Sinead Delany- Moretlwe, Co-PI for Crown Coronation
Moderator: Tian Johnson
Complied by: Anna Matendawafa – with inputs from Wilfred Gurupira & Maaza Seyoum
Webinar Recordings & Supplementary Materials:
Date: 03 September 2020
Professor Sinead Delany- Moretlwe is the Director of Research at Reproductive Health and HIV Institute(Wits RHI) and a Research Professor in the Faculty of Health Sciences at the University of Witwatersrand in Johannesburg. She’s an experienced clinical trials with a strong interest in the development of prevention interventions for infectious diseases, including HIV, HPV, and other STIs and, more recently, COVID-19. She’s currently the national Co-PI for the Crown Coronation platform trial to prevent symptomatic COVID-19 in health care workers.
Professor Delany unpacked some of the work that she’s doing in the space and speak to in general around COVID, about how COVID research has evolved and changed in a particular context in the last few months. She also gave detailed information around Crown Coronation, community engagement, and the need to engage trade unions.
QUESTIONS AND ANSWERS *This section contains a transcribed account of the Question and Answer Session
So Sinead over a decade ago, South Africa had this massive measles outbreak, and it was attributed to insufficient vaccine coverage and highly populated areas. Do you think that urgency and the democratic nature of COVID will change this landscape in terms of possible eventual access and coverage?
Yeah, Tian, so you raised an incredibly important question just about childhood vaccinations and for people on the call. Measles is an incredibly infectious disease, and World Health Organisation (WHO) has set elimination targets and achieved those elimination targets. We need vaccination coverage above 90% among kids under one year, and we’re not achieving that quite in South Africa. And there are a variety of reasons for that. And definitely, people working on API programs are looking at ways to increase that coverage. One way to do that is through these sort of immunization campaigns where kids of any age are vaccinated to achieve coverage. So I think that sort of increasing information about MMR’s benefits so that it may protect measles, mumps, and rubella. However, it may also protect against pandemic infections; we need to define what that period is, potentially increasing the attractiveness. And you and I were talking just before the call about sort of anti-vaccination sentiments. So I do think there’s room for work in places like Southern Africa, where we assume that there’s high acceptability of vaccines to understand why we’re not achieving coverage rates that we need to, and, you know, understand where the, what the concerns of people are, is it about access? Is it about acceptability? Is it about cost? Is it about anti-vaccine sentiment to drive uptake of these vaccines and ensure that people are protected?
So in a country where we have these national shortages of PPE ongoing shortages, some resulting in work stoppages and strikes and at centers. How does the trial like the one that you will be leading that targets healthcare workers as participants? What is your position in terms of will your trial provide, procure at your cost and provide personal protective equipment to the healthcare workers that you recruit into the trial?
Yeah, we have watched with massive interest that discussion around the BCG trial and that was before even going ahead with the MMR. And at the time, what we discussed both with the partners that we’re working with and with the National Department of Health and with the clinician society, which will also run a stock-outs HIV clinician society that we’re again running out stock out hotline is that for us adequate PPE following the Infection Prevention and Control guidelines. It’s a standard of care. We would expect that in all the facilities that we work that, it’s available. When engaging with facilities to recruit health care workers, part of what our team of investigators is very attentive to is, are they concerned about stock-outs? Is there an adequate supply of PPE? Are there concerns and that we try to work with partners to solve those problems before going into an area? I think all investigators have a responsibility to ultimately ensure that we collectively contribute to ensuring that there is a standard of care. It is the obligation of the Department of Health to protect its workers in accordance with occupational health and safety. But we’re in a position where we can identify gaps, stock-outs, and then you know, bring people together. So we have planned to assess facilities ahead of time, engage with providers there, identify any challenges work with the provincial PPE coordinators, and work with the stock-outs health plans to flag urgent issues to solve these problems. And this has seemed acceptable to all the stakeholders that have been involved in this discussion so far.
I think certainly the follow-up question could potentially be around what resources really because I guess in many instances, it just comes down to the dollars, and will this particular trial perhaps have some form of buffer if facilities cannot? Or is the principal if a facility has a history and current environment of shortages and stock-outs? Might the trial not go ahead at those facilities? Is that the approach of the trial?
Yeah, I think I mean, these trials are not necessarily able to fill a vast void. We’ve said that we can look at what contingencies might be available by working with the network of partners. We’ve sort of spoken to people at the Solidarity Fund, and other partners. In the end, we’ve wanted to understand what the problems are and work to strengthen the Department of Health. So they can fundamentally support these sites to kind of resolve their supply chain issues so that providers are protected. In prevention trials, mainly because it’s about prevention, it’s not about treatment. The first sort of approach would be to ensure that you have a robust standard of care and that you’re able to deliver that before you start testing new interventions that are layered on top.
The question from social media is asking if this vaccine was developed for childhood illnesses. Could you explain a bit more? Would it be adapted for using adults, or is this a similar approach to like the BCG revaccination concept where you just revaccinate? A tied-on question would be: what would the situation be with health care workers who are enrolled? Would the trial enroll health care workers who have been vaccinated with the MMR as children?
Yeah, great questions. Essentially, it’s a bit like BCG, where we would offer health care workers vaccination irrespective of their prior vaccine status. We are aware that there can be some primary vaccine failures, so maybe they were vaccinated at another time point, but we’ve never assessed whether they were protected. We will draw samples at baseline to understand the prevalence of antibodies to the vaccine at the time of vaccination. However, in the end, we believe that the sort of sciences that were priming the innate immune system to recognize an infection mount a response which essentially would lead to reprogramming of cells that will generate new cells that would be better able to respond to infections when they encounter them in future like SARS-COV- 2. So there seems to be a fundamental idea about the recency of vaccination. And while they may be antibodies from prior vaccination, this is kind of just boosting sort of response. So, in short, it doesn’t matter if you’ve been vaccinated before. We will measure, and we will offer people vaccination irrespective of their vaccination history.
You’ve described this trial as a light touch trial. Could you tell us what that means?
Light touches. I feel like it’s a term that we coined, but it essentially describes the idea that we have as much as possible try to adopt principles of social distancing within the trial. So in the traditional way of doing trials, people would come to study sites; they would sit in queues, be in waiting rooms, and see health care providers. With these types of trials where we’re using repurposed interventions, we can do a lot of the interaction with participants over the phone or through the internet. And so we will have a process to screen and consent people via mobile technology. We’ll meet them in person to deliver the vaccination. However, then we’ll follow them up over the phone; we will give them kits to collect samples themselves if they become symptomatic, we will follow them up with them when they potentially have to go to the hospital. But they will be limited in-person physical contact, or they will have regular contact with them over the phone.
So the trial is enrolling healthcare workers. This is all healthcare workers. Is there a specific criterion within that healthcare workgroup that you would be enrolling in?
Yeah, again, that’s a question that came up a fair bit during the process of development. And I think it’s an important question. The way that we’ve responded to it is that we’re interested in all healthcare workers that play a role in the health care system and that are potentially through their work exposed to SARS-COV-2, so we appreciate that those rates of exposure are changing as sort of as we go through the kind of the downturn of the case rates. However, we know the infection has not got away; we don’t know whether there will be subsequent waves. So it’s working with health care workers because of their contact with patients who might be infected, they might be exposed, and that’s the population we would recruit, which means that it’s not just nurses and doctors but other essential workers who are involved in making the health system work.
Age, sex, HIV status, any bearing on your selection of participants
The age criterion is very straightforward. Eighteen years or above. So able to give independent consent, no gender requirements. We invite people living with HIV. The only restriction is that people need to be aware of their HIV status. Ideally, on antiretroviral therapy and with CD4 counts that are above 200 just of the because of the concern of giving live attenuated vaccines to people who are not well.
Thank you. We’ve got a question in the chat from Kathy Slack, who says, in my view, that the approaches standard of prevention sounds consistent with ethics recommendations and approaches in HIV vaccine trials. Ethics guidelines do not necessarily mandate who should provide prevention, mortalities, and where study teams will rely on government providers to assess gaps and strengthen gaps in advance and monitor the issue overtime during trials. So what do you think Sinead is the ethical complexities that will face the Crown?
Thanks, Kathy, for that question. I think, having watched what happened with the BCG trial, I think we’ve learned something. And importantly, we’ve learned that it’s essential to engage stakeholders and have a plan and identify how to essentially provide the standard of prevention, which is often it may end up being a hybrid model. But essentially trying to leverage the fact that as investigators, we have the opportunity to identify gaps and work with other role players to strengthen the system such the system can begin to provide. So, I mean, in terms of what could I foresee?Well, we could end up with situations where we have stock-outs of PPE and some facilities, and we’re going to have to work with those facilities to address that. I think if before recruiting, we would, as I mentioned, we would sort of try to fix the system. If things happen during the trial process, we will have to work with partners to address that. And think about what that means in terms of recruiting during, you know, kind of during these periods, which is why we’ve sort of it’s been incredibly important to also engage with the Department of Health to understand their system to know where the problems have been and to understand who are the providers of PPE so that if we need to call them for help, we can. So I see the role of researchers is trying to make the system work. It might not mean that we can put everything in to fix the system, but really to make that work in terms of your other question just about ethical complexities. I think the other things that come up in discussions about ethics are sort of informed consent. We’re going to be using a novel approach, which is electronic informed consent. We’re going to be doing discussions over the phone. We’ve gone to much trouble to make sure that then consent process is still adequate, that people do not rush into things. So there are going to be things we learn as we go along. And as much as possible. I think it’s essential to be thoughtful to try to anticipate or the challenges but also to build a broad partnership that can help solve them because I believe in the end, collectively, we’re all interested in trying to find interventions that work. And we do need the support of a broad range of stakeholders. But as researchers, I would like to reiterate that we are acutely sensitive to the environment we’re working in. And you know, this answer is not everything, it’s our obligation to ensure participants’ safety, and that’s always at the forefront of our minds.
Sinead, could you help us understand a bit better? And I guess that doesn’t only apply to the Crown trial; it would apply across the board to some of the ethical issues around using a placebo. And so the question might be, well, why aren’t you putting everyone on MMR? If we already know, it’s safe and already giving it to children? What are the ethical issues that you can share with us around using a placebo both in this trial in general?
Yeah, brilliant question. It reminds me that I should talk to you about the platform nature of this trial. So the value of a placebo is so that we have a comparison against which to evaluate the new intervention. And this is because we have equipoise. It means we have evidence to suggest there may be a benefit. But there’s also uncertainty. We don’t know whether this will prevent SARS-COV-2, so it’s justified in this instance, to offer people a control because we don’t have a guarantee of the benefit of the MMR, although we think there’s a higher probability. One of this trial’s novel features is that it’s an adaptive Bayesian platform trial, which has many words. But essentially, what that means is that we’ve designed it to make these comparisons between MMR and control. Because it’s Bayesian, we can do regular interim reviews and, if necessary, can recommend stopping arms if we don’t see signs of benefit. But we also have the potential in a platform to add additional interventions. And so that’s the ultimate intention of Crown that we start with MMR. But as data emerges about the potential for other interventions, either drugs or vaccines, to work, we could add them to the platform. And the third sort of novel feature about this trial design is that its factorials. In addition to comparing, say, MMR to placebo, if we add in other interventions, we could compare those interventions singly to placebo, or we could compare them in combination to placebo. But with a platform trial, what’s great is that you’re adding an arm, so you actually reduce, you only have one control arm, and you make all your comparisons with that control arm. So over time, it will be that the proportion of people who are allocated to a control may become smaller. So many people could potentially be in an arm that provides benefits. And suppose we see benefits during interim reviews. In that case, we can potentially then drop the placebo arm and make a beneficial intervention, the backbone comparison, and compare all new interventions to that. The idea is that we’re aware that some people may not want to be allocated to a control, there are good arguments in this instance for starting with the control, but over time, the ratio of active to control may decrease. And in fact, if we show benefit, we may drop a placebo arm.
Sinead, could you speak to us a bit more about the drug. Where is it from? Who makes it? Do you have any thoughts on cost? What are the implications because the role of Pharma, specifically being Pharma, has characterized a lot of these weekly discussions? And of course, the spin-off around profiteering excess price gouging instead, etc.
The measles, mumps, and rubella vaccine. Two companies make the vaccine registered in South Africa, GSK, and Burke. We approached both companies. And there was one that was able to provide the MMR to us. It was imperative that we do not look for a central supplier but that we get a supply that would be available in-country. And the second consideration is that we didn’t want to interfere with the National Measles Program. So we didn’t want to take vaccines from the Expanded Program on Immunization (EPI) program. And we knew the EPI program is considering moving to an MMR vaccine. But they were in the middle of sort of getting that vaccine registered. So we approached, in the end, GSK is providing us with the MMR vaccine, they’re not donating it free of charge, but they’ve given it to us at a reduced cost. And as a consortium globally, we’ve already started to have or initiate or flag the need to have discussions with, for example, at WHO about this approach to live attenuated vaccines, which are available much more cheaply to national EPI programs, particularly at bulk so that they’re aware of the potential demands. Kind of the potential access issues and that in addition to the work that’s being done around specific vaccines, we’re also managing potential issues around supply and scale-up of manufacturing of these other vaccines.
Do you have an idea of what the current vaccine costs in the public health sector?
Well, because we don’t use MMR in the public sector at the moment. I can’t make a direct comparison. But I imagine that if MR once MR is licensed in South Africa, and the costs are, my understanding is that the price, you know, kind of US cents or small dollars as opposed to substantial amounts, which might be associated with some of these new vaccines, particularly that have complex technology.
Could you now speak to us a bit more about the timeline? When is this trial going to be launched? What is your timeframe looking like? And then as a follow on, could you flesh out and describe a bit more of your community engagement and stakeholder engagement outreach plans for the trial?
So timelines as you know Tian, there’s a bit of history to this trial, we’ve managed to pivot, so we’re going through sort of the review of the new interventions with SAHPRA and the ethics committees, we receive responses, and I’ve just kind of submitted our responses. So we’re hoping that any day now we will get approvals. We’re working with about ten sorts of institutional partners in South Africa who are experienced trial sites. Many of them have done some kind of traditionally from HIV prevention trials and TB trials. They have each of those teams very experienced with stakeholder engagement and have developed local stakeholder engagement plans. They have community advisory boards, many of them include health care workers, and they’ve done local outreach. And also, there’s work that we’ve done to sort of coordinate sort of at a national level, so doing outreach to groups like yourself, participating in a range of webinars talking with the Department of Health as I mentioned earlier, working with, through our networks of professional societies, I suppose so like the Infectious Disease Society of South Africa or the HIV Prevention Society, to sensitize people to the trial to the issues and to have conversations like this where you flag up, for example, the critical concerns about PPE, and that was sort of informative in the early days. And because we live in a virtual world, I think there have been several sorts of webinars. We have a website if people are interested in called the crowncoronation.com. We have some videos that explain how the trial is operated. We also have some investigators and Q &A explaining parts of the trial. So those I think, have been sort of through broad brushstrokes. There’s sort of levels that we worked at—local around sites at a national level and across the global Consortium. And I know that there are colleagues involved in the trial who are on the call who may actually be more eloquent than me about sort of the strategy’s detail. So if anyone wants to find out more, we can certainly call on them.
Great, thanks for that. Sinead so, mental health has been a massive issue around trials, and I’m particularly interested in finding out a bit more from you. What interventions have you put in place as a core principal investigator for all of these trial teams and site teams, your team? What support is accessible for your team on this trial for their mental health and their well being? Have they been any specific interventions or additional capacity provided for them to access that?
So that’s an excellent question. I could say that this has not necessarily been sort of at the forefront of our planning, but I would say that I can reflect on my own team’s experience. I think we’ve all had efficient experiences of dealing with COVID, both in terms of the impacts on staff and planning for how to run clinics and see participants who might have COVID. And clearly, we’ve felt the surge that people experienced in July where many people were ill when there were many decisions about how to manage work, how to make sure that people are safe, what to do about sort of return to work and post COVID symptoms. And it was a very practical experience. Yes, that was what that means in terms of day-to-day stresses and mental health implications. So, in our team, we do have a program of debriefing, we do have access as part of our COVID SOP’s. We have a reference to resources for mental health. We’ve worked quite closely with Lifeline as a very interested group in providing support to health care workers. And we have identified several other providers that are providing access to mental health services for frontline health care workers so that they can at least have someone to at the best provider or at the sort of most straightforward kind of provide therapeutic listening and provide a space I think, to articulate some of the concerns and stresses. Just yesterday, by the way, we were on a very interesting call with the Joburg district research Committee, which is encouraging researchers to present their work. And there was some exciting information just on people’s mental health experiences during COVID, and they clearly, it was not specific to health care workers. But there was some evidence to suggest that people who had high anxiety about getting COVID were more likely to experience depression. And often, those people may have had a history of sort of childhood trauma. So that already gives us some insights into how we might want to encourage facilities and investigators at a local level to talk to people about access to mental health resources. So it’s a fundamental issue indeed. I think we’ve all experienced, and I imagine that at a local level, investigators will be thinking about how to manage or support their staff and what that might mean in terms of what you know, what facilities might need to do.
Thanks for that. Sinead, so apart from Crown. We know there’s this tsunami of research happening as has been happening for at least these last few months. So within this whole melting pot of vaccine treatment research, what excites you the most? Which particular trial excites you the most and gives you the most hope? And what makes you think? Or what trial? Are you keeping your eye on? The whole landscape? Yes.
I’ve got to be a proud mom and say, you know, I think that we’ve put together a fantastic group of investigators. And I think this is a very exciting concept. But I also as a scientist, would say that the most important thing is to explore a range of options and to do trials that are going to provide robust results, that can quantify risks and benefits because, in my long history of working in HIV prevention, a flat result is as essential as a positive result. I think we’ve learned through the Chloroquine debacle, that, you know, it’s been important to have data in the face of lots of politics and spin and opinion. And what people need, I think, is clarity. And the trials will provide that. So I am interested in all the outcomes because I believe all of them are important. And again, Tian and I think we’ve learned from HIV prevention; there isn’t probably going to be a magic bullet. There will be some exciting early results; there will be results that say maybe if we do things in combination, this will be good. And all of it will be important because you know, kind of this pandemic I think, needs a range of responses. And hopefully that we will have lots of essential results in the coming years.
Could you just remind us who are the Funders of this trial?
Yeah, the biggest funder at the moment is the COVID Therapeutics Accelerator. That is a consortium that includes the Gates Foundation, DFID, the Wellcome Trust, MasterCard, and a range of other philanthropic organizations. Then, locally in South Africa, the South African Medical Research Council (SAMRC) has also provided funding. And then I think in some of the other countries, they’ve also had access to funding either from their research, funding agencies or other philanthropic or in some instances, crowdfunding sources.
Sinead. So, I guess my last question to you really would be, what message do you have to those who are perhaps sitting on the fence in terms of vaccines as a concept? Firstly. Secondly, to the anti-vaccine movement, precisely, in two regards. Number one, of course, in the time of COVID and the urgency of the pandemic. And secondly, considering one of your funders, the Gates Foundation, who will have on a webinar in the coming weeks. And one of the controversies, the rumor mill, the fake news, the misinformation going out, have you experienced any backlash? Do you anticipate any backlash on this trial due to Gates and providing you with the support that it does?
Tian, you asked such a great question. And it’s right at the end. And you know, kind of the vaccine confusion is not helping. Suppose I were to try and provide clarity of thought. The first is that I think, as someone working in infectious diseases, vaccines are a fantastic innovation. Essentially, they have learned how the immune system works and responds to infections and provided basically as a technology that can prevent people from getting those diseases. We often need vaccines to control infections because I think we’ve all seen these non-pharmacological interventions are challenging to implement. They’ve been painful, both at a social-economic level, and they don’t necessarily protect people from severe disease.Ultimately, vaccines are needed to control infectious diseases, particularly pandemic potential, like Ebola, like SARS-COVI-2, like HIV, and vaccines are the Holy Grail. And they have prevented a tremendous amount of death and disease. I am old enough that I can say that I, you know, I had measles. I had whooping cough. I wonder if my mother was a delinquent mother or an anti-vaxxer. But, you know, many of us don’t remember people who got seriously ill from those diseases. My grandfather had polio, and he had difficulty walking. He was unable to practice as a doctor after he contracted polio because it limited his mobility. But we’ve been so fortunate to live in a world of vaccines that we have forgotten about the severe disease that it causes until we see outbreaks as we did of measles. So I think for those people sitting on the fence, these vaccines have revolutionized human health, and they’ve changed things like childhood mortality significantly, particularly in low and middle-income countries, and are an essential intervention in our toolbox against really severe infections. So I think we need to ask ourselves, why are people concerned? And what I’ve understood is that for many anti-vaccine people, it may be a philosophical issue. There may be reasons that they have, but for the majority of us, most of us are concerned about our health are concerned when we hear about safety issues. And so I think it behooves us as scientists, advocates, and researchers to talk to people about what we do and don’t know about safety, to talk to them about how we generate data around safety. I think to try to address the concerns that the middle ground has to feel comfortable adopting vaccines to see that benefits potentially rapidly outweigh the risks. And if those risks are there, they’re infinitesimal and can be managed. But it’s a complicated issue. So it will require much work from all of us.
Certainly within our work around the BCG revac trial, some of our greatest allies have been in the trade and labor unions. Are you working with the trade unions given the dynamics of the frontline workers and their challenges?
So it was precisely so that we could reach out to unions to have conversations about this trial and about this research, and we’re definitely keen to talk offline about sort of whom we need to engage with further. Indeed, we have been talking to healthcare workers through our networks and, you know, kind of can extend that further but recognize the vital role that groups like trade unions play in sort of potentially advancing health care worker literacy and active participation.
How was your interaction with The South African Health Products Regulatory Authority(SAHPRA)? Were their concerns reasonable? And were you able to efficiently respond to them? And perhaps could you share some of those concerns if you can?
Yeah, so I think that generally, we’ve had an excellent working relationship with SAHPRA and the ethics committees. I think it may help that we’ve been working on HIV for a long time. And I’ve understood that it’s crucial to build good relationships and create the ability to have conversations in; both times where we’ve gone to SAHPRA with the protocol, we have asked for the opportunity to have a phone call. And indeed, in the first iteration of this trial, we had several calls with the clinical trials committee, and we’re able to have a good conversation about what their concerns were and to come up with a set of responses. Similarly, with the ethics committee, we’ve been able to have phone calls with many chairs; we also worked initially through a process with the chairs to get a combined review across ethics committees. And it’s not to say that we all have the same opinion. But I think that during this time of crisis, where everyone has been working so hard, it’s been incredibly important to try to talk to each other, hear each other’s concerns, and try to be responsive. In terms of what their concerns were on this trial, there have been relatively few. It’s been more about explaining the concept of a platform trial and how it would work and working through the processes for how we include new interventions because I don’t think this is something that we’ve used a lot in infectious diseases. And so that’s sort of been an area of development for all of us. But I think that’s quite exciting if we can lay the foundation for how we do platform trials for infectious diseases going forward and In South Africa.
Speak to us a bit more about the political support for this trial. Do you enjoy a widespread, unconditional political support for this trial? Or is there more you would like to see?
Well, Ntando has saved the most exciting question for last, it seems. I don’t think that. So it’s an interesting question. And I will say it as a conversation that I have had, I mean, and I’m curious to hear other people’s views. It’s been my observation that there has been tremendous support around one of the SARS-COV-2 specific vaccines. It generated a lot of positive citizen response. People from all walks of life have signed up to join this trial, practically a safety, and early efficacy. It’s not yet the phase three trials. And it struck me that it was important that, you know, kind of it is essential when significant figures in society endorse these trials because it inspires other people to join. And so I think political support in the broad sense is really important, that having representatives from across civil society that say these trials are important, we’re joining them. We believe in science. We believe that vaccine research is vital for South Africa. It’s crucial for us as a middle-income country who’s going to have to procure these vaccines. We also need to be at the table when they negotiate access, which is one way to do it. So I would be curious to hear from you how we do generate that broad political support. We, I think, as a trial that’s not promoting a specific SARS-COV- 2 vaccine, have tried to make arguments about why MMR might be for some people. But between you and the people on the call, I recognize that it may not be as sexy as a kind of a new vaccine. So how do we make it appealing? And how do we generate enthusiasm and excitement for this intervention, which may have benefit compared to some of the interventions? And how do we articulate that these ideas are all important? And we have kind of stakeholders or leaders that can support the full range of trials that are being done for us as a country. So, I think it’s a great question, and Ntando and I’m curious to hear your thoughts on some of these ideas.
Any last closing messages to society on a general role and how they could support the work you do?
Well, just to thank everyone for their questions, for the comments, and for the opportunity to engage. We welcome the partnership. We’re going to follow up with you offline, Tian, about several sorts of discussion points. We’d love to come back and give you updates as things progress. Certainly, sort of a lot of what you’ve said has provided, the investigators on the call food for thought. So thanks very much. And we look forward to sharing the good news with you, but even if we don’t have results, I think it will just be necessary to answer the question definitively. And to do it together, because this is a pandemic that needs a range of responses. So thanks very much.