O951 - Does an attack of acute anterior poliomyelitis confer adequate immunity? Report of four second attacks in New York City in 1935

There've been other reports of reinfection with polio after an initial infection (077), so it seems immunity is not always lifelong or perfect from natural infection.

Fischer and Stillerman collected a number of reports of such second attacks, 13 from others and four of their own in New York City in 1935. These four were in children 3-9 years old, and the attacks all came 2-5 years apart.¹

The first had some paralysis in the first attack, recovered, and then had some more in the second and took years longer to recover from that. The second had paralysis the first time but none the second; the infection was nonparalytic. The third had some mild paralysis both times. The fourth had a nonparalytic infection first (it was questionable whether it was even polio), but the second attack was fatal.

So from this and other statistics, the authors calculated that second attacks happen around 2 per thousand first attacks. Considering the low attack rate in the first place, they wonder whether there's actually any immunity to polio at all. But others disagree:

"Fischer and Stillerman have raised the question as to whether the low morbidity rate in poliomyelitis would not make the incidence of second attacks rare even if no immunity occurred following the disease. In the 1935 New York City epidemic they observed four second attacks, a rate of 2 per thousand, which was within the limits of expectancy if no immunity resulted from a previous attack. However, these figures were not based on age specific rates and cannot therefore be taken as final."²

References:

1.Fischer, A. E. & Stillerman, M. Does an attack of acute anterior poliomyelitis confer adequate immunity? Report of four second attacks in new york city in 1935. JAMA 110, 569–572 (1938). 

2. Horstmann, D. M. Clinical aspects of acute poliomyelitis. The American Journal of Medicine 6, 592–605 (1949).

O860 - Investigation on Volunteers Infected with the Influenza Virus

Apparently back in the 30s, the Soviet Union was doing research on influenza, some of which used human volunteers.¹ Well, better flu research than smallpox or something, and it seems to have worked out alright.

Here, they tried infecting 72 volunteers with virus taken from infected mice, by aerosolizing it and letting them inhale it. It seemed to work in some of the volunteers, though their illness was mild; the authors speculate that the virus might have been attenuated by passage through animals.

The most interesting result was the antibody levels in the volunteers before and after inoculation. They measured antibodies by drawing blood, mixing it with live virus, and injecting it into mice. If the mice survived, the virus had been neutralized by the antibodies.

What they saw was that volunteers who did get sick had pretty low antibodies to begin with, almost none in some cases; afterward their levels were 25-100 times higher. In those that didn't get sick, the levels had started out high and risen only a little (to about the same level as the others). So antibody levels correlated well with immunity to influenza.

The authors thought this infection with somewhat-attenuated virus method might be a good strategy for immunization. The editor of this study's journal disagreed with that statement, as did later researchers:

"A paper published from the Soviet Union by Smorodintsev[sic] et al. in 1937 - frequently cited as the first paper on live virus vaccine - described the administration of a mouse-lethal strain of the...virus by protracted inhalation of atomized virus. Typical febrile influenza developed in 20% of volunteers, hardly an acceptable vaccine by present standards, and certainly not attenuated, as claimed by the authors. Remarkably, they claimed, as well, that the virus appeared not to multiply in men, but the study was a landmark in establishing unequivocally the role of the virus in the development of the disease and in demonstrating antibody response to the virus during convalescence."⁴

Others questioned whether this study could really be compared to natural infections:

"These results suggested that the level of neutralizing antibodies was of significance in determining susceptibility or immunity to influenza A in man. But the conditions under which the experimental disease was produced and the relatively large quantities of virus suspensions used seem so different from conditions encountered in the natural epidemic disease as to make comparisons between these two conditions hazardous."²

"Whether experimentally induced influenza A in human beings is entirely analogous to the naturally occurring epidemic disease may be open to some question."³

Seems like a reasonable question, but at least it's easier to control this kind of study for unwanted variables.

References:
1. Smorodintseff, A. A., Tushinsky, M. D., Drobyshevskaya, A. I., Korovin, A. A. & Osetroff, A. I. Investigation on Volunteers Infected with the Influenza Virus. The American Journal of the Medical Sciences 194, 159–170 (1937).
2. Rickard, E. R., Horsfall, F. L., Jr., Hirst, G. K. & Lennette, E. H. The Correlation between Neutralizing Antibodies in Serum against Influenza Viruses and Susceptibility to Influenza in Man. Public Health Reports (1896-1970) 56, 1819–1834 (1941).
3. Horsfall, Jr., F. L. Recent Studies in Influenza. Am J Public Health Nations Health 31, 1275–1280 (1941).
4. Kilbourne, E. D. in History of Vaccine Development (ed. Plotkin, S. A.) 137–144 (Springer New York, 2011).

089 - Treatment of pertussis with the New York State pertussis vaccine

Some investigators in 1936 questioned the effectiveness of any whooping cough vaccine developed thus far, though most thought they were helpful. So Thomas Bumbalo studied a vaccine produced by the New York Department of Health, made of killed bacteria.

The study was in children with siblings, half of whom got the vaccine and the other half didn't. All subjects had been exposed to pertussis though. There were four groups of subjects:

• those who were sick with whooping cough and were treated by vaccination
• those who were sick but were not treated with the vaccine
• those who had been exposed but hadn't yet shown symptoms, and were vaccinated
• those who had been exposed but weren't vaccinated

The first two groups both had 152 subjects, of similar ages and sexes and in the same families if possible. The latter two had 29 and 58 subjects, respectively. Bumbalo explained that mothers in group 3 were hesitant to have their children injected for no apparent reason, and:

"To quote the sentiment of many mothers, whooping cough is 'a mild disease which all kids get sooner or later and they might just as well get it over now.'"

Some things don't change.

So, the results: the average difference between the first two groups in how long they were sick was 32 hours, about 1.3 days. Not too great.

Of the second two, there were 5 cases (17%) in the vaccinated and 6 (10%) in the unvaccinated, though the average severity was milder in the treated. Still, not great.

Still, it wasn't a great study either. Vaccine therapy had already been pretty well demonstrated to be useless, and vaccinating right after the children had been exposed wouldn't help much either; there wouldn't be enough time to form a good immunity. So not much can be concluded.

Reference:
Bumbalo, T. S. Treatment of pertussis with the New York State pertussis vaccine. Am J Dis Child 52, 1390–1396 (1936).

088 - Studies in whooping cough: Diagnosis and immunization

First, the scary numbers: in 1936, there were more than 300,000 cases of whooping cough in the US, and 15% of infected infants died from it.

Leila Daughtry-Denmark wanted to help make this situation better, so this study was partially to figure out how to diagnose it early, partially to figure out how to determine who was susceptible, and partially to see if it was possible to make people less susceptible (by vaccination).

The cultures and vaccine used in this study were provided by Eli Lilly.

First Daughtry-Denmark tested white blood cell counts and agglutination to see if they correlated with infection, recovery, or immunity. Infection or vaccine seemed to increase the former but didn't seem to affect the latter.

Complement fixation (relating to antibody levels) seemed a much better indicator. Even young children (under 6 months) showed a good response to vaccination. Letting the vaccine age to 4 months didn't reduce its effectiveness. And the Georgia Public Health Lab repeated the test on their own and saw similar results. And they never observed fixation without either the vaccine or the actual disease.

Complement fixation also seemed to correlate with immunity, at least in a small sample (2 brothers), where when they were both exposed later, the brother with good fixation was protected and the other got sick.

Then there were some bigger tests of the vaccine, both with Sauer's version and a more concentrated kind that required fewer injections, making it more convenient. Apparently Sauer's sometimes took more than 8 injections to work, while this double-strength one only took three. They sure had some tolerance to shots back then; though I guess the current recommendation is four shots of DTaP before 1.5 years of age, so that's not so much better.

Anyway, there were 240 subjects who got the vaccine, but only 73 actually got exposed to the disease. Of these, 10 got the disease. So you could say it was 86% effective. But there was no control group, so it isn't possible to make firm conclusions. Also, only those who got Sauer's vaccine got exposed, so there wasn't really a test of the double-strength version.

So it seemed to work, but it's hard to know how effective it really was; exposure doesn't always mean disease, even in the unvaccinated.

A final comment mentioned in the article: there was a test of 50 college students who claimed to have had pertussis as children, and it found that only one had very good complement fixation, while 46 had no detectable fixation. So natural immunity doesn't seem that great for pertussis.

Reference:
Daughtry-Denmark, L. Studies in whooping cough: Diagnosis and immunization. Am J Dis Child 52, 587–598 (1936).