Ashish Kamat: It gives me great pleasure today to welcome Dr. Paul Hegarty, who's a consultant urologist at Mater Misericordia University in Ireland and Dr. Andrew DiNardo who is an Assistant Professor of Infectious Disease at Baylor College of Medicine and is extremely active and does a lot of work in global health and TB programs. Thank you, gentlemen, for joining us today.

Andrew DiNardo: Great to be here.

Paul Hegarty: My pleasure.

Ashish Kamat: We'll get right into the meat of the matter. There's been a lot of activity recently in the press and elsewhere about the potential of BCG vaccination for healthcare workers and others to protect against the COVID-19 pandemic. Paul and Andrew, you have both led the effort in a recent publication that's currently in pre-print and potentially in the press in a reputable journal. And Andrew, you're leading the efforts in getting this trial up and going in the US at Baylor College of Medicine. And of course, we at the MD Anderson are hoping to join as well. If I could ask you, Andrew, first, to just tell our listeners a little bit about the background as to why BCG protects and might be protective against this viral infection.

Andrew DiNardo: Sure. We've known for a very long time that BCG induces nonspecific immune benefits. There are studies from back in the 1970s that show that if you vaccinated an animal with BCG and then challenged that animal weeks later with a different infection, they would have an improved nonspecific immune response and an improved innate immune response. A kind of confounded immunology because the innate immune response doesn't have so-called memory. Well, over the past 10 years, mostly led by Dr. Mihai Netea in the Netherlands at Radboud University Medical Center, they've documented the mechanisms of this. Upon immune stimulation with BCG and a couple of other antigens, there is a metabolic shift, an increase in glycolysis and [inaudible] which triggers epigenetic changes. And those epigenetic changes are long-lived. They last at least one year. It induces a beneficial epigenetic change such that the innate immune response is primed and able to respond to things like Candida, or staph aureus, or pneumococcus, or viruses in an improved manner down the road.

BCG has been shown epidemiologically to decrease the rate of respiratory infections. It's very safe. A most recent study in humans showed that BCG followed by a virus challenge decreased yellow fever viremia using the yellow fever virus. The attenuated form, of course. It has nonspecific immune benefits. These nonspecific immune benefits help with viral specific immunity as well. It's a safe vaccine. It's been given more than any other vaccine in the almost 100 years that we've had BCG. It's been dosed almost three billion times and it's safe in adults. It's safe in healthcare workers. We know how to use it, so we have something that's ready now. We don't expect that it will completely prevent COVID but we think it will decrease COVID-related injury.

Ashish Kamat: Great, and we'll circle back a little bit to the specifics of the trial, but I want to segue now to Paul. Paul, based on this information about the BCG and its potential protective effects, you then conducted an analysis of the current COVID incidence and mortality and that's the paper that I was referring to earlier. Could you elaborate on that a little for our listeners?

Paul Hegarty: Sure. When you look at the incidence in Europe, specifically, the countries that have been hit by far the hardest are all countries that either never had a BCG vaccination program or gave it up. And so what we did was we then looked at the whole world, 178 countries and territories and looked at whether they had an intact BCG vaccination program for neonates. When we dichotomize those into those who have BCG programs and those that don't, there was a striking difference both with regard to the incidence and death among those. The death per million if you have BCG positive was less than one death per million whereas 15 per million in the countries without BCG programs. This was very striking and of course, there are many possible confounders into this, but we said let's lay it out there and see where it goes. And then with an epidemiology student from Houston, we looked at pairing countries according to their healthcare systems and economics, et cetera. And again, there was a very striking difference between the countries with BCG vaccinations and those without, so this has created a lot of excitement.

Ashish Kamat: Clearly with that information and the information that Dr. DiNardo provided, it makes perfect sense for us to move forward with the trial. And the trial is now been given an acronym, the BACTIR study, the BCG against COVID and trained immune responses. That's the short form of the long form of the name. But Andrew, one question that comes up from a lot of folks is how long would a trial like this last? And how do you account for or plan for the potential seasonality of this viral pandemic that we have?

Andrew DiNardo: Well you raise a couple of good questions there. What we would like to do is show that the BCG vaccine is safe and efficient and decreases COVID related illness. We don't know if there's going to be multiple waves of COVID-related injury and proper epidemiologists can speak more to this. But looking at what we saw in the 1918 pandemic, there were at least three waves. Our goal and effort is to do this safely and efficiently in the United States in places that have not been hit too hard yet. And therefore see how well it works, get the data analyzed before the proposed second wave of COVID hits in the fall if that's when a second wave will hit us.

Ashish Kamat: Great, thank you. And of course in the United States, we have always had this shortage of BCG relative to the demand for patients who have bladder cancer and that's why we did actually reach out to the Bladder Cancer Advocacy Network and had patient representatives and representatives of the advocacy network weigh in on this study because it might potentially divert some of the BCG that's used for bladder cancer to the trial. And I'm really pleased that we have full support not only from patients but also the officials from BCAN so long as we're good stewards of the supply and don't deplete it unnecessarily. Which raises a very important point that I want you to elaborate on Andrew and Paul, you as well. We clearly need support for a study like this and obviously we need funding, we need drug supply, et cetera, et cetera. If you had a wishlist of the top three things that you need for this study to move forward in an expeditious manner, what would they be, Andrew?

Andrew DiNardo: We have support from experts with clinical trial design and that continued support is critical. We've had support from healthcare workers that understand BCG, understand its safety profile and are eager to see how well it works. We obviously need funding to push this forward and we are battling against the clock. The clock is coming. There are cities that have been hit with this pandemic, obviously New York, Michigan, New Jersey, but there are some cities that have not yet seen the full front of this. Battling against the clock I think is top on my wishlist. You don't have a time-turner or DeLorean or something we can go back in the clock, but working as efficiently as feasible to get this implemented before the rest of the US cities are affected.

Ashish Kamat: Your top two things are expeditious review by the various regulatory bodies and funding sources from whoever and wherever it might be able to be achieved. I completely agree. And Paul, your top two or three items on the wishlist to make this happen?

Paul Hegarty: I think clarity with regard to which form of BCG we will use and then the agreement from the regulatory bodies to allowing the available BCG for access to this. There also needs to be a central database so that anyone can upload their data from within the group very quickly. And then multiple interim reviews just for safety reasons.

Ashish Kamat: Yeah, no, very good points. Again, because this trial is not a trial that any one of us is trying to embark on for ulterior motives. It's purely an altruistic help to healthcare workers and then help the population. Transparency is absolutely key, but also interim analyses to make sure that we are first doing no harm. Absolutely. Great point. Well, gentlemen, I do want to thank you for taking time off during this busy, hectic day and weeks that we have. In closing, any last thoughts for our listeners, Paul?

Paul Hegarty: I just want to thank you for hosting this. It's a very exciting time. We're bringing together top people from different strands of medicine and science together and everybody's so keen to unravel and crack this terrible crisis. And I thank you very much for hosting this.

Ashish Kamat: Oh, my pleasure. Thank you for joining. I will give Dr. DiNardo the last words since you have been working on this tirelessly, we've been exchanging emails at 2:00 AM and 3:00 AM so Andrew, final words for our listeners?

Andrew DiNardo: No, I just want to thank everybody for coming together in times of crisis. That's exactly what we need and it's a horrible crisis, but we are coming together and there are some silver linings and I appreciate everyone's effort on this. Thank you.