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:
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:
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.
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."5So 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).
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