072 - Progress Report on Pertussis Immunization

Other than Louis Sauer and Madsen and others, Pearl Kendrick and Grace Eldering were trying to develop a good pertussis vaccine. They did a trial of the one they made in Grand Rapids, Michigan, which from what I can tell was pretty historic. This report was not their final conclusion, but they had enough data to make an interesting preliminary report.¹

They used a virulent strain of B. pertussis for the vaccine, growing it on sheep’s blood, then killing it with merthiolate (AKA thiomersal or thimerosal) or phenol. In terms of dose, they used closer to Sauer’s preferred dose, much higher than Madsen’s, but tried a few different doses (though this didn’t seem to make much difference).

The subjects in the study were children, 8 months to 5 years old, especially 1-2 years. As controls, they followed children the same age, preferring children in the same families as those who received the vaccine (to ensure similar circumstances).

They worked with nurses from the city’s public health department to follow up with the subjects at 3- or 4-month intervals, verifying reports of pertussis cases or exposures. Exposures were classified as definite (coming from someone in the home), indefinite (coming from elsewhere), or unknown (a case of whooping cough from an unknown source). Cases were rated by severity based on quantitative definitions of duration of disease, cough, whether there were complications, etc.

So what did they find? It was pretty good. By the time of publication, sixty vaccinated subjects had been exposed, but only four got sick. That’s less than 7% (or 0.5% of the total group, including non-exposed subjects, 712 subjects total).

In contrast, there were 63 cases in the control group, from 84 exposures (880 subjects total). That’s 75% infection rate (or 7% overall). So the vaccine seemed to protect more than 90%.

And even considering the four vaccinated subjects that got sick, their disease was either light or very light, while 85% of the control cases were of medium severity or higher.

The researchers warn that the numbers might be too small to make any solid conclusions, and the trial is not up to today’s standards (in terms of blinding, randomization, placebos, etc) but for what it’s worth it seems impressive.

A later historical account gives the following description of the response to this report. Keep in mind that requirements for trials in the 1930s were much less rigorous than they are now, and that yet Frost basically admits he can’t find much fault with the design: 

"Although it was well controlled, the 1934-1936 field trial had to surmount considerable initial skepticism within the national public health community. Shortly after Kendrick and Eldering announced their results, James Doull, a prominent Cleveland epidemiologist, reported that children received no protection from a vaccine he had designed and produced (065). The APHA subcommittee on whooping cough, which included both Kendrick and Doull, evaluated the contradictory results of the two studies but was unable to explain why they differed. The committee then asked Wade Hampton Frost, a Johns Hopkins epidemiologist and head of the APHA, to review both studies.
     Frost was predisposed to find fault with Kendrick's study. In a "personal" note...Frost voiced his doubts: 'I very strongly suspect that Miss Kendricks field studies are not set up in such a way as to give a really good control. My reason for this suspicion is that, as you know well enough, the satisfactory set-up of such an experiment is an exceedingly difficult matter. Not 1 out of 10—perhaps not 1 out of 50—attempts is successful and as a mere matter of probability the odds are strongly against Miss Kendrick's experiments being sound.'
     Unable to find the faults he expected in Kendrick and Eldering's study, Frost journeyed twice to Grand Rapids to examine their data and recommend suggestions for improving statistical accuracy and coding. In the end, Frost said to Kendrick, 'I think it may be assumed, not as a conclusion but merely as a working hypothesis, that your data when finally analyzed are likely to show some protection in the vaccinated group.'"²

Citations:

1.  Kendrick, P. & Eldering, G. Progress Report on Pertussis Immunization. Am J Public Health Nations Health 26, 8–12 (1936).

2.  Shapiro-Shapin, C. G. ‘A Whole Community Working Together’: Pearl Kendrick, Grace Eldering, and the Grand Rapids Pertussis Trials, 1932-1939. Michigan Historical Review 33, 59–85 (2007).

O722 - Safeguards in the Publicity Use of Vital Statistics

Not specifically about vaccines, but interesting nonetheless, because vital statistics are often used (or misused) in support of (or opposition to) vaccines. Also the author was the one who wrote the article for post 060 about measles attack rates.

Anyway, it's a good lesson and a good reminder about how it is difficult to convey accurate information with statistics, especially if you have some personal interest in what is being conveyed.

"To reason correctly from such complex data is not easy, and even the most acute and careful persons will at times fall into error in the process. But no confusion can be quite so profound as that of the individual who rushes into this maze with the intention of finding support of a preconceived idea."

Hedrich gives several examples of how statistics can go wrong that are worth checking out. It reminds me a bit of the book How to Lie with Statistics, though not quite as in-depth or entertaining.

But for we who want to examine the truth of a matter without bias, it is important to be twice as careful with our own statistics as we are when examining others', especially those on the other side of the issue.

"Public health certainly aspires to as high an ideal as is professed by business: Truth in Advertising. To that end, the first safeguard proposed in the publicity use of statistics is to try to be more critical of the materials and of the reasoning which favor our cause, than of those which oppose it—more critical, because otherwise we shall certainly not be critical enough; the instinct to defend one's beliefs and interests is so strong that desire too often pulls the wool over the eye of reason."

And keep in mind that finding the truth is not as simple as just finding a reasonable hypothesis and sticking with it:

"It is a fundamental theorem of scientific procedure that a given explanation cannot logically be accepted as the preferable one, unless all other reasonable hypotheses have been eliminated."

Anyway, it's a good article. Go check it out! It's even open access.

Reference: Hedrich, A. W. Safeguards in the Publicity Use of Vital Statistics. Am J Public Health Nations Health 24, 336–341 (1934).

071 - The Immunization of School Children Against Whooping Cough

In addition to the Sauer vaccine, which used whole bacterial cells to prevent whooping cough, others had developed the Krueger vaccine, which was made from bacterial cells broken up mechanically and then filtered thoroughly so that only the soluble cellular components remained. Basically this was an acellular version, intended to be less likely to cause serious reactions in subjects, but still induce a good immune response because the important parts were still there.

So Frawley had been testing this vaccine in school-aged children, not younger, reasoning that the disease mostly passed through a population in schools, so preventing transmission in schools could prevent children from bringing it home to younger siblings. Apparently in Fresno, where this study took place, 70% of school children hadn't had pertussis yet.

The first trial was in January 1933, 345 children, but it didn't seem to help much in the following pertussis outbreak, because only a very small dose was given. So in November they did another trial with 505 children, with a larger dose.

During the time of the trial, 80 vaccinated children were exposed to pertussis, but only 31 of them got sick; 61% were protected. These were mostly only mildly sick, with a short duration of the characteristic cough; 25 coughed for less than a week, and only 1 for more than 2 weeks.

There was no control group to compare how many unvaccinated got sick, but Frawley did observe a group of 174 unvaccinated children who did come down with the disease, to see if they had it worse than the sick vaccinated group. It seemed so: only 9 of the 174 (5%) coughed less than a week, while 116 (67%) coughed more than 2 weeks. So it was a pretty big difference in severity, by that measure.

Frawley noted that the vaccinated subjects didn't have any serious reactions, though some who had had pertussis recently had more serious local reactions, possibly allergic. Not very serious though. He also noted that these reactions stopped when the pertussis had happened more than a few years before, indicating fading natural immunity.

Overall, the results are interesting in the difference in disease severity, but it wasn't a very well-controlled study, so not much can be concluded.

Reference: Frawley, J. The Immunization of School Children Against Whooping Cough. JAMA 103, 960–962 (1934).