Recap: Diphtheria is a bacterial respiratory disease spread by air or contaminated surfaces/objects. The majority of symptoms, if not all, are caused by diphtheria toxin, a particular protein produced by the bacteria. This means that inactivating the toxin prevents the disease.
This is the basis upon which the practice of treating diphtheria cases with antitoxin came about. Antitoxin, or a solution of antibodies against the toxin, could inactivate it and reduce symptoms when given at the right time. Not good for prevention though. So people were trying to immunize people with combinations of toxin and antitoxin—the toxin to induce an immune response to immunize patients against the toxin, and the antitoxin to prevent the toxin from causing harm. But this was risky.
Then came toxoid: an inactivated form of the toxin that still induced an immune response, more safely. Much better.
So in this report, four Canadian researchers at the School of Hygiene and Connaught Laboratories at the University of Toronto discuss how toxoid vaccination is the first really effective measure in preventing diphtheria in Canada. To quote from the introduction:
"Before the introduction of active immunisation against diphtheria, no substantial reduction in that disease was evident in the Dominion of Canada. Although diphtheria antitoxin was made freely available to practitioners by the public health authorities in almost all parts of the country, for prevention as well as for treatment, the morbidity-rates maintained their previous high levels.
"This is not to say, however, that all efforts at control—isolation of cases and quarantine of contacts, separate of other members of the family, and prophylactic antitoxin—were entirely barren of results. The recorded morbidity-rates of diphtheria are the resultants of different influences in different periods. For example, environmental changes, such as urbanisation of the population, with greater opportunities for human contact, might well have caused a real increase in cases if there had been no control measures; the wider use of laboratory services may have revealed cases otherwise undiagnosed; the use of public health nurses and school nurses may have resulted in more complete notification; and the changing clinical conception of the disease may have included cases of a kind that would not have been included in earlier years. While correction cannot be made accurately for such factors, their possible influence on recorded rates cannot be neglected in making comparisons."Between 1920 and 1924, diphtheria killed between 128 and 232 per million people in Canada, around 1600 deaths a year total. More than 40% of these deaths were in children under 5, and almost 80% in children under 10. Between ages 2 and 14, it was the chief cause of death, 15% of deaths. So, not good.
But then, in 1925, health workers in Canada decided that toxoid was adequately safe and effective, so Connaught Laboratories started making enough of it to vaccinate many Canadians. Not everyone can tolerate toxoid as well; some have a bad reaction to it, but these can almost always be distinguished using the Moloney test. These people are usually older and have been exposed to diphtheria more in the wild, but aren't always adequately immune despite this, so another dose of dilute toxoid is helpful and safe. Using this test, the risk from immunization was much lower.
The Schick test was often used to determine immune status, but it hadn't been standardized between countries, and different test methods gave different results, so no firm conclusions could be drawn. The authors here recommend another technique: titration of blood antitoxin (i.e. antibody response). I believe this is the technique used today.
They did some tests of immunity with different doses or preparations of toxoid: one to three doses of unmodified toxoid, or 1-2 doses of alum-precipitated toxoid (bound to aluminum as an adjuvant, I believe). They found that three doses of unmodified toxoid, just plain, worked better than alum-precipitated toxoid, in terms of antibody levels induced (titres), and also in terms of how long the antibody titres lasted after immunization (at least 2-3 years, it seemed). At least at first, those receiving three-dose toxoid had higher antibody titres than people who were naturally immune from exposure to diphtheria, though titres decreased over time. The rate of decrease does get slower though, so titres might level out, and re-exposure to diphtheria seem to increase them again.
Epidemiology
Now for the exciting part. They vaccinated 27,000 children in Toronto public schools, and left another 90,000 unvaccinated as controls. Some of the vaccinated had received one dose of toxoid, some two, and some three.
So from the 90,000 controls, they derived expected case rates: how many cases per 10000 or whatever that could be expected given the same exposure. And they found that, compared to these expectations, the actual number of cases they saw in the vaccinated children was always lower. For those who received 1 dose, the number of cases was 29% lower than expected; for two doses, 74% lower, and for three doses, an amazing 90% lower. Only 10% of the children expected to get sick actually did! And these results fit well with the antibody titres observed previously for these dosages.
Then for another 5 years, they brought the number of children vaccinated with 3 doses up to 47,000, and saw similar results: 87 to 97% fewer cases of diphtheria than expected, averaging 91% reduction. Protection did seem to decrease over time since vaccinated, as would be expected from the antibody titre patterns too.
After 1932, though, the amount of diphtheria going around was too low to have a good estimate of protection. The authors credit the toxoid vaccine with this decrease, with reason. Connaught Labs had made 3 million doses of toxoid over 11 years, and it wasn't clear how much of this was used, but it must've changed things a lot. Nothing before had helped this much, even when Canada made antitoxin available for free in 1916 and diagnostic labs had increased and such. The decrease was even greater than would've been expected for the number vaccinated, and the authors attributed this effect to herd immunity.
As an example, the city of Hamilton in Ontario had especially good results. Observe this graph:
Recall that the vaccine had been in increasing distribution starting in 1925. So for 30 years, the cases and deaths had been pretty steady, but then suddenly there was a steep decline with the vaccine. And in Hamilton, they had no deaths since 1930, at least up to this publication in 1938, and no cases since 1933.
Toronto was also doing pretty well; it went from 1640 cases per million in 1930 to 35 per million in 1934, and from around 65 deaths per year in the early 1920s to less than 10 between 1933 and 1937, with zero deaths in two of those years.
Other places in Canada offered free toxoid immunizations to their citizens, such as Brantford, who saw no diphtheria at all between 1931 and 1936. All provinces noticed a decrease in mortality due to widespread vaccination. Seems good.
The last question this paper addressed was that of herd immunity and asymptomatic carriers (those who might be immune enough to not get sick, but could still spread disease to others who were susceptible). Some suggested that many more might be in the latter camp, so spread might not decrease much at all.
However, some people tested a number of people from the population in the early 1920s and 30s, to see how many were positive for the bacteria. If immunization didn't prevent infection, only symptoms, then you would expect that the number of positive tests would be constant even as immunity increased. What they saw, though, was that about 1 in 10 cultures in the 20s was positive for bacteria, whereas very few carriers (fewer than 10) were found anywhere in the 30s, even when thousands of children were tested. So immunity does seem to prevent carrier status also.
Overall: It's difficult to find anything specific to criticize in this data. The differences between vaccinated and unvaccinated are so dramatic; it's pretty obvious that there is some effect. And since the vaccine seems to have been distributed for free by a public institution, at least some of the time, it's not a money question.
Of course, it's not really good enough to stand on its own as proof that the vaccine is worthwhile, I suppose. It's very light on details, like an overview, not going into many methods or diagnostic criteria or anything, or subject selection. In the epidemiology, which might've been like a clinical trial, but we don't know, because it doesn't say how the subjects were selected, or randomized, or if there were a placebo, or any kind of blinding. And they do say that the diagnostic criteria had changed over time, so it's difficult to compare across years. I suppose it's likely that the number of positive diagnoses would've increased with increasing sensitivity, rather than decreasing, but who knows?
So overall, it seems like it fits well into the pattern of research I've been finding up till now, that vaccines work well, but is not so great on its own.
Citation: Fitzgerald, J. G., Fraser, D. T., McKinnon, N. E. & Ross, M. A. Diphtheria—a Preventable Disease. The Lancet 231, 391–397 (1938).
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