🔒 BCG vaccine trial update and SA’s low Covid-19 death rate, with Professor Andreas Diacon

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In late April, we had a fascinating discussion with Professor Andreas Diacon from Stellenbosch University about BCG and the trial to see whether this vaccine, that we all get in South Africa as babies, is going to shield us in any way. Prof. perhaps you can update us. Has the trial kicked off?

Yes, a trial has kicked off. Thanks for asking that. Usually, the buzz in the press disappears very quickly once the activity has started, but you are following up and I’m really appreciative of that. So far, we have 570 participants that have had this vaccination, either with BCG or with placebo. We’ve also started seeing events happening. So far we have about 120 recorded events. Of whom, I think, five are people that actually had to go to the hospital and a few others were quite serious. At this point, I have to tell you that, because it’s a so-called blind study, I do not know if the people that had these bad outcomes that want to protect them from, had the placebo vaccine or not. This is not very informative for your audience, but you’re looking live into a clinical trial and that’s how it is.

That’s interesting. More than 500 people are part of the trial, these are all health workers if I recall?

These people are all working in hospitals. We have observed that not only the doctors and the nurses are exposed. It’s just as much the people in the laboratories, running with materials in the hospitals, even the kitchen staff. They have all been shown to have high infection rates because they work in that environment where a virus is frequently around.

With these cases that you’ve just told us about, that’s roughly 20% of the people in the trial. That sounds like a very high percentage of infections. Help us through that.

These are not all infections. We are recording every disturbance to people’s health. Even if it’s mild, because we might only afterwards find out that it was Covid-related. So I think three months, six months and 12 months, we will measure people’s antibodies against the virus.

Even if people did not go for a test, we will be able to tell: you must have developed antibodies in this time, so what you reported to us then probably was due to Covid-19. The testing strategy currently isn’t such that every mild disease in every person will be tested by the government.

We might miss out on some but we will find out at some point. All these events, they can be something from a mild, temporary feeling of having a cold – to being hospitalised, it can be anything. We have to also appreciative that our vaccination might actually make things worse. I can’t really imagine how that could happen, but we have an obligation to capture really everything. If we somehow make people’s outcome worse, we would also know.

To bring those up to date who perhaps weren’t aware of the trial. BCG is administered to South Africans. Has been done so since the 1970s, perhaps even earlier than that. It has been shown in some correlative study, that it might be protecting nations that do have BCG vaccinations in infants. What you are doing now is revaccinating healthcare workers to see whether you can disprove this or prove it. It’s really a scientist’s look at whether there’s any truth in what the numbers are suggesting.   

It’s interesting, most people have perhaps heard that compared to the rest of the world the mortality in South Africa remains relatively low. This means that percentage of people who have the infection that die from it is lower than expected. This gives me hope that this might actually have something to do with the high exposure to diseases like TB that we have here, that the immune systems are prepared to fight off this kind of infection. This might have something to do with that observation and that we with the TB vaccine might actually be doing the right thing, that we are waking up that immune system, even if it’s not directly against Covid-19, but to prepare it for these type of infections optimally so that there might be some protection that we can show.

You can’t draw any conclusions yet because you haven’t seen the results or you haven’t had that kind of insight, but I recall in our last conversation you said that, because of the urgency of fighting Covid-19, that you’ll be trying to get the insights as soon as possible.

This is complicated. We have a very efficient system that my co-workers here have set up beautifully. All these 116 events that we have already recorded are within a very short time, a day or two, on the table of a statistician that sits in Sweden. That statistician is monitoring the data continuously and knows who was vaccinated with what. Periodically they do a formal analysis of the accumulated data and submit that to an independent committee, that we call a data safety monitoring board. There are four South African experts on this and two non-South African experts. All very experienced clinicians, researchers, statisticians that work in the field of public health, infectious disease, tuberculosis.

They will inform us if there is a signal strong enough that we can stop this study, that we can say BCG should now be offered to everyone who could have participated in this study and fits these criteria. We will know from them, they will approach us and say you should consider stopping this trial and making the result the public. Until then, I have no further information to give. It’s not very glamorous to be the main investigator of such a study if it’s blinded because I am the last person that’s going to know, but I will know one day.

They’re not giving you any inkling of when they would be able to inform you?

No, they are strongly encouraged not to do this. Imagine we know who has been vaccinated with what. My people all believe that we are doing something good and they will subconsciously then start rating events in these patients according to what they know they were vaccinated with. Everybody who had the placebo will be rated higher in their symptom scores and everybody that had the BCG will be asked, are you sure this was really so bad? The team would start influencing the results, so by no means must anyone in my team must know who was vaccinated with what. Only then the result that people have is credible.

Have you had any feedback from the other international trials that are in progress at the moment?

We do, none of these trials has a result. Many of them actually struggle because their epidemics in these places are mostly under control. For instance, if you do a trial in Australia, you will have very few events. Even if you have thousands of people on your trial, you will probably not accumulate Covid-19 related events at the rate that we are currently doing that.

Our epidemic in the Western Cape, it’s still growing and appears to reach a plateau in the next month and it’s probably not going to go away that quickly either. So we are in the best position, I think, currently to actually show results in this study just because we have events to report and to record. We hope to accumulate a bit more funding so that we can expand the numbers. Currently, we have enough money for 1,000. Our assistant assigned at the University of Cape Town is currently doing the numbers from about 600 to 1,000, but we would really like to continue to 2,000 to be sure that we will be able to show the effect of BCG vaccine                          

Who would help you to fund, where would use the resources from?                    

Covid-19 is a global epidemic and lots of people are testing a lot of good ideas out there, we are just one of them. We would hope that some donors like the government or other charitable organisations, perhaps the WHO, that someone would top up these numbers because the most expensive part is to get it started. We have been funded by the European Union for the first 1,000 participants and a start-up plus private funders have helped us. A private hospital chain has actually quite significantly assisted us in getting both the health care workers recruited and a trial funded. You can call it a spontaneous private-public partnership where everyone donates a little bit to its success. If we could top it up a little more, it would probably make the power of the trial to have a higher outcome.

Are you in touch with Dr Gonzalo Otazu from the New York Institute of Technology? I ask that because he was the man driving the very first correlative study of BCG. Can you swap notes with someone like that, is that ethical?

We do. He is not in any way involved in our study, but he’s made the interesting observations from where he sits, which is not here in South Africa. He observed that it appeared to him and his team just by looking at the numbers, that areas where BCG vaccination is applied routinely, these are the areas where tuberculosis is frequently found.

Those seem to be doing better with the Covid-19 numbers than other regions. This is an interesting observation, but there’s so many differences between countries, the age, the genetics, how they handle the epidemic, how close people live on top of each other or HIV prevalence. It’s hard to consider his observations good enough evidence to roll out the medical intervention.

We are basically follow up on this observation and trying to verify it in a real-world scenario, but with very, very well collected data that will live up to any quality cheque that would afterwards have to be done. So we are in touch and he is interested in what we do and he is interested in a personal level to see if his predictions turn out to be right.

He is not formally part of our team, but I’m grateful for his work, even if it turns out wrong. Its was a good idea and it needs to be tested even if the outcome would be negative. It would also, for us be interesting to see why all these lines of evidence that would make it probable that it works, why this is not so. There are interesting scientific questions where both are yes and no actually bring you further because it shows you that they are on a good path or you’re not. That’s why I would like to have more numbers, that I’m sure I can have a firm yes or no for the theory behind it.

The good news is it’s not such good news in that South Africa has all these events, as you call them, these infections of Covid-19, which is going up and that makes the trial or makes the evidence that you’re getting from the trial very rich. On the other hand, we also know that health workers have now got private protective equipment. They are being less infected than they were in the past. The question here is, what about extending the study, given that you get funding to older people, those who are really at risk and perhaps in those high-risk areas, seeing whether the BCG revaccination does assist?

It’s a good question. Perhaps one should look at it from the point of view of the risk of infection and the risk of a bad outcome once one is infected. I’m not entirely sure if old people are at a higher risk of being infected. The higher risk is that they become more ill once they are infected.

If you look at this, assuming that older people are at higher risk of dying, I’m not sure if it’s ethical to use them as a study population. You would probably want to do this the way we do it, I’m making this up now, but I am thinking aloud. If you do this in health care workers, you will have an age span of something between 20 and 65 in your study, and if we have something like two thousand participants, we can then look at an age-adjusted analysis.

I don’t think that the risk from 65 to 66, will make it jump up. If older people are different we would see a trend from young to old. From that, we can then probably figure out if it’s worthwhile extending the study to older people or not. We would then do this based on data and in consultation with people who would advise us if that’s doable. We’ll probably also consult the representatives of the community of older people if they feel that’s a fair thing to do.

Right now, I would rather not do this because it’s a high risk. If you do clinical research, the welfare of the participants in it, is always the very biggest concern. We don’t do anything where people would come to harm. It is probably safer to do it in people at low risk.

We also, for instance, exclude HIV positives from the study because there is a potential that the vaccination itself might be harmful in HIV patients. We have also been discussing this with these communities and the solution was that we would do this trial in non-HIV infected people and if we had a positive signal, we would immediately start another study in HIV positives that are stable on their treatments and see if we can use the vaccination safely in that population and perhaps similar approach could be done with elderly people.

We certainly could be popping in every three months to see how things are going on the BCG vaccine trial. It’s lovely to have a South African trial that’s being done. All the very best in getting those results, we look forward to hearing from you and hopefully, for the country’s sake in a positive way.

Oh, I hope so much that this will be true. Though, I have explained to you that I can’t influence it, it beyond putting on as many patients as quickly as possible. Thank you for following up, it’s great to see that people are interested not just in the hype of setting up something new, but also going through the hard work of actually doing it.