COVID-19 vaccines and PH: The facts Written by Mary Ferguson on Tuesday 8th of December 2020. As well as playing a key role in the Oxford COVID-19 vaccine trial, Dr Mark Toshner is also a pulmonary hypertension consultant at Royal Papworth Hospital and a Cambridge University lecturer. His experience of running PH trials landed him a pivotal role in the fight against coronavirus and on the day the news broke about the Oxford vaccine being 90% effective, Dr Toshner turned down a BBC interview to give us an hour of his time. We’d like to thank Dr Toshner for his time, his honesty, and the part he has played in paving a path out of the coronavirus pandemic. This interview was conducted on 23rd November 2020 and was informed by questions submitted by PHA UK members. Back to basics to begin with – what is a vaccine? A vaccine is a substance that helps provoke your immune system to respond to what’s known as a ‘pathogen’ – a virus or bacteria that can attack you. Your immune system – which fights infection – develops a defence mechanism against that pathogen and then goes into hibernation, ready to swing into action at a later stage if it ever comes across it again. Vaccines have been around for over 200 years and there is a strong case that they are the single most important advance in medical research in its history. Along with clean water, vaccines are probably responsible for saving more lives than anything else on the planet. They have a long and glorious history of protecting us against predominantly infectious diseases. Do the COVID-19 vaccines work by giving you some of the disease they aim to protect against? Sometimes that is what we do with vaccines. We give a low level of exposure to the pathogen and then you develop an immunity, but the pathogen has been weakened. But that is not the case with all of the COVID-19 vaccines that have been developed so far. Some of them have taken some really novel approaches to this. For example, the ones by Pfizer and Moderna have taken a revolutionary approach by coding for the bit of genetic material that the DNA produces to make protein – they directly give you that bit of message, and fool your cells into making a protein that the virus expresses on its surface. So you haven’t been exposed to the virus, you’ve been exposed to that one protein that the body recognises. And it means when a virus attacks you, the body already has a pre-formed defence mechanism. In our case, with the Oxford vaccine, we’ve used a different method, and that’s to use a cold virus and re-engineer it so that when it goes into your cells, it does that next step of making your cells produce that protein. So, it has the same effect, but it’s just a slightly different way of doing it. There are a number of different ways of different vaccines getting to the same end product – which is the body recognising a bit of the virus so that if it ever comes in contact with it again, it can immediately act to destroy it. Lots has been reported this week about the Oxford vaccine. What are the crucial bits for you? There are two important things that we look for in a vaccine – whether it prevents severe infection and whether it prevents transmission. If we can prevent both, that’s the quickest path to us getting back to some sort of normal, and we now have evidence from our trial that this vaccine does both. There is a lot of focus on percentages in the media. The headline figure is that the Oxford vaccine prevents 90% of symptomatic infections at what’s known as a ‘two-dose regimen’ – where you get a lower dose and then a higher dose. But this is early data, as it is in all trials, and it will be a changing space. That headline figure is amazing but it’s not the be-all-and-end-all. The most important thing is that it prevents infection and transmission. One of the good things about the Oxford trial, which is slightly unusual, is that we were surveying all of the participants weekly – so we have very good data on asymptomatic carriers [people who have COVID-19 but don’t show symptoms]. So we’ve got good data to show we prevent severe disease, good data to show that we prevent symptomatic disease, and some data that really excitingly suggests we also prevent asymptomatic disease. It’s an amazing thing to be part of. How long would it normally take to develop a vaccine? The figure being bandied about at the moment is about ten years, but it’s a false term and a false timeframe. It’s a bit like in pulmonary hypertension trials. If you look at the PH drugs that have been developed, ten years happens to be about the same timeframe, and it’s for the same reasons. Most of the time is spent not doing very much, and that’s not because of laziness. A lot of time is spent trying to convince either funding agencies or drug companies to invest in therapies, then trying to get them through the regulatory process, and then trying to find volunteers to sign up to the trials. The trials are often run on a tight budget, and at the end of all that, if I’m really lucky, I go back to the regulators again. [Regulators are the bodies that decide what drugs can be given to human beings, and in the UK it’s the MHRA – Medicines & Healthcare products Regulatory Agency]. Has the COVID-19 vaccine you’ve been working on been rushed? And has that compromised its safety? I hear the word ‘rushed’ a lot but it’s the wrong word as it suggests there might be a degree of changes in our normal safety procedures – and that’s absolutely not the case. I can be unequivocal about that because I was involved in the trial. In fact, I’ve been astonished by the level of regulatory oversight and the reporting of safety in vaccine trials, and it’s made me think about some of the trials I run in pulmonary hypertension. For example, the last PH trial I had recruited less than 30 people and there were four ‘serious events’ in that trial. [An ‘event’ is a reaction or adverse experience, and may mean someone being admitted to hospital, even if there is nothing really wrong]. So that’s four in a trial of 30 patients. I would not classically stop my trials for that number, because of how serious PH is and the benefits outweighing the risks. In the vaccine trials, hundred of thousands of people were being vaccinated and the media were reduced to reporting single events. Trials were completely suspended until those single events were pored over in great detail. It’s a bit like if you were take the city of Sunderland, and watch every single person in Sunderland for medical emergencies and report every single person admitted to hospital, everyone who had a heart attack, stroke, or cancer – we’d be doing that hundreds of times a day. So in some ways it’s astonishing that we were reduced to talking about one, two, or a handful of individual cases. And that just shows the safety of vaccines. Vaccines have an amazing safety record, particularly compared to drug therapies, and I will be first in line to have a vaccine the minute I possibly can. How was the Oxford vaccine able to be developed so quickly? I know the Oxford trial has been run safely. It’s also been run quickly, but that’s not the same as being rushed. It’s been allowed to run quickly because we were given lots of money, and the whole of the world’s trials infrastructure. So, every single unit in the world that considered running a vaccine trial was able to utilise all of its staff. I had 90 people working for me at one point on this trial, compared to four when I ran the aforementioned PH trial. There were hundreds of people across the country working 16 hours a day on this trial and that’s another reason we were able to run it so quickly. The last reason, and possibly the most important reason, is that there are some amazing altruistic people in our country, so when we asked for volunteers, for an experimental vaccine study, tens of thousands of people put there hands up and said ‘I’ll do that’. They did that, so you don’t have to. All of the normal barriers I have in my everyday frustrating life of clinical trials just melted away. It’s like sitting in traffic in central London or Glasgow, and somebody just clears all the traffic and turns the lights from red to green. So, it’s not that there was any compromising of safety [in this trial], in fact if anything it was of a higher standard, but all of those ‘real world’ trial frustrations just melted away. The results announced this week [about the effectiveness of the Oxford vaccine] include patients from Brazil and South Africa, so this was not done in isolation. It was part of a coordinated effort on the part of researchers across the world. I think I’ll look back on this period of my life with great pride, to have been part of something that is frankly astonishing. Science has come to the rescue and I’m very positive about the next six months. I think we have a light at the end of the tunnel to look forward to. Should people be worried about long-term side effects of the COVID-19 vaccines? History tells us there are vanishingly rare side effects to vaccines in the long term so I think we can be confident from previous evidence – from all vaccines – that it’s unlikely that people will have long-term events. But I don’t think anyone would sit right now and say ‘we want to wait ten years before we use this vaccine because we’re worried about rare long-term events’. We can be confident that when the data’s published we will have a very large accumulative body of safety in the right timeframe, which is in the first two to six months after a vaccination. The reason vaccinations have such a short-term of side effects is because you only get one or two doses, and those doses have a short-term effect. The vaccine has been tested on ‘healthy’ volunteers. Will it be safe for people with pulmonary hypertension or other health conditions? No vaccine has ever been specifically tested in the pulmonary hypertension patient population and you’ll find that for most diseases. PH doesn’t have a very strong immunological basis, unless you’re looking at [it in association with] connective tissue diseases. One of the risk groups we worry about are immunosuppressed patients and some PH patients are immunosuppressed – so for example, if you have something like scleroderma, you might be on a drug that dampens down your immune system. But the good news is we have a number of different vaccines that work in a number of different ways. For example, with the Pfizer vaccine and the Moderna vaccine, there is no reason to suspect that there is going to be a safety issue with people who are immunologically compromised. That’s because you’re not dealing with a live virus, you’re dealing with something that translates DNA into proteins. We have a suite of potential vaccines that will be suitable for a lot of people. How well they will work, for example on someone who is immunocompromised, is a different question [to how safe they are]. We need to get to a point where we reduce the prevalence [of COVID-19] in the population, so even if you don’t get a vaccine, if enough other people do, we’ll get rid of the disease by herd immunity. Is there a timescale for these vaccines to be rolled out? That’s the big question. I expect vaccines to be rolled out in the UK in December. It might be the middle of December, or the end, but every indication is that we will have two or three licensed vaccines rubber-stamped by the regulators by the end of the year. Once that happens, it’s then about the practicalities of administering them. I’m expecting rollout to start in December, but it’s going to be focused on healthcare workers and the elderly first, because they are the highest risk. Why are healthcare workers taking priority? One of the highest risk places to be in the first wave was in a hospital. In Royal Papworth I looked after patients in intensive care and around half of those patients were healthcare workers. My colleagues were turning up every day and putting themselves right in the line of fire. It’s critical that our healthcare infrastructure is able to cope with the pandemic. So, to make it as robust as we can, the logical thing is to make sure healthcare workers are vaccinated first. The Government is also planning to start in the high-risk populations and in particular the elderly. How soon will you be protected once you’ve had a COVID-19 vaccine? This is information that isn’t widely available… but the answer is in a period of weeks. You don’t get protection immediately, and the best protection in all of the studies so far has been afforded by getting a vaccine and then a booster, and that’s a period of usually four to six weeks. At the end of that period, you are pretty effectively protected against getting coronavirus (the protection increases over those weeks). However, it takes up to that timeframe for it to take the full effect. It’s not a case of vaccinating everybody and then four weeks later life goes back to normal. It’s going to take months for us to eat into the proportion of at-risk people out there, and it’s going to be a little while before we are approaching ‘normal’. But we can now see the route to it and we can see our way out of this. It might not be quite as quick as people are hoping for, but it is going to be next year. What is the situation with children and vaccines? Vaccines [in general] are almost always never rolled out to children first, because of obvious and understandable anxiety about children being prominent in the first wave of experiments. So, nobody really has data yet on studies and children. That will be planned next, but I think there is a very good argument that children are the least of our priorities because they don’t appear, from the evidence, to be a big reservoir for infection. The current state of our knowledge is that most of the transmission doesn’t seem to be happening inside of schools for example. The international consensus is that children are not a strong reservoir for the virus circulating through communities. The other thing is that they are also, thankfully, the lowest risk group. What about children with PH? Will they be seen as more of a priority for a vaccine? The short answer is I don’t know. It will partly depend on how the trials evolve. We haven’t seen big reports of excess deaths in pulmonary hypertension patients. Not yet convincingly, certainly in children, and perhaps not yet in adults – although that is a much more controversial area. It’s hard with PH as it’s obviously not a common disease to get the point to be really confident that your observations are correct. And it’s complicated by the fact that a lot of our patients were shielding so we think some of the sickness we saw, and perhaps even some of the deaths, during the lockdown, were actually related to patients not being able to get access to full care – rather than lots of patients having COVID-19. Will the COVID-19 vaccines interact with PH medications? No. There are very, very rare instances of vaccines having been demonstrated to interact with any medications. There was one instance where, after a swine flu jab a number of years ago, there was an excess of younger patients getting narcolepsy. It was rare – around one in 50,000 – and some links were made to a protein involved in narcolepsy. But not drugs. Vaccines very rarely interact with anything else. So how safe are vaccines overall? It’s important that we’re honest – vaccines are not without any risks, but then very few things in life are. You could argue that climbing up a ladder at work, or crossing the road, is less safe than having a vaccine. As we go through life, we continually evaluate the risks of things around us, and sometimes we are good at it, and sometimes not so good. For example, some may be scared of flying but they will get in a car. That risk balance is wrong, but it doesn’t mean it’s wrong to them. There are people that feel the same way about vaccines. There are a lot of people with anxieties about vaccines, even though their track record is higher than many of the drugs they are on. I acknowledge those fears and concerns, they are appropriate, but they are to some extent stoked by the media. To those people, I’d say take some time. How can people make sure the information they read about vaccines is of good quality? Try not to take your information from social media. That is not a good source. If you are able to, and you wish to, read the source literature – the actual published papers. If you feel that’s a level above what you’re comfortable with, find someone you trust, who is an expert at understanding that literature [and listen to them]. One of the good things about many of the pulmonary hypertension patients that we look after is that they have a high degree of trust in us, and incredibly personal relationships with the teams that look after them. So, go and speak to your healthcare teams – they are a good source of high quality information and will be able to address your questions. Hopefully your relationship with them is such that you won’t feel you are being pushed into anything, but that you are given information to help you get to a decision you are comfortable with. The flu vaccine can leave you feeling a bit groggy for a few days afterwards. What would you say to people worried about similar things happening with a COVID-19 vaccination? I understand that. I always have my flu vaccine on Friday as I always feel terrible for a day or two, as it’s the body responding as if it has seen the virus. But you have to weigh up the risk to both yourself and wider society. I’m going to have the COVID-19 vaccine for myself, but also to protect my family. I couldn’t live with myself if I thought that I had passed the virus on to my wife or kids. I’m also going to have the vaccine for my patients and the people in my life who are higher risk. My dad has been very unwell recently and I’m not sure he would make it through COVID-19, so if I didn’t do it for myself, I’d do it to protect those I love. Do you think a COVID-19 vaccine will become an annual event in the same way that flu jabs are? It’s guesswork right now [in that respect]. If you were to ask me to guess, and I’m not usually a betting man, I’d say this will become an annual fixture and it will become part of the other vaccines you have in your life that you may not even think twice about. But we just don’t know yet. The really great news is that we now have three COVID-19 vaccines that work really well. And they are different, so they will be suitable for different populations of people. We are starting to really build a great army of different approaches to vaccinating and it is likely that we are now in the beginning of the end of the pandemic. I’m really positive, and really hopeful, that life will return to a version of normal next year. It’s just a case of getting through these next few months, because better times are coming.