092 - Immunization against pertussis

This is another trial of a pertussis vaccine, similar to the others. The justification was that whooping cough is contagious before it is easily recognizable, so it's hard to prevent by anything but immunization.

The subjects were children of 6 to 30 months old, most under 1 year. They were selected from those attending the Stanford Well Baby Clinic randomly, and controls were chosen randomly from the same group, so it was pretty well randomized (except that presumably the parents in the vaccine group had to agree to the vaccine).

The vaccine was whole killed bacteria, a normal dose like Sauer's, 3 doses each a week apart. They started counting after the last dose was given, to make sure everyone was fully immunized. From these shots, they saw 4 systemic reactions, which were just a day of fever.

Then they got the parents to inform them of any known cases of pertussis, and any exposures to others with pertussis. These were diagnosed either by the typical coughing symptom or by culturing the bacteria on cough plates. Some had neither but were counted as "probable" because of history of exposure.

Results
Over the 2.5 years of the study, the vaccinated group had 26 exposures resulting in 7 cases (2 of which were questionable). So the infection rate was 26.9%.

The controls had 25 exposures resulting in 22 cases (1 questionable), so 88% infection rate. The difference between the two groups was statistically significant, both in infection rate and attack rate (the proportion of all subjects infected vs. not), so it seemed like the vaccine was protective.

The control group had 11 cases from unknown exposures, and the vaccinated group had only one, so it's possible to assume the vaccinated group actually had 10 more unknown exposures that would otherwise have resulted in disease, lowering the infection rate to 23%.

In terms of severity, the vaccinated cases were never severe; a few were typical, some mild or questionable. The control cases were mostly typical, 3 severe, 5 mild or questionable. So the vaccine seemed partially protective even in those that got sick.

In terms of immunity duration, of those that got sick in the vaccinated group, most had been vaccinated over 1.5 years before, so the authors recommend small yearly boosters.

Overall, not as rigorous as possible, but pretty good, and the vaccine was helpful but not super-great.

Reference:

Miller, Jr., J. J. & Faber, H. K. Immunization against pertussis. JAMA 112, 1145–1148 (1939).

091 - Active immunization against whooping cough with various specific vaccines

Since various different trials of whooping cough vaccines had given confusing positive and negative results, Morris Siegel wanted to settle the question of whether any version was effective. Sadly, he failed.

This study vaccinated 1324 children in Brooklyn with different versions: Sauer's version from Eli Lilly, a similar version from the NY Department of Health, some versions from Lederle Labs or Povitzky, and then the NY Dept Health version delivered partially subcutaneously instead of all intradermally.

The subjects were under 6, with no history of pertussis, recruited or volunteers from the community. Controls were selected from the same neighborhoods and families. So it wasn't really randomized or placebo-controlled at all.

They followed up once a month with the subjects to get histories of pertussis. Cases were considered cases if whooping was present, or probable cases if there were other symptoms and exposure to a typical case. And cases that happened within a month of vaccination weren't counted either, since immunity hadn't kicked in yet.

So overall there were 1270 vaccinated subjects and 1016 controls that were observed throughout the study. about 80-90% were 1 to 4 years old, and 7-15% were less than a year.

Results
Overall, 3.6% of the vaccinated subjects got whooping cough, vs. 4.2% of the controls. Of the vaccinated, 76% of the cases had received what was considered a full course, three doses.

Not great. However, looking at the breakdown of vaccine versions, no one who got Sauer's vaccine or the similar NY Dept Health one got sick; most of the cases came from the Lederle Labs versions or similar. The intradermal route seemed best. So considering only the good versions, only 1.7% of subjects got sick, vs. 5.4% for all the other versions; worse than the controls. The biggest difference between them is the concentration: there were a lot more dead pertussis bacteria in the seemingly more effective versions.

One other positive thing though was that the age distribution of vaccinated cases was centered on children 2-3 years old, with fewer young infants getting sick than controls, which had a center around 1-2 years. So it's possible the vaccine shifted the age distribution toward older children, who can deal with it better.

Most of the cases happened after four months had passed since vaccination, possibly an indication of waning immunity; or possibly not, since diseases have some seasonality.

Overall, since it wasn't blinded or randomized, and there were so many different versions used in the vaccinated, it's hard to say much about the results. Though some versions seemed to do better than others, it's unclear whether all groups were exposed to the disease equally. So, almost worthless.

Reference:

Siegel, M. Active immunization against whooping cough with various specific vaccines. Am J Dis Child 56, 1294–1303 (1938).

O850 - Tetanus Bacillus Recovered from Scar Ten Years after Attack

When active, the bacteria that cause tetanus can only survive in conditions completely lacking in oxygen, but they can form very tough spores that can survive oxygen, heat, drying, whatever.

In this case report, a woman had some surgery on her uterus and showed some signs of tetanus paralysis afterward; the doctors treated her with anti-tetanus serum and she recovered.

Ten years later, she needed more surgery in the same place. The doctors feared a tetanus recurrence so they gave her anti-serum prophylactically, and tried isolating bacteria from the scar tissue they removed from her body. They successfully grew some typical Clostridium tetani, which produced tetanus toxin capable of killing mice. I don't know how they tried to avoid contamination though.

They tested the patient's serum to see if there were any sign of immunity against the tetanus that seemingly had been in her body for ten years, aside from the immunity from the anti-serum they had given. But they didn't find any indication of immunity.

They cite other reports of tetanus remaining dormant in the body for long periods, even up to 14 years, and advise that surgeons treat for tetanus prophylactically when a patient has had tetanus before. Bacteria can be pretty tough.

Reference:

Bonney, V., Box, C. & MacLennan, J. Tetanus Bacillus Recovered from Scar Ten Years after Attack. BMJ 2, 10–11 (1938).

090 - Serologic Studies in Epidemic Influenza: With Particular Reference to the Persistence of Antibodies After Infection

Many virus infections seem to lead to long-term immunity, so you get it only once; at least, that's how it seemed. But one obvious exception is influenza, which you can get every year almost. Part of the reason for this is its ability to mutate frequently, becoming different enough each year that our immune system doesn't recognize it as well; but Fairbrother and Martin wondered whether this were really the whole story.

So they studied the antibody levels of people before and after an epidemic of flu and for about a year after. There were two kinds of tests they used: complement fixation, and neutralization where they mixed antibodies with virus and injected it into mice to see if they died.

As we saw before (O860), antibody levels seem to correlate with immunity, and definitely increase after infection. They saw the same thing here: after being infected in the epidemic, people's levels were much higher. For those that didn't get infected, levels were pretty variable, some high, some low.

But after about a year, antibodies in people who had been infected were much lower than they had been, nearly back to where they had been before the people were infected.

So it's possible that natural immunity to influenza wanes after a year, though that can't be concluded here because they didn't actually test immunity, only antibody levels.

Reference:

Fairbrother, R. W. & Martin, A. E. Serologic Studies in Epidemic Influenza: With Particular Reference to the Persistence of Antibodies After Infection. The Lancet 231, 718–720 (1938).