068 - Fatality Rates of Small-Pox in the Vaccinated and Unvaccinated

This is more a series of studies than a single one, all with the same title. A sort of discussion between physicians, regarding the value of vaccination against smallpox.

It started with a letter in the British Medical Journal from R.P. Garrow, which presented some data over 4 years of deaths from smallpox in Britain, comparing vaccinated and unvaccinated cases.¹ As Garrow says, it should be expected (assuming vaccination is helpful) that there be more deaths among unvaccinated than among vaccinated, but in these data the case-fatality rates (proportion of people with the disease who died from it) was higher among the vaccinated, 30 in 10000 vs. 6 in 10000. The number of cases of smallpox is higher in the unvaccinated (almost 7000 vs. 4000 in vaccinated), but we don’t know what proportion of these populations these numbers represent. All these cases are in subjects over 15 years old. Garrow remarks that the cause of death may sometimes be questionable, and this might explain the discrepancy, but he’s not sure.

This letter is followed by another collection of letters from other physicians, in the same journal.² First, Dr. Percy Stocks tries to explain the strange data by pointing out that the age distributions of the two groups are pretty different. Check out the number of cases:

It appears there are a lot more cases in unvaccinated in general, though again the proportion is unknown, but most of the cases are in the young, decreasing with age. Compared with this is the vaccinated population, where the median age seems to be around 40-50 years. Similar results are seen with the number of deaths from smallpox by agegroup:

 This seems to indicate a limited duration of immunity from vaccination, such that those vaccinated as children are no longer as well-protected as they used to be, and thus get sick again in old age. And the number of deaths in any group is so small that it’s hard to compare the groups.

Dr. Fred Wynne repeats the explanation of waning immunity in his letter, though I’m not sure why this makes everything okay. He also admonishes Dr. Garrow for giving support to antivaccinationist arguments, which apparently was a problem even then.

Dr. C. Killick Millard points out that smallpox comes in two forms: variola major, the serious, deadly form, and variola minor (AKA alastrim), which is much milder. Cases of the latter are much more common, but Dr. Garrow didn’t distinguish between the two, so it’s hard to say what exactly is going on. Thousands of minor cases with a few major ones just makes for a complicated situation.

Finally, L.A. Parry comes in with a bunch more questions, about how supposedly less vaccination means fewer deaths and cases from smallpox, etc, without providing reference to any such data, prompting the BMJ editor to admonish Parry for introducing “assumptions of fact into framework of his questions.”

I tried to figure out who this Parry guy is, but everything else he published (judging by titles, at least) didn’t seem that different from what I would expect from a typical medical doctor. Weird.

In the third letter, this one in the Lancet, Dr. Duncan Forbes provides more data from the early 1900s in Britain.³ This data is purely serious smallpox, variola major, as far as he knew, excluding all variola minor. The number of cases was much smaller, about 500 total, but the case-fatality rates are very different. For the unvaccinated, 19.2% who caught the disease died (10 of 52), vs. 1.9% of the well-vaccinated (more than one vaccination scar) (7 of 362). In between were those who were said to be vaccinated but had no scar, or had only one scar: with no scars, the rate was 17.1%; with one scar, 10.8% (combined 13%). From this, Dr. Forbes points out the importance of good vaccination.

Finally, Stallybrass wrote to the Lancet to point out differences in smallpox between northern and southern Britain.⁴ Apparently many people in the north were unvaccinated, and variola minor (the mild kind) was rampant there, but in the south, where most people were vaccinated, variola major occasionally came in from visitors from France or Spain. Stallybrass tracked down all the deaths from smallpox and discovered that among the vaccinated, almost all deaths were in the south in people over 30, whereas almost all deaths in unvaccinated were in the north in people under 15. Overall, case-fatality rates were lower for vaccinated (10 in 10000 compared to 11.2 in 10000), and lower in age groups under 15 and over 30. In the middle, there was just one death in either group, so it’s hard to compare; could be just due to chance.

He also points out that older people may be more susceptible to smallpox, especially the worse version in the south, and indeed most deaths in the vaccinated are in the south in older people. In contrast, even the mild version is dangerous for the very young when unvaccinated.

Summary

It’s tricky to say what’s really going on exactly with these data. What it does show is how a complicated question like this can be confused more and more by a lack of details. It’s all too easy to distort the data to show what you want to show, if you have an agenda, simply by leaving out certain details, like age or geographical distributions.

Citations:

1.  Garrow, R. P. Fatality Rates of Small-Pox in the Vaccinated and Unvaccinated. British Medical Journal 1, 74–74 (1928).

2.  Stocks, P., Wynne, F. E., Millard, C. K. & Parry, L. A. Fatality Rates of Small-Pox in the Vaccinated and Unvaccinated. British Medical Journal 1, 115 (1928).

3.  Forbes, D. Fatality-Rates of Small-Pox in the Vaccinated and Unvaccinated. The Lancet 211, 208 (1928).

4.  Stallybrass, C. O. Fatality-Rates of Small-Pox in the Vaccinated and Unvaccinated. The Lancet 211, 313–314 (1928).

067 - Active immunization of tuberculous children against whooping cough with Sauer's vaccine

It seems to be the age of whooping cough vaccine testing, at least in this blog. This is another.

Given other questionable results (065), though not with Sauer's vaccine exactly, Siegel and Goldberger decided to do a more controlled trial, in the Sea View Hospital for people with tuberculosis. This place had a bunch of children with TB that were kept together by age and sex (after a certain age), with limited contact with the outside world. Since they were monitored and isolated, pertussis would be easier to track among them.

So Siegel and Goldberger got vaccine from Sauer and Eli Lilly, and vaccinated a total of 101 children over 2 years, keeping a second group as controls. They stopped vaccinating when an outbreak of pertussis occurred in the hospital. Sixty-four children in total were exposed over 3.5 months, and there were 27 definite cases of characteristic whooping cough. The staff isolated each child when they started having symptoms of course, but symptoms don't show up until after the child starts being able to spread the bacteria to their playmates. Another 5 children got sick but didn't have the characteristic whoop, so they were counted as probable cases.

At the time of the outbreak, the average age of vaccinated children was 4.2 years, vs. 2.3 years average for controls. This is a big difference, and could affect the results. The groups didn't have significantly different severity of tuberculosis though.

There were only 36 children in the final study, too: 17 vaccinated and 19 controls. The others either had left the hospital, or had certainly or possibly encountered pertussis previously (and thus maybe had some natural immunity). They only considered those with no known history.

So now for results: considering only definite cases, vaccinated did better, 29% (5 of 17) getting sick, vs. controls with 53% (10 of 19). 44% decrease. Not very good at all. Especially when adding in probable cases, which brought the numbers up to 53% vs. 58%.

Most of these cases were mild; there was one moderately severe case among the vaccinated, and four more in the controls. Pertussis didn't seem to aggravate TB in either group. The average durations of whoop and severe period in the vaccinated group were 21 and 2.8 days, vs. 32.5 and 7.5 days in controls. And considering more of the cases in the vaccinated group weren't even certainly whooping cough, it seemed like the disease was less severe in those vaccinated. However, these children were older too, so it's possible the age might've contributed more than the vaccine to this effect.

So these aren't great results for the vaccine, especially considering the lack of blinding or placebo. It's possible some things complicated the results: having tuberculosis may have increased the children's susceptibility, but according to studies of antibodies, they seemed to respond to the vaccine as well as normal children do. Also, being so closely intimate in the hospital setting, there might've been just too heavy an exposure to the pathogen for the vaccine to be adequate. But it seems like if it were a good vaccine, that shouldn't be an issue. So, more work to do perhaps.

Citation: Siegel, M. & Goldberger, E. W. Active immunization of tuberculous children against whooping cough with Sauer’s vaccine. JAMA 109, 1088–1092 (1937).

066 - Neurologic Complications Following the Administration of Vaccines and Serums: Report of a Case of Peripheral Paralysis Following the Injection of Typhoid Vaccine

NOTE TO READERS: Unfortunately, my free time this summer is very limited, so I won't be able to update VoT as frequently as I have been. I'll try to continue working on it as time permits though. It should pick back up in August.

So, now on to today's paper. It starts off with a case report (basically a well-documented anecdote) of a man who suffered a minor temporary nerve disorder after receiving a vaccine against typhoid. The man was admitted to a hospital with some problems of epilepsy, probably from alcoholism. While there, he was given the vaccine, as protection from hospital-acquired disease, I guess. Staff and patients there routinely received the vaccine with no problems.

At first there was no problem with this man, but then four days after getting the second dose, he had "foot drop." I guess this meant he wasn't able to move his foot as much as he should've been able to. They couldn't find any infection or anything, and tried treating it with different ways, but a month later it was still the same. After 3 and a half months though, it was almost completely recovered.

So the man's doctors diagnosed this as vaccine-induced peripheral paralysis. It seems a little post hoc, but no other explanation presented itself.

Then Robinson discusses nerve problems relating to vaccines and different kinds of serum in general. It seems like besides the rabies and smallpox vaccines, it's mostly sera that cause problems, which makes sense because I think at this time they were animal-derived (and thus liable to cause sensitivity reactions perhaps). But still somewhat a problem.

People weren't sure what caused the problems, though they had some suggestions: some kind of toxin, possible disruption of nerves somehow, or a contaminating pathogen like a virus. Robinson suggests that a virus would also be a problem in other kinds of injections, but it doesn't seem to be. And he adds one possibility: the preservatives used in these products.

Many of these products, and many of those producing them, used phenol-based preservatives, like phenol or tricresol, or others. Obviously preventing growth of bacteria in injectable products is a good thing, but some studies seemed to show similar serious nervous symptoms after injection with phenol-related compounds. Some seemed safer than others, though studies weren't entirely clear. So Robinson suggests recording whether each product contained a preservative when reporting this kind of side effect.

He concludes thusly:

"There is no way of knowing what patients may be unexpectedly affected by this unusual complication. The physician should not be held responsible for its occurrence, and the possibility of its happening is not a contraindication to the intended injection."

My conclusions: Not really sure. Doesn't seem especially relevant to the question of vaccine safety today, but worth paying attention in the future.

Citation: Robinson, L. J. Neurologic Complications Following the Administration of Vaccines and Serums: Report of a Case of Peripheral Paralysis Following the Injection of Typhoid Vaccine. New England Journal of Medicine 216, 831–837 (1937).