Inside Out Quality
Inside Out Quality
The Lubeck Disaster: Expecting the Unexpected
In this episode, we explore a vaccine contamination disaster in the early 1930's Germany. Dr. Gregory Fox, Professor and Pulmonary Physician at the University of Sydney, joins us to discuss what went wrong, and how expecting the unexpected can alert us that something could be awry.
Read Dr. Fox's Paper on the Lubeck Disaster Here
Hi, I'm Aaron Harmon, and this is inside out quality, a podcast about real life events and experiences shared by our guests of when things have gone wrong, and how we can learn from them to build better products, companies and improve lives through an effective quality system. White plague and consumption are synonyms for tuberculosis in 2018, over one and a half million people die globally from this pathogen. What caused the most deaths in the United States in 1880? It was tuberculosis. Number one then pneumonia, diptheria fall by heart disease, malaria, scarlet fever and dysentery all beat out cancer, seven of the top 10 causes of death or infectious diseases. One more detail. 756,000 Americans died in 1880 40% of those were under the age of five. Those ages 15 up only accounted for 24% of the deaths. If we were to adjust those numbers to our population now, that would be the equivalent of 1.9 million children dying in the US this year. The robot was desperate for a way to stop infections and a German city named Lubich near the Baltic Sea vaccinations were underway, which will later end as a tragedy. Quality is a high priority, and it's legislated in the preparation of medicines and vaccines. Each element of the production process is carefully monitored. So things don't go wrong. What could go wrong? contamination. The vaccination program later called lubic disaster span from 1929 to 1933 251. Newborns were accidentally infected with tuberculosis, which infects mainly the lungs and can cause weakness, weight loss, fever, or cough. While the intent was to administer the safe BCG vaccine, it was instead contaminated with a very long pathogen mycobacterium tuberculosis, which vaccine was intended to prevent. The contaminated vaccine was fed to infants through breast milk between February and April of 1930. At that point, the first 72 Children given the faulty doses died, and the hospital immediately stopped administering any more of the vaccine. 173 of the infants got TB and survived. When they stopped giving out the contaminated vaccine, they destroyed all the samples, so no more could accidentally be given out. But this also made the after in fact investigation more difficult. So what happened to these doses back in the 1930s? And how does it affect quality today? Here to tell us all about it is Dr. Gregory Fox, respiratory physician and epidemiologist with the University of Sydney, and author on the research paper titled tuberculosis in newborns, the lessons from the Lubbock disaster. Welcome to Inside Out quality. Dr. Fox,
Gregory Fox:thank you. Great to be here.
Aaron Harmon:So first, can you tell us how you ended up studying tuberculosis and publishing about this disaster from years ago.
Gregory Fox:So I've been interested in tuberculosis for a long time as a respiratory physician, working in Australia with people who have tuberculosis, TB is a lung disease, and it tends to affect people in poorer parts of the world. So I've been fascinated as to how we can deal with that problem. And about seven years ago, I was at McGill University doing a postdoctoral fellowship in tuberculosis. And one of the focuses of my research was, was susceptibility to TB. Why is it that some people get TB, and other people don't. And I was fortunate to attend a lecture by one of the faculty at McGill, Professor Irwin. Sure. He was German by background and talked about this event in Germany in the late 1920s, and early 1930s, called the Lubeck disaster. And he spoke of it as an example of why some people may be susceptible to tuberculosis. And so after this lecture, he and I got talking, and this led to us working together, to go look back at the original report and try to bring to life this really significant event that had been forgotten by many people working in tuberculosis. How when
Aaron Harmon:I came across what you had published, that was the first I had seen of it. I felt like I had known quite a bit about tuberculosis and its history, but this was totally new to me. So with the the contamination, are there any speculations on like, how the contamination could occurred and, and why it went undetected?
Gregory Fox:So undoubtedly, back in Lubec General Hospital in the 1920s, the procedures around handling contaminated strains of bacteria probably were not very well developed. And at the time, the lab used to grow BCG for vaccinating kids. BCG is essentially a related bacteria to tuberculosis, but it's not likely to cause disease and has been given for a century for people to protect them against getting TB. And so, in this case, there was a agar preparation where the BCG was being grown. And somehow, active tuberculosis found its way into one of these culture media. And so because the tuberculosis bacteria like BCG grows very well on these media, that small amount of contamination resulted in the whole batch being contaminated. So it could have been something as simple as a person handling a contaminated sample from a child, and accidentally injecting a sample from from a child into one of these, these vials. And at that stage, there wasn't really a quality control process in place to pick it up. And so that the first that they noticed, it was when they started to see really unexpectedly high rates of death amongst these children. And by the time it was realized, unfortunately, quite a lot of children had already been infected, and then ultimately succumbed
Aaron Harmon:from a timeline of disease, when the child was first exposed, when would symptoms show up.
Gregory Fox:So in this particular situation, the children were given this vaccine orally. And so you can imagine a small newborn baby, when they give them something early, they're probably not that good to good at, at swallowing, and so some of them would have accidentally breathed the vaccine into their lungs. And that might have then resulted in them becoming unwell, or for others, when they swallowed it, it came, came into their, to their body and then spread systemically. So the time between when the person would have ingested it, and when they actually became unwell, would have been in a matter of weeks. So typically, we see in tuberculosis today that the time for progression from initial exposure to active disease in young and very susceptible kids is very rapid. And so it's likely that these kids would have become sick, you know, within a month or two of being affected. But the difficulty is that TB takes time. And so by the time people became aware of it, a lot of other children had already been
Aaron Harmon:affected. Sure, and with the initial symptoms, can Emir other respiratory pathogens, or would it be unique enough that they could have identified it? Yeah, so
Gregory Fox:it's really difficult to diagnose tuberculosis in children, even today. And that is partly because the signs are very nonspecific. So like you say, people who have TB can have loss of appetite, they get fevers, they can maybe have some respiratory symptoms, like cough, or they may have swelling and lymph nodes. And all of those things can be caused by other conditions. And so that that was one of the reasons why it was unlikely to being detected early on. And the second thing is to be able to actually detect TB in children is also quite difficult, because in children, tuberculosis is often what we call posse bacillary, which means that there's not that many bacteria that are present, even when kids are really sick. And so it can be quite hard to actually find the bacteria. These days, we use methods such as PCI, which is a method of molecular diagnosis, which is quite sensitive. But in those days, I didn't really have access to those tools to detect it. And so it took a while before the diagnosis was considered,
Aaron Harmon:would there be any risk that those kids could have transmitted to their family as well, it would have stayed with me when you mentioned their small bacterial numbers.
Gregory Fox:Yeah, so we find that in children, the greatest risk really is of adults infecting kids rather than the other way around. And the reason is that children both tend to produce a smaller number of bacteria, but also, they don't tend to generate aerosols, to the extent that adults do. And so in general, in this situation, and and today, for children who have TB, the risk of transmission from children is pretty limited.
Aaron Harmon:They were also getting the vaccine strain to is there any way that that vaccine strain could have reduced the effects for the ones that did survive.
Gregory Fox:So because the contaminated vials would have contained the mycobacterium tuberculosis as well as the BCG, they really would not have had a protective effect from the BCG because that was given at the same time. So there wasn't really a chance for the children's immune system to be primed to TB. Everything was given was given at once. And in fact, it's likely that the mycobacterium tuberculosis was the the dominant bacteria present in these vials. Okay, so even so I don't think that the BCG would have been effective. I noticed
Aaron Harmon:in your paper that it was hard to understand what happened to the children partly because the levels of bacteria in the vaccine weren't quantified, and details and how the vaccine was drawn from the flask wasn't documented. Is that what happened? And like, Would you ever imagine seeing that now in a clinical trial?
Gregory Fox:So I think the important thing to point out here is this was really not a trial, so much as observation of what happened. So when the hospital noticed that there was a high rate of mortality and the contamination was detected. So what happened was an expert researcher modelling was commissioned to go and look at what had happened. And he found that he could group the children according into the day that they had been inoculated against tuberculosis with these contaminated vials. And what he found was fascinating. He found that with certain vials that up to 71% of children died. Whereas in the vials, which he presumed to have a low level of contamination, just 2% died. So there was a really clear correlation between which samples the children received, and what the outcomes were. And so he worked backwards from that. And he said, well, that must indicate that there was a higher concentration of bacteria present in these vials. But unfortunately, we're not able to verify that against the actual lab data, because that wasn't available at
Aaron Harmon:the time. And a curiosity. Was there any notes about his investigation? Like was it possible that there was an employee that had tuberculosis that would contaminate the vials early on the preparation or something like that,
Gregory Fox:unfortunately, it's not really possible to know how the bacteria came to be in these vials. Normally, even in a lab, where a person has tuberculosis, it's not really possible to easily infect a culture medium from the person who who has disease, it's, it's more likely that there was a contaminated sample that was mixed in with the with the medium. That's because generally, even if a person is sick, and they're coughing into the air, the actual concentration of bacteria in the air is pretty low, compared to say, the concentration of sputum sample, so it's more likely that it was related to contaminated capitalism. So
Aaron Harmon:I'm thankful that they aren't spewing lots of TB into the air, that would be a bad thing. Now we'll take a quick break to hear from one of our sponsors.
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Aaron Harmon:But I think about manufacturing, and with the state of where we are now in the pharma or biologics industry, everything is so regimented around making sure that whatever goes out the door, or could go into a patient has been tested for any kind of contaminants and the exact quantity of what's in there, even to the levels, making sure that the organism that's in there is behaving the way you expect it to behave. And so the like, we do a lot of things now, but all of its for very good reason. So you don't have these issues happening.
Gregory Fox:That's right. I think, though, one lesson from the Lubeck disaster, is that you tend to not expect the unexpected. So in this case, it wouldn't have been routine practice to test for tuberculosis bacteria, in a BCG sample, because it wouldn't have been conceived of that you would somehow have the contamination. And, and it really goes down to the quality control processes that were in place at the time. I think that allowed for samples, which contained tuberculosis and samples, which were used for the vaccine program to be co located. That is they use the same cabinets to store both samples. And so I think that until this contamination happened, it wasn't really conceived of that some something like this could occur. Sure. And and obviously, you know, once this disaster was really revealed to the public and caused enormous consternation at the time that resulted in changes to the process by which these vaccines were, were managed. And I think similarly, you know, we need to learn today in the 21st century, that these sorts of very unexpected things can happen. And when they do, they'll have disastrous consequences unless we have in process methods of picking up unexpected things and looking constantly for problems in manufacturing processes.
Aaron Harmon:One tool that I use, so think if something was to go wrong, and whatever we're doing, and then you went back, what would you find the cause to be? And so just thinking about having pathogenic bacteria in the same room, where you have any kind of preparation of a human product would certainly be something that would be a flag,
Gregory Fox:it would it would end. And I think also just thinking through what are the other populations who are receiving these treatments as well. And in this case, newborn children are quite susceptible. So they are particularly high risk for getting the severe effects of tuberculosis. If you'd given the same oral dose to an adult who had been able to swallow properly and who had an immature immune system, the consequences would have been much less. But because this was a highly susceptible population. Kids have underdeveloped immune systems it takes probably five years before the human immune system reaches maturity to protect against tuberculosis optimally. And so therefore, it was a very unfortunate combination of, of a manufacturing problem in combination with very great susceptibility,
Aaron Harmon:the children were getting this vaccine. Was there any mention if adults had gotten it? So you mentioned like the, it might not cause the same kind of problems in adults? So is there any potential for that to have happened?
Gregory Fox:So in this population, the BCG vaccine was given at birth, and it wouldn't have been given to adults, because it would have been assumed that the adults would have either been vaccinated themselves or the benefits, you know, we're not as clear and in fact, today, in most of the world where BCG is given, it's given to kids in the first year of life, and they're not given again later on. So I think adults would not have been exposed.
Aaron Harmon:So where are we at with TB, currently, how much progress has been made and vaccines therapies are there still gaps leftover,
Gregory Fox:so TB, unfortunately, remains a major global public health problem. Before the COVID 19 pandemic began, tuberculosis was the top infectious killer globally. And to this day, there's about 10 million people each year who developed tuberculosis, and almost one and a half million people who die of tuberculosis, which is incredible to think, despite the fact that we have effective treatments, we have tools that are very good at diagnosing TB. And we also have good public health measures that we can use to protect people. Now, in terms of vaccines, unfortunately, there's there's really been still limited progress in developing a highly effective vaccine against mycobacterium tuberculosis. The BCG vaccine is still the most widely used vaccine in the world for children in endemic settings. And this is the same vaccine that was used back in the 1920s in Germany. And the reason that we haven't really had major advances in vaccine development is that the tuberculosis bacteria has been so effective at evading the human immune response. Even if you've had active tuberculosis, or even if you've been vaccinated, it's still possible to get infected with TB. And so therefore, we still urgently need new vaccines. Now, there have been some recent breakthroughs. So there's been a vaccine that has been tried and found to be more effective in certain populations in South Africa. And that's been evaluated. And and published in the last couple of years. There's certainly, I think, emerging some, some promising new vaccines, and also further ongoing research looking at revaccination in adults as well, and whether that can increase protection. But unfortunately, at the moment, BCG still remains really the standard of care that we have around the world.
Aaron Harmon:Back when Robert Koch was working on tuberculosis, he had thought he has stumbled across the treatment. And that treatment ended up becoming that tuberculin test. If I know my history, right, he knew anything about that incident.
Gregory Fox:Yeah, Robert Kok was really the, the father of tuberculosis, because he was responsible at the end of the 19th century for describing the bacteria mycobacterium tuberculosis, which, which causes TV. Unfortunately, Robert Koch, later in his career pursued this idea of tuberculosis as potentially a treatment for tuberculosis. And that ended up not being the case. And, and unfortunately, his reputation, which had been built upon his success in bringing the world's recognition to tuberculosis was was damaged considerably by his promotion of the use of tuberculin, as you say, tuberculin, which is a protein that is derived from tuberculosis, but it is not itself, able to cause disease is still use to this day in many countries, including in the US, including in Australia, where I am as a method of diagnosing TB infection, but it is not effective as a treatment. And so, unfortunately, despite his efforts to prove otherwise, that does not seem to be a way of protecting people against getting TB.
Aaron Harmon:And that has been a case where he really didn't have the clinical data before he kind of going out with it. But it has survived all these years as a test. I've been tested with it.
Gregory Fox:It fortunately, in the 20th century, in the 21st century, we now use randomized control trials as a way of evaluating the effectiveness of treatment, which Robert Koch didn't have back in the early 20th century. And that means that we can compare a new test against the existing standard of care and see whether it actually makes a difference. And rather than looking by purely trying out a new treatment or a new vaccine and seeing if it works without a contract And then potentially drawing false conclusions. The method of a randomized control trial allows us to, to make sure that it is the, the actual intervention that we're looking at that is causing an improved outcome and not some other factor, which is not measured. So I think that Robert Koch, unfortunately didn't evaluate the tuberculin treatment in a way that would have been effective in in testing that method. So I think that our trial design processes these days are much better suited for evaluating new therapies.
Aaron Harmon:It's really easy to like, talk about things that had gone wrong and kind of speculate on what they did wrong. But they learned so much in such a short amount of time, kind of mind blowing to think in the late 1800s, were still trying to figure out parts of germ theory and what back to doing, which and
Gregory Fox:that's right. That's right. I mean, it's, it's really incredible the learning curve, once it was realized that, that many diseases which were thought to be incurable, actually could be attributed to bacteria, which we could then in turn treat with antibiotics. And so from the 1890s, when there was just a realization that this this disease, which was thought of like cancer is today, disease where there was really poor outcomes within 60 years to having effective treatments that could cure the disease. And it was a really dramatic change for a disease that had and has plagued humans throughout history,
Aaron Harmon:that both our mind occasionally how far we've come and so quickly, and just think of like PCR. And now it'd be kind of be a no brainer to do a test to make sure you didn't have a contaminant and you can use different PCR tools or sequencing approaches. And those are all modern things that we've picked up over the last 30 years.
Gregory Fox:Yeah, I think it's, you know, it's still, the lesson from the Lubeck disaster, I think is still that it's important to look for things that are not expected. And contamination still can occur today, you know, own laboratories. And an example of how we use modern techniques to pick this up is, sometimes when you test somebody, you might come up with a positive diagnosis for tuberculosis, that is very unexpected. And you might think, well, the person didn't look very sick, they don't have the typical symptoms of tuberculosis, or the X ray doesn't really look like it. And then the labs will go back and they will check and say well was there are another patient who was diagnosed with tuberculosis on the same day in the same lab. And if there was to go back and compare the strains and occasionally even very good labs, you can get contamination between the culture of one patient and another patient and so very much built into the the laboratory quality control processes is looking for these unexpected contamination events, even where there is very good infection control practice in place.
Aaron Harmon:That's a good point and kind of like having a radar for something going awry.
Gregory Fox:Yes.
Aaron Harmon:Thank you for joining us.
Gregory Fox:It's great to be with you. Thanks for listening to this episode, and stay tuned for our next one.
Aaron Harmon:We hope you enjoyed this episode. This was brought to you thanks to South Dakota biotech Association. If you have a story you'd like us to explore and share, let us know by visiting www. SD bio.org. Also, if you live in the Sioux Falls area, check out QUIBIT a local Quality Assurance Professionals Network. You can find out more about QUIBIT by clicking on the link on our website too. Thanks for listening