Measles and Disneyland: Just the Facts

This is a bit different from my usual style, but a friend of mine on Facebook posted a link to a blog called "Measles Shmeasles Goes to Disneyland" by someone named Jessica Gianelloni, and asked for my input/opinion about what it said, and I put a lot of work into putting together a response, so I figured I might as well post it here too. Note: The original blog no longer exists, as the owner shut it down for some reason, but the content can probably still be found online if you desire it.

Overall I think in this article Jessica gets a bunch of stuff wrong, and at least some of the things she gets right are badly out of context. An interesting thing to note is that I searched for the headline she cites ("Disneyland Measles Outbreak Linked To Anti-Vaccine Movement") and could only find it on The Onion. Make of that what you will.

One thing that seems correct is that the vaccine is not as effective as expected in the 1960s; one dose is not adequate. I don't know why Jessica says 3 or more doses are recommended now though; all the recommendations I could find said only two. But that's not super-important at this point.

HERD IMMUNITY
The next thing is a claim that at least 80% of people being immune is required for herd immunity, which seems accurate based on her "citation." And levels are even higher than that, around 90% vaccinated; I doubt this is incorrect. The question is that if we have such high coverage, which is predicted to prevent spread of measles, why do we have measles outbreaks? And the implication is that the vaccine must not be capable of preventing the spread.

This is a very unsophisticated analysis though. Measles is considered eradicated in the US, which doesn't mean there are no cases, but it means that any outbreaks that start are imported from other countries; once a given outbreak ends, the virus is not present in that area anymore to start any more outbreaks.

And when outbreaks do happen, it's pretty consistent that a majority of the cases are people that never had a measles vaccine; there are areas where the coverage is well below 80% of people. For examples: there was a study on outbreaks from 1989 to 1991, and the risk of catching measles was 35 times higher for unvaccinated people. In 1990 for example, unvaccinated people made up 0.5% of the population but had 17% of the cases of measles in the outbreak. That's a lot higher than would be expected if the vaccine weren't very good. This number was worse in some years, better in others.

In the current Disneyland outbreak, of 34 cases in which the vaccination status of the people was known, 28 hadn't been vaccinated (82%). Similarly, in outbreaks in the first half of 2013 and 2014, of those cases with known vaccination status, 91% and 87% (respectively) were known to be unvaccinated. Only 2% of cases in the 2013 data had received both recommended doses. So it's not really possible to say these were outbreaks in highly vaccinated populations, since it spreads mostly only between unvaccinated. This is something Jessica seems to get wrong.

One thing to note is that of those unvaccinated cases, some of them were too young to be vaccinated. This is important in light of Jessica's Palevsky quote: the reason people who vaccinate are upset with those who don't is that when outbreaks occur, it's mostly the unvaccinated that spread disease to those too young to be vaccinated.

NATURAL MEASLES IS NICE
Next is claims about how before there was a vaccine, measles was a one-time thing, a normal part of growing up, and even contributed to a person's health in many ways other than just the disease itself. But now the vaccine makes it so that instead of measles being found mostly in older children (where it is mildest), it's more common in young children (too young to be vaccinated). The numbers Jessica gives are from less than 0.5% of cases in infants before the vaccine, to 30% now. In addition, implications are that the vaccine A) does not allow mothers to pass protective antibodies to their infants, at least not as well; B) does not offer life-long protection; and C) does not provide the same alleged general health benefits as actual measles infection.

First, about epidemiology before and after the vaccine: I don't know where Jessica got these numbers, but they aren't nearly in line with what I could find. First, from a couple of studies in the US in the 1930s, that I've blogged about before: One in Detroit in 1935 (081) found that in children 0-9 years old, 6% of cases were in children under 1 year old (and 66% in 1- to 4-year-olds). The other, in 1930 in Baltimore (060) found that of cases in children 0-14 years old, 4% were in under 1 year, 8% in 1 year, and most in 1-8 years old. So that's a lot higher than under 0.5%, long before the vaccine.

In more recent outbreaks: In the Disneyland outbreak so far, 6% of the cases have been infants under 1 year old. Again in the first half of 2013, 11% of the cases were under 1 year old. So that's a bit higher than the 1930s numbers, but nowhere near the 30% that Jessica claims.

It's also worth mentioning that in the population overall, in the 1930 Baltimore study, 0.8% of children under 1 year old got sick with measles; so 8 per 1000. Compare that to today, in the 1st half of 2013, there were 18 cases in children under 1 year out of a nationwide population of about 4 million in that age range; so that's 0.0009% of infants got measles. That's 9 per million, almost 1000 times less than before the vaccine. And Jessica acknowledges that the seeming 98% decline in measles was the death rate, not the incidence rate ("Does the incidence rate when the vaccine was introduced even matter?"), so we can attribute this 1000-fold decrease to the vaccine. That seems pretty impressive. I would say, is it important that a slightly higher proportion (2x) of outbreak cases are in younger children, if younger children are much less likely (1000x) to catch it overall?

Next, implication A: the vaccine does not allow mothers to pass protective antibodies to their infants, at least not as well the actual disease. Mothers who had the natural infection pass antibodies to their infants that generally protect them for 12-15 months (as Jessica says). But studies show that mothers who only had the vaccine can also pass protective antibodies to their infants. In this 2010 study, the protection passed from vaccinated mothers to infants was similar to that from naturally immune mothers, though it faded a bit more quickly (1-3 months less time). Here is a nice graph from this study:

Leuridan 2010, Figure 2

Is this significant? Probably somewhat, but not nearly as big a difference as Jessica makes it sound, and measles is a lot more rare now too.

Next, implication B: the vaccine does not offer life-long protection like the actual disease. I didn't look too hard into the claim that the wild virus provides life-long immunity (though one of the first detailed accounts of measles did include an observation of someone who seemed to still be immune to measles after having caught it 60 years earlier. No idea if that is a common thing though). As for the vaccine, a 2012 study found that after 20 years, only 10-15% of people who had received 2 doses had no antibodies. There was also a 1998 study that found that after 12 years, about 98% of people who got the vaccine seemed to have adequate antibody levels to protect them.

At this point in my writing, Jessica shut down her blog. Not sure why. Luckily I found another copy online so I can continue to go back and see what she said.

Next, implication C: the vaccine does not provide the same alleged general health benefits as actual measles infection. Immune diseases, tumors, allergies? I think I know what she's talking about here, something I had heard of before: there was a 1985 study that compared children who got measles and either had a rash or didn't have a rash. There wasn't any comparison with vaccinated or anything, just measles infections. And it seemed to show that children who got the rash had fewer health issues later in life than those who didn't. The lack of rash was explained by children having some sort of passive immunity, either from maternal antibodies or from injections of antibodies; there was no discussion about how the vaccine might affect things. But the hypothesis was that if the body didn't completely deal with the virus all at once, the virus might lurk around and cause health problems later (the ones Jessica claims it prevents). But I don't know if there was any follow-up to this study to clarify anything.

As it stands, it seems like the vaccine might be just as helpful as full-blown measles in preventing these health issues. Other research in Africa found that "vaccine efficacy against death was much greater than the proportion of deaths attributed to acute measles disease...These observations suggest that standard titre measles vaccine may confer a beneficial effect which is unrelated to the specific protection against measles disease." And another study found maybe a slightly increased risk of allergy for those who got wild measles infections.

Overall, it doesn't seem like the data supports Jessica's claims and implications.

MEASLES IS NOT NECESSARILY DANGEROUS
Jessica then claims that measles is not something to be feared, at least not in developed countries such as the US, so a vaccine is not necessary. And even in developing countries such as Africa, the vaccine is not as helpful as sanitation and nutrition would be, especially vitamin A. The implication, I think, is that the costs and risks from the vaccine are greater than the benefits, compared to other treatments or the disease itself.

I'll address the costs and risks of measles first. The CDC in 1998 claimed that measles kills 1 or 2 people for every 1000 it infects, and this is about the same rate as for the encephalitis it causes, a serious brain inflammation. In developing countries, it can kill as many as 1 out of 4 people it infects. I don't know where these numbers come from though.

For encephalitis, I didn't find any other good numbers on that, but it seems like we haven't seen any for a while. However, you can see in the outbreaks I've cited above (Disneyland, 2013, 2014), at least 11% of those who caught it needed to be hospitalized; up to 25% sometimes. Seems pretty serious. I guess I can appreciate Jessica's faith in modern medicine, though, if she thinks being hospitalized is no big deal.

As for death rates, two people died from measles in 2003, and considering the number of cases since 2000, about 1500, that's right in the 1-2 per 1000 range. The two deaths weren't exactly in the healthiest people, but unhealthy people do exist (often through no fault of their own) and should be protected; also, it's not always possible to know who is particularly susceptible to the disease. It could be you!

Another confirmation of the death rate: in the 1999 study mentioned above, there were 26672 cases and 89 deaths. This works out to 3 per 1000 cases; right on target, unfortunately.

But risk of death is not the only factor to consider; there's also cost burden, both to individuals and to the healthcare system overall. Being hospitalized is not cheap, I'm pretty sure, especially for those who have no insurance. A study estimated that each case of measles costs about $20,000 (and that's a conservative estimate!). This is costs for treatment and also public health efforts to track and control the outbreaks. Definitely a cost worth avoiding if possible.

What about vitamin A? That's a fairly cheap and low-risk treatment, right? I don't know what African study Jessica is referring to in the blog, of course, but the World Health Organization agrees that it's worth giving vitamin A to people with measles in developing countries, and agrees with Jessica's 50% figure. A review of other studies concludes that vitamin A might help reduce severity, at least in hospitalized cases. So that's nice, though I don't know how much of an impact it could really have on the risks overall. It seems better to avoid being hospitalized and needing treatment in the first place.

So overall, a fairly high risk of hospitalization (and associated costs), a fairly low (but not negligible) risk of death, perhaps less risk with vitamin A treatment, at least in developing countries. The obvious next question: is the vaccine any better, or is it worse?

THE MEASLES VACCINE IS MORE DANGEROUS
Jessica claims that the vaccine is associated with "seizures, encephalitis, blood disorders, sensory impairments, learning disabilities, immune system suppression, inflammatory bowel disease, inflammation of the brain, and many other severe allergic reactions." Some of those are redundant or too vague for me to figure out what she's talking about, but the Institute of Medicine released a report a few years ago reviewing vaccines and the evidence for their risks, so I'll summarize some of that.

Keep in mind that, for measles itself, if we didn't have a vaccine, there would be about 500,000 to 5 million cases in the US each year, so with a 1 in 1000 to 1 in 10000 death rate (I'm being conservative, giving a range), that means 50 to 5000 deaths and 55000 to 750000 hospitalizations. Are vaccines worse than that?

Regarding encephalitis/brain inflammation, there were studies looking at more than 500,000 children. In that sample, 199 got encephalitis, which overall is about 4 in 10000, except that only 9 of those cases happened within 3 months of vaccination; 80 of them were actually before the children got vaccinated, and the rest were more than 3 months after. So hardly any were likely associated with the vaccine. Another study found no association either.

Regarding febrile seizures, the report concluded evidence was pretty good that they were associated with the vaccine, but they don't seem to cause any permanent harm or learning disability.

Regarding autism, there have been a lot of studies of that with the MMR, some better and some worse. Even of the better ones, they're consistent with their reporting of a lack of association of the vaccine with autism.

Not sure what Jessica means by "blood disorders," but studies consistently report a lack of association of the vaccine with type 1 diabetes at least.

For sensory impairments and other things, the report authors considered the link between measles itself and the vaccine as some evidence for an association, but other than that there wasn't good evidence for a link with the vaccine in particular.

For allergic reactions, there is good evidence that the vaccine is associated with anaphylaxis, but this is rare, happens right after the shot, and is treatable.

Considering all that, it seems pretty clear that we aren't aware of any reason why the vaccine should be considered more risky than measles itself for most people. And it's pretty clear from recent outbreaks that we need to choose one or the other. So those are my thoughts on the issue, based on the data I could find. Just the facts.

O851 - The pathology of tetanus

I read this review from 1930, which was basically everything that was known in 1930 about how tetanus works. I'm not sure how much of the claims are still held as true today though.

One interesting claim was that the wound that introduces the tetanus bacteria into the body could be as small as flea bites or bee stings. Another was that the spores can remain in the body for weeks to months.

There's a claim that the tetanus vaccine is unnecessary because all that's needed to prevent tetanus is keeping wounds cleaned out. Ignoring the difficulty that cleaning wounds isn't always a possibility, the above statements from this review make that more questionable. Though of course cleaning out wounds (debridement) is important too, as this review mentions.

Other interesting stuff related to how the toxin (which causes the paralysis) passes through the body, and how the antitoxin works to prevent that. The toxin definitely interacts with nervous tissue mainly, though it wasn't quite clear if it only passes through nerves or also through the bloodstream and such. Some had found that injecting toxin into the blood caused systemic tetanus, while intramuscular or subcutaneous injection only caused local paralysis. Antitoxin (with its antibodies) doesn't really interact with nerves or affect toxin that's already bound to nerves; it only binds to circulating toxin to prevent it from getting to the nerves. Which is why it's important (for non-immunized people) to get antitoxin quickly, before the toxin does too much damage.

There was a mention of an unfortunate incident in St. Louis, where horse serum was used as diphtheria antitoxin, but apparently it contained tetanus toxin, and people died. But that might've been pretty bad luck, since the toxin doesn't stay in the blood very long, only until it starts causing symptoms.

I'm not sure of the quality of the evidence for these claims, but this is what people thought in 1930 at least.

Reference: Hall, I. C. The pathology of tetanus. Arch. Pathol. 9, 699–709 (1930).

O843 - The Rôle of the Vaccination Dressing in the Production of Postvaccinal Tetanus

(First, a note: apparently the word "role" has sometimes been spelled with a hat over the "o"; this is a sign of its French derivation. It surprised me too when I first saw it.)

In my ongoing quests for finding things that might be wrong with vaccines that people aren't talking about, I encountered this article. I don't think it quite qualifies, but I'm mentioning it for the sake of completeness.

The article, by Charles Armstrong, dealt with an issue with smallpox vaccination: sometimes tetanus occurred after the vaccination, because the bacteria that cause tetanus, Clostridium tetani, had been introduced to the wound and had multiplied there, producing their toxin. So Armstrong wanted to figure out when and why this happened in some cases and not others, in order to prevent it from happening.

He examined 116 cases of postvaccinal tetanus, and figured out that what they had in common was that the vaccination site had some sort of dressing wrapped around it. It didn't really matter what kind of dressing, just some kind of tight wrapping of the area. This agreed with studies in animals that showed something similar. So the US Public Health Service recommended against wrapping the area, and cases of postvaccinal tetanus dropped from a consistent 30 per year to less than 13.

Armstrong looked into why the dressing might cause this problem. It didn't seem to be related to keeping air away from the wound, because a good number of dressings he saw in cases did allow airflow. It also didn't seem to be an issue of contamination of the vaccination material, since no tetanus could be detected in it with animal studies. But it seemed like the problem was that the dressing was tight enough to cause some swelling, and held all the dead tissue in place on the site, so stuff could start growing under it.

So Armstrong recommended that, instead of putting a dressing on the site, just cover it with a loose sleeve of material; this can move back and forth over the area, wiping away any moisture and dead material that might appear, keeping the area clean and dry.

So it sounds like the issue was for the most part resolved nearly 100 years ago, and presumably only got better since then. But I will be sure to look into any relevant papers I encounter in the future.

Reference:

Armstrong, C. The Rôle of the Vaccination Dressing in the Production of Postvaccinal Tetanus. Public Health Reports (1896-1970) 44, 1871–1884 (1929).

086 - Studies on the Relation of Tetanus Bacilli in the Digestive Tract to Tetanus Antitoxin in the Blood

One big thing about vaccines (in some circles) is the question of what the best approach is for producing the best immunity. More specifically, because many vaccines are injected into the muscles, some ask whether this might not be ideal, because the immune system naturally encounters pathogens via other routes, usually, including by swallowing, breathing, or on other mucous membranes (as with sexually transmitted diseases). Of course, some diseases do naturally transfer across the skin mainly (such as those transmitted by mosquitoes or other biting arthropods) or secondarily (HIV can pass from blood to blood if this contact is made).

Anyway, it seems intuitive that the immune system would respond better to vaccines that use the same route as the actual pathogen, rather than a different route. Intuition like this is not always accurate, though; it's important to test. There could be good reasons that using a different route could produce a better immune response for some reason, depending on the specific disease and how it interacts with the immune system. If you listened to the podcast I linked to a few weeks ago, it talks a bit about how inert antigen in the gut doesn't really do much, even if it comes from a gut organism; there needs to be some activation of the immune system, and this is easier to obtain intramuscularly (or with an attenuated live pathogen).

So specifically, the topic of this post is tetanus, and the potential for natural immunity from colonization with the tetanus bacillus, Clostridium tetani (formerly sometimes called Bacillus tetani). Tetanus usually happens when C. tetani spores get into a wound and multiply, producing a toxin called tetanospasmin, which interferes with nerves and prevents muscles from relaxing, causing paralysis. It isn't really transmitted between people, that we can tell, or from animals; the spores are pretty much just everywhere. Getting an infection with it, if survived, doesn't seem to produce useful levels of immunity against future infections, so the vaccine is useful. The modern vaccine is just tetanospasmin, deactivated so that it doesn't cause problems, but does induce an immune response. Immunity to the bacteria specifically isn't necessary.

But some might wonder, is it true that it's not possible to become immune to tetanus naturally? Wouldn't that be better than getting a vaccine (because natural, and thus presumably more effective)? These five studies looked at people and animals that seemed to carry C. tetani around in their gut without apparent symptoms, and tried to figure out if they derived any sort of immunity from their passengers.

Studies on the Relation of Tetanus Bacilli in the Digestive Tract to Tetanus Antitoxin in the Blood
In the first, TenBroeck and Bauer, living in China, had isolated C. tetani from stools of about 35% of the patients they tested. They used basic microbiological techniques; pasteurizing to kill off everything but spores, then growing the spores in specific medium. They tested the isolates for toxin production by injecting culture medium into mice to see if they got tetanus.

So then, they wanted to see if carriers of these bacteria had antitoxin in their blood; that is, antibodies that neutralized tetanospasmin.¹

Others had looked but not found any antitoxin, though some seemed to find it in cattle, but hadn't correlated it with bacteria in the gut. So what TenBroeck and Bauer did was take blood samples from people who were or were not carriers, mix it with standardized tetanus toxin in varying proportions, and inject it into mice, then observe the mice for tetanus.

Without serum, the toxin generally killed mice in 4 days. Serum from most carriers could protect mice from doses of toxin up to 25 times the minimum that would normally kill a mouse (Minimum Lethal Dose, MLD). From the others, non-carrier serum couldn't protect against 2 times the MLD, except for two that got up to 10x MLD. From carriers though, serum consistently protected against at least 10x MLD, up to almost 50x, but mostly 25x. So the presence of C. tetani in the gut seemed to correlate with the presence of antitoxin in the blood for this population.

This doesn't necessarily indicate that the carriers of C. tetani were immune to tetanus though, just that their serum could protect mice from the toxin. The authors do note that there was a low incidence of tetanus in the area though, but it's not a rigorous observation.

They also wondered if these carriers might be a source of tetanus infection for other people. They concluded it was probably a negligible effect, considering how ubiquitous the spores are anyway.

One of the authors actually swallowed a bunch of spores to see if he could become a carrier. He noticed a bit of constipation that might not've been related, and when it went away, he didn't have spores in his gut anymore. Oh well.


Others discuss the inability of others to replicate this work:

"TenBroeck and Bauer have shown that an appreciable amount of tetanus antitoxin was found in the blood serum of persons in China who carried tetanus bacilli in the digestive tract. No one else has been able to corroborate this work. They expressed the belief that this accounts for the low incidence of tetanus in China, where a large percentage of the population harbors tetanus bacilli in the digestive tract."²

"Immunization against tetanus is quite a different problem from that against diphtheria. There are no naturally immune persons. Tetanus antitoxin has never been detected in nonimmunized men, except in China, nor has it been found even after recovery from clinical tetanus."³

I will probably come back to this issue at sometime in the future with more recent studies though.

The Immunity Produced by the Growth of Tetanus Bacilli in the Digestive Tract
The second study is by the same authors (TenBroeck and Bauer), a followup to the first. In this one, they colonize guinea pigs with tetanus spores and see if that makes the animals immune to tetanus.⁴

Guinea pigs are apparently pretty easy to colonize, which is why they used them. They fed the animals one or more of five serologically distinct types of C. tetani, waited six months for antitoxin to appear in the animals' serum, and then injected them with spores or tetanus toxin to test their immunity.

They expected that having any type in the gut would produce immunity to toxin from any other type, since the toxin seems all the same. What they saw, though, is that animals fed a certain type only had immunity when injected with that same type. If they were fed multiple types, they had immunity to multiple types. When the toxin itself was injected, none seemed immune. So immunity seemed to be specific against the bacteria, not the toxin, which isn't necessarily that helpful.

They speculated that maybe immunity to other types might develop if they waited longer than six months, but that's a long time to wait for immunity. It's possible that the antitoxin might work as protection when mixed with the toxin before injecting, but not when the toxin is already in the body.

In the discussion they mentioned having seen cases of tetanus in people who were carrying spores in their gut, even of the same serological type. So it's questionable whether this route produces immunity.

Others comment on these results:

"Ten Broeck and Bauer claimed that animals fed or injected with Cl. tetani developed a type specific resistance in which antitoxin played no part. Since such immunity was specific for the serologic type it would seem that H antigen must have been involved. On the other hand Coleman (Am J Hyg 1931, 14:515) was unable to immunize guinea pigs by feeding tetanus organisms; and Coleman and Gunnison (Am J Hyg 1931, 14:526) could not demonstrate any humoral protection, other than that due to antitoxin, even against the homologous type whether H or O antigens were used for production of antiserums."⁵

So far it doesn't look that useful.

Human Intestinal Carriers of Tetanus Spores in California
The next one is also from Bauer and another author, Meyer; it's another sample of C. tetani in people's guts, this time mostly from California.⁶

Strangely, different people doing this study in different places had found very different proportions of carriers, between 0 to about 40%. California seemed to have a pretty high rate of tetanus at the time (245 cases in 3 years, 67% mortality), so Bauer and Meyer looked at people there, from San Francisco and Los Angeles hospitals.

From 487 specimens, they found spores in 120, so 24.6%. From specimens from other states, they got 26.6%. The rate in areas of CA varied from 7% to 40%. But there didn't seem to be any particular correlation with climate, geography, sex, age, or occupation (outdoors or indoors workers). Most of the spores were of one particular serological type, which they called type 1; this corresponds to the findings of others. And... that's about it.

The Distribution of B. tetani in the Intestines of Animals
The next study was by John Kerrin.⁷ He looked at stools from 100 people, presumably in the UK (since that's where he worked), and found C. tetani in none of them. So he looked in animals and other places to get a more general survey.

Half the isolates he got didn't produce tetanospasmin, but seemed to be C. tetani anyway. Dogs and rats had the highest proportion of carriers, and spores were pretty common in soil and guinea pigs too. Rabbits, horses, cows, mice, sheep, and pigs all had some (cats didn't). He also tested chickens, and some of them seemed to also.

He tried colonizing rat guts with the spores, but after he stopped feeding the spores, they all left the gut before too long. And he tested some rats that were already carriers for antitoxin, and didn't find much. It's not clear what these results mean.

Can Immunity to Tetanus be Produced by the Oral Route?
Finally, a study by Melville Manson again looked at trying to immunize guinea pigs by feeding them tetanus spores or toxin.⁸ 

The first 8 animals got fed tetanus spores. Manson confirmed them by re-isolating them from the animals' stool and injecting them into mice to make sure they produced disease. He tested the animals for immunity by injecting the toxin. Two of these animals died before the test of other stuff, but of the six that remained, none of them lasted longer than control animals (actually somewhat less time). So that didn't work. He didn't wait six months for immunity though, I notice; only 3 months, at most.

Then he fed another 8 guinea pigs the actual toxin. Two died again of other stuff, but of the six left, 2 survived and the others died. Serum from one survivor didn't seem to protect other animals against the toxin though, so there wasn't much antitoxin; maybe they just happened to be resistant.

Finally he fed toxin to another 12 animals. Three of them survived one minimum lethal dose (MLD) but 2 killed them quickly. The others died like the controls.

So overall, there might've been a little immunity after eating the toxin, but it wasn't much.

Conclusions
My take on all of this is that even if some people do have some natural immunity from colonization with C. tetani, it doesn't seem to be enough to protect against very much (at least in guinea pigs), and trying to colonize people with the organism doesn't seem reliable (and might not be safe anyway). So not a very good alternative to the modern vaccine.

There definitely could be more done to study the issue more rigorously though, and I will be on the lookout for other/better studies in the future.

References:

1. TenBroeck, C. & Bauer, J. H. Studies on the Relation of Tetanus Bacilli in the Digestive Tract to Tetanus Antitoxin in the Blood. J. Exp. Med. 37, 479–489 (1923).

2. Bigler, J. A. & Werner, M. Active immunization against tetanus and diphtheria in infants and children. J. Am. Med. Assoc. 116, 2355–2366 (1941).

3. Miller, Jr., J. J. Immunization procedures in pediatrics. J. Am. Med. Assoc. 134, 1064–1069 (1947).

4. TenBroeck, C. & Bauer, J. H. The Immunity Produced by the Growth of Tetanus Bacilli in the Digestive Tract. J. Exp. Med. 43, 361–377 (1926).

5. Gunnison, J. B. Agglutination Reactions of the Heat Stable Antigens of Clostridium tetani. J. Immunol. 32, 63–74 (1937).

6. Bauer, J. H. & Meyer, K. F. Human Intestinal Carriers of Tetanus Spores in California. J. Infect. Dis. 38, 295–305 (1926).

7. Kerrin, J. C. The Distribution of B. tetani in the Intestines of Animals. Br. J. Exp. Pathol. 10, 370–373 (1929).

8. Manson, M. H. Can Immunity to Tetanus be Produced by the Oral Route? Exp. Biol. Med. 29, 561–564 (1932).

Vaccines-related Podcast Episode - BacterioFiles 196

This blog is not my only project, nor even my primary: I also have a podcast, called BacterioFiles, which in some ways is sorta the opposite of this blog. It is about how microbes (bacteria, viruses, archaea, fungi) are awesome and useful, whereas this blog is more about how they are deadly and unpleasant.

But sometimes, in happy coincidence, they overlap, and the latest episode was one of those times:

BacterioFiles 196 - Flagellin Facilitates Flu-shot Function

Gut bacteria are important for a good immune response to unadjuvanted influenza vaccines!

It's a much more recent study than the ones on this blog have been so far, but interesting context to keep in mind while reading (or in my case, writing) the entries for this blog, so I thought I would share. Enjoy!

085 - The clinical severity of diphtheria in certain cities in Great Britain

So what is the reason all these people were trying to develop all these vaccines? This study is one that provides some justification, which is that these diseases can be pretty deadly. Hedley D. Wright looked at the clinical severity (that is, case-fatality rates, number of cases that ended in death) of diphtheria in seven cities of Great Britain over a number of years.¹

So Wright looked at the data of diphtheria cases and deaths in Liverpool, Birmingham, Manchester, Glasgow, Leeds, Hull, and Edinburgh from 1911 to 1935. Keep in mind that diphtheria antitoxin/serum treatment had been around at least 20 years in this case.

One difficulty in such a study is the issue of reporting: you don't really see things if you're not looking. And diagnostic criteria matter too: if something is not diagnosed as diphtheria, it's not reported as such, even if it should be (the same is true in reverse). Wright estimated that there could be as few as 40% of actual cases being reported, so more than half went unreported. Since deaths are more likely to be reported, this means the case-fatality rate appears higher than it actually is. But it's still possible to use it to compare cities, and also to get an idea of deadliness by death rates overall.

And this is how it seems: the average case-fatality rates ranged from 6% (Hull) to 10.1% (Manchester): this means that of 100 people who got diphtheria, 6-10 of them died. That's not great. On the other hand, looking at death rates per 100,000 people (based on 1931 census data), the rankings are almost reversed: Manchester is the lowest, with about 10 people out of each 100,000 dying (so in a population of about 800,000 that's 80 deaths), while Hull has a rate of almost 14 (so in 300,000, that's 42 deaths). The highest rate is Liverpool, with 17 (in 850,000, that's 144-145 deaths). So it seems like Hull might have a pathogen that spreads better between people but is not as deadly, compared with Manchester.

There was change over time though. Early in the data, around 1915, there was a pretty bad epidemic, and then cases and deaths fell off. But in the last five years of observation, cases and deaths picked up again. This trend was broadly similar over the seven cities, though not exactly. The new epidemic seemed to have a lot more cases but not as much death. Possibly the ability to diagnose had improved, though not everywhere.

Also important was the analysis of different age groups. In almost every case, death and case-fatality rates were worse in younger children than in older. This is consistent with what we've seen before; youth makes this disease deadlier. So ages 0-4 have case-fatalities from around 10-20%, 5-9 years have 5-10%, and 10-14 have 1-5%. 20% is a pretty high severity.

There's some good news though: the deadliness for the youngest age group went down over the period in question. It started out around 20%, and went down to about 10%. However, in the 5-9 years group, it dropped initially, after the 1915 epidemic, and then rose again. So it seemed like the later epidemic was worse for older children.

Wright and others speculated that this pattern could be due to children going to school together more, or better treatment for younger patients somehow, or changing sizes of families. Not sure. But this is the kind of disease that is why people were trying to develop vaccines.

There aren't really many studies citing this one that I can quote from, but here's one that's also by Wright, sort of an update on the Liverpool situation.²

References:
1. Wright, H. D. The clinical severity of diphtheria in certain cities in Great Britain. Journal of Pathology and Bacteriology 49, 135–155 (1939).
2. Wright, H. D. Diphtheria in Liverpool during the years 1937-40. Journal of Pathology and Bacteriology 52, 283–294 (1941).

084 - A study in active immunization against pertussis

In the early 20th century, lots of people were working on developing a vaccine against whooping cough. Makes sense, because it was one of the biggest causes of death in young children. But arguably two of the most important of these researchers were Pearl Kendrick and Grace Eldering.

I've done a couple posts about studies by them before (072 and 079); the former of those was a progress report, and this post is the full report on the first large pertussis vaccine trial that they undertook in Grand Rapids, Michigan.¹

The study started in late 1933 and went for 44 months, following thousands of subjects. Soon after the progress report came out, another study (actually another progress report) came out that seemed to have negative results for pertussis vaccination (065), which motivated Kendrick and Eldering to be extra-careful in their own final report.

It was a pretty big effort, not just these two; many nurses and public health workers in Michigan were involved, though supervised by the authors. It took place in Grand Rapids, as I mentioned, and the final count involved 1,815 subjects in the vaccinated group and 2,397 unvaccinated controls. These were children with no history of whooping cough (so, presumably susceptible) that lived nearby and could be followed over the course of the study.

Not all of them remained in the study for the whole 44 months, of course, because once they actually caught pertussis, they were presumably not susceptible anymore. Or if they moved away or something. Or if they grew out of (or into) the age range, which was 8 months old to 5 years old. But the results were corrected for how long each was followed.

The groups were selected by families presenting themselves at clinics to receive the vaccine. These were the vaccinated subjects; others were selected from the same districts as controls. So it wasn't randomized or blinded at all, which is a limitation. Kendrick and Eldering recognized this, and took special care to try to make the groups as equivalent as possible:

-The average time they were part of the study was 15 months for vaccinated, 11.6 months for controls. This was corrected for though, and could be due to some of the controls getting vaccinated and thus being removed from the study, which is something that couldn't happen to those already vaccinated. The proportions that moved away weren't significantly different.
-The proportion of each sex in each group wasn't significantly different.
-The proportions of ages weren't significantly different.
-The proportions in each district of the city weren't significantly different.
-The proportions of family sizes weren't significantly different.
-The proportions of each group getting measles and scarlet fever were equivalent, so it didn't seem like either was healthier or less exposed than the other.
-The average interval between nurse visits for each group was the same.
So overall, the groups seemed equivalent, at least in these characteristics.

As mentioned in 072, the vaccine was made of freshly isolated and lab-cultured bacteria, killed with phenol and/or merthiolate (AKA thimerosal) in small amounts. It was produced continuously on small scales, so none of it got older than about a year. It was injected under the skin of the arms.

In terms of reactions, most of the ones they observed were local—soreness, etc.—and only slight otherwise. One report of the 1815 was of convulsions, and 2 had high fever and vomiting, though it is only correlative because there wasn't a placebo control. Mostly it seemed ok.

Finally, a word on diagnosis and severity ratings: diagnoses were made based on cough plates (that is, culturing the organism), clinical symptoms, and history of exposure. Severity was rated somewhat arbitrarily, based on frequency of whooping and vomiting or the occurrence of complications/weight loss.

Results
The results were corrected for amount of time each subject was participating in the study, and how many subjects there were in each group, so they're reported as annual attacks per 100 subjects. So with that in mind, the incidence of whooping cough overall was:
2.3 annual attacks per 100 vaccinated subjects
vs.
15.1 annual attacks per 100 controls.
This is a significant difference, which could be expected to occur by random chance only once if they repeated the trial millions of times.

Compared to other reports of the rates of pertussis in Grand Rapids, the control group followed the same up-and-down trends, but had a higher incidence, probably because the closer observation detected cases that would've gone undetected otherwise, due to low severity. And speaking of severity:

Even of the vaccinated subjects that did get whooping cough, the severity was much lower. 73% were rated as light or very light severity, compared to 27% in the controls. And only 4% were severe in the vaccinated, and these didn't have serious complications, only frequent coughing/vomiting; that's compared to 13% severe in the controls. And considering that the "very light" cases were questionable about whether they could even be considered cases at all, by removing them from both groups, the difference in incidence increases even more.

Kendrick and Eldering also looked specifically at their data on known exposures of subjects to the disease, and found similar patterns. The vaccinated group actually had a higher number of exposures than the controls, but many fewer cases from them. Calculating the number of cases expected (based on the cases in the controls and the exposures in the vaccinated), it appears that the vaccine prevented about 81.3% of cases in the test subjects. Not excellent, but pretty good.

The differences were not as big when the exposures were more intimate, like within a household. The attack rates were about 35% vaccinated vs. 90% controls. Still, that's significant protection.

Another thing they controlled when watching exposures was coughs that weren't diagnosed as pertussis, of which there were more in the vaccinated group. These were mild, taking place right around an exposure incident, and could be classified as slightly less than "Very light" whooping cough. So if they added these coughs to the numbers, incidences overall would be 24% vaccinated vs. 72% controls, which means only 67% protection. Which is still pretty good, especially considering that these extra cases are barely cases at all.

So overall, this study is very good compared to others at the time or before, though not quite good judging by modern standards: not randomized, not placebo-controlled, though more controlled than it could've been. And the protection seemed pretty good, though arguably it would be better to have higher complete protection rather than just reducing the severity of cases.
It isn't a study that looked at the duration of immunity, or whether it reduced transmission at all (thus providing herd immunity), or if the vaccine was safe, especially in the long run, or if it could be effective in more than just this population. But what it does look at is how well it protects young children over at least a few years after it's given.

Oh, and it's not funded by any pharmaceutical company.

It's hard to make any judgments overall, so I'll just cite some comments from later publications that cited this one, both positive and negative:

"There is ample evidence in the literature now that individuals inoculated with suitable doses of a proper vaccine have a high degree of immunity against whooping cough."²

"The Sargent-Merrell method of evaluating the success of an immunization program has been applied to data covering a 6-year period in the city of Grand Rapids...the proportion of cases prevented is 84%. The validity of the result has been verified on the basis of controlled field data."³

"The controversy dates back to the first trials of pertussis vaccines, which were carried out during the 1930s. These were criticized as biased in favor of the vaccines because they were not randomized; vaccinated volunteers were compared with unvaccinated 'nonvolunteers.'"⁴

"Methodologically, the original field trial design was flawed. The experimental group was self-selected and only control subjects were randomly chosen. Despite careful attention paid to case detection and diagnosis, 1603 observations from the study's early years had to be excluded from the final analysis. Several featuers of the trial nonetheless make it an important contribution, not simply to the development of an effective pertussis vaccine, but to the history of controlled trials: ... 2) The trial was unusual for the level of attention given to case diagnosis and follow-up, and to the discussion of unknown factors which might have biased the results; 3) a similar level of detail was given in reporting the analysis and the methodological limitations of the field trial"⁶

Also, if you want a really detailed historical account of this study and everything that went into it, before and after, check out Shapiro-Shapin 2007.⁵

References:

1.

Kendrick, P. & Eldering, G. A study in active immunization against pertussis. Am. J. Hyg. 29, 133–153 (1939).

2.

Cohen, P. & Scadron, S. J. The placental transmission of protective antibodies against whooping cough: By inoculation of the pregnant mother. JAMA 121, 656–662 (1943).

3.

Weiss, E. S. & Kendrick, P. L. The Effectiveness of Pertussis Vaccine: An Application of Sargent and Merrell’s Method of Measurement. Am. J. Epidemiol. 38, 306–309 (1943).

4.

Fine, P. E. M. & Clarkson, J. A. Reflections on the Efficacy of Pertussis Vaccines. Reviews of Infectious Diseases 9, 866–883 (1987).

5.

Shapiro-Shapin, C. G. ‘A Whole Community Working Together’: Pearl Kendrick, Grace Eldering, and the Grand Rapids Pertussis Trials, 1932-1939. Michigan Historical Review 33, 59–85 (2007).

6.

Marks, H. M. The Kendrick-Eldering-(Frost) pertussis vaccine field trial. J R Soc Med 100, 242–247 (2007).

083 - Immunity and susceptibility to disease in early infancy

Similar to the last poat (082), this one is about how newborns are surprisingly immune to certain diseases, because they receive disease-targeting antibodies from their mothers. Charles McKhann and Israel Kapnick wrote this review, and sadly there's no new data, but it's a good summary of the topic (for the time).¹

So most interesting is that newborns are immune to several important diseases—measles, scarlet fever, polio, and diphtheria—for up to half a year after birth. This is especially true if their mothers had immunity to those diseases. The duration is impressive because when physicians attempted to produce immunity in people by injecting them with serum from recovered patients (so-called passive immunity, because it is not derived from the patient's own immune system), it only lasted a few weeks at most. Somehow the infant is able to maintain the passive immunity from the mother.

This is not the case with every disease though. Stuff that causes fevers or gut infections and diarrhea, and whooping cough, are not prevented in these newborns quite so well. Other things are intermediate, like chickenpox and pneumonia.

The duration of the immunity might seem to suggest that the antibodies are coming repeatedly from the mother, perhaps from breastmilk, but McKhann and Kapnick say that seems only to happen in cattle, not humans. The evidence seemed to show that infants' passive immunity came through the placenta in the womb. Though it's possible that some components of immunity come through breastmilk and others don't. But it seems possible that antibodies from the placenta get stored up somewhere in the infant.

So the importance of this study as pertains to vaccines is two-fold: first, as discussed in the last post, it may be possible to make the infant immune for some time by vaccinating the mother. Apparently this is pretty helpful with tetanus, as it prevents neonatal tetanus which is common in places in Africa.

Second, it is important for determining when the first vaccines should be given. With stuff like measles, which is an attenuated live virus, if there are already antibodies present, the vaccine won't produce as much of a good response. McKhann and Kapnick recognized this with certain things. So knowing when infants will become susceptible is important for immunizing them at the right time, not too early or too late. For some things, this may be late in the first year of life.

However, immunology is pretty complicated, with things we didn't understand until recently, and things we still don't understand. So it's not clear (to me, anyway) how much of this review is accurate. A later publication made these comments about older reviews, including this one:

"A large and useful part of the data bearing on the immunology of the newborn infant has come from clinical studies of immunizing schedules. There have been many careful reviews of this subject [like this one]...[But] quantitative interpretation of these studies and separation of the factors involved has often been difficult for reasons such as the following: 1. Antigen-antibody reactions may have been used for which there were no accurate methods of titration. Only rough, qualitative conclusions could be drawn. 2. Some studies used antigen-antibody reactions that require complement. The blood of the newborn infant has a low level of complement. This may have caused an undetermined error in the antibody estimation."²

I expect to have more to say in later posts.

References:
1. McKhann, C. F. & Kapnick, I. Immunity and susceptibility to disease in early infancy. The Journal of Pediatrics 13, 907–918 (1938).
2. Osborn, J. J., Dancis, J. & Julia, J. F. Studies of the Immunology of the Newborn Infant 1. Age and Antibody Production. Pediatrics 9, 736–744 (1952).

082 - An Attempt to Increase Resistance to Pertussis in Newborn Infants by Immunizing Their Mothers During Pregnancy

With vaccine-preventable diseases, young children are often most at risk of serious health impacts or death; the younger, the higher the risk. At least, this is true of whooping cough, which had mortality rates of 26-55% in the 1930s among infants less than a year old.

However, some observed that newborns up to six months old seemed to have some resistance to some diseases—diphtheria, polio, measles, and scarlet fever, for example—especially when the mother had resistance of her own, such as immunity from having had the disease. So it seemed like the mother was transferring her immunity to the infant, probably through the placenta.

So John Lichty, Betty Slavin, and William Bradford thought it might be wise to take advantage of this transfer to give newborns more resistance until they could be vaccinated themselves around 6 months. In this study, they try immunizing mothers during pregnancy and then observing the immune response in mother and infant.¹ This was building on previous work in humans and animals with the same or other diseases, to some extent.

So they selected healthy women with normal pregnancies in obstetrics departments of Rochester hospitals, assigned them randomly to be immunized or be a control, using Sauer's whole-cell pertussis vaccine from Eli Lilly. No placebos, so no blinding of patients. They did separate observations of mothers and infants based on whether mothers had had pertussis before; i.e. history or no history. So they had four study groups: no history or vaccine, history but no vaccine, vaccine but no history, and both history and vaccine.

The way they measured immunity was a bit unusual: opsono-cytophagic index. They took blood from subjects, mixed it with dead pertussis bacteria, and observed how many dead cells the white blood cells gobbled up. They compared subjects based on the number of white cells that ate at least 20 dead bacteria; the "index" value. Presumably the immune status would affect how likely the white cells were to eat the bacteria. There was blinding in this test somewhat: the examiner counting the index didn't know the status of the subject from whom the blood was taken, so as not to be biased in counting.

Results

In total, there were 28 women immunized and 22 as controls. They observed in most groups, most infants had a lower index than their mothers; the exception was the vaccine+history group, in which a third of infants had a higher index.

I made a graph showing the values for the four groups, mothers and infants (in mothers' cases, after the vaccine, when relevant):

Opsono-cytophagic index for mothers (post-vaccine) and their infants; error bars are standard deviations reported in the study.

Overall, looking at the error bars, it doesn't seem like there's much significant difference anywhere. But looking at trends, two things stand out: infants from mothers with no history or vaccine seem lower than from mothers with either, and with both it's highest. Second, the difference between mothers and infants is largest with neither history nor vaccine, lower and similar for history or vaccine, and mothers and infants are closest with history plus vaccine.

The authors looked at a couple other things too. They observed some of the infants before they had nursed and then again after nursing for one week, to see if the colostrum affected the immunity at all. It didn't seem to make a difference.

Secondly, they looked at some clinical data for other patients; specifically, of 31 infants that died from pertussis. Eighteen of them died before 6 months of age, and 13 after. Of those that died younger, 28% of their mothers had had pertussis before giving birth; of those that died older, the number was at least 54%. Sample sizes were pretty small, but it suggests that mother's immunity does have a protective effect for the infant up to 6 months. Seems like just correlation though.

The authors concluded that vaccinating mothers seemed to help. Comparing each infant's index to mother's, the group with neither immunity had only 50% the index in infants compared to the mother; with either vaccine or history, that number went up to 75%; and with both, 100%, almost identical index. So perhaps an additive effect.

Overall, not a very rigorous study, but suggestive. Later articles were somewhat critical of the study, perhaps explaining the weak results:

"Lichty, Slavin, and Bradford attempted, as they put it, to increase resistance against pertussis in newborn infants by immunizing the mother during pregnancy. They confessed their failure. An analysis of the data revealed the following facts: The injections were given at two week intervals in the last six weeks of pregnancy. The total dose administered was 20-25 billion [cells]. Thus the dose was inadequate and too late for antibody formation which reaches its climax between one and two months after the last inoculation. The test for immunity which they employed, cytophagocytosis of the blood, has distinct limitations and has been abandoned by them in favor of mouse tests. Their figures showed no increase in cytophagocytosis of the inoculated mother's blood. Granted the validity of the test, they found no increased immunity in the mother, so that there were no antibodies transferable to the baby through the placenta."²

Even later, though, most studies citing this one seemed to focus on the safety aspect (which I forgot to mention above): of the mothers in the vaccinated group, almost the only side effect was a sore arm that wasn't bad enough to interfere with daily life. One woman had a systemic reaction with nausea and vomiting. Here's an example of a mention:

"Although phase 1 studies of maternal immunization with Tdap are in progress, studies many decades ago with whole-cell pertussis vaccine administration late in pregnancy resulted in high levels of pertussis-specific antibodies in infants and no safety concerns."³

Sometimes I wonder if people actually read old studies before citing them, but I guess usually it doesn't make much difference.

References:

1. Lichty, J. A., Slavin, B. & Bradford, W. L. An Attempt to Increase Resistance to Pertussis in Newborn Infants by Immunizing Their Mothers During Pregnancy. J Clin Invest 17, 613–621 (1938).

2. Cohen, P. & Scadron, S. J. The placental transmission of protective antibodies against whooping cough: By inoculation of the pregnant mother. JAMA 121, 656–662 (1943).

3. Healy, C. M., Rench, M. A. & Baker, C. J. Importance of Timing of Maternal Combined Tetanus, Diphtheria, and Acellular Pertussis (Tdap) Immunization and Protection of Young Infants. Clin Infect Dis. 56, 539–544 (2013).

081 - Measles in Detroit, 1935 I. Factors Influencing the Secondary Attack Rate Among Susceptibles at Risk

Before you can say much about a disease or treatments for it, it's useful to actually understand how it works. One aspect of that is attack rates: When a number of susceptible people are exposed to the disease, how many actually get it?

This was discussed for measles a bit in entry 060, concluding that about 95% of people in cities caught measles by age 15. Here, Franklin H. Top looked at attack rates on a smaller scale, following a number of families in Detroit that experienced one or more cases of measles and seeing how many other susceptible individuals in each family caught it.

Measles is one of the most contagious diseases we know about; this figure compares it to other diseases we know about:

Source: NPR

This is probably why it's showing up so much in the US, despite the very effective preventative measure we have (vaccination).

Franklin had observed high attack rates in Detroit, so much that he says, "parents often consider it unfortunate when all susceptible children in the family do not take the disease at one time, reasoning that it is more convenient to be done with it at once."

So he looked at more than 27,000 cases reported in Detroit in 1935, focusing on families that didn't have any kind of prophylaxis against measles (not that there was anything particularly effective, but we'll talk about that in a later post). He selected a fifth of these families for study, excluding those with no susceptible children or with difficulty in keeping records.

Then he looked at the influence of the sex and age of the primary case of measles, the sex and age of the susceptibles, the period in the seasonal measles cycle in which the case happened, the number of primary cases in a family, and the frequency and intensity of exposures, to see if any of these influenced the attack rate.

Some definitions: the primary case is the first case of measles in a family, so the exposure must've come from somewhere outside. Secondary cases presumably came from the primary case, infecting susceptible contacts in the family. It was assumed (based on previous study) that each case was contagious for 8 days: the exposure period.

There were 1,253 families in the study with one primary case, and 1,380 secondary cases resulting from them. The effect of the sex of the primary case was negligible: the attack rate from male cases was 84.3%, and 84.7% from females. Broken down by age groups, sometimes the male rate was slightly higher, sometimes female.

Looking at age groups of the primary case specifically, cases aged 5-9 years had by far the most susceptible contacts. Those under 1 year or over 15 had too few to make good conclusions. But in the middle, the attack rate was consistently 70-90%. So it didn't seem to matter much; if anything, 5-9 years was the highest, but not statistically significant.

For secondary cases, again sex didn't really matter (84.4% vs. 84.7%). In this case though, age did, a little: contacts between 1-9 years had significantly higher attack rates than those under 1 year, about 85% vs. 45%. I wonder if this is because of maternal antibodies.

Regarding time of year/period within seasonal disease cycle, rates stay constant from January through April at around 86%, then fall off by July until the next winter. Makes sense; measles might transmit better in cold weather, like influenza, or because people are huddled together inside more than when it's warm.

Now about intensity of exposure: comparing families with just one primary case to those with more than one, there didn't seem to be a significant difference in attack rate. It was all maxed out around 80-85%. If a second primary affected anything it would only be another 15%, and those are possibly already somewhat resistant somehow; otherwise they would've caught it from the first primary.

The same is mostly true for those exposed more than once: Not many who have been exposed once will escape, and the attack rate for them when exposed again is much lower. This makes sense; if they escaped the first time, they're more likely somewhat resistant (or records of past illness are incorrect, and they're immune). Still, the attack rate got up to 63% in contacts aged 1-4 exposed twice, so just being exposed once doesn't mean there isn't anything to worry about from later exposures.

Lastly, the influence of intensity of exposure: apparently exposure to multiple cases at the same time doesn't significantly increase the attack rate either.

So overall, it seems like time of year and age of the susceptible person matter the most, while sex and intensity of exposure don't affect much, though repeated exposures can increase the number of victims. And more than 80% of susceptible children exposed to a case of measles will catch it. Pretty hard to prevent.

Reference: Top, F. H. Measles in Detroit, 1935 I. Factors Influencing the Secondary Attack Rate Among Susceptibles at Risk. Am J Public Health Nations Health 28, 935–943 (1938).

080 - Whooping-Cough or Pertussis

As mentioned before, whooping cough can be pretty hard on children, especially young ones. In this article from 1938, Robert Cruickshank discusses whooping cough and how it compares to some other diseases in the UK at the time.

What Should We Call...

"Whooping cough" is the common term, referring to the shrill intake of air after a bout of intense coughing, but Cruickshank pointed out that even in severe cases of the infection, not all patients actually whoop. And since just "cough" or maybe "whooping and/or non-whooping cough" don't work too well, he suggests "pertussis" as a good alternative. On the other hand, as I discussed in 079, this could cause some confusion too, since not all cases of coughs with whooping are caused by B. pertussis. But obviously both names have stuck with us throughout the years.

Mortality

Different people had different estimates of how many people died from whooping cough. The case-fatality rate seemed to be between 1 and 8.5%, generally higher for younger patients. Though in Glasgow, the reported rate was 27%, and up to 44% for those less than a year old. Pretty bad.

For comparison, the rates for measles, diphtheria, and scarlet fever were 5%, 4%, and 0.4% respectively. So pertussis was the fourth leading cause of death in London ages 0-5 years, killing 434 people per year. The three leading causes were congenital causes, pneumonia, and diarrhea (presumably infections of unknown etiology). Measles was 5th.

Though despite these numbers, the death rates for these diseases had actually been decreasing over the past 70 years, at least for younger children. Cruickshank doesn't discuss why this might be. Could be better treatments, supportive care, immunization (at least for diphtheria), increasing public health in general... not clear.

Prevalence

Keeping track of cases of whooping cough wasn't mandatory throughout the UK at this time, though some areas did so. So it was only possible to estimate the prevalence. Some estimated that 44% of children in London got pertussis before age 5, and 60% by age 10. Measles was similar, diphtheria and scarlet fever less so.

In England, it seemed like pertussis came in two-year intervals, though it seemed different in other countries. This seemed to be because of the addition of susceptible people to the population (newborns), but could also because immunity after infection didn't last too long (possibly only a year; I wasn't clear on this part).

Lab Tests

It was pretty clear at this point that B. pertussis caused whooping cough (most of the time), not some virus. People infected with these bacteria developed antibodies, and antibodies produced from vaccination correlated with immunity to infection. Cruickshank discusses methods for diagnosis, those that work and those that don't.

Treatment and Prevention

Cruickshank says: "Pertussis is a disease of which it may be said that the multiplicity of remedies is an index of therapeutic failure." I think what he means is there a lot of suggestions but not many that actually seem to work. Probably like what I discussed in 078. Supportive care is good, of course, and anything that helps children breathe better. Some thought vaccine therapy or antiserum worked well, especially in the early stages of disease, but it didn't seem clear.

For controlling spread, Cruickshank mainly recommended keeping infected patients away from susceptible children, which makes sense. Pertussis isn't as contagious as measles or chickenpox, for example, so it wouldn't be too hard, even in hospitals. He thought that patients shouldn't be contagious anymore after the 4th week of disease.

If isolation of cases were impossible in any situation, he recommended vaccination as something that seemed effective. He cited Madsen's data (069) and Sauer's, showing effectiveness of their vaccines. But in the interest of more solid data, he recommends a more controlled study, and possibly a program similar to the one in place for diphtheria at the time.

Overall, not much new here, but an interesting perspective.

Reference: Cruickshank, R. Whooping-Cough or Pertussis. The Lancet 232, 33–37 (1938).

My Methods

It occurs to me that, if I were reading this blog instead of writing it, I would wonder, "how is this guy finding these studies and choosing which to blog about? And what isn't he telling me?" And these are good questions, worth asking of anyone who claims to be any kind of knowledgeable. So I thought it'd be worth going into my methods for this blog a little.

I started out by going to PubMed and searching for "vaccine", then saving all of the results as far back as they went, so far up to 1940. Each time I completed a decade of studies, I could go to PubMed for another. I save these studies in my favorite reference software, Zotero.

This method of searching is likely to miss out on a great deal, if not the majority, of potentially interesting studies: those that don't have "vaccine" in the title, for example, but instead say "immunization" or whatever. For this reason, I also gather studies from other sources on the web: pro-vaccine ones, like Science-Based Medicine, I Speak of Dreams, or this one; and also, perhaps more especially, anti-vaccine ones, like IMCV (now there's a place where it's important to ask yourself the questions mentioned above!). I also look at what the scientific journal Vaccine puts out, to see what's going on in that field.

And finally, for each study I blog, using Web of Science, I look up all the later studies that cite that study and save them, as well as any interesting studies cited by the blogged study. This helps give me an idea of what later scientists thought of the studies I'm reading, and also broadens my net to catch things that I might not otherwise encounter. With these methods, I've accumulated more than 2,000 articles I might someday blog about, and I'm sure I'll find many more as time passes.

How I Choose
You might've noticed that I don't blog about every study I've found. Part of this is practical: it takes a while to write a blog post, and I have a lot of other stuff going on.

The other part is that a lot of the studies just aren't that relevant to my purpose. I want to research vaccines' safety and effectiveness, and a lot of studies I've found are about basic bacteriology or virology, methods or vaccines that have been abandoned to history and thus aren't relevant today, or just don't add anything new to what I've already blogged about. For example, almost 400 articles cited reference 1 in 040, but the majority of those are about an experimental form of multiple sclerosis in animals, not very related to vaccine safety or effectiveness. So those I put aside.

I try to be careful not to be dismissive of articles that seem to show some problems with vaccines; I hope that's apparent. Those are the ones most likely to be interesting (aside from large, well-done trials of safety and efficacy, of course), so I give them some priority. So my goal for the answer to the question, "what isn't he telling me" is "not much."

I must reiterate, though, that I'm not an expert on this subject, so instead of telling you what is true, I'm trying to show you where to find that information. If anyone wants the full list of my references, blogged or not, shoot me an email and I'd be happy to share.

079 - Bacillus para-pertussis: A Species Resembling Both Bacillus pertussis and Bacillus bronchisepticus but Identical with Neither

This is a topic I've heard mentioned before as related to the effectiveness (or lack thereof) of the pertussis vaccine. And perhaps more distantly related to other vaccines. The idea is that there are other, rare, related pathogens or mutants of common pathogens that may take the place of pathogens made rare by vaccination, essentially refilling the niche. 

Or, in a more conspiracy-prone vein, that after a vaccine is widespread, cases of the vaccine-preventable disease are recorded instead as caused by a different strain, species, whatever; essentially changing the definition of disease so that artificially it looks like the rate of the disease declines drastically post-vaccine.

Personally I haven't found much evidence to bear out the latter idea yet. Definitions do change, a notable example being the broadening definition of autism artificially increasing the number of cases, but to say it's as simple to change a case rate as to reassign a set of symptoms to a different cause is to ignore the fairly modern ability to identify pathogens using very precise molecular techniques and such.

The former is an interesting idea, but I don't think it has borne out well in history. Though it may sometimes appear that there is a parallel increase in a parallel disease as one declines due to vaccination, often that's just because the vaccine-preventable was so common before, it masked instances of the parallel one, and now that's not so common, the parallel one becomes more apparent.

Anyway, the specific case today is infection with the bacterium Bordetella parapertussis as a rare alternative cause of whooping cough. Normally the disease is caused by Bordetella pertussis, which seems generally more severe than its cousin. Grace Eldering and Pearl Kendrick worked on pertussis a lot in the early 20th century, and in this study they identified B. parapertussis as similar but distinct from its cousins.¹

These researchers had collected almost 1500 isolates from whooping cough patients over 5 years. But 10 of them seemed unusual: on agar, colonies grew larger than expected over time, and could grow without blood in the medium. Another species, B. bronchisepticus, also caused disease, but was also different in some ways from this new isolate (chiefly, motility).

Of the cases from which these isolates came, half were less than moderately severe, but almost all of them whooped, so it seemed like regular whooping cough. Apparently at least one had a co-infection with this isolate and regular B. pertussis.

Then Eldering and Kendrick did a bunch of biochemical bacteriological tests on one of the isolates, called 309, and compared it to B. pertussis and B. bronchisepticus. This was neat because I remember learning about most of these in basic microbiology lab, and here I see them applied, many decades ago. Overall, 309 was similar to B. pertussis in some ways and similar to B. bronchisepticus in others, but to neither in all.

Finally they tested the immunological characteristics of the three strains. They found when antibodies were generated to any one of them, they cross-reacted somewhat with each of the others, but not completely. So they seem to share some antigens.

So apparently B. parapertussis is a separate agent, that occasionally (around 0.7% of cases) causes whooping cough in humans. One important question related to vaccines is the one raised at the beginning (if B. parapertussis could come fill a niche left if B. pertussis is eliminated by vaccines); more on that later, but J.J. Miller Jr. mentioned this in a study about a decade later:

"Some apparent failures of immunization in vaccinated children are due to infections with the Bacillus parapertussis. These infections will seldom be diagnosed correctly, as the cough is clinically indistinguishable from that of pertussis: in other words they are cases of whooping cough but not of pertussis."²

Another question, kind of on the other side, is whether a vaccine against B. pertussis could give cross-protection against B. parapertussis (or vice versa). Since they do share antigens, it's not unlikely. Today's study doesn't say much about this, but I think Eldering and Kendrick did address this question in later studies.

A final note on taxonomy: it seems like the taxonomy of Bordetella was pretty confused at least until the 1950s, so B. pertussis was referred to as Bacillus pertussis, Hemophilus pertussis, and probably others until people finally settled on Bordetella. So if you see those other names, you know.

References:

1.

Eldering, G. & Kendrick, P. Bacillus para-pertussis: A Species Resembling Both Bacillus pertussis and Bacillus bronchisepticus but Identical with Neither. J. Bacteriol. 35, 561–572 (1938).

2.

Miller, Jr., J. J. Immunization procedures in pediatrics. JAMA 134, 1064–1069 (1947).

078 - Treatment of Whooping Cough with Vitamin C

Another thing I've seen from those who think vaccines are not useful is that vaccines are unnecessary, because large doses of vitamins are cheap and adequate to treat or prevent the relevant diseases. Especially vitamin C, which somehow got a reputation as a disease-busting super-drug. So today I'll be looking at one study that I've seen cited on multiple articles, as well as a couple other related studies.

A. Ascorbic Acid (Vitamin C) Treatment of Whooping Cough¹

Interestingly, Ormerod and Unkauf start off their paper by saying that vaccination so far was the only thing that seemed effective against whooping cough:

"While some protection has been afforded against it by vaccination, treatment of the active disease has not progressed as has treatment of other infectious diseases such as scarlet fever and diphtheria. Madsen reports that, of 1842 vaccinated children, about 25% escaped infection, while of 446 non-vaccinated children less than 2% escaped."

But for those who caught the disease anyway somehow, it'd be very helpful to have a way to treat it, to remove its status as a scary childhood disease:

"In the years 1932-34 there were 45,755 cases of whooping cough reported to the Dominion Bureau of Vital Statistics, with 1982 deaths. Of the fatal cases over 50% occur in the first year of life."

Others had studied the effects of ascorbic acid (vitamin C) on other things, like seeing if it could inactivate diphtheria toxin or inhibiting bacteria directly, but it wasn't clear that its effects weren't only due to its acidity. Even if it can inhibit bacteria in culture, anyway, doesn't mean it can do so in the human body.

Some thought they observed cases of scurvy in pertussis or pneumonia patients, and hypothesized that the body might use vitamin C as a defense mechanism somehow, thus using up its stores. And children seemed to need more than adults. So Ormerod and Unkauf decided to test ascorbic acid's effectiveness in treating whooping cough.

It's actually not so much a study as a series of case reports, since there was no control group. The authors treated pertussis patients with a synthetic form of vitamin C, sold by Roche. All but two of the patients were seven or under; one was 12, and the last was 22. The children all had the characteristic whoop from under a week up to 6 weeks, and starting at various points in the disease, the authors gave them between 125 and 500 mg vitamin C daily. It didn't seem very standardized. Their coughs all disappeared in from 3 days up to 15 days.

Ormerod and Unkauf admit that the data isn't robust enough for good conclusions, but claim that vitamin C seemed to reduce the duration from weeks to days. They don't have any controls though, so it's not really known how the patients would have done without the treatment. Is this study worth anything?

B. Pertussis Endotoxin in the Treatment of Whooping-Cough²

As a comparison, let's look at another study done around the same time, using a treatment that everyone has pretty much discarded as worthless (and had even been discredited at the time, in 1936): vaccine therapy. This is the idea of inducing a better immune response against pathogens currently infecting a person, so the body can better fight it off, rather than producing immunity before an infection is present.

In this study, Thompson wanted to try to induce an immune response against bacterial toxins produced in whooping cough patients by injecting purified toxin. Others had tried this, but the studies weren't done well, so it was hard to tell if there was really an effect.

Thompson used a procedure similar to Krueger's (076) for producing the toxin. He found that it had little effect when injected into rodents, but it often produced an allergy-like reddening in children. Possibly an immune reaction. In whooping cough patients, it seemed to exacerbate the symptoms sometimes, which doesn't seem surprising. So he tried to use lower doses to avoid this reaction.

He studied a group of 403 children admitted to the hospital with whooping cough. He gave 132 of them daily injections with the toxin, and the others were controls. Some of the controls even got placebo in the form of saline injections. The children received some other treatments too, seemingly to treat symptoms.

But even so, it was tough to compare the two groups, because there weren't specific endpoints. It didn't seem like severity was different, but maybe the duration was shorter, like the treatment accelerated the disease process, making it end sooner.

Possibly there was an effect in those treated early in their infection, shortening the case and reducing severity. But Thompson tried to replicate the result in another 71 patients, treating them early, and again it seemed to reduce the duration but not severity. So of questionable use overall.

C. Vitamin C in Treatment of Whooping-cough³

Responding to both of the above studies, apparently Douglas Gairdner was dubious:

"It also seems true to say that although 'nearly every newly discovered remedy in ancient and modern times has at one time been advocated for treatment of this disease', there is not one that has been proved to have an appreciable effect on its course. Of vaccine or endotoxin therapy, lately so enthusiastically recommended, the conclusion...'that the more carefully the results are controlled the less impressive do they become' seems inescapable in light of recent reports."

Ormerod's results from North America using vitamin C showed a much shorter whooping cough duration than what was common in the UK, so Gairdner wanted to try to replicate those results. He used naturally derived ascorbic acid, donated by Roche, to avoid a possible difference in effect from the synthetic (like Ormerod used); a few younger children got the synthetic kind because it was less bulky. He tried to use doses similar to Ormerod, several hundred mg, much more than the daily requirement for normal children (about 25 mg). Control subjects were given a placebo, cod liver oil and a couple other things that were known not to affect the disease.

In total, Gairdner treated 21 children, and kept another 20 as controls. 20% of each dropped out. Cases were confirmed by culturing the bacteria and hearing the cough. All cases had been coughing for less than 3 weeks when they started treatment. He followed them by getting the mothers to record the number of coughs each day and night until they stopped coughing at night. He also weighed the children to see if the disease was impairing their growth.

In Ormerod and Unkauf's study, they started treating an average of 9 days after disease started, and it lasted an average of 14 days longer, for 23 days total. 

Gairdner started treating his patients 10 days after the disease started on average (14 days for controls), and the disease lasted an average of 25 days after treatment (27 days for controls), for a total of 35 days (or 41 for controls). Apparently there was no statistically significant difference between the groups, nor for the difference in weight gained during the disease period (0.01 lb difference). Severity wasn't really measured.

So both treated and controls had much longer disease than in Ormerod's study, at least 12 days. Gairdner's conclusions:

"The assertion of Ormerod and UnKauf that the paroxysmal period of the disease is shortened 'from a matter of weeks to a matter of days' was not confirmed."

"As there were no controls in the Canadian series, however, it is impossible to judge whether the natural course of the untreated disease varies in the two countries, or whether the considerable difference in the course of the disease in the present and in the Canadian series is due, for instance, to the application of a more rigorous standard of cure in the former series."

"It is considered that the statement that the administration of vitamin C in whooping-cough has an effect upon the course of the disease is at present unproven."

It's possible that synthetic vitamin C worked better than naturally-derived kind, though these studies can't really be used to conclude that either. But it would be interesting.

Later studies commented on the vitamin C studies discussed:

"Gairdner has reported a failure to affect the course of whooping cough using the method of Omerod (sic), but Gairdner also failed to test for a deficiency before instituting treatment."⁴

"Gairdner in a controlled experiment found that the duration of illness in a group receiving vitamin C was shorter than in controls. The difference in the two groups was not a significant one, and he considered that the alleged benefits of vitamin C in whooping cough were unproven."⁵

The first statement, by J.B. Youmans, is slightly puzzling to me, because the original paper doesn't indicate that Ormerod and Unkauf tested for deficiency either. All just assumed that the doses they were giving were high enough to correct any deficiency. If it is a legitimate criticism, it seems to show that vitamin C would only be beneficial if there is a real deficiency.

References:

1.

Ormerod, M. J. & Unkauf, B. M. Ascorbic Acid (Vitamin C) Treatment of Whooping Cough. Can Med Assoc J 37, 134–136 (1937).

2.

Thompson, A. R. Pertussis Endotoxin in the Treatment of Whooping-Cough. The Lancet 230, 733–736 (1937).

3.

Gairdner, D. Vitamin C in Treatment of Whooping-cough. British Medical Journal 2, 742–744 (1938).

4.

Youmans, J. B. The Influence of Vitamin Deficiencies on Other Diseases. Ann Intern Med 13, 980–986 (1939).

5.

Glazebrook, A. J. & Thomson, S. The Administration of Vitamin C in a Large Institution and Its Effect on General Health and Resistance to Infection. The Journal of Hygiene 42, 1–19 (1942).