070 - Immunization with Bacillus pertussis vaccine

As today's article states near its beginning:

"Most whooping cough patients need no physician, but those who do, need him badly." -Pospischill

Louis Sauer was one of the first to develop a whooping cough vaccine that actually seemed to work, at least sometimes. This was another article giving some data of efficacy.¹

As usual, the bacteria to make it were from fresh isolates of the disease, grown on human blood and suspended/killed in saline plus a little phenol.

Sauer first determined that the vaccine didn't work for vaccine therapy (i.e. using a vaccine to treat a disease, rather than prevent it). Not surprising; that concept didn't work too well in general.

So the next test would be for prophylaxis, preventing the disease by giving the vaccine to people before they were exposed to the disease. So he injected it into 394 children, most of whom had an older sibling known to be likely susceptible to pertussis (i.e. they hadn't been vaccinated or caught the disease before); these siblings were the controls. He used 3 injections total; he tried a single larger dose for some, but it seemed more prone to side effects.

Sauer reported that he did warn parents of the children about potential side effects, such as temporary fever and reactions at the site of injection, but all of them were eager for the treatment except for two, who refused it.

So within these children, over the course of 5 years, there were about 191 exposures to whooping cough, but not a single vaccinated subject got the disease. Of the controls, 31 got it, including many who were siblings of the vaccinated. There was definitely a lot of exposure of the vaccinated from their siblings, including as intimate as kissing (platonic, of course).

So Sauer concluded that his vaccine produced immunity after four months, at most, which lasted at least a few years. He recommended vaccination at ages 6-12 months, because immunity could definitely be produced at that age, and pertussis is most dangerous within the first two years.

This study had problems, of course, and isn't up to modern standards at all, but the results are fairly striking.

There was some discussion between physicians published after the main article, some of which was related and interesting:

"Dr. Sauer seems to have found a method of preparation and a method of administration of pertussis vaccine that will protect a child from whooping cough just as certainly as toxoid protects against diphtheria. His success in immunizing against pertussis is probably due to two factors. The first factor is the preparation of the vaccine. He uses only fresh cultures obtained every few months from active proved cases of pertussis. The second contributing factor is the tremendous dosage." -Dr. Raymond Schowalter

"Three or four months should elapse or intervene between completion of the vaccine administration and exposure to the disease. During the five years that this work has been going on, people wanted their children injected while whooping cough was in their neighborhoods. This was done and in a number of cases, within one or two months after the injections were begun, these children contracted pertussis. But in no case in which the time interval was more than three months has any child contracted pertussis, although, as the charts show, eighteen were intimately exposed to control cases in the family." -Louis Sauer 

 Also a later publication made an interesting remark on the quality of this study:

"Sauer's reports since 1933 as to the prophylactic value of [his vaccine] seem convincing, except for the fact that he does not fully discuss his results in an adequate number of control children."²

References:
1. Sauer, L. Immunization with Bacillus pertussis vaccine. JAMA 101, 1449–1453 (1933).
2. Siegel, M. & Goldberger, E. W. Active immunization of tuberculous children against whooping cough with Sauer’s vaccine. JAMA 109, 1088–1092 (1937).

069 - Vaccination against whooping cough

More about whooping cough. In Denmark, the State Serum Institute (a kind of non-profit government-run lab for making immunity-related products, I think) in Copenhagen made a vaccine against whooping cough, using recently isolated strains of the bacteria, killed and washed and suspended in saline with 1% formaldehyde. These were given in 3 injections, 3-4 days between them.

In this study, Thorvald Madsen discusses the results of vaccination in two whooping cough epidemics in the Faroe Islands using this vaccine.¹ In his experience, the vaccine was a good one because it didn’t cause many bad reactions, though he noted that a couple young infants died within 2 days of receiving it; any connection to the vaccine was unclear, so it could easily have been coincidence, no way to know. Still, he recommended against the vaccine for children under 1 month old.

The Faroe Islands, off the coast of Denmark, were pretty isolated, at least at that time, so contagious diseases often came in waves. After one outbreak, a while would pass before a second, and then the disease would break out and spread through the population again.

In the outbreak just at the beginning of the study, lots of people had just been vaccinated, and many others hadn’t, so there was a good comparison. Apparently the vaccine had come too late, so nearly everyone caught the disease, vaccinated or not. However, the disease appeared to be much milder in the vaccinated group: only 5 people died of 2094 vaccinated, compared to 18 deaths in 627 unvaccinated. That’s twelve times fewer in the vaccinated. The disease was reportedly more severe in the unvaccinated too, even those that survived. Best results were seen in those who had been vaccinated at least a week before the outbreak.

Then in 1929 there was another epidemic. 1832 people had been vaccinated, and 446 had not. Of the vaccinated, 458 were disease-free! And of the ones that weren’t, most of their disease was mild; only 1 died. Of the unvaccinated, only 8 had no disease, and of the rest only half had mild disease; the rest was more severe. 8 died. So the mortality in the vaccinated was 1/16th that of the unvaccinated. The vaccination had been done at the right time. These were pretty good results.

Combining the results from the epidemics, the vaccinated mortality rate was 0.15%, vs. the unvaccinated mortality rate of 2.4%. A big difference, especially combined with milder disease in general.

Madsen says the subjects were comparable in terms of age, time of epidemic, and other factors between the vaccinated and unvaccinated groups, and the ones vaccinated were chosen pretty much randomly.

Other scientists studying whooping cough vaccines at the time acknowledge the positive results, and point out differences between Madsen’s vaccine and other contemporary version:

"The chief difference between Madsen's and [Sauer's and ours] is in dosage, Madsen using a total of only 2 c.c. as compared with the 7 or 8 c.c. given by the others. The other differences are in kind of blood used to enrich the medium, in certain details of seeding and harvesting, and in choice of a killing agent. There is no experimental proof that these differences have any marked effect on the final product."²

Another article complains (fairly) about how little information there is in Madsen’s account:

"Madsen says practically nothing about his two groups except that they were unselected and were comparable in respect of age, time of epidemic, and surrounding conditions."³

This is true, it wouldn’t really pass muster as a modern study. There was no placebo or blinding either. However, while many people have cited this study as the first evidence of harmful side effects from a pertussis vaccine, the same complaints may apply:

"Madsen, it is true, recorded two examples of fatal convulsions after injection of fluid vaccine in newly born infants, but it seemed likely that age was the precipitating factor."⁴

"Although there have been reports of neurological illness after pertussis immunisation since 1933, none has been based on established epidemiological methods using relevant controls."⁵

In summary, it seems like low-quality but positive results in favor of vaccination, and at most a warning of something to watch for as an adverse effect in future studies.

References:

1.  Madsen, T. Vaccination against whooping cough. JAMA 101, 187–188 (1933).

2.  Eldering, G. & Kendrick, P. L. Some Practical Considerations in B. pertussis Vaccine Preparation. Am J Public Health Nations Health 26, 506–511 (1936).

3.  Vaccination against Whooping-cough. BMJ 2, 222–223 (1945).

4.  Pertussis Vaccination and Encephalopathy. BMJ 1, 110–112 (1950).

5.  Miller, D. L., Ross, E. M., Alderslade, R., Bellman, M. H. & Rawson, N. S. Pertussis immunisation and serious acute neurological illness in children. BMJ 282, 1595–1599 (1981).