麻豆传媒

Panelists will discuss breakthrough cases and the possible need for booster shots, as well as their recent research on strength of post-COVID immunity and effectiveness of masks and social distancing

Recent reports suggest that current COVID vaccines may be less effective against the delta variant than earlier studies predicted. The FDA announced emergency use authorization for boosters for immunocompromised patients. Meanwhile breakthrough infections account for very few hospitalizations and almost no deaths. We’ll ask the experts: are breakthrough cases becoming a problem in spreading the virus, even if the cases are mild? Is immunity among the vaccinated, and recovered COVID patients waning over time? Should we get used to the idea of COVID boosters?

Panelists:

• Dr. Julie Swann, MS, PhD, Department Head and A. Doug Allison Distinguished Professor at North Carolina State University and affiliate faculty in the joint Department of Biomedical Engineering at both North Carolina State University and the University of North Carolina at Chapel Hill. 
• Dr. Juan Wisnivesky, DrPH, MD, Chief Division of General Internal Medicine at Mount Sinai Health System. 

When: Wednesday, August 18, 2PM-3PM EDT

Where:  

Transcript:

Thom: Welcome to this 麻豆传媒 live expert panel. Today we have with us two experts to talk about issues surrounding the COVID vaccines, issues related to the current surge happening in many states across the US and the recent announcements about the availability of booster shots for the immunocompromised, and later this year for all adults. We have with us – first I'd like to introduce Dr. Juan Wisnivesky. He's a doctor of Public Health and an MD, and he's Chief Division of General Internal Medicine at the Mount Sinai Health System. Juan, thank you so much for joining us. And I'd like to ask if you could tell us a little bit about some recent research that you did, published just a couple of weeks ago, showing relatively strong immunity for those who have recovered from COVID. Tell us about those findings and give us your thoughts about when that immunity is shown to begin to wane. Does that mean that recovered patients should consider getting vaccinated? And what does that tell us about the new announcements about the need for boosters among those who've already gotten vaccinated?

Juan: Sure. Good afternoon. I'm happy to be here. Thank you for having me. Yeah, we recently published some findings. We are the Mount Sinai School of Medicine conducting a prospective registry of COVID-19 patients evaluating the long-term effects of COVID. And one of the issues we're interested in is to understand how lasting is natural immunity after infection with the virus. So, we study a cohort of around 700 patients that we're seeing at different times post COVID. And none of them were vaccinated and we found that the percentage of patients that have high titers, titers have been correlated with protective immunity in in-vitro studies was relatively high, ranging from around 80 to over 90% more than a year after infection. So, while we did not specifically evaluate the rates of reinfection in these patients, we found that most of them seem to be protected. We also found that patients that have more severe infection regarding hospitalization were more likely to have high titers over time. In terms of waning immunity, reports have been mixed. But in general show that several months to a year or a bit over a year post infection titers remained relatively high. 

Now, you mentioned how to interpret this in the context of new variants and increasing rates, well, we do not know for sure. There is some data from experiments in-vitro not in-vivo in the lab, which show that the natural immunity against COVID infection with the alpha variant which was the early infection is still protective for the Delta variant that maybe less so that from the original virus. So, it's possible that over time, some patients that were infected but not vaccinated maybe have an increasing risk of getting reinfected but with new variants. And that finding suggests that vaccination, even from patients that had the infection, is probably warranted.

Thom: Thank you, Dr. Wisnivesky. I want to introduce our other panellist. This is Dr. Julie Swann. She's a Master of Science and a PhD. She's Department Head and the A Doug Allison Distinguished Professor at North Carolina State University. Dr. Swann is also an affiliate faculty in the joint Department of Biomedical Engineering at both NC State and UNC Chapel Hill. Dr. Swann, thanks for joining us. 

Swann: Thanks for having me. 

Thom: You had some recent research that backs up the use of non-pharmaceutical interventions. So, I want to ask you about those findings related to mask requirements, social distancing, other factors such as that, tell us what your study found and let's draw a connection to what that means in terms of the need for these measures still as this fourth wave surges through the US, especially in the south, and where we can go from here understanding that better?

Swann: Sure. So, I do computer modelling, simulations of what may happen with COVID-19 under different scenarios. We've been doing this work for about a year and a half and before that working with other diseases, and we are one of the teams selected by the CDC and the Council for State and Territorial Epidemiologists to do forecasting, modelling of interventions and communication with stakeholders. One of the papers that we have, we looked at the question of what happens when you start lifting these non-pharmaceutical interventions, so things like masks and distancing and all of these different things that people have put into place in our schools, our workplaces and our community. And we found that if you lift it before this population is really fully vaccinated, that you will see another surge. We published this work back in January and really that is exactly what we saw happen. We had infections come around through the holiday season. We then of course had lots of people going back to normal after some of them had been vaccinated and we had another surge, some of which was attributed to alpha but some of it was attributed to behaviours that people in decisions that they were making. We are in a different situation now with the Delta variant. It's about twice as infectious as the virus variant that was circulating last year at this time. We do have some of our population vaccinated, but not all. And with this Delta variant, it does appear that the possibility of reinfection or a disease case breaking through vaccination can occur. So, that makes it even more important to consider using non-pharmaceutical interventions while we continue to vaccinate people. And even as this recent announcement has come out that we continue to get people the full amount of protection if it's recommended by CDC and ACIP, that would come from a booster shot.

Thom: Thank you, Dr. Swann. Back to Dr. Wisnivesky. Is there any such thing as over vaccinating? This is a question here in the chat from Deb Wood, that nurse zone. Is there such a thing as over vaccinating?

Juan: Interesting question, and I want to be careful how I answer that. But I would say, well, we know that people are relatively well protected for several months post vaccination, particularly individuals who are not immunocompromised or have other chronic conditions that preclude them from forming antibodies. So, I would say, yeah, if you're fully vaccinated, probably you need to be revaccinated a month later and that will be over vaccination. But at the same time, everybody is trying to project and collect data about how lasting immunity is, and in particular, in certain populations, trying to understand what is the best timing for a second node. So, I think vaccination in general, particularly the first dose is highly recommended and we just heard about the public health consequences of not doing that. And the work isn't going to try to determine what is the best time to give a booster or which subset of patients may need additional doses. Yeah, but we should follow public health official recommendations regarding vaccination and doing additional doses early on may not add protection. There is always a small, almost negligible, risk of adverse events. And also, they need to have enough doses to vaccinate everybody in the US and in other countries because as we saw very clearly, we need to treat this as a global problem. It's not just a US problem. And we know that many countries are still waiting and do not have enough doses of vaccine to vaccinate their entire population.

Thom: Thank you so much. To Dr. Swan, you mentioned changes in these non-pharmaceutical interventions and the various requirements earlier this year as I'm sure everyone is aware, the CDC made the announcement that vaccinated persons could stop using masks. It seems that in the time between then and now, many of the unvaccinated have gone and sort of blended in also not wearing masks. And that seems to be what's gotten us where we are today with a seven-day average of 140,000 cases nationally. Do you agree with that assessment? Am I getting that right in your opinion, and what might you suggest to have done differently in hindsight, in a case like this?

Swann: Well, certainly behaviours drive the spread of disease, and there are a number of behaviours that can contribute to it – masks or not masks is one of those. It's also about how many different people you're interacting with and what size environment and what kind of environment. Is it inside? Is it outside? I think what we saw across the board is that many people really wanted to go back to normal as much as they could. And we went back to normal a little bit too soon, especially given this new version of the virus that was circulating. It was circulating, it's more infectious or some of these other kinds of cases, and it intersected at a pretty important time. And that has led us to these situations where we have lots of cases and hospitalizations, especially in places that have low vaccination rates but really, in many places around the country. 

Thom: Dr. Wisnivesky, the study that you did showed a slight drop in the immune protection after a year, I believe, between 80 and 90% approximately. Let's compare that to recent studies that have come out about the mRNA vaccines and in particular, I want to mention a report in Axios about a study done at Mayo Clinic that the Pfizer vaccine only showed 42% efficacy in the month of July as the Delta variant continued to spread. The average over six months was higher than that but if we're looking at every other person who got the Pfizer vaccine potentially vulnerable to a breakthrough case, if exposed to Delta, what does that tell us about the need for boosters and justifying that? And what could also explain the difference between the vaccine-induced immunity and the recovered patients’ immunity being higher?

Juan: Sure. Well, clearly they do reports that point to different protection from both vaccine and immunity over time. There are multiple reasons that can explain these different findings from different populations, different study designs, unexpected differences from natural immunity versus the vaccine - in general natural immunity that has to produce a more robust vaccine, but by a response, but that may depend also on the innocuous and how sick the patient is, etc., etc. So, the differences are not surprising. 

Again, the consistent pattern is that over time immunity both from natural infection and from the vaccine wanes not extremely rapidly. At the beginning there was a concern that it may drop after a few weeks, but we know that now it persists for several months and is relatively robust after one year. We also know that in general, their response in-vitro, the ability to stop the virus in-vitro and seems to be also in-vivo is lower for the Delta violence when you had the Alpha virus infection, or you're vaccinating with the vaccines that were about based on the Alpha variant. So, yeah, it is expected that over time we'll see more cases of Delta virus infection among vaccinated people and it points towards the need for as we say, but these are the booster vaccines and/or eventually modifications of the vaccine to capture new variants in the future.

Thom: Thank you, Juan. Back to Dr. Swann, a question from the chat asking about the quantity of doses needed to issue these boosters. We have every reason to believe that there is ample supply to do this, will there be need for additional manufacturing or anything to be expected with the rollout of such a thing? 

Swann: Well, so what I anticipate is that there is some initial supply that's sitting all over the country and providers, refrigerators and freezers and health departments and hospitals. And so that would be the first – I'm sorry, my Internet's a little unstable. That would be the first supply that will get used for these boosters. I anticipate that if everyone who received the two doses or the full dose needs a third, that there would be additional supply that would be shipped from the manufacturers and the McKesson distribution centre just as we saw before. We do know that the US has agreed to purchase a number of doses, both for the United States and for other countries. And so I don't anticipate that we're going to see major problems with the manufacturing at this point in the process after they've worked out a lot of those early troubles that were stopping them.

Thom: Thank you, Dr. Swann. Dr. Wisnivesky, a question that occurred to me, I got the Pfizer vaccine. So, when I look at a story like that Axios one I referred to, worrying obviously that the Pfizer vaccine is trailing behind the Moderna vaccine, for example, is there any reasoning to get if you were to get the booster to switch to a different vaccine or anything like that?

Juan: To begin with, the vaccines have not been compared side by side. So, we only know the effectiveness of the inter-vaccine versus placebo but we don't know one versus the other. So, extrapolating from this type of studies that one vaccine is more effective than the other is a bit tough because of many, as I say, different populations, different study size, random error, etc., etc. So, that's challenging. I think we do not know what is the impact of changing vaccines, so it's hard to say one way or another. I think that we will need to see how things go and what are the probably good health recommendations about it but I'm not sure if there is any science to recommend one approach versus the other right now.

Thom: Dr. Swann, you want to comment further on the Pfizer data in that Axios report. What would you like to add? 

Swann: Yeah, so one thing to look at is what is their measure that they're comparing and they were looking at measures of infection. However, when they also looked further to measures of preventing hospitalizations and death, they still saw a really high effectiveness for the Pfizer vaccine as well as the Moderna. So, it's important to keep in mind, we were never promised that the vaccines would prevent all infections but they are still remarkably good against preventing hospitalizations and deaths. But what that means is that vaccinated people do need to be careful still because a vaccinated person can potentially spread that virus to someone else. 

Thom: That's definitely the concern that I'd like to dig further into and in even as the vaccines are showing very, very high effectiveness, you know, 99.8% in some cases of preventing death. There is now the new evidence that the Delta variant causes high viral load in those breakthrough cases and could be spread. So, Dr. Swann, what would you say at this point is the most crucial thing for even vaccinated persons to be doing to take precautions from spreading if they were unlucky enough to get that breakthrough case? 

Swann: Well, I think the first step is to wear a mask. And it's not wear a mask after you know you have an infection because this virus can transmit when you're still asymptomatic, and maybe you never really have any strong symptoms. I sometimes get a stuffy nose from allergies. How do I know if it's from allergies or from COVID if I've been vaccinated, it would be really difficult? So, even before mask mandates came down the line or mask encouragement, I wore a mask around my building and I encouraged all of my faculty staff and students to keep doing it. We're not requiring surveillance testing for people who are vaccinated, but I am encouraging people to get tested periodically so that they would know if they have gotten the disease and then they can break that cycle of transmission.

Thom: Dr. Wisnivesky, on a similar kind of vein, what should people who, I am kind of asking you to respond to the same question, what should people be doing in the most urgent manner to prevent potential spread of the Delta variant, especially and if you know any of the data on this, asymptomatic cases. This has been a huge factor in this disease and one of the major reasons why it's been so hard to get a hold on, are we seeing similar rates of, as far as you know, of asymptomatic infections in these breakthrough cases and what would your advice be about taking more precautions?

Juan: Yeah, I think clearly there is a trend and what Julie mentioned, Dr. Swann mentioned, is that while the vaccines may not be as effective as in terms of mild infections, they still remain pretty effective in terms of protecting for severe infection. So, it is expected that there will be more asymptomatic or mildly symptomatic cases among vaccinated patients but as we discussed before, those individuals can transmit the disease. So, I fully agree – maintaining precautions, social distancing, mask, being careful, testing yourself if you're having symptoms, being careful even if vaccinated after being exposed to somebody, those are very important issues. And as we discussed before, keep pushing the message of vaccination, data shows that vaccines are mostly safe and probably is very clear from the data we have so far that vaccination, there are risks of being vaccinated which obviously is getting COVID and getting sick from it, and seems pretty clear that those risks outweigh the minor risk of vaccination itself. 

Thom: A lot of the conversation about boosters early on had been sort of framed as it's not needed yet. And we don't know if it'll be needed and even the WHO issuing a request around the world to say, hold off on any boosters until we can get more people their first doses. This is, in many ways, kind of preaching to the choir people who've already gotten vaccinated, and them being concerned about the need for boosters is still maybe not the highest priority in terms of getting those people getting their first doses. So, Juan, I want to ask you, if a sceptic might ask, if getting COVID and recovering gives me better immunity than the vaccine, why should I even get the vaccine? What would you say to convince a sceptic who kind of put it that way to convince someone to go ahead and get vaccinated with their first dose?

Juan: Yeah, well, really remind them of all the suffering that we have seen from patients getting very, very sick, and for just some not even making it through COVID and also something that we're still studying and we don't know the full extent of which is the chronic symptoms that many patients post COVID are having, and we have a large number of post COVID patients that have multiple complaints and struggling with long term consequences of getting sick. So, all those are pretty significant downsides of having the infection and it seems to be wise to try to avoid them. 

Thom: Dr. Swann, what would your advice be to a sceptic asking a question like this and how to convince someone to go ahead and get their first shot?

Swann: Well, I'm not going to convince that person right now. What I would say is that you need to meet people where they are and understand their reasons for not wanting to get vaccinated. It's not always about scientific facts; it's also about opinions and feelings and other kinds of things. But in general, I talk about a couple of different kinds of risks that they're balancing. One is the risk to their own self, their health, the possibility of not just hospitalization or death, but long COVID symptoms that could last for weeks or months. It's also the risk to their household and then the risk to the community, because they wouldn't even know it but potentially be spreading it to others that's contributing to the hospitalizations. And that, in turn is leading to greater mortality even for other things like heart attacks, or car wrecks because the hospitals are just so full right now. So, I would ask them to think about all of those things. If the vaccine is yes, for them, but it is also for these other groups around them that are so important.

Juan: Yeah, if I may add to that, that was a very important point. And we have to remember that children under 12 are not yet candidates for vaccines. So, they depend on – while COVID is mild in kids, there are still some that have problems. So, it's up to the rest of us and hopefully having been vaccinated and being careful that we have to protect that. So, that's another important group that we need to be careful about. 

Thom: That's certainly a major issue as children around the country are already back in the classroom or preparing to go back to the classroom. We've seen reports from several places where kids have been back in school for a day or two, and already have to go home and quarantine. How important is that emergency use authorization for children under 12 to get these vaccines? I'd like to pose that to both of you with your different perspectives on it. Dr. Wisnivesky, children under 12, is that authorization coming soon hopefully?

Juan: We hope so. I am not to be attrition and definitely the FDA, and everybody is extra careful when it comes to giving things to kids because it could be more vulnerable. But I think the expectation is that the vaccines will also be safe and effective in children. And as you said, we hope that can happen soon. Everybody can go back to class. Obviously, for kids that social impact of not being able to go to class and also the lack of the potential long-term impacts of remote education are major and are things that hopefully we can be back soon, and safely.

Thom: Thank you, Juan. Dr. Swann, how crucial is this? I mean, we have classrooms of hopefully socially distance and mass students, but in some places they're not allowing that or not adhering to it. How important is this for the children under 12 to have access?

Swann: It's important not only for the children under 12, but for our entire society. We cannot really even hope to stop this pandemic until we're able to vaccinate children under 12 as well. We've also done some studies around what happens when you open schools without interventions in place. You don't have room to do social distancing in most classrooms. You have some ventilation systems, but it's not enough when you're spending six hours breathing the same air. It's not always popular, but we do find that masks can greatly reduce infections by more than half in the first two months, which will give us a little more time to get that EUA in place, that emergency use authorization and start to get our children vaccinated.

Thom: Media on the call, please do submit your questions. We got several from the chat and by email earlier that I've worked into the program. I'd love to know if there are further questions. I want to pivot back to Dr. Swann again, just about the children in the classroom and vaccine authorization. Similarly, how important do you think it is for the full authorization to come from the FDA? And what would you anticipate that might do to give the vaccination numbers a boost?

Swann: That is a great question. I am anticipating that that full authorization will make a difference 

in vaccination. There are individuals who are waiting for that, there are also companies and other organizations who would like to put in a vaccine mandate but don't want to do that until there is full authorization. So, I think what we'll find is once that full authorization happens, we will have these cascade of events that will then lead to another increase in vaccinations which will be good for the individuals and for the communities as well.

Thom: A question from the chat. Dr. Wisnivesky, I think maybe you'd like to answer. Deb Wood is asking about the decision for eight months to be the timing of this. I've heard some analysis suggests that this might be because we were rolling the vaccine out originally in January to a lot of people and so eight months is next month. And that would account for all the people who got the vaccine first, people with conditions or people who work in health care. So, it's kind of a rational approach in that way but are there medical reasons for it to be eight months versus sooner or later? Is there anything you're aware of in that kind of decision making that would help explain why eight seems to be the magic number?

Juan: Yeah, no, I'm not 100% sure. I imagine also related to how long lasting the immunity is and when you started seeing increased cases, cases of reinfection or, but not 100% sure about what was the rationale for choosing that timing. Maybe Dr. Swann can know more about that.

Swann: Well, I know that Pfizer has said that they think a booster sometime between six and 12 months would be reasonable. I think that it is possible that eight is associated with the amount of time that we've been able to follow large groups of people, especially those who are 65 and older.

Thom: Another question from the chat from Lissy. Will it be likely that when it gets approved for the children under 12, will that similarly be tiered with immunocompromised or other cases where they need access sooner, and have it be kind of tiered like it was with adults? Dr. Swan or Dr. Wisnivesky, either of you.

Swann: I have not heard discussion about having it tiered. I also have not looked carefully at the trials. It is possible that they didn't even include immunocompromised children in the adult trials. There were some categories included and some were not. So, my guess is that we won't really see a tiering for children that we will see it for five- to 11-year-olds, which is what was I believe covered in the Pfizer trial. There is another trial of Moderna that goes down to six months and so at some point we would see that potentially as well. But at this point, we also have a sufficient supply of vaccines and sufficient providers to be able to administer to all the children pretty quickly.

Thom: So, while it certainly would be beneficial for a child with an immunocompromised condition to go ahead and get it first, there aren't the same needs in terms of the logistics to do it that way as there was in January. Am I getting that right?

Swann: Except I would say they should check with their doctor because it may depend on their specific situation or specific condition.

Thom: Dr. Wisnivesky, any thoughts about that? About that roll out among the under 12?

Juan: No, I agree with the comments. It clearly weighs the different situation now in the beginning of the vaccination and period for adults, there were limited doses. But over time, more doses are available, so all the need for doing that roll out for the higher risk at the beginning, it may not be as necessary.

Thom: Any further questions from our audience? Please chat those to me and I'll work it into the conversation. One topic that I think would be an important one to touch on as we may work toward a close, vaccinated persons who may be a little bit resistant to the idea of the booster. This is where, in my opinion, some people could slip through the cracks, some people who kind of might shrug and not take the time to do it or maybe develop some scepticism of their own about things with the changing messages about this, or the uncertainty. Are there any points that either of you doctors would like to make to someone in that kind of situation that might be hesitant to go in for that booster? What would you say to convince them?

Juan: Well, we – Dr. Swann mentioned some of the reasons are multiple and I personally heard that there are many different reasons not to get vaccinated and you have to be respectful about it. At the same time, I think patients who have already went through vaccination know that it is safe. Again, having received one dose or two are not reacting doesn't guarantee that you may not have any adverse events, but it clearly puts you in a safer category. And we know the risk of the infection is real and may increase over time, as immunity wanes. And so, there are good reasons. At a personal level as well as all the reasons that we discussed from a public health perspective, we all want it to go as quickly as possible to and live as normal as possible. And vaccination seems to be one of the main pathways to get that there.

Thom: Dr. Swann, are you concerned at all that those who've gotten their full vaccination, then changing their mind or meeting the offer of boosters with some resistance?

Swann: Well, I think it will be a challenge to get everyone who is fully vaccinated to come in for that booster if that is what is recommended. In the early days of the campaign and then even continuing, there were many, many sites that were open and drive through and weekend and night-time hours. And they were doing everything they could to make it as easy as possible to get the vaccine. But at this stage in it, we might see that rollout look a little bit differently. You might be able to go to your pharmacy or go to your primary care physician, but we may not see as many weekend events. So, it is going to be, I think, easier to get some people a booster than others, it may depend on their perceived risk. I would not be surprised at all if people, 65 and over, have much higher uptake on that booster shot. We see that kind of result already for seasonal flu vaccination along with other things. And even for COVID-19 vaccine, we see much higher uptake with older populations than we do with younger populations. So, I think we will probably see that with boosters. One interesting thing will also be whether a booster is effective at actually preventing you from giving a disease to someone else. That could make a difference as well because that might play into whether companies or hospitals or universities or others require a booster. And then finally, I wanted to remind people we have boosters for several of the vaccines that we have, that is not anything new. There are several different vaccines that you receive in series or you may come back and get another one five years later. So, there are plenty of precedents for that kind of thing, just as there is for seasonal influenza which changes a little bit with the viruses that are circulating over time.

Thom: So, you'll be looking for as this rolls out, the idea that the booster is effective at potentially reducing the viral load in those breakthrough cases, you mentioned that it may prove to be more effective at reducing the transmission. Is that something that you think should be studied and looked at closely as if it reduces that viral load in a breakthrough case?

Swann: Well, I suspect that that's not the main driver behind the boosters. I really think it probably is reinfection, especially maybe in populations, let's say, 65 and over or people who are regularly exposed to their job like healthcare workers, really were concerned if the vaccine is allowing reinfection, some of which proceed to hospitalization or death. And maybe that's a little bit more likely either over time or with the Delta variant. I'm thinking more that it would be a nice bonus if it's true that a booster also shortens your infectious period, reduces the likelihood of you having an infection. I don't think it's going to be 100% perfect, but I do think that there would be some benefit from it.

Thom: That news about the viral load in breakthrough cases was certainly a wakeup call, and as we look at the impending delivery of the booster shots and hopefully for children under 12, I want to ask you about another very important area, Dr. Swann, and that's equity and disparities. How can we make sure that as these renewed efforts at the vaccine push roll out that there is appropriate focus on making sure that that equity and access, is it here too?

Swann: It is a great question. In the early phases of the vaccine back in January and February, the focus was really on population 65 and over, many of whom, a large proportion of them are White. We do know that the COVID-19 disease burden has been quite high among communities African-American, Hispanics, Native American and some others, perhaps because of their job, perhaps because of access to health care, or other reasons. And in some cases, the method of distributing vaccines makes it easier or harder for someone to get access. So, as we move into this booster phase, I think it's even more important that we continue to focus on uptake across all of the different subgroups in the population, and ensure that we're bringing up that level of vaccination in ways that are appropriate, and making it easy for people to get it, making sure that we have multiple languages, making the transportation easy for those who might be not mobile, might not have cars. And we should do this with boosters and we should also do this for vaccines rolling out to children. It is really important that we're vaccinating all the segments of our communities.

Thom: Dr. Wisnivesky, another question in the chat from Damien, asks about the potential of similar side effects to the third dose of the mRNA vaccines. You mentioned this in your comment in response to an earlier question. Is this something that is known? Or can we only sort of guess at it and need to study are the side effects likely to be similar with a third dose, as it was maybe considered by many a little bit more intense with their second doses? Any thoughts about that?

Juan: I am not aware of any data suggesting that. I anecdotally know that their reactions are very viable. Some patients have it more after the first, after the second or on both. So, I'm not sure if there is enough information to predict that. In turn I also know that the reactions are relatively mild and manageable and not a major barrier, a major impact on patients that have been vaccinated.

Thom: There's a real strong sense I get in the question that even those who are willing to get vaccinated, they really want to know what to expect, and it's still a developing picture, it's a dynamic situation but both of your answers today have really helped to shed light on a lot of this and I hope that it's given the reporters on our call good information. I'd like to encourage those reporters, if you have any further questions, please chat with me. I want to remind you that we will have a recording, a video and a transcript that we'll share with everyone first thing tomorrow morning. If you registered for the program, you'll get that information automatically. If you didn't register, if you just kind of clicked a link to come in here that we might have sent or shared and you'd like to get that info, please email us and we will make sure to include you in the list for that. Email us at [email protected], and we will make sure to share the recording and the transcript with you. Dr. Swann and Dr. Wisnivesky, we don't have any further questions. So, we'll go ahead and close things up. I want to thank you both very much for your time. And for the reporters, again just a reminder, we'll make sure to share the contact information so that you can get in touch with the doctors for any further up questions. With that, I will say thank you all. Stay safe, stay healthy and good luck. 

Swann: Thank you.

Juan: Thank you. Thank you for having us. 

Thom: Thanks very much, docs.