase three is really your efficacy, your two arm trial against placebo or something else. And most pharmaceutical companies, what they do because of financial risk is they don't overlap all of those trials that much, right? They'll take it step- by- step. And so by overlapping them, that's a relatively... Once the phase one safety goes far enough in a pilot study, they can start the phase two, and then they also roll those phase two patients who get the vaccine, they just start adding more patients into the phase three. So it's like these rolling trials, these waterfall trials. And so, that's just innovation and clinical trial design. It's not really shortcuts it is a way to accelerate it. But again, it requires substantial financial investment and without the government's financial assistance and Operation Warp Speed to help them de- risk that. Drug company usually would take it much slower because they just don't want to throw that much money into a vaccine that doesn't work, sort of like the government's help, help them just say, look, we're just going to go as fast as we can to enroll patients and tests without taking it step by step and worrying about how much money we lose. And then they also, on the other side of Operation Warp Speed gave the manufacturers money to make manufacturing, right? So they started to scale up manufacturing while they're doing clinical trials, which again is not common. They would usually say, does this work? They'd get pretty solid phase three data. Then they would scale up their manufacturing before the total trial ended. But they would start to make manufacturing somewhere in that phase three, probably. And in this case they were making manufacturing capacity immediately, as soon as they had a vaccine candidate, even almost before they were putting it in people, right. They were almost putting it in monkeys, they were starting to say, how are we going to scale this up if it works? So that's things that are not necessarily safety shortcuts, they are financial based shortcuts. So, those concerns, they definitely did everything they could to bring these to market as soon as possible.

Paul Anderson: And the thinking there being right with the government backing that risk, if I've got a vaccine candidate that it turns out at any one of those phases is not going to work, but I've already made a half a zillion doses of this, the government is absorbing the financial loss. Yes. I have to throw them out, but it's not going to put my company out of business.

Marcus Lynch: Right. Yeah.

Paul Anderson: Right.

Marcus Lynch: Exactly.

Paul Anderson: Yeah.

Marcus Lynch: Exactly. And so, I think that, that's a little bit of the problem that they're running into now though, too, is that the government hedge their bets. Right. And a lot of the manufacturers who are far ahead, they bought a hundred million doses from multiple companies. And so now you have the Pfizer and Moderna who have come to the forefront and people are saying, " Well, why didn't we buy, 300 million or 600 million of those?" But it was like, well, we didn't know. Right. Who was going to come to the forefront first. So it was like, well, I'll give you some money. I'll give you... So there was still a little bit of diversification of risk there to move everybody forward, because nobody really knew what was going to work. And just for instance, this morning, there was a report from Merck who's decided to drop out of the vaccine race because their vaccine doesn't work as good as a natural infection or the other vaccine. So for instance, you just didn't know who is going to come to the forefront, so that still has to play out for a number of these vaccines, like how safe and effective they're going to be.

Alfredo Penzo Mendes: Paul, I wanted to quickly circle back to the quality of the trial just for a little bit before we move to the next question. Just to restate that this time- saving with Operation Warp Speed trial was as Marcus detailed the financial involvement, the regulatory process itself, but it was really not the study design. The study design is extremely robust, really it was an incredible endeavor that Moderna and Pfizer did. It's one of the biggest and more detailed trials that I have ever seen in my years of clinical evidence assessment. So we can be confident that the data that we have is very high quality. The issue though is with the data that we do not have. So FDA went and rolled out the vaccines. We just two months average followup data. There is still the question, how long is the vaccine going to protect you? Is that immunity going to wane? It is a possibility. The preliminary data that is available from the phase one and two studies inaudible much, much smaller. Suggest that yes, the immunity might last for six months to a year, but it would have been great to have that certainty.

Paul Anderson: And that's the thing that we will only gather with time, right? You can't accelerate that piece of it that only comes with time.

Alfredo Penzo Mendes: Yes. Unfortunately does. And we will get some manner of an answer of course as time goes by, it's just it will be much more difficult to get it.

Paul Anderson: Right. So finally, I wanted to talk about how the virus is changing. Late in 2020, there was a lot of news coverage about a variant of the virus that we think originated in the UK and made it more contagious. But at the time we thought maybe it doesn't make the effects more severe. The last time I checked the current understanding is that these mutations aren't expected to affect vaccine effectiveness, but I could be out of date. So is that still our understanding and what else do we know about some of these variations that have been detected since you'd say again, late 2020?

Alfredo Penzo Mendes: Well, the issue with mutations, they are normal part of the evolution of the virus and Corona viruses are rapidly mutating viruses, not as much as, for example, the influenza viruses, but still quite significant. And the mutations can affect the way an antibody interacts with the virus, with the spike protein, which is the target of the vaccines here. And over time they might eventually reduce the effectiveness. However, it's important to know that this is not a one step process. So you get immunized with the entire spike protein, mutations are going to occur at different sites. And the rest of the protein is gonna still be the same and it's still available so that the immune system can produce antibodies against them. So it's very unlikely that a single mutation is going to make the proteins so different that you cannot recognize it anymore. However, over time, the mutations do accumulate. And at some point the vaccine might not be representative enough of the whole protein of the new protein, the mutated one that you can produce effective antibodies. So regarding the specific mutations that are now being discussed the UK mutation and the South African mutation, the preliminary in vitro data shows that the vaccines are still effective. There is some production on the immunogenicity of the response to the UK strain, but it's still on a safe level, the interaction between the antibodies in people who received the vaccine and the virus, it's still strong enough that the vaccine should protect you. However, time is not working on our side. The viruses will keep mutation as time goes by. So it's very important that we get the epidemic under control as quickly as possible. And that's why it's also very important, and even as the vaccine gets distributed, and even as you get the vaccine, that we maintain the social distancing, the use of masks and PPE, travel restrictions, all other measures that can help keep control of the virus and that can make the vaccine even more effective.

Marcus Lynch: Yeah. And something I just want to add to that is again, with just the biology of, why do mutations happen? Corona virus has the RNA genome, it's genetic material that encodes the virus is RNA. And basically the machinery that makes RNA is more error prone than the machinery that makes DNA. Right. So we have a DNA genome, and when we replicate ourselves, we have a lot of spell check or whatever, ever proofing machinery that if there's a mistake, it gets fixed and stuff so that we don't harbor a lot of mutations. And essentially that's a lot of times how cancer and things like that happen is when the spell check doesn't work Right. So, when you make an RNA genome, there isn't as much of that error proofing. And so you just have that gradual mistakes. You have these gradual changes that again, eventually in the right spot can lead to vaccines not working or your immune response, not remembering it. There's also the possibility of what they call recombination. So if that RNA gets close enough to another RNA, like a different animal or something like that, different animal Coronavirus, then they can have a crossover of DNA and recombine the DNA. So that's a way that people believe that SARS- CoV- 2 came about was there was a recombination event that made it different. That's why they said, well, this is something we haven't really seen before. Influenza, the issue with influenza, a lot of people make the parallels of, well, we're going to get these mutations as quickly as influenza. We need the influence a vaccine every year, but influenza has a different genome. Coronavirus has a single genome, one strand. And the way that influenza is, is it actually has multiple pieces that are strung together with proteins. And every time they replicate, they assort them, they say, well, you're number, part one, two, three, four, five, six, seven, eight, and then it shuttles them. And it's much easier for those pieces to get swapped. Like if you have avian influenza and you have a pig influenza and the same cell, when the cell divvies them up, it's like doling out candy at Halloween, right. So it's much more likely to re- assort them with influenza. Whereas with Coronavirus, it either needs to be those gradual mutations or a crossover. So, sometimes just theoretically when people say, are we going to need a new vaccine as often as influenza? Maybe not. But we do have to continue to monitor mutations because we know that it's definitely bound to mutate because of the RNA being error- prone like RNA, just machinery. So again, we have to try to get on top of these as quick as possible and continue to monitor them with surveillance. Those are all important strategies for public health.

Alfredo Penzo Mendes: A little piece of good news though, is that mRNA vaccines are very easy to alter and adjust so that they can match a new strain. That is one of the powerful features of this mRNA technology, as opposed to the classic way of doing vaccines. And Moderna is already planning to test booster design for the UK strain.

Paul Anderson: Nice.

Marcus Lynch: Yeah.

Paul Anderson: Fine. And I could just say Marcus, as an editor with a sweet tooth, I always appreciate analogies that have to do with spell check and Halloween candy used to be right in my wheelhouse there. So, we always try to wrap up with some quick steps that our listeners can take to get started making care safer. And usually that's around implementing some program in a healthcare provider organization, but this is a little bit of a different topic. So I think I'll ask it this way. Can each of you give maybe your bottom line takeaway with regard to the COVID vaccine? What's something that we should really be looking to as we make decisions for ourselves and for our families?

Alfredo Penzo Mendes: Yes, Paul. I would say that it's important to keep in mind that the trials after they have been conducted are high quality. However, some evidence gaps remain, this should not be a deterrent for people getting the vaccine, once it's made available to you. I think that it's perfectly reasonable to consider at your individual level, your potential benefits and what's the potential risk to you, balance them out, when you decide whether you're going to get the vaccine or not. For instance, if you have someone at home who is elderly or frail, and you're worried about them, then it makes sense that you get a vaccine earlier, rather than later. If on the other hand you work from home, you don't have a lot of social contact, it would make you just feel safer to wait out a little bit until we have more data on long- term effectiveness, for example, then that could be okay as well. Consider your own benefit risk profile when you make your decision. And also no matter what, I think it's important to re- stress again, that we are not safe until we are safe. So the vaccine is not a panacea and it's not a magic bullet. It's important that we keep with everything else we're doing to help control the epidemic even as the vaccine gets distributed. And even after you take the vaccine yourself, we know for example that the vaccine will prevent inaudible, but the trust will not design to test, for example, if the vaccines can prevent you from getting asymptomatic disease and from being an asymptomatic carrier and infecting others. So keeping up with social distancing, PPE use, travel restrictions, it's been a year, we're all exhausted, but that is precisely the more reason to keep going right until the end, because otherwise, if we ever have to go back to square one, I don't want to even imagine that.

Paul Anderson: Yeah, me neither.

Marcus Lynch: Right. Yeah. I think from my perspective working in Horizon Scanning, we tend to look out like a year, how is this landscape going to look in a year? Right now, there's two vaccines with EUA, again, full approval might be coming. But like I mentioned earlier that the government has divvied up its portfolio. And so there are other vaccines that are going to come on the market. So, continue to keep up with those data, hopefully in developments just keep an ear to the ground. I know not everybody's comfortable reading clinical data and stuff, but continue to look at trusted sources like ECRI and CDC, about some of these developments, whether or not they're going to be as effective as the two that are available. That's what I'm referring to is are they going to be as effective? Are they going to have different safety concerns? That's unknown. And so, we need to wait for that data to unfold. But again, by the end of the year, it's quite possible that there could be five different vaccines that could be on the market in order to get as many of the 330 million people in America vaccinated, right. There might be five different potential options by this time next year. So, we have to be careful to try to limit the spread of infection and again, keep up with the recommendations.

Paul Anderson: Marcus, Alfredo, thanks so much for your time and for sharing these insights.

Marcus Lynch: Thanks, Paul. We really enjoyed being on the podcast. Thanks for inviting us.

Alfredo Penzo Mendes: Yep. Thank you very much for having us today, Paul.

Paul Anderson: You can find more publicly available resources for responding to the pandemic in ECRI's COVID-19 resource center. And members of all of ECRI services could find additional members only resources on our healthcare recovery center. Be sure to subscribe to Smart Healthcare Safety on Spotify, iTunes, Google Play, or wherever you get your podcasts to get these latest episodes. We welcome your feedback. Again, visit us at ecri. org, or you can email us at ecri- podcast @ ecri. org.