026 - VII. Report on the Prophylactic Vaccination of 1536 Persons Against Acute Respiratory Diseases, 1919–1920

Considering the difficulties of previous prophylactic vaccine studies, especially during the 1918 flu pandemic, there was something of a movement to improve the quality of future studies. Two things were the focus in particular:

• previous studies had immunized during the pandemic, so there was a question of whether immunity had been established in time before the subject was exposed; it would be better to immunize long before the expected exposure, and
• previous studies' control groups hadn't always been very similar to the experimental groups in size or demographics, so it was difficult to compare the populations.

So some tried to do better. In the current study, vaccines were made to try to protect against all known causes of respiratory disease (which known causes, at the time, were all bacterial), such as pneumococcus. The subjects were employees at the Metropolitan Life Insurance Company (MetLife) in New York City. Those who volunteered, 1536 in total, received a vaccine; 1293 got three doses, the rest only one or two (probably due to side effects). There were another 3025 employees as controls, who got nothing. In order to ensure that the two groups were similar, the scientists administered questionnaires about personal history, home conditions, and habits, and the groups did seem pretty similar in sex, age, and habits.

In terms of side effects, there were the common local (redness, soreness) and general (headache, malaise) ones; a few people got fever and such, but nothing was very alarming.

For results, one impressive thing was that vaccinated employees were absent about half a workday less than controls, on average.

Other than that, the results were not very impressive: for almost all diseases, the inoculated group had more cases than the control group, sometimes more than twice as many. The main exception to this was pneumonia: there was one case in the vaccinated group (0.05%) in a girl who had only one of the three recommended doses, compared to 11 cases (0.29%) in the control group. That's a five-fold difference.

The authors said, "One might infer from the tabulated figures that it were wiser not to be inoculated." They make a good point, though, by reminding the reader that the vaccinated subjects had volunteered for it, and were thus more likely to be more susceptible to respiratory infections. Indeed, according to questionnaires, about 22% of the controls said had been fairly free of infection, while only 10.5% of the volunteers said the same.

So overall, it seemed that the vaccine helped against pneumonia and not much else, not surprisingly (since many respiratory infections are viral, not bacterial). This seems like a pretty good example of a negative study. With its accounting for previous history and attempting to ensure similarity between groups, this study seems better than the ones I've written about previously. Clinical trials seem to have taken a step forward at this point. But there was still no blinding, placebo, or randomization, so there's a lot of improvement yet to be made. Right now it's still pretty much correlational (an observation of people who choose to be vaccinated compared to those who don't). So we'll see.

Citation: Von Sholly, A. I. & Park, W. H. VII. Report on the Prophylactic Vaccination of 1536 Persons Against Acute Respiratory Diseases, 1919–1920. J Immunol 6, 103–115 (1921).