PH & COVID-19 vaccines: An update Written by Mary Ferguson on Tuesday the 8th of December 2020. Interview conducted 6th December 2020 Following the announcement that the Pfizer / BioNTech vaccine has been approved for use in the UK, we caught up with Dr Mark Toshner to dig a little deeper and discover what it means for the PH community. Dr Toshner is a pulmonary hypertension consultant at Royal Papworth Hospital, Cambridge University lecturer and local investigator (LI) for the Oxford vaccine trial. Firstly, what does a vaccine have to achieve to become licensed for use? Drug therapies are assessed by an independent regulator, the MHRA (Medicines and Healthcare products Regulatory Agency). They are ‘professional pedants’; they absolutely and utterly love detail and are obsessed by safety processes. They go over all of the trial data and the questions they will be asking themselves are: was the trial well conducted and can we have confidence in it? Is the therapy effective? Does it work? Is the safety profile acceptable? These are all hard and fast things. They vary between diseases and therapies and if you think about pulmonary hypertension, there are a number of different causes and we have a number of different potential expectancies of what implications there are for things like side effects and life. And often what you will balance off in your assessment is not just the safety of the therapy in isolation, but the safety of the therapy in the context of the disease. And that’s really important because with vaccines, we’re delivering it to everybody. So actually, they have to pass a safety bar that’s miles higher than anything I would have to do for pulmonary hypertension trials or therapies. But you also then have to compare it to the effects of actually getting the disease. So, when they come to a decision about whether [a vaccine] is safe, it’s an unbelievably high bar. But it’s not judged in isolation. The question you have to ask yourself is ‘is this vaccine safe?’, but also ‘how does it compare to actually getting the disease’? Why has the vaccine been approved for use in this country before any other country? The UK is a world leader in the regulation around therapy safety and that’s a widely held opinion. There are, in some other countries, some significant political pressures on the regulators. So, each country has a slightly different calculus over the regulators’ approach to the same data. I have no qualms about how our regulators will have assessed this because I know how independent they are, but there are other countries where the calibration of those decisions is quite different. So, for example, in the UK we generally sit at the higher end of vaccine confidence. If you look at international surveys over the years, the general population has trust in vaccinations and in our regulators to get this right. But if you look at somewhere like America, that trust is much lower and one can therefore imagine a situation where the regulators have to approach this in a different manner, because the population they are speaking to is different. I’m not worried about the fact the [approval] decision was made quickly. I trust the regulators. But you don’t have to have the same level of trust as I do, that’s ok, we all come from a different position. The likelihood is that the majority of people are not going to get a vaccine for quite some time, even though we have a licensed vaccine ready. And that’s because of the way we will have to approach giving vaccines to the whole population. So, you can sit and wait for the data to come out. Some of the data hasn’t come out yet, and you can make your own mind up. Even if you’re not comfortable assessing that data, get someone you trust to explain it to you. I am very powerfully against mandatory vaccination and I don’t think that’s what’s going to happen. We have months for people to satisfy themselves that vaccines are safe. I am satisfied right now because I ran a trial and I saw the safety process from the inside, but most people don’t have that privilege. I’m confident in both the safety of the trials and the approach of the regulators, but if you’re not, then wait. See the data, and gain confidence from seeing other people get the vaccine. Can you remind us how this Pfizer / BioNTech vaccine, and others, have become available so quickly? It’s a major concern for some people at the moment, and it’s a valid one, but it’s addressable. The ‘normal’ process of drug and vaccine development is slow and that’s because of a lot of red tape and issues with funding, and the process of running trials is generally a slow and difficult process. The ‘normal’ timeframes aren’t there because of safety, in fact, they very rarely have anything to do with safety. It’s just ‘real-world’ barriers. This year, what’s happened is all those barriers have been removed. We have a wonderful clinical trials infrastructure in the UK and that infrastructure has been pointed at vaccine studies. We were given as much money as we needed, and all the usual barriers were swept away from us. The speed of it has nothing to do with safety. If anything, the safety processes were slightly higher, because no trial in history has ever been so carefully watched by the whole world. The focus on safety within the trials was absolutely laser-like, and I’m incredibly confident that the Pfizer vaccine will have gone through the same process, along with the other vaccine studies. How has the priority list for vaccines been decided? The pressing question for people with pulmonary hypertension is now ‘when will I get a vaccine’? And ‘should I take a vaccine’? We have an answer to one of those questions, but the other is a little less clear. The answer to whether you should take a vaccine is an unequivocal yes. We don’t yet fully understand the risks of [having] pulmonary hypertension in the context of COVID-19. There is some data that suggests our patient groups are at increased risk, and I think it’s much safer to have a vaccine than put yourself at risk of getting COVID-19. That’s simple, but when you will be offered a vaccine isn’t simple, and that’s because vaccinating a whole country is going to be a very complicated process. I think we’re only at the start of realising how complicated it’s going to get. For example, plans have changed already. The original plan was to have healthcare workers first, with over 80s, and vulnerable over 80s in particular in nursing homes in a parallel group running just behind. And that has been reversed because of the decision about who is felt to be most vulnerable and what the safest way to do this is. It’s likely we will see some slight changes as things go along, but also as we hit the practical barriers of how do you ensure that you set up rules and then follow them? My expectation is that the pace will slightly vary from place to place. If you think about it, this isn’t like the Ryanair priority queue at an airport. Some centres are going to be more efficient than others and some local decisions will be made about the applicable practicalities of some of the general rules. Right now it’s difficult to judge [when people with pulmonary hypertension will get a vaccine] as it’s a complicated thing. It’s coming, but I’m not sure of the exact timeframes and I don’t want to overstep and say that we have complete clarity over that. Will the vaccines interact with any pulmonary hypertension drugs? The history of vaccines is that they don’t interact with drugs. It’s as rare as hens’ teeth to find any interaction and that’s because they are not medications like you would classically think of and they are also incredibly strong acting. Studies have not specifically demonstrated yet the current vaccines and if there are any interactions (often vaccines don’t do those studies) but I expect these will be no different. So, I don’t expect there to be any drug interactions but one of the good things about the set-up in the UK is that we have a very well matured, tertiary response to looking after people with pulmonary hypertension. As you know we are all in specialist centres, so it’s something we will be able to evaluate from the specialist centres and it’s something we will be keeping an eye on. So, I think I can offer reassurances, but we don’t actually have clear data. However, historically vaccines just don’t interact with therapies, it’s just not a recognised problem. Do you have any idea when the Oxford vaccine may get approved? I think it will be within weeks. The data is with the regulator and that’s in the public domain. Remember, our trial [at Oxford] was different to the others. It wasn’t a drug company trial, it was an investigator-led trial, and that is an important distinction. We were completely independent; we had no interaction with Pfizer during our trial and they had no control or input into the trial and didn’t get the data until the very last moment. The only reason they have it now is because they are experts at putting the regulatory submission together and that usually requires a completely expert team, and we don’t have that type of resource. The data gets packaged up, given to Pfizer, and Pfizer then put their submission in. They then take it forward. Scaling up on an industrial level requires a commercial enterprise. That’s all important, because what’s good about the vaccine we worked on, is that from day one there has been a commitment to provide it at low cost, and that means there will be a variety of options for the whole world and not just for those [countries] that can afford it. Obviously, my bias is that I have been involved in the study so I have that emotional attachment but I like to think I retain a bit of independence here – and that independence extends to the fact this was not a drug company sponsored or run trial. So, we were able to make completely independent decisions. And that’s where the trial looks a little bit different to some of the other trials as well… our decision-making is not the same as a drugs company, we are not throwing unlimited money at this, and although we had fantastic resources for this it was delivered in a way that PH patients might recognise. When we have a few vaccines approved and that work, how will we decide which one is the best? It’s horses for courses here, there’s no single answer to that. It will be a mixture of practicality (what do we actually have in doses?), and how easy they are to get out to the general population. For example, the Pfizer one (as everyone knows) has big restrictions around its cold chain transport, and that’s where it can be kept at any one time during its life cycle (often at minus 70 or 80 degrees). That’s not the case with some other vaccines, like ours for example, which has a reasonable amount of time it can be left in a fridge. Then there’s going to be the question of what’s the definition of ‘works’? And that’s something we haven’t communicated really well. There are different definitions of ‘works’, which might surprise you. For me as an individual, the most important thing is, am I going to get severe disease? I don’t want to get really unwell. Then the next thing after that is, am I going to get unwell at all? So, am I going to get mild disease? That’s actually what we’re looking at in most of the reported figures. So, when you see those figures of 90, 95% [effectiveness] that’s about mild symptoms, not hospitalisations. And we may find there are differences in the trials as we go through, in their effect from that perspective. The next thing is we want to do is get to down to the point of affecting asymptomatic disease and transmission. So, there are different definitions of ‘works’ and it kind of depends on your value system. If I’m a 75-year-old with heart disease and diabetes, ‘works’ for me means the most important thing is I don’t get hospitalised and have a risk of death. But if I’m a 30-year-old, maybe living with an elderly relative, the most important thing to me may actually be that I just don’t want to pass this on to my parents / relatives, or [if I’m a healthcare professional], to my patients. ‘Works’ is more complicated than just a number and it will take a little bit of time for us to understand if there are differences in how the different vaccines work across those different domains. Ultimately, we’re in a brilliant position because in our wildest dreams we never thought we’d be talking about 90% effectiveness in any of those domains. The fact that we have any vaccines that hit that minimum bar of 50% reduction in mild to severe disease is an astonishing achievement. So, what next? Will the studies continue? I think one of the big risks is that everyone now thinks this is finished and we move straight to licensing and everyone gets vaccinated. There are big unanswered questions and we’re probably going to need to do comparative studies to look at one vaccine versus another, and we might have to look at multiple vaccines – doses of vaccines from different companies given together. We’re also going to have to look at how long immunity lasts for, and that’s going to be really important. We don’t know that yet as there’s not enough data. The altruistic, wonderful people out there who volunteered for an experimental vaccine were amongst the best of us, but what we now need is some more people to put their hands up and say they recognise there are still questions to be answered, and these trials still need participants. The more vaccines we have the better, and the more evidence we have the more confident we can be, but I think it’s going to be challenging to [get people to] enroll in some of the studies that open. In the context of the vaccine developments, when do you think we might get ‘back to normal’? It’s not going to be January or February. It’s definitely going to be longer than that. I know there are a lot of people out there confidently predicting ‘when’ but I can’t put myself in that camp. If you asked me to guess, I would say that in six months’ time we will definitely be in a position where life looks a lot more normal than it does at the moment. So, there is definitely light at the end of the tunnel, but we still have a bit more tunnel to get through. And that six months might be shorter, or it might be longer, but it’s going to be measured in months not years. We have something to aim for now and that’s the difference. Whereas before, we just had a lot of uncertainty about what the future held, I think we know the path now. Vaccines are going to reduce frequency of disease and we are going to get back to ‘a normal’. We need to have solidarity as a community and as a country to get to that end point. I know that’s challenging but at least we now know there is a light at the end of that tunnel. For the pulmonary hypertension community, the key message is to keep on doing what you’ve been doing. I am very confident the vaccines are going to be safe in my patients but I also recognise there is a lot of anxiety out there and some people aren’t at that point where they are ready to put their hand up and say ‘I’m ready to have a vaccine’. That’s ok, you’ve got time. Wait and watch, don’t close your mind to it, and when the time comes, I trust my patients to make good decisions.