Alicia Morgans: Hi, this is Alicia Morgans, Associate Professor of Medicine and GU medical oncologist at Northwestern University in Chicago, Illinois in the United States and I'm so excited to have here with me today Mr. Paul Hegarty, who is a urologic oncologist, a consultant and your urologic surgeon at the Mater Misericordiae in Dublin, Ireland. Thank you so much for being here with me today.

Paul Hegarty: Thank you for having me.

Alicia Morgans: Wonderful. So, Paul, you have been working with several collaborators to come up with a really exciting and interesting study that evaluates BCG vaccination in the setting of SARS-COV 2 really an attempt to vaccinate against it. And I'm wondering if you could tell us a little bit about the background, where this idea came from and why it should work and then we can talk about what that trial entails.

Paul Hegarty: So in my training, I trained at MD Anderson Cancer Center in Houston, Texas and the Director of Training there was Dr. Ashish Kamat and I was in correspondence with him soon after the coronavirus was becoming a problem for Western Europe and he has a strong background in BCG for its use in bladder cancer. BCG is used for about 40 years in bladder cancer to prevent recurrence and progression of bladder cancer with quite good success and Dr. Kamat has been at the forefront of that work in the last two decades. And we were discussing BCG and he mentioned that people were wondering was there an association between people having BCG injection in childhood and having a reduced risk of the COVID-19. So I got busy with databases and put together databases on the whole world population, each country by country looking at their incidents and death rate from this virus and then correlated it with the coverage of BCG based on what's called the BCG Atlas, which is a free source online, which has been very helpful.

And from that, we had 178 countries and 21 of them did not have a BCG program or never had one. And we looked first at that, even eyeballing it when we overlapped the countries that were being hit the hardest in Europe such as Italy, France, Spain, UK. Those countries do not have a BCG vaccination program, not for the whole population, Italy for example, never had one. And so, we then looked at country by country, and it was very clear that there was a negative correlation of countries that did not have BCG vaccination had a much higher rate of incidents and deaths from COVID-19. We were worried that this might be an anomaly due to poor recording and so, we then went country by country looking at neighboring countries, comparing countries with similar healthcare systems, similar wealth, similar climate, so various health economics and again, we found that the countries without the BCG vaccination had a three times higher death rate than countries with BCG. So non-BCG was a poor indicator for the likelihood of survival at a national level.

And this has been submitted and is currently under peer review, so we cannot speak definitively on it until then. This then is hypothesis-driven, so we have to be very careful when looking at population-wide studies as to whether they can be applied to the individual because it might be that there are some other factors in play here. But this is generally the hypothesis, that somehow the BCG vaccination may be causing a benefit to patients and there are lots of theories as to how that is.

This has led to a trial set up internationally for the BCG vaccination as a defense against SARS-COV 2, a randomized controlled trial to protect healthcare workers by enhanced trained immune responses. And the idea of this is to randomize healthcare workers who are at high risk of the disease. For example, in my country, 27% of cases of COVID-19 are healthcare workers and I think in China 41% of cases were in-hospital transfers. And so, these are the high-risk areas, so the initial phase of the trial is to randomize healthcare workers who have consented to being in the trial to either BCG or a placebo. Then they self report and there will be blood drawn at various time points and then hopefully within about three months we will have an idea as to whether the BCG vaccination is conferring an individual benefit or not and also to know the magnitude of that benefit. After we had the first interest in the observation paper many people said to us, "Why don't you just go ahead and start vaccinating the whole population?" And while in the current pandemic it would be very tempting to do that but we don't know really how to integrate this. If there is a benefit, we don't know the magnitude of the benefit and how would you integrate it with other measures.

So if it would mean that we could relax the social distancing or allow certain people back to work, et cetera, then we would like to know how much BCG is a part of that and whether we still need to continue with other means such as very tight disease tracing, so that's where we're at with that. There's a number of centers in the U.S. and we're now currently looking at the setting up of this trial also in Ireland. So I'm in contact with Dr. Arthur Jackson who is an infectious disease consultant in Cork where I grew up in Ireland and he has been very helpful with regards to sourcing BCG for this trial.

There are other considerations with regard to the practicalities of the trial that we're working through at the moment. It would be hopeful of setting this up soon so that we can get the answers. It would be particularly useful to do the trial also in the Irish population because most of the Irish people have been vaccinated at birth and a lot of our healthcare workers who come from abroad have also come from countries that have been vaccinated before and so again, it would be great to have a subset of subjects who have previously been vaccinated and see whether they boost closer to the time has a benefit or not.

Alicia Morgans: I think this is really fascinating and so noble really to try to engage healthcare workers in a clinical trial that's not necessarily typically the population our studies are usually in and so really, really exciting, really interesting. As you mentioned, this study is opening in California, Massachusetts, multiple sites in Texas and so, is certainly listed on clinicaltrials.gov and we will make sure that we have the reference there so anyone interested and who lives in those areas can engage and potentially participate in this trial. One of the things that you mentioned though that is certainly a question that came to my mind is that we have to get this vaccine, we have to obtain it from somewhere. Has it been difficult getting enough stock of BCG vaccine to get to all of these sites because it's not traditionally used in the United States at this point and so, probably is not around in large quantities here in the U.S. I'm not sure in Ireland if routine vaccination occurs there, whether it may be more easily obtained?

Paul Hegarty: Well they stopped the routine vaccination in 2015 for the specific reason that it was difficult to get it anymore. There's been a debate that lots of European countries whether to stop BCG vaccination anyway as the rate of tuberculosis has dropped and as social conditions have improved but there are non-TB benefits to BCG as well, which are pertinent to the decision of this. The shortage of BCG has been worldwide partly due to one of the main manufacturers having to shut down their unit a number of years ago and this has led to a lot of stress among urologists who use it on a routine basis in the bladder.

What's good is that the amount of BCG that's typically given to a patient who has bladder cancer would be enough to inoculate probably about 500 individuals if you could get them all lined up on the same day once you make it up, it lasts the number of hours once it's been reconstituted. So the actual amount needed for the subcutaneous, the injection level into the upper arm is very low, very low. And so, I think it would be okay in that regard. Furthermore, in other countries, there is easier access. I know in India they have much easier access to it and the biggest producers in the world are in India and the issue is that regulation has only allowed for a single strain in North America and that's caused a lot of anxiety as far as I'm aware.

Alicia Morgans: Interesting. And I'm glad that you are able to get it and of course it is a very small amount that would be needed but I'm glad that we are able to get it and we're able to move this forward. It's also exciting that urologists are really involved in an infectious disease trial because again, this is not necessarily the area where your urologic oncologists would normally put their time, so really exciting that this is something that you're going after. Now as you were designing this trial one other question that comes to mind is the variable incidents of developing COVID-19 in the different areas that are going to be covered by the trial. Was this something that you thought about and tried to work through in terms of the statistical design?

Paul Hegarty: Yes, and that's why we're going to have randomization done locally in each unit and therefore we should be able to correct accordingly if there is one area which is pre-peak and one area which is post-peak, and so, for example, the word coming out of China was that once the healthcare workers had a very high level of PPE, they had no further transfer or infections recorded among them and they were wearing these double layer, very severe double layering of PPEs that takes about 15 minutes to apply. And so, again, there can be local reasons for a much lower instance of this, so we don't know. We don't know but that's why as you alluded to the design of the trial will be to have randomization per unit as opposed to centralized randomization which could then end up skewing the results.

Alicia Morgans: Great. And I knew that you had thought that through I just thought it would be interesting to hear how you ultimately decided to deal with it and randomization, of course, is the purest way and the best way. How many patients are you expecting to have, not patients, I guess participants are you expecting to have in the study overall?

Paul Hegarty: Well, we're hoping between three and 700 per hospital, and that'll be helpful. Now how to power a study like this when we don't know what the instance per person, the individual personal risks will be difficult but we will have data managers independently following this, monitoring this and so, if we start getting answers early on, then we can put the brakes on with regard to the numbers. But I think anecdotally there's a high interest among healthcare workers getting involved. I think most of them have a strong belief in science anyway, have a strong belief in vaccination and so, they would want to be engaged. The next thing is there's a fear element to going to work every day for so many healthcare workers and having a chance to have extra protection will be useful and I don't think any of them will then think that somehow makes them immune. And so, I don't think they would drop their standards either, so I think that they are the perfect group to start with and then if we get positive results or useful results with them, then other vulnerable groups may be applied such as the elderly.

I heard of a trial which was done in Greece about a year ago among the elderly population using BCG to prevent the flu, the standard annual seasonal flu and what would be interesting would be to do a Post hoc analysis of that population to see whether they had reduced coronavirus incidents or mortality. That would be very helpful. The problem, which we shouldn't call it a problem, is that Greece has had a relatively lower instance of the due to manufacturer's increase, they take took very early action and very draconian factors pretty quickly in the population, took them on board very quickly, so the numbers in Greece are probably the best in all of Europe.

Alicia Morgans: That is definitely a good thing for Greece but if it does change or if the numbers of participants in the trial are high enough that it could still be assessed, it would be absolutely a very interesting analysis and if you end up doing it, we are happy to hear about that here, too. One more question before we wrap up and I hear your closing thoughts and this one is sort of a silly one, but I remember while I was in training seeing actually a number of people who had had BCG vaccines in the past and I haven't seen anyone recently with a vaccine history, but I do remember seeing those arms of previously vaccinated people that had left quite a scar on their arm where they had had the vaccine. I'm just curious, is the vaccination method similarly causing scars or do we expect it to?

Paul Hegarty: It is unfortunately and in Ireland, because most of us are vaccinated, when we joined med school, they actually checked us to see whether we had a scar and they did an intradermal test, a Mantoux test to see whether we still had antibodies. And so, yes there still is a scar and that would be part of the consenting process, to let them know that and they will probably feel like they've been given a shot in the arm for a few days. So again, that might be relevant to their work, very, very low risk of local skin reaction or an infection of the lymph nodes is phenomenally rare. There have been over three billion doses of BCG given worldwide and so, it's been given since 1921, so it's the vaccine that we have so much experience with and relative converge. And again, that's why urologists are among the physicians keen push it through because it's in our daily practice and we have a familiarity with it.

Alicia Morgans: Absolutely. And certainly, resistance against COVID-19 infection is something that I would definitely say is worth a scar on the arm, at least from my perspective. Of course, people who don't enroll in this study may feel differently but I think that that would be a small price to pay. So as we wrap up, I would love to hear your message to those who are eagerly awaiting seeing this study open and enroll and see where the results take us. Any closing thoughts?

Paul Hegarty: I think it's a difficult time for the whole world. Everybody is looking for good news and the doctors of the world are all working in various ways to try and combat this in whatever way we can and we look forward to the time when we can have some return to normality and health again.

Alicia Morgans: I could not agree more. And I appreciate so much you taking the time despite a busy practice and all the work that you're doing in terms of prevention to talk with us about your trial and again, as I said before, I do really look forward to hearing updates as time goes on. Thank you so much for your time, Mr. Hegarty.

Paul Hegarty: It was my pleasure. Thank you.