099 - Secondary Familial Attack Rates from Pertussis in Vaccinated and Unvaccinated Children

This study is a follow-up analysis of previous results by Kendrick and Eldering of a clinical trial in Grand Rapids, Michigan, of a whole-cell pertussis vaccine.

Rather than the whole study population, this study focused only on 165 families that were definitely exposed to pertussis from one of their own members. The other members' immunity status was known from history of vaccination or the disease itself.

What they saw was that, of all 78 vaccinated subjects, only 28 got whooping cough (36%). All these were under age 7. In contrast, of those without history of vaccination or disease, 79% got sick. Of those unvaccinated under age 7, 92% were attacked (the rate decreased with increasing age of subject). 36% vs. 92% for those most vulnerable? Not bad.

Most of the primary cases, that brought the disease to a family, were in the older category, confirming that older children often bring it to their younger siblings. Interestingly, with the subjects who had the disease before, 5 of the 6 that got sick were over 7 years old, so it seems there's a period after which the immunity is not so great, even after natural infection. The study was set up to analyze that in depth though.

Also noteworthy is that, of 172 primary cases that brought the disease to the families, 157 were unvaccinated (91%), 12 were vaccinated (7%), and 3 had the disease previously. There's some herd immunity in action, perhaps, but it's hard to tell.

This wasn't a very rigorous study (lack of blinding or placebo), but considering that an intimate exposure, such as in the same household, is probably the most difficult to have immunity against, there seems to be some effect. And apparently whooping cough is so contagious that 80-90% get sick when exposed to it this way, if not immune somehow.

References:

Kendrick, P. L. Secondary Familial Attack Rates from Pertussis in Vaccinated and Unvaccinated Children. Am. J. Epidemiol. 32-SectionA, 89–91 (1940).

O953 - Prophylactic immunization against measles, scarlet fever, diphtheria, whooping cough, and influenza

This paper was a speech given by Sir Ledingham, director of the Lister Institute in London. He says some interesting things. Speaking on the safety of vaccines:

"The safety of any method to be applied to man must always be a prime consideration. There must be no risk to life, and even the minor inconveniences, local and general, incidental to the introduction of a prophylactic through the skin must also, so far as possible, be reduced to a minimum consonant with the effectiveness of the product."

The first topic is diphtheria, a bacterial disease that can be prevented simply by inducing an immune response toward the toxin the bacteria produce (diphtheria toxin).

"Diphtheria undoubtedly merits chief consideration because we now know quite definitely from field trials...that intelligent and persistent immunization of the child population, starting with the pre-school child one year old, can bring the diphtheria morbidity down to zero."

The best approach to this is using something called toxoid, which is toxin treated such that it produces an immune response but doesn't cause problems.

"By the end of 1938 some 800,000 troops had been so vaccinated [with diphtheria toxoid], and Ramon was able to state that clinical diphtheria was disappearing from the French army."

"It is only when the proportion of vaccinated children reaches 70 to 80 per cent. that, as Ramon says, one sees the real fruits of one's work in a great reduction of the diphtheria incidence, perhaps to zero."

"Among the immunized children there have been since March, 1935, seventy-three notifications of diphtheria, giving an attack rate of 26 per 10,000 children, while among the unimmunized, including some 3,000 known Schick-negatives, the attack rate was 251 per 10,000, or ten times that among the immunized."

The Schick test was a way to test immunity in a person (though not perfect): if there was no reaction (Schick-negative), that indicated some immunity.

Considering the success of immunization, Ledingham makes a statement that seems relevant still today:

"When liberty becomes anti-social and impedes the application of scientific truth to the improvement of human well-being then I think some form of compulsion is the only remedy, though one might hope it would be merely temporary, pending the wider diffusion of scientific knowledge in the community."

It was a bit more complicated than just toxoid though, for diphtheria vaccine options. There was formol-toxoid, toxin-antitoxin floccules, alum-precipitated toxoid, and toxoid-antitoxin mixture, each with different properties in terms of safety or immune stimulation. Ledingham has some opinions:

"T.A.F. and T.A.M. are relatively innocuous at all ages, while A.P.T. is well borne in young children. In older children and adults it may give rise to painless nodes, which take some time to disappear. A.P.T., by virtue of the slowness of absorption of the antigen and consequent longer stimulus to the antibody-forming mechanism, can give rise...to considerably higher antitoxin titre, given in a single dose, than any of the other antigens. For this reason it may well become the antigen of choice for young children, the group we wish above all to see in course of time fully immunized"

In terms of stimulation, alum-precipitated toxoid seemed the best (probably the alum was an adjuvant); two doses of it was equivalent to three of formol-toxoid. Ledingham also stressed that trials of the vaccine should have prevention of diphtheria as their endpoint, not Schick test results; with a good vaccine, the test shouldn't be necessary. One dose with APT followed by another of FT might be good.

Then he moved on to whooping cough:

"As a killing disease of infancy, therefore, whooping-cough closely rivals diphtheria"

He cites Kendrick and Eldering's study that showed only 3.8% of vaccinated subjects with severe disease, compared to 13.1% in the unvaccinated, and other studies giving similar results.

"The age at which a pre-school child, say 9 months, may be submitted to immunization against diphtheria is also the age at which this same child might very desirably be immunized against whooping-cough. What is to be done? I am not aware that diphtheria toxoid has so far been administered in combination with a pertussis vaccine, but I see no reason why this should be attempted if Ramon's claim holds that the potency of diphtheria toxoid in mixture with T.A.B. [typhoid] vaccine is in now way interfered with and indeed appears to be enhanced. Such mixtures would first require to be tested on animals in which, at any rate, the rise in antitoxin titre can be accurately evaluated."

Then moving on to scarlet fever, he thinks it isn't worth trying to vaccinate most people, even if there were an effective vaccine, because it wasn't a serious disease anymore. Also it seemed that there was a patent preventing good vaccine development.

He thought treating measles with immune serum seemed to help, but there hadn't been much effort to acquire or store it. For active immunization, not enough was known yet about the disease.

With influenza though, more was known and a vaccine was closer, with some animal trials.

"One finding, however, which is likely to complicate the problem of active immunization as applied to man is the multiplicity of antigenic types among the strains recovered from different outbreaks of human influenza."

But he was frustrated by public health policy in general to some extent:

"When I reflect that, owing to ignorance, vested interest, or complacency in high places, a municipality is still prevented from ordering the pasteurization of all milk that comes into it, I sometimes despair of getting preventative science across."

One final quote:

"It may sound a totalitarian policy, if you like, but in essence it seems to me quite democratic, for it involves a negligible sacrifice on the part of the individual for his own and the common good."

Reference:

Ledingham, J. C. G. Prophylactic immunization against measles, scarlet fever, diphtheria, whooping cough, and influenza. British Medical Journal 2, 841–846 (1939).

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.

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).

060 - The Corrected Average Attack Rate from Measles Among City Children

Today’s post is not directly related to vaccines, but indirectly: it’s about measles epidemiology, or the observation of patterns of measles in populations over time; how many cases, in which ages, when it’s fatal, etc.¹

Specifically, A.W. Hedrich suspected that reports of measles cases in cities didn't always indicate the true level of measles that existed; the reports were incomplete. So he calculated a correction factor that should help health workers determine if their reports were complete, or estimate what the true rate might be.

The rate of measles varies seasonally, attacking more in winter than in summer (like the flu I guess), but it also cycles up and down in what’s called “epidemic swing,” as you can see in Figure 1 from the paper. Sometimes there could be 13 times more cases in one year than in the next.

Figure 1: Reported measles case rates. Baltimore, MD. 1897-1927. Hedrich 1930.

This is because in a high year, many people are infected and become immune naturally, so there aren’t as many susceptible people to be infected the next year. Levels of immunity might even be high enough to produce some herd immunity effect, where the virus can’t transmit from infected people to susceptible people, because the only contact between those groups is via immune people (who block the transmission). So that’s a low year. But as more people are born, the proportion of susceptible people rises until there’s another epidemic. That’s the natural cycle of measles, in cities at least.

This cycle made it difficult to compare between cities though, because obviously comparing a low year in one city to a high year in another would be inaccurate. So it’d be better to compare averages, say over ten years, to even out the variation.

Measles is pretty much a disease of childhood, or at least it was in pre-vaccine days in cities, because hardly anyone avoided it for that long, and generally one time is enough to be immune for life. (Not to say it can’t infect adults if they’re susceptible; see Panum's report on measles in the Faroes to see what the disease could do to a completely susceptible population.²) But in these days, almost everyone in cities had been exposed by age 15, so Hedrich decided that comparing case rates in people under 15 would be the best strategy. This was especially true because including those over 15 could introduce bias in cities that had a lot of immigrants from the countryside, who were often over 15 but still susceptible (since measles didn't spread as well in rural settings due to low population density), so that could inflate the case rate.

Hedrich compared some surveys of different cities, figuring out what proportion of the population had ever been exposed to measles by their 15^th birthday. It was pretty consistent between cities, countries, and over time that this proportion was about 95%.

Figure 2: Measles history rates by age. Hedrich 1930

So one might think, if reports of measles cases over different ages up to 15 don’t add up to 95%, they’re incomplete, and one can calculate a correction factor from that! But one thing this doesn't take into account is the children that have died before reaching age 15, either from measles or from other causes. The 95% figure is based on surveys of living children. So Hedrich looked at some data to see what measles mortality was and if it could affect the correction factor.

He found that in Baltimore from 1906 to 1915, measles killed about 4 out of every 1000 children under 15. The deadliest age was around 1 year old, with about 14 in 10000 dying from measles. This isn't necessarily indicating severity at these ages; it could be that the longer one lived, the more likely one had already survived measles.

Figure 3: Data from paper, figure I made. Deaths from measles per million people in Baltimore at a given age.

But anyway, this allowed calculation of the correction factor, and it turned out that fatal cases of measles didn't really affect it much. Though this wouldn't be the case with diseases that had higher mortality, or even sometimes measles epidemics that were especially deadly (like in Aberdeen, Scotland from 1883 to 1902, where the estimated death rate from measles was 2 of every 100 people; pretty scary).

Using this correction factor, Hedrich calculated with remarkable consistency that on average, 6.5% of city children under 15 get measles each year. He discusses a number of potential confounding factors that could introduce error but decides they don’t change the results significantly. So this could be useful for further study of measles epidemiology.

A number of later papers cite this one as important for later epidemiology, but I think some may have confused this paper with another of Hedrich's, since I didn't find what they say is there in it. Still, it’s interesting:

"Hedrick [sic] demonstrated, in Baltimore, that measles epidemics did not develop when the level of immunity was above 55 per cent. Though all the figures do not necessarily apply to urban areas, his findings do point out that considerably less than 100 per cent of the population need become immune before an epidemic is prevented or halted."³

"Based on the study of Hedrich (1930), Sencer et al. (1967) estimated that in Baltimore during the period 1897-1927 a level of immunity of 55 per cent was sufficient to prevent the development of epidemics."⁴

"The meticulous studies by A.W. Hedrich of measles diffusion in Baltimore from 1897 to 1927 formed the basis for epidemiological studies of measles for nearly 35 years. By carefully tabulating monthly measles rates and correlating them with the proportion of the population under fifteen years of age, Hedrich was able to develop a ratio of susceptible to immune children and thus account for fluctuations in the incidence of measles. It was determined that when the level of natural immunity exceeded 55 percent, the diffusion rate decreased. However, children escaping epidemics were still susceptible, and as more children were born, the number of susceptibles was augmented. Increased numbers of susceptibles led, in turn, to further epidemic fluctuations in measles."⁵

Citations:

1. Hedrich, A. W. The Corrected Average Attack Rate from Measles Among City Children. Am. J. Epidemiol. 11, 576–600 (1930).

2. Panum, P. Observations made during the epidemic of measles on the Faroe Islands in the year 1846. Bibiliothek for Laeger, Copenhagen 3R, 270–344 (1847).

3. Kogan, B. A. et al. Mass measles immunization in Los Angeles County. Am J Public Health Nations Health 58, 1883–1890 (1968).

4. Griffiths, D. A. The Effect of Measles Vaccination on the Incidence of Measles in the Community. Journal of the Royal Statistical Society. Series A (General) 136, 441–449 (1973).

5. Pyle, G. F. Measles as an Urban Health Problem: The Akron Example. Economic Geography 49, 344–356 (1973).

055 - Diphtheria—a Preventable Disease

Scroll down if you only care about the epidemiology, the exciting part.

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).