October 20, 2021 • 23 mins
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
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Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Aaron Harmon (00:00):
Hi, I'm Aaron Harmon, and this is inside out
(00:02):
quality, a podcast about reallife events and experiences
shared by our guests of whenthings have gone wrong, and how
we can learn from them to buildbetter products, companies and
improve lives through aneffective quality system.
White plague and consumption aresynonyms for tuberculosis in
2018, over one and a halfmillion people die globally from
(00:26):
this pathogen. What caused themost deaths in the United States
in 1880? It was tuberculosis.
Number one then pneumonia,diptheria fall by heart disease,
malaria, scarlet fever anddysentery all beat out cancer,
seven of the top 10 causes ofdeath or infectious diseases.
One more detail. 756,000Americans died in 1880 40% of
(00:46):
those were under the age offive. Those ages 15 up only
accounted for 24% of the deaths.
If we were to adjust thosenumbers to our population now,
that would be the equivalent of1.9 million children dying in
the US this year. The robot wasdesperate for a way to stop
infections and a German citynamed Lubich near the Baltic Sea
(01:08):
vaccinations were underway,which will later end as a
tragedy. Quality is a highpriority, and it's legislated in
the preparation of medicines andvaccines. Each element of the
production process is carefullymonitored. So things don't go
wrong. What could go wrong?
contamination. The vaccinationprogram later called lubic
disaster span from 1929 to1933 251. Newborns were
(01:29):
accidentally infected withtuberculosis, which infects
mainly the lungs and can causeweakness, weight loss, fever, or
cough. While the intent was toadminister the safe BCG vaccine,
it was instead contaminated witha very long pathogen
mycobacterium tuberculosis,which vaccine was intended to
prevent. The contaminatedvaccine was fed to infants
(01:52):
through breast milk betweenFebruary and April of 1930. At
that point, the first 72Children given the faulty doses
died, and the hospitalimmediately stopped
administering any more of thevaccine. 173 of the infants got
TB and survived. When theystopped giving out the
contaminated vaccine, theydestroyed all the samples, so no
more could accidentally be givenout. But this also made the
(02:13):
after in fact investigation moredifficult. So what happened to
these doses back in the 1930s?
And how does it affect qualitytoday? Here to tell us all about
it is Dr. Gregory Fox,respiratory physician and
epidemiologist with theUniversity of Sydney, and author
on the research paper titledtuberculosis in newborns, the
lessons from the Lubbockdisaster. Welcome to Inside Out
(02:35):
quality. Dr. Fox,
Gregory Fox (02:37):
thank you. Great to be here.
Aaron Harmon (02:38):
So first, can you tell us how you ended up
studying tuberculosis andpublishing about this disaster
from years ago.
Gregory Fox (02:45):
So I've been interested in tuberculosis for a
long time as a respiratoryphysician, working in Australia
with people who havetuberculosis, TB is a lung
disease, and it tends to affectpeople in poorer parts of the
world. So I've been fascinatedas to how we can deal with that
problem. And about seven yearsago, I was at McGill University
doing a postdoctoral fellowshipin tuberculosis. And one of the
(03:09):
focuses of my research was, wassusceptibility to TB. Why is it
that some people get TB, andother people don't. And I was
fortunate to attend a lecture byone of the faculty at McGill,
Professor Irwin. Sure. He wasGerman by background and talked
about this event in Germany inthe late 1920s, and early 1930s,
(03:31):
called the Lubeck disaster. Andhe spoke of it as an example of
why some people may besusceptible to tuberculosis. And
so after this lecture, he and Igot talking, and this led to us
working together, to go lookback at the original report and
try to bring to life this reallysignificant event that had been
(03:52):
forgotten by many people workingin tuberculosis. How when
Aaron Harmon (03:55):
I came across what you had published, that was the
first I had seen of it. I feltlike I had known quite a bit
about tuberculosis and itshistory, but this was totally
new to me. So with the thecontamination, are there any
speculations on like, how thecontamination could occurred
and, and why it went undetected?
Gregory Fox (04:13):
So undoubtedly, back in Lubec General Hospital
in the 1920s, the proceduresaround handling contaminated
strains of bacteria probablywere not very well developed.
And at the time, the lab used togrow BCG for vaccinating kids.
(04:34):
BCG is essentially a relatedbacteria to tuberculosis, but
it's not likely to cause diseaseand has been given for a century
for people to protect themagainst getting TB. And so, in
this case, there was a agarpreparation where the BCG was
being grown. And somehow, activetuberculosis found its way into
(04:57):
one of these culture media. Andso because the tuberculosis
bacteria like BCG grows verywell on these media, that small
amount of contamination resultedin the whole batch being
contaminated. So it could havebeen something as simple as a
person handling a contaminatedsample from a child, and
accidentally injecting a samplefrom from a child into one of
(05:21):
these, these vials. And at thatstage, there wasn't really a
quality control process in placeto pick it up. And so that the
first that they noticed, it waswhen they started to see really
unexpectedly high rates of deathamongst these children. And by
the time it was realized,unfortunately, quite a lot of
children had already beeninfected, and then ultimately
succumbed
Aaron Harmon (05:41):
from a timeline of disease, when the child was
first exposed, when wouldsymptoms show up.
Gregory Fox (05:47):
So in this particular situation, the
children were given this vaccineorally. And so you can imagine a
small newborn baby, when theygive them something early,
they're probably not that goodto good at, at swallowing, and
so some of them would haveaccidentally breathed the
vaccine into their lungs. Andthat might have then resulted in
them becoming unwell, or forothers, when they swallowed it,
(06:10):
it came, came into their, totheir body and then spread
systemically. So the timebetween when the person would
have ingested it, and when theyactually became unwell, would
have been in a matter of weeks.
So typically, we see intuberculosis today that the time
for progression from initialexposure to active disease in
(06:30):
young and very susceptible kidsis very rapid. And so it's
likely that these kids wouldhave become sick, you know,
within a month or two of beingaffected. But the difficulty is
that TB takes time. And so bythe time people became aware of
it, a lot of other children hadalready been
Aaron Harmon (06:49):
affected. Sure, and with the initial symptoms,
can Emir other respiratorypathogens, or would it be unique
enough that they could haveidentified it? Yeah, so
Gregory Fox (06:57):
it's really difficult to diagnose
tuberculosis in children, eventoday. And that is partly
because the signs are verynonspecific. So like you say,
people who have TB can have lossof appetite, they get fevers,
they can maybe have somerespiratory symptoms, like
(07:18):
cough, or they may have swellingand lymph nodes. And all of
those things can be caused byother conditions. And so that
that was one of the reasons whyit was unlikely to being
detected early on. And thesecond thing is to be able to
actually detect TB in childrenis also quite difficult, because
in children, tuberculosis isoften what we call posse
bacillary, which means thatthere's not that many bacteria
(07:40):
that are present, even when kidsare really sick. And so it can
be quite hard to actually findthe bacteria. These days, we use
methods such as PCI, which is amethod of molecular diagnosis,
which is quite sensitive. But inthose days, I didn't really have
access to those tools to detectit. And so it took a while
before the diagnosis wasconsidered,
Aaron Harmon (08:01):
would there be any risk that those kids could have
transmitted to their family aswell, it would have stayed with
me when you mentioned theirsmall bacterial numbers.
Gregory Fox (08:09):
Yeah, so we find that in children, the greatest
risk really is of adultsinfecting kids rather than the
other way around. And the reasonis that children both tend to
produce a smaller number ofbacteria, but also, they don't
tend to generate aerosols, tothe extent that adults do. And
so in general, in thissituation, and and today, for
(08:33):
children who have TB, the riskof transmission from children is
pretty limited.
Aaron Harmon (08:37):
They were also getting the vaccine strain to is
there any way that that vaccinestrain could have reduced the
effects for the ones that didsurvive.
Gregory Fox (08:45):
So because the contaminated vials would have
contained the mycobacteriumtuberculosis as well as the BCG,
they really would not have had aprotective effect from the BCG
because that was given at thesame time. So there wasn't
really a chance for thechildren's immune system to be
primed to TB. Everything wasgiven was given at once. And in
(09:07):
fact, it's likely that themycobacterium tuberculosis was
the the dominant bacteriapresent in these vials. Okay, so
even so I don't think that theBCG would have been effective. I
noticed
Aaron Harmon (09:19):
in your paper that it was hard to understand what
happened to the children partlybecause the levels of bacteria
in the vaccine weren'tquantified, and details and how
the vaccine was drawn from theflask wasn't documented. Is that
what happened? And like, Wouldyou ever imagine seeing that now
in a clinical trial?
Gregory Fox (09:35):
So I think the important thing to point out
here is this was really not atrial, so much as observation of
what happened. So when thehospital noticed that there was
a high rate of mortality and thecontamination was detected. So
what happened was an expertresearcher modelling was
commissioned to go and look atwhat had happened. And he found
(09:57):
that he could group the childrenaccording into the day that they
had been inoculated againsttuberculosis with these
contaminated vials. And what hefound was fascinating. He found
that with certain vials that upto 71% of children died. Whereas
in the vials, which he presumedto have a low level of
(10:19):
contamination, just 2% died. Sothere was a really clear
correlation between whichsamples the children received,
and what the outcomes were. Andso he worked backwards from
that. And he said, well, thatmust indicate that there was a
higher concentration of bacteriapresent in these vials. But
unfortunately, we're not able toverify that against the actual
(10:40):
lab data, because that wasn'tavailable at
Aaron Harmon (10:42):
the time. And a curiosity. Was there any notes
about his investigation? Likewas it possible that there was
an employee that hadtuberculosis that would
contaminate the vials early onthe preparation or something
like that,
Gregory Fox (10:53):
unfortunately, it's not really possible to know how
the bacteria came to be in thesevials. Normally, even in a lab,
where a person has tuberculosis,it's not really possible to
easily infect a culture mediumfrom the person who who has
disease, it's, it's more likelythat there was a contaminated
sample that was mixed in withthe with the medium. That's
(11:16):
because generally, even if aperson is sick, and they're
coughing into the air, theactual 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 contaminatedcapitalism. So
Aaron Harmon (11:30):
I'm thankful that they aren't spewing lots of TB
into the air, that would be abad thing. Now we'll take a
quick break to hear from one ofour sponsors.
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that SD bio.org. Now back to theshow.
Aaron Harmon (12:18):
But I think about manufacturing, and with the
state of where we are now in thepharma or biologics industry,
everything is so regimentedaround making sure that whatever
goes out the door, or could gointo a patient has been tested
for any kind of contaminants andthe exact quantity of what's in
there, even to the levels,making sure that the organism
(12:40):
that's in there is behaving theway you expect it to behave. And
so the like, we do a lot ofthings now, but all of its for
very good reason. So you don'thave these issues happening.
Gregory Fox (12:50):
That's right. I think, though, one lesson from
the Lubeck disaster, is that youtend to not expect the
unexpected. So in this case, itwouldn't have been routine
practice to test fortuberculosis bacteria, in a BCG
sample, because it wouldn't havebeen conceived of that you would
somehow have the contamination.
And, and it really goes down tothe quality control processes
(13:16):
that were in place at the time.
I think that allowed forsamples, which contained
tuberculosis and samples, whichwere used for the vaccine
program to be co located. Thatis they use the same cabinets to
store both samples. And so Ithink that until this
contamination happened, itwasn't really conceived of that
some something like this couldoccur. Sure. And and obviously,
(13:39):
you know, once this disaster wasreally revealed to the public
and caused enormousconsternation at the time that
resulted in changes to theprocess by which these vaccines
were, were managed. And I thinksimilarly, 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 havedisastrous consequences unless
(14:01):
we have in process methods ofpicking up unexpected things and
looking constantly for problemsin manufacturing processes.
Aaron Harmon (14:12):
One tool that I use, so think if something was
to go wrong, and whatever we'redoing, and then you went back,
what would you find the cause tobe? And so just thinking about
having pathogenic bacteria inthe same room, where you have
any kind of preparation of ahuman product would certainly be
something that would be a flag,
Gregory Fox (14:29):
it would it would end. And I think also just
thinking through what are theother populations who are
receiving these treatments aswell. And in this case, newborn
children are quite susceptible.
So they are particularly highrisk for getting the severe
effects of tuberculosis. Ifyou'd given the same oral dose
to an adult who had been able toswallow properly and who had an
(14:51):
immature immune system, theconsequences would have been
much less. But because this wasa highly susceptible population.
Kids have underdeveloped immunesystems it takes probably five
years before the human immunesystem reaches maturity to
protect against tuberculosisoptimally. And so therefore, it
was a very unfortunatecombination of, of a
manufacturing problem incombination with very great
(15:14):
susceptibility,
Aaron Harmon (15:18):
the children were getting this vaccine. Was there
any mention if adults had gottenit? So you mentioned like the,
it might not cause the same kindof problems in adults? So is
there any potential for that tohave happened?
Gregory Fox (15:29):
So in this population, the BCG vaccine was
given at birth, and it wouldn'thave been given to adults,
because it would have beenassumed that the adults would
have either been vaccinatedthemselves or the benefits, you
know, we're not as clear and infact, today, in most of the
world where BCG is given, it'sgiven to kids in the first year
of life, and they're not givenagain later on. So I think
(15:51):
adults would not have beenexposed.
Aaron Harmon (15:54):
So where are we at with TB, currently, how much
progress has been made andvaccines therapies are there
still gaps leftover,
Gregory Fox (16:02):
so TB, unfortunately, remains a major
global public health problem.
Before the COVID 19 pandemicbegan, tuberculosis was the top
infectious killer globally. Andto this day, there's about 10
million people each year whodeveloped tuberculosis, and
almost one and a half millionpeople who die of tuberculosis,
(16:23):
which is incredible to think,despite the fact that we have
effective treatments, we havetools that are very good at
diagnosing TB. And we also havegood public health measures that
we can use to protect people.
Now, in terms of vaccines,unfortunately, there's there's
really been still limitedprogress in developing a highly
(16:46):
effective vaccine againstmycobacterium tuberculosis. The
BCG vaccine is still the mostwidely used vaccine in the world
for children in endemicsettings. And this is the same
vaccine that was used back inthe 1920s in Germany. And the
reason that we haven't reallyhad major advances in vaccine
development is that thetuberculosis bacteria has been
(17:08):
so effective at evading thehuman immune response. Even if
you've had active tuberculosis,or even if you've been
vaccinated, it's still possibleto get infected with TB. And so
therefore, we still urgentlyneed new vaccines. Now, there
have been some recentbreakthroughs. So there's been a
vaccine that has been tried andfound to be more effective in
(17:31):
certain populations in SouthAfrica. And that's been
evaluated. And and published inthe last couple of years.
There's certainly, I think,emerging some, some promising
new vaccines, and also furtherongoing research looking at
revaccination in adults as well,and whether that can increase
protection. But unfortunately,at the moment, BCG still remains
(17:54):
really the standard of care thatwe have around the world.
Aaron Harmon (17:57):
Back when Robert Koch was working on
tuberculosis, he had thought hehas stumbled across the
treatment. And that treatmentended up becoming that
tuberculin test. If I know myhistory, right, he knew anything
about that incident.
Gregory Fox (18:11):
Yeah, Robert Kok was really the, the father of
tuberculosis, because he wasresponsible at the end of the
19th century for describing thebacteria mycobacterium
tuberculosis, which, whichcauses TV. Unfortunately, Robert
Koch, later in his careerpursued this idea of
(18:32):
tuberculosis as potentially atreatment for tuberculosis. And
that ended up not being thecase. And, and unfortunately,
his reputation, which had beenbuilt upon his success in
bringing the world's recognitionto tuberculosis was was damaged
considerably by his promotion ofthe use of tuberculin, as you
(18:53):
say, tuberculin, which is aprotein that is derived from
tuberculosis, but it is notitself, able to cause disease is
still use to this day in manycountries, including in the US,
including in Australia, where Iam as a method of diagnosing TB
infection, but it is noteffective as a treatment. And
so, unfortunately, despite hisefforts to prove otherwise, that
(19:16):
does not seem to be a way ofprotecting people against
getting TB.
Aaron Harmon (19:21):
And that has been a case where he really didn't
have the clinical data before hekind of going out with it. But
it has survived all these yearsas a test. I've been tested with
it.
Gregory Fox (19:30):
It fortunately, in the 20th century, in the 21st
century, we now use randomizedcontrol trials as a way of
evaluating the effectiveness oftreatment, which Robert Koch
didn't have back in the early20th century. And that means
that we can compare a new testagainst the existing standard of
care and see whether it actuallymakes a difference. And rather
(19:52):
than looking by purely tryingout a new treatment or a new
vaccine and seeing if it workswithout a contract
And then potentially drawingfalse conclusions. The method of
a randomized control trialallows us to, to make sure that
it is the, the actualintervention that we're looking
at that is causing an improvedoutcome and not some other
(20:14):
factor, which is not measured.
So I think that Robert Koch,unfortunately didn't evaluate
the tuberculin treatment in away that would have been
effective in in testing thatmethod. So I think that our
trial design processes thesedays are much better suited for
evaluating new therapies.
Aaron Harmon (20:32):
It's really easy to like, talk about things that
had gone wrong and kind ofspeculate on what they did
wrong. But they learned so muchin such a short amount of time,
kind of mind blowing to think inthe late 1800s, were still
trying to figure out parts ofgerm theory and what back to
doing, which and
Gregory Fox (20:48):
that's right.
That's right. I mean, it's, it'sreally incredible the learning
curve, once it was realizedthat, that many diseases which
were thought to be incurable,actually could be attributed to
bacteria, which we could then inturn treat with antibiotics. And
so from the 1890s, when therewas just a realization that this
(21:08):
this disease, which was thoughtof like cancer is today, disease
where there was really pooroutcomes within 60 years to
having effective treatments thatcould cure the disease. And it
was a really dramatic change fora disease that had and has
plagued humans throughouthistory,
Aaron Harmon (21:27):
that both our mind occasionally how far we've come
and so quickly, and just thinkof like PCR. And now it'd be
kind of be a no brainer to do atest to make sure you didn't
have a contaminant and you canuse different PCR tools or
sequencing approaches. And thoseare all modern things that we've
picked up over the last 30years.
Gregory Fox (21:44):
Yeah, I think it's, you know, it's still, the lesson
from the Lubeck disaster, Ithink is still that it's
important to look for thingsthat are not expected. And
contamination still can occurtoday, you know, own
laboratories. And an example ofhow we use modern techniques to
(22:04):
pick this up is, sometimes whenyou test somebody, you might
come up with a positivediagnosis for tuberculosis, that
is very unexpected. And youmight think, well, the person
didn't look very sick, theydon't have the typical symptoms
of tuberculosis, or the X raydoesn't really look like it. And
then the labs will go back andthey will check and say well was
there are another patient whowas diagnosed with tuberculosis
(22:27):
on the same day in the same lab.
And if there was to go back andcompare the strains and
occasionally even very goodlabs, you can get contamination
between the culture of onepatient and another patient and
so very much built into the thelaboratory quality control
processes is looking for theseunexpected contamination events,
even where there is very goodinfection control practice in
(22:48):
place.
Aaron Harmon (22:50):
That's a good point and kind of like having a
radar for something going awry.
Gregory Fox (22:54):
Yes.
Aaron Harmon (22:54):
Thank you for joining us.
Gregory Fox (22:56):
It's great to be with you. Thanks for listening
to this episode, and stay tunedfor our next one.
Aaron Harmon (23:01):
We hope you enjoyed this episode.
This was brought to you thanksto South Dakota biotech
Association. If you have a storyyou'd like us to explore and
share, let us know by visitingwww. 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 aboutQUIBIT by clicking on the link
on our website too. Thanks forlistening
Hi, I'm Aaron Harmon, and this is inside out
(00:02):
quality, a podcast about reallife events and experiences
shared by our guests of whenthings have gone wrong, and how
we can learn from them to buildbetter products, companies and
improve lives through aneffective quality system.
White plague and consumption aresynonyms for tuberculosis in
2018, over one and a halfmillion people die globally from
(00:26):
this pathogen. What caused themost deaths in the United States
in 1880? It was tuberculosis.
Number one then pneumonia,diptheria fall by heart disease,
malaria, scarlet fever anddysentery all beat out cancer,
seven of the top 10 causes ofdeath or infectious diseases.
One more detail. 756,000Americans died in 1880 40% of
(00:46):
those were under the age offive. Those ages 15 up only
accounted for 24% of the deaths.
If we were to adjust thosenumbers to our population now,
that would be the equivalent of1.9 million children dying in
the US this year. The robot wasdesperate for a way to stop
infections and a German citynamed Lubich near the Baltic Sea
(01:08):
vaccinations were underway,which will later end as a
tragedy. Quality is a highpriority, and it's legislated in
the preparation of medicines andvaccines. Each element of the
production process is carefullymonitored. So things don't go
wrong. What could go wrong?
contamination. The vaccinationprogram later called lubic
disaster span from 1929 to1933 251. Newborns were
(01:29):
accidentally infected withtuberculosis, which infects
mainly the lungs and can causeweakness, weight loss, fever, or
cough. While the intent was toadminister the safe BCG vaccine,
it was instead contaminated witha very long pathogen
mycobacterium tuberculosis,which vaccine was intended to
prevent. The contaminatedvaccine was fed to infants
(01:52):
through breast milk betweenFebruary and April of 1930. At
that point, the first 72Children given the faulty doses
died, and the hospitalimmediately stopped
administering any more of thevaccine. 173 of the infants got
TB and survived. When theystopped giving out the
contaminated vaccine, theydestroyed all the samples, so no
more could accidentally be givenout. But this also made the
(02:13):
after in fact investigation moredifficult. So what happened to
these doses back in the 1930s?
And how does it affect qualitytoday? Here to tell us all about
it is Dr. Gregory Fox,respiratory physician and
epidemiologist with theUniversity of Sydney, and author
on the research paper titledtuberculosis in newborns, the
lessons from the Lubbockdisaster. Welcome to Inside Out
(02:35):
quality. Dr. Fox,
Gregory Fox (02:37):
thank you. Great to be here.
Aaron Harmon (02:38):
So first, can you tell us how you ended up
studying tuberculosis andpublishing about this disaster
from years ago.
Gregory Fox (02:45):
So I've been interested in tuberculosis for a
long time as a respiratoryphysician, working in Australia
with people who havetuberculosis, TB is a lung
disease, and it tends to affectpeople in poorer parts of the
world. So I've been fascinatedas to how we can deal with that
problem. And about seven yearsago, I was at McGill University
doing a postdoctoral fellowshipin tuberculosis. And one of the
(03:09):
focuses of my research was, wassusceptibility to TB. Why is it
that some people get TB, andother people don't. And I was
fortunate to attend a lecture byone of the faculty at McGill,
Professor Irwin. Sure. He wasGerman by background and talked
about this event in Germany inthe late 1920s, and early 1930s,
(03:31):
called the Lubeck disaster. Andhe spoke of it as an example of
why some people may besusceptible to tuberculosis. And
so after this lecture, he and Igot talking, and this led to us
working together, to go lookback at the original report and
try to bring to life this reallysignificant event that had been
(03:52):
forgotten by many people workingin tuberculosis. How when
Aaron Harmon (03:55):
I came across what you had published, that was the
first I had seen of it. I feltlike I had known quite a bit
about tuberculosis and itshistory, but this was totally
new to me. So with the thecontamination, are there any
speculations on like, how thecontamination could occurred
and, and why it went undetected?
Gregory Fox (04:13):
So undoubtedly, back in Lubec General Hospital
in the 1920s, the proceduresaround handling contaminated
strains of bacteria probablywere not very well developed.
And at the time, the lab used togrow BCG for vaccinating kids.
(04:34):
BCG is essentially a relatedbacteria to tuberculosis, but
it's not likely to cause diseaseand has been given for a century
for people to protect themagainst getting TB. And so, in
this case, there was a agarpreparation where the BCG was
being grown. And somehow, activetuberculosis found its way into
(04:57):
one of these culture media. Andso because the tuberculosis
bacteria like BCG grows verywell on these media, that small
amount of contamination resultedin the whole batch being
contaminated. So it could havebeen something as simple as a
person handling a contaminatedsample from a child, and
accidentally injecting a samplefrom from a child into one of
(05:21):
these, these vials. And at thatstage, there wasn't really a
quality control process in placeto pick it up. And so that the
first that they noticed, it waswhen they started to see really
unexpectedly high rates of deathamongst these children. And by
the time it was realized,unfortunately, quite a lot of
children had already beeninfected, and then ultimately
succumbed
Aaron Harmon (05:41):
from a timeline of disease, when the child was
first exposed, when wouldsymptoms show up.
Gregory Fox (05:47):
So in this particular situation, the
children were given this vaccineorally. And so you can imagine a
small newborn baby, when theygive them something early,
they're probably not that goodto good at, at swallowing, and
so some of them would haveaccidentally breathed the
vaccine into their lungs. Andthat might have then resulted in
them becoming unwell, or forothers, when they swallowed it,
(06:10):
it came, came into their, totheir body and then spread
systemically. So the timebetween when the person would
have ingested it, and when theyactually became unwell, would
have been in a matter of weeks.
So typically, we see intuberculosis today that the time
for progression from initialexposure to active disease in
(06:30):
young and very susceptible kidsis very rapid. And so it's
likely that these kids wouldhave become sick, you know,
within a month or two of beingaffected. But the difficulty is
that TB takes time. And so bythe time people became aware of
it, a lot of other children hadalready been
Aaron Harmon (06:49):
affected. Sure, and with the initial symptoms,
can Emir other respiratorypathogens, or would it be unique
enough that they could haveidentified it? Yeah, so
Gregory Fox (06:57):
it's really difficult to diagnose
tuberculosis in children, eventoday. And that is partly
because the signs are verynonspecific. So like you say,
people who have TB can have lossof appetite, they get fevers,
they can maybe have somerespiratory symptoms, like
(07:18):
cough, or they may have swellingand lymph nodes. And all of
those things can be caused byother conditions. And so that
that was one of the reasons whyit was unlikely to being
detected early on. And thesecond thing is to be able to
actually detect TB in childrenis also quite difficult, because
in children, tuberculosis isoften what we call posse
bacillary, which means thatthere's not that many bacteria
(07:40):
that are present, even when kidsare really sick. And so it can
be quite hard to actually findthe bacteria. These days, we use
methods such as PCI, which is amethod of molecular diagnosis,
which is quite sensitive. But inthose days, I didn't really have
access to those tools to detectit. And so it took a while
before the diagnosis wasconsidered,
Aaron Harmon (08:01):
would there be any risk that those kids could have
transmitted to their family aswell, it would have stayed with
me when you mentioned theirsmall bacterial numbers.
Gregory Fox (08:09):
Yeah, so we find that in children, the greatest
risk really is of adultsinfecting kids rather than the
other way around. And the reasonis that children both tend to
produce a smaller number ofbacteria, but also, they don't
tend to generate aerosols, tothe extent that adults do. And
so in general, in thissituation, and and today, for
(08:33):
children who have TB, the riskof transmission from children is
pretty limited.
Aaron Harmon (08:37):
They were also getting the vaccine strain to is
there any way that that vaccinestrain could have reduced the
effects for the ones that didsurvive.
Gregory Fox (08:45):
So because the contaminated vials would have
contained the mycobacteriumtuberculosis as well as the BCG,
they really would not have had aprotective effect from the BCG
because that was given at thesame time. So there wasn't
really a chance for thechildren's immune system to be
primed to TB. Everything wasgiven was given at once. And in
(09:07):
fact, it's likely that themycobacterium tuberculosis was
the the dominant bacteriapresent in these vials. Okay, so
even so I don't think that theBCG would have been effective. I
noticed
Aaron Harmon (09:19):
in your paper that it was hard to understand what
happened to the children partlybecause the levels of bacteria
in the vaccine weren'tquantified, and details and how
the vaccine was drawn from theflask wasn't documented. Is that
what happened? And like, Wouldyou ever imagine seeing that now
in a clinical trial?
Gregory Fox (09:35):
So I think the important thing to point out
here is this was really not atrial, so much as observation of
what happened. So when thehospital noticed that there was
a high rate of mortality and thecontamination was detected. So
what happened was an expertresearcher modelling was
commissioned to go and look atwhat had happened. And he found
(09:57):
that he could group the childrenaccording into the day that they
had been inoculated againsttuberculosis with these
contaminated vials. And what hefound was fascinating. He found
that with certain vials that upto 71% of children died. Whereas
in the vials, which he presumedto have a low level of
(10:19):
contamination, just 2% died. Sothere was a really clear
correlation between whichsamples the children received,
and what the outcomes were. Andso he worked backwards from
that. And he said, well, thatmust indicate that there was a
higher concentration of bacteriapresent in these vials. But
unfortunately, we're not able toverify that against the actual
(10:40):
lab data, because that wasn'tavailable at
Aaron Harmon (10:42):
the time. And a curiosity. Was there any notes
about his investigation? Likewas it possible that there was
an employee that hadtuberculosis that would
contaminate the vials early onthe preparation or something
like that,
Gregory Fox (10:53):
unfortunately, it's not really possible to know how
the bacteria came to be in thesevials. Normally, even in a lab,
where a person has tuberculosis,it's not really possible to
easily infect a culture mediumfrom the person who who has
disease, it's, it's more likelythat there was a contaminated
sample that was mixed in withthe with the medium. That's
(11:16):
because generally, even if aperson is sick, and they're
coughing into the air, theactual 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 contaminatedcapitalism. So
Aaron Harmon (11:30):
I'm thankful that they aren't spewing lots of TB
into the air, that would be abad thing. Now we'll take a
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Aaron Harmon (12:18):
But I think about manufacturing, and with the
state of where we are now in thepharma or biologics industry,
everything is so regimentedaround making sure that whatever
goes out the door, or could gointo a patient has been tested
for any kind of contaminants andthe exact quantity of what's in
there, even to the levels,making sure that the organism
(12:40):
that's in there is behaving theway you expect it to behave. And
so the like, we do a lot ofthings now, but all of its for
very good reason. So you don'thave these issues happening.
Gregory Fox (12:50):
That's right. I think, though, one lesson from
the Lubeck disaster, is that youtend to not expect the
unexpected. So in this case, itwouldn't have been routine
practice to test fortuberculosis bacteria, in a BCG
sample, because it wouldn't havebeen conceived of that you would
somehow have the contamination.
And, and it really goes down tothe quality control processes
(13:16):
that were in place at the time.
I think that allowed forsamples, which contained
tuberculosis and samples, whichwere used for the vaccine
program to be co located. Thatis they use the same cabinets to
store both samples. And so Ithink that until this
contamination happened, itwasn't really conceived of that
some something like this couldoccur. Sure. And and obviously,
(13:39):
you know, once this disaster wasreally revealed to the public
and caused enormousconsternation at the time that
resulted in changes to theprocess by which these vaccines
were, were managed. And I thinksimilarly, 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 havedisastrous consequences unless
(14:01):
we have in process methods ofpicking up unexpected things and
looking constantly for problemsin manufacturing processes.
Aaron Harmon (14:12):
One tool that I use, so think if something was
to go wrong, and whatever we'redoing, and then you went back,
what would you find the cause tobe? And so just thinking about
having pathogenic bacteria inthe same room, where you have
any kind of preparation of ahuman product would certainly be
something that would be a flag,
Gregory Fox (14:29):
it would it would end. And I think also just
thinking through what are theother populations who are
receiving these treatments aswell. And in this case, newborn
children are quite susceptible.
So they are particularly highrisk for getting the severe
effects of tuberculosis. Ifyou'd given the same oral dose
to an adult who had been able toswallow properly and who had an
(14:51):
immature immune system, theconsequences would have been
much less. But because this wasa highly susceptible population.
Kids have underdeveloped immunesystems it takes probably five
years before the human immunesystem reaches maturity to
protect against tuberculosisoptimally. And so therefore, it
was a very unfortunatecombination of, of a
manufacturing problem incombination with very great
(15:14):
susceptibility,
Aaron Harmon (15:18):
the children were getting this vaccine. Was there
any mention if adults had gottenit? So you mentioned like the,
it might not cause the same kindof problems in adults? So is
there any potential for that tohave happened?
Gregory Fox (15:29):
So in this population, the BCG vaccine was
given at birth, and it wouldn'thave been given to adults,
because it would have beenassumed that the adults would
have either been vaccinatedthemselves or the benefits, you
know, we're not as clear and infact, today, in most of the
world where BCG is given, it'sgiven to kids in the first year
of life, and they're not givenagain later on. So I think
(15:51):
adults would not have beenexposed.
Aaron Harmon (15:54):
So where are we at with TB, currently, how much
progress has been made andvaccines therapies are there
still gaps leftover,
Gregory Fox (16:02):
so TB, unfortunately, remains a major
global public health problem.
Before the COVID 19 pandemicbegan, tuberculosis was the top
infectious killer globally. Andto this day, there's about 10
million people each year whodeveloped tuberculosis, and
almost one and a half millionpeople who die of tuberculosis,
(16:23):
which is incredible to think,despite the fact that we have
effective treatments, we havetools that are very good at
diagnosing TB. And we also havegood public health measures that
we can use to protect people.
Now, in terms of vaccines,unfortunately, there's there's
really been still limitedprogress in developing a highly
(16:46):
effective vaccine againstmycobacterium tuberculosis. The
BCG vaccine is still the mostwidely used vaccine in the world
for children in endemicsettings. And this is the same
vaccine that was used back inthe 1920s in Germany. And the
reason that we haven't reallyhad major advances in vaccine
development is that thetuberculosis bacteria has been
(17:08):
so effective at evading thehuman immune response. Even if
you've had active tuberculosis,or even if you've been
vaccinated, it's still possibleto get infected with TB. And so
therefore, we still urgentlyneed new vaccines. Now, there
have been some recentbreakthroughs. So there's been a
vaccine that has been tried andfound to be more effective in
(17:31):
certain populations in SouthAfrica. And that's been
evaluated. And and published inthe last couple of years.
There's certainly, I think,emerging some, some promising
new vaccines, and also furtherongoing research looking at
revaccination in adults as well,and whether that can increase
protection. But unfortunately,at the moment, BCG still remains
(17:54):
really the standard of care thatwe have around the world.
Aaron Harmon (17:57):
Back when Robert Koch was working on
tuberculosis, he had thought hehas stumbled across the
treatment. And that treatmentended up becoming that
tuberculin test. If I know myhistory, right, he knew anything
about that incident.
Gregory Fox (18:11):
Yeah, Robert Kok was really the, the father of
tuberculosis, because he wasresponsible at the end of the
19th century for describing thebacteria mycobacterium
tuberculosis, which, whichcauses TV. Unfortunately, Robert
Koch, later in his careerpursued this idea of
(18:32):
tuberculosis as potentially atreatment for tuberculosis. And
that ended up not being thecase. And, and unfortunately,
his reputation, which had beenbuilt upon his success in
bringing the world's recognitionto tuberculosis was was damaged
considerably by his promotion ofthe use of tuberculin, as you
(18:53):
say, tuberculin, which is aprotein that is derived from
tuberculosis, but it is notitself, able to cause disease is
still use to this day in manycountries, including in the US,
including in Australia, where Iam as a method of diagnosing TB
infection, but it is noteffective as a treatment. And
so, unfortunately, despite hisefforts to prove otherwise, that
(19:16):
does not seem to be a way ofprotecting people against
getting TB.
Aaron Harmon (19:21):
And that has been a case where he really didn't
have the clinical data before hekind of going out with it. But
it has survived all these yearsas a test. I've been tested with
it.
Gregory Fox (19:30):
It fortunately, in the 20th century, in the 21st
century, we now use randomizedcontrol trials as a way of
evaluating the effectiveness oftreatment, which Robert Koch
didn't have back in the early20th century. And that means
that we can compare a new testagainst the existing standard of
care and see whether it actuallymakes a difference. And rather
(19:52):
than looking by purely tryingout a new treatment or a new
vaccine and seeing if it workswithout a contract
And then potentially drawingfalse conclusions. The method of
a randomized control trialallows us to, to make sure that
it is the, the actualintervention that we're looking
at that is causing an improvedoutcome and not some other
(20:14):
factor, which is not measured.
So I think that Robert Koch,unfortunately didn't evaluate
the tuberculin treatment in away that would have been
effective in in testing thatmethod. So I think that our
trial design processes thesedays are much better suited for
evaluating new therapies.
Aaron Harmon (20:32):
It's really easy to like, talk about things that
had gone wrong and kind ofspeculate on what they did
wrong. But they learned so muchin such a short amount of time,
kind of mind blowing to think inthe late 1800s, were still
trying to figure out parts ofgerm theory and what back to
doing, which and
Gregory Fox (20:48):
that's right.
That's right. I mean, it's, it'sreally incredible the learning
curve, once it was realizedthat, that many diseases which
were thought to be incurable,actually could be attributed to
bacteria, which we could then inturn treat with antibiotics. And
so from the 1890s, when therewas just a realization that this
(21:08):
this disease, which was thoughtof like cancer is today, disease
where there was really pooroutcomes within 60 years to
having effective treatments thatcould cure the disease. And it
was a really dramatic change fora disease that had and has
plagued humans throughouthistory,
Aaron Harmon (21:27):
that both our mind occasionally how far we've come
and so quickly, and just thinkof like PCR. And now it'd be
kind of be a no brainer to do atest to make sure you didn't
have a contaminant and you canuse different PCR tools or
sequencing approaches. And thoseare all modern things that we've
picked up over the last 30years.
Gregory Fox (21:44):
Yeah, I think it's, you know, it's still, the lesson
from the Lubeck disaster, Ithink is still that it's
important to look for thingsthat are not expected. And
contamination still can occurtoday, you know, own
laboratories. And an example ofhow we use modern techniques to
(22:04):
pick this up is, sometimes whenyou test somebody, you might
come up with a positivediagnosis for tuberculosis, that
is very unexpected. And youmight think, well, the person
didn't look very sick, theydon't have the typical symptoms
of tuberculosis, or the X raydoesn't really look like it. And
then the labs will go back andthey will check and say well was
there are another patient whowas diagnosed with tuberculosis
(22:27):
on the same day in the same lab.
And if there was to go back andcompare the strains and
occasionally even very goodlabs, you can get contamination
between the culture of onepatient and another patient and
so very much built into the thelaboratory quality control
processes is looking for theseunexpected contamination events,
even where there is very goodinfection control practice in
(22:48):
place.
Aaron Harmon (22:50):
That's a good point and kind of like having a
radar for something going awry.
Gregory Fox (22:54):
Yes.
Aaron Harmon (22:54):
Thank you for joining us.
Gregory Fox (22:56):
It's great to be with you. Thanks for listening
to this episode, and stay tunedfor our next one.
Aaron Harmon (23:01):
We hope you enjoyed this episode.
This was brought to you thanksto South Dakota biotech
Association. If you have a storyyou'd like us to explore and
share, let us know by visitingwww. 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 aboutQUIBIT by clicking on the link
on our website too. Thanks forlistening
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