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).