O983 - Active Immunization Against Tetanus Infection with Refined Tetanus Toxoid

This study compared unrefined tetanus toxoid and also a refined version, precipitated with alum (aluminum potassium sulfate) in guinea pigs. The former gave 0.5 units antitoxin after 6 months, and the latter 1 unit after 3 months. They conclude the latter is better (though it doesn't quite seem like a good comparison to me).

Then they used this refined toxoid to immunize 30 people. None had reactions to it, local or general, which is good. Their antitoxin went from as much as 0.0005 to up to 0.04 units in 90 days. After a 2nd dose, levels got up to 9 units, but were widely variable between people. The highest levels 1 and 2 years after the 2nd dose were 0.4 and 0.35 units, respectively; high enough for protection, they judged.

"The amount of antitoxin found in the serum of human beings thirty days after receiving a second dose of the toxoid was considered to be sufficient to protect them by giving a third dose of toxoid, on injury, instead of a prophylactic dose of tetanus antitoxin."

There was some variation too on whether it lasted a whole 2 years protectively. It seemed to depend more on the individual's general health than on age.

The authors state that the Societe de Chirurgie of Paris committee recommends:

"vaccination against tetanus [is] the best method to decrease the mortality. The vaccine (anatoxin of the Pasteur Institute) is harmless, not being followed by any local or general reaction. The vaccination should be repeated every year or two...In war, vaccination should be made obligatory."

The authors recommend this vaccination for soldiers and others who regularly get injured (farm workers, etc), and also for pregnant mothers:

"The antibodies contained in the placental circulation before birth and the antibodies contained in the mother's milk, afford protection to the new-born child."

And the final recommendation is that if a person has been vaccinated with toxoid and gets injured (more than 1-2 years after the vaccination) they should receive another dose of toxoid to rapidly stimulate a response, just in case. But if they haven't received any toxoid doses, they should get toxoid and also a protective amount of antitoxin serum, because the toxoid won't stimulate a response in time, if necessary.

So that's what they say.

Reference:

Bergey, D. H. & Etris, S. Active Immunization Against Tetanus Infection with Refined Tetanus Toxoid. J Immunol 31, 363–371 (1936).

098 - Anaphylaxis after Injection of Tetanus Toxoid

I once read an article questioning the safety and usefulness of the tetanus vaccine. This vaccine is made of the tetanus toxin itself, denatured such that it doesn't cause problems, only induces an immune response. Preparing it requires growing large quantities of the organism, Clostridium tetani, so components of the bacterial medium are involved in the production process. This is relevant, because some of the problems this anti-tetanus-vaccine article mentioned were anaphylactic shock from the vaccine, and cited several case studies to demonstrate this.^1-4

So is anaphylaxis a real risk of the tetanus shot? Let's look at the data.

These four studies pretty much all say the same thing, with slight variations. The first, by Parish and Oakley, is a case report of a person who experienced an anaphylactic reaction after the second in the two-shot series of tetanus toxoid, though she hadn't reacted at all to the first injection, or to previous injections of diphtheria toxoid, typhoid, or Staphylococcus toxoid. It didn't seem too serious and she didn't have any breathing problems, but they gave her some adrenaline and the symptoms mostly went away. Everything was better after two days. This person was the only one to experience such a reaction out of 300 others that received the series from the authors.

The second study, by Whittingham, discusses how toxoid is a much safer way to prevent tetanus than the other option at the time, antitoxin serum, because 10-15% of subjects got something called serum sickness (an immune reaction to the serum, not as serious as anaphylaxis, though some got anaphylaxis too). And immunity was better from toxoid. But he reports that, out of more than 61,000 soldiers who got the tetanus toxoid series, 651 (about 1%) had local reactions, 14 (0.023%) had headache and body pains and such lasting up to 8 hours, and 2 (0.0033%) had anaphylaxis. So anaphylaxis occurred in 1 out of 30000. These two cases were fine after adrenaline injections.

The third study, by Cooke, Hamptom, Sherman, and Stull, was another case report of a reaction soon after the second injection of toxoid: the patient had hives, itching, and swelling, but was fine after epinephrine injection.

The fourth, by Cunningham, was a report of a nurse who had had a reaction to a diphtheria toxoid before: hives and malaise. This person had a reaction 3 weeks after the 1st tetanus injection, so it wasn't clear that it was connected at all; she was playing tennis and got hives and irritation. Adrenaline solved it. The second injection was given, along with some adrenaline, and the patient had more problems, but recovered after 24 hours. The author recommends keeping patients under observation for 30 minutes after injection.

So it seems that reactions happened, but didn't seem serious and were pretty rare, based on these studies.

"Anaphylactic reactions following tetanus toxoid injection have also been reported in the medical literature. Fortunately, sensitivity reactions to tetanus toxoid are very rare."⁵

"Systemic anaphylaxis has been reported following administration of tetanus toxoid also, but this is extremely rare."⁶

Relevant Component Removed
The other thing that all these studies talk about is that when the patients mentioned were tested for allergy to components of the vaccine, they all showed reactions to a particular component of the bacterial medium, a kind of peptone (digestion of protein). So it's this component that seemed to be the culprit. Fortunately, it seems that since these reports, steps have been taken to remove this component from production, thus greatly reducing the risk of anaphylaxis:

"From data collected early in the program, it appeared that the proportion of reactions of sensitivity following the injection of these toxoids was at least six times that following the use of toxoids free from these particular peptones.
"As a result of these findings, the procurement and distribution of tetanus toxoid containing Witte or Berna peptones were discontinued. As indicated above, the incidence of reactions of sensitivity has fallen sharply since that time."⁷

"The production of tetanus toxin on a medium free from peptone has been accomplished with one strain of Cl. tetani. As good, or somewhat better, toxin titers have been obtained as this strain repeatedly yields on peptone-infusion media."⁸

"Employed on a tremendous scale for military immunization, its initial preparation on the traditional media containing Witte's peptone has had to be modified because of the presence, in that brand of peptone, at any rate, of a substance inducing severe anaphylaxis in certain individuals. Other varieties of peptone are still considered admissible, largely because no serious accidents have thus far been reported following their use."⁹

"A formula is given for large-scale production of tetanal toxin on a medium initially free from antigenic components."¹⁰

"This observation, considered in the light of the experience of Cooke and Whittingham and associates with the sensitizing properties of Witte's and Berna's peptones in toxoids, led to cessation of the use of toxoids containing these peptones with a resultant much lower rate of reactions to tetanus toxoid. In the early immunization toxoids of these types had been used for about 75% of the injections reported and were responsible for 90% of the sensitivity reactions observed."¹¹

"It should be noted, however, that such proteoses were eliminated from all toxoids by 1942."¹²

So overall, the reaction was rare to begin with, but much rarer after the chief offending component was removed. The original article I mentioned did talk about the peptones, but didn't mention how rare the reaction was to begin with (or how easily treated), and didn't mention that the peptones were removed from vaccines in the future. So I have corrected this misinformation.

Note that this is not a thorough review of the subject; there are other reports of reactions like this, some of which are probably more serious than these four, but I haven't gotten to those reports yet, except insofar as they address these four.

References:

1. Parish, H. J. & Oakley, C. L. Anaphylaxis after Injection of Tetanus Toxoid. Br Med J 1, 294–295 (1940). 

2. Whittingham, H. E. Anaphylaxis following Administration of Tetanus Toxoid. Br Med J 1, 292–293 (1940). 

3. Cooke, R. A., Hampton, S., Sherman, W. B. & Stull, A. Allergy induced by immunization with tetanus toxoid. JAMA 114, 1854–1858 (1940). 

4. Cunningham, A. A. Anaphylaxis after Injection of Tetanus Toxoid. Br Med J 2, 522–523 (1940). 

5. Buff, B. Fatal anaphylactic shock: Following intradermal skin test with dilute horse serum tetanus antitoxin. JAMA 174, 1200–1201 (1960).
6. Vessal, S. & Kravis, L. P. Immunologic Mechanisms Responsible for Adverse Reactions to Routine Immunizations in Children. Clin Pediatr 15, 688–696 (1976).
7. Long, A. P. Tetanus Toxoid, Its Use in the United States Army. Am J Public Health Nations Health 33, 53–57 (1943). 

8. Mueller, J. H., Schoenbach, E. B., Jezukawicz, J. J. & Miller, P. A. Production of Tetanus Toxin on Peptone-Free Media. J Clin Invest 22, 315–318 (1943). 

9. Mueller, J. H., Seidman, L. R. & Miller, P. A. A Comparison of Antigenicities of Hydrolysate and Peptone Tetanus Toxoids in the Guinea Pig. J Clin Invest 22, 321–324 (1943). 

10. Mueller, J. H. & Miller, P. A. Large-Scale Production of Tetanal Toxin on a Peptone-Free Medium. J Immunol 47, 15–22 (1943). 

11. Moursund, C. & Hirschmann, C. Telangiectasia macularis eruptiva perstans: Review of the literature, report of a case and discussion of the etiology and pathology of generalized telangiectasia. AMA Arch Derm Syphilol 63, 232–249 (1951). 

12. Tetanus Toxoid Wound Booster Interval Recommendations, Serum Sickness After Tetanus Toxoid Injection. JAMA 220, 136–137 (1972).

O843 - The Rôle of the Vaccination Dressing in the Production of Postvaccinal Tetanus

(First, a note: apparently the word "role" has sometimes been spelled with a hat over the "o"; this is a sign of its French derivation. It surprised me too when I first saw it.)

In my ongoing quests for finding things that might be wrong with vaccines that people aren't talking about, I encountered this article. I don't think it quite qualifies, but I'm mentioning it for the sake of completeness.

The article, by Charles Armstrong, dealt with an issue with smallpox vaccination: sometimes tetanus occurred after the vaccination, because the bacteria that cause tetanus, Clostridium tetani, had been introduced to the wound and had multiplied there, producing their toxin. So Armstrong wanted to figure out when and why this happened in some cases and not others, in order to prevent it from happening.

He examined 116 cases of postvaccinal tetanus, and figured out that what they had in common was that the vaccination site had some sort of dressing wrapped around it. It didn't really matter what kind of dressing, just some kind of tight wrapping of the area. This agreed with studies in animals that showed something similar. So the US Public Health Service recommended against wrapping the area, and cases of postvaccinal tetanus dropped from a consistent 30 per year to less than 13.

Armstrong looked into why the dressing might cause this problem. It didn't seem to be related to keeping air away from the wound, because a good number of dressings he saw in cases did allow airflow. It also didn't seem to be an issue of contamination of the vaccination material, since no tetanus could be detected in it with animal studies. But it seemed like the problem was that the dressing was tight enough to cause some swelling, and held all the dead tissue in place on the site, so stuff could start growing under it.

So Armstrong recommended that, instead of putting a dressing on the site, just cover it with a loose sleeve of material; this can move back and forth over the area, wiping away any moisture and dead material that might appear, keeping the area clean and dry.

So it sounds like the issue was for the most part resolved nearly 100 years ago, and presumably only got better since then. But I will be sure to look into any relevant papers I encounter in the future.

Reference:

Armstrong, C. The Rôle of the Vaccination Dressing in the Production of Postvaccinal Tetanus. Public Health Reports (1896-1970) 44, 1871–1884 (1929).

084 - A study in active immunization against pertussis

In the early 20th century, lots of people were working on developing a vaccine against whooping cough. Makes sense, because it was one of the biggest causes of death in young children. But arguably two of the most important of these researchers were Pearl Kendrick and Grace Eldering.

I've done a couple posts about studies by them before (072 and 079); the former of those was a progress report, and this post is the full report on the first large pertussis vaccine trial that they undertook in Grand Rapids, Michigan.¹

The study started in late 1933 and went for 44 months, following thousands of subjects. Soon after the progress report came out, another study (actually another progress report) came out that seemed to have negative results for pertussis vaccination (065), which motivated Kendrick and Eldering to be extra-careful in their own final report.

It was a pretty big effort, not just these two; many nurses and public health workers in Michigan were involved, though supervised by the authors. It took place in Grand Rapids, as I mentioned, and the final count involved 1,815 subjects in the vaccinated group and 2,397 unvaccinated controls. These were children with no history of whooping cough (so, presumably susceptible) that lived nearby and could be followed over the course of the study.

Not all of them remained in the study for the whole 44 months, of course, because once they actually caught pertussis, they were presumably not susceptible anymore. Or if they moved away or something. Or if they grew out of (or into) the age range, which was 8 months old to 5 years old. But the results were corrected for how long each was followed.

The groups were selected by families presenting themselves at clinics to receive the vaccine. These were the vaccinated subjects; others were selected from the same districts as controls. So it wasn't randomized or blinded at all, which is a limitation. Kendrick and Eldering recognized this, and took special care to try to make the groups as equivalent as possible:

-The average time they were part of the study was 15 months for vaccinated, 11.6 months for controls. This was corrected for though, and could be due to some of the controls getting vaccinated and thus being removed from the study, which is something that couldn't happen to those already vaccinated. The proportions that moved away weren't significantly different.
-The proportion of each sex in each group wasn't significantly different.
-The proportions of ages weren't significantly different.
-The proportions in each district of the city weren't significantly different.
-The proportions of family sizes weren't significantly different.
-The proportions of each group getting measles and scarlet fever were equivalent, so it didn't seem like either was healthier or less exposed than the other.
-The average interval between nurse visits for each group was the same.
So overall, the groups seemed equivalent, at least in these characteristics.

As mentioned in 072, the vaccine was made of freshly isolated and lab-cultured bacteria, killed with phenol and/or merthiolate (AKA thimerosal) in small amounts. It was produced continuously on small scales, so none of it got older than about a year. It was injected under the skin of the arms.

In terms of reactions, most of the ones they observed were local—soreness, etc.—and only slight otherwise. One report of the 1815 was of convulsions, and 2 had high fever and vomiting, though it is only correlative because there wasn't a placebo control. Mostly it seemed ok.

Finally, a word on diagnosis and severity ratings: diagnoses were made based on cough plates (that is, culturing the organism), clinical symptoms, and history of exposure. Severity was rated somewhat arbitrarily, based on frequency of whooping and vomiting or the occurrence of complications/weight loss.

Results
The results were corrected for amount of time each subject was participating in the study, and how many subjects there were in each group, so they're reported as annual attacks per 100 subjects. So with that in mind, the incidence of whooping cough overall was:
2.3 annual attacks per 100 vaccinated subjects
vs.
15.1 annual attacks per 100 controls.
This is a significant difference, which could be expected to occur by random chance only once if they repeated the trial millions of times.

Compared to other reports of the rates of pertussis in Grand Rapids, the control group followed the same up-and-down trends, but had a higher incidence, probably because the closer observation detected cases that would've gone undetected otherwise, due to low severity. And speaking of severity:

Even of the vaccinated subjects that did get whooping cough, the severity was much lower. 73% were rated as light or very light severity, compared to 27% in the controls. And only 4% were severe in the vaccinated, and these didn't have serious complications, only frequent coughing/vomiting; that's compared to 13% severe in the controls. And considering that the "very light" cases were questionable about whether they could even be considered cases at all, by removing them from both groups, the difference in incidence increases even more.

Kendrick and Eldering also looked specifically at their data on known exposures of subjects to the disease, and found similar patterns. The vaccinated group actually had a higher number of exposures than the controls, but many fewer cases from them. Calculating the number of cases expected (based on the cases in the controls and the exposures in the vaccinated), it appears that the vaccine prevented about 81.3% of cases in the test subjects. Not excellent, but pretty good.

The differences were not as big when the exposures were more intimate, like within a household. The attack rates were about 35% vaccinated vs. 90% controls. Still, that's significant protection.

Another thing they controlled when watching exposures was coughs that weren't diagnosed as pertussis, of which there were more in the vaccinated group. These were mild, taking place right around an exposure incident, and could be classified as slightly less than "Very light" whooping cough. So if they added these coughs to the numbers, incidences overall would be 24% vaccinated vs. 72% controls, which means only 67% protection. Which is still pretty good, especially considering that these extra cases are barely cases at all.

So overall, this study is very good compared to others at the time or before, though not quite good judging by modern standards: not randomized, not placebo-controlled, though more controlled than it could've been. And the protection seemed pretty good, though arguably it would be better to have higher complete protection rather than just reducing the severity of cases.
It isn't a study that looked at the duration of immunity, or whether it reduced transmission at all (thus providing herd immunity), or if the vaccine was safe, especially in the long run, or if it could be effective in more than just this population. But what it does look at is how well it protects young children over at least a few years after it's given.

Oh, and it's not funded by any pharmaceutical company.

It's hard to make any judgments overall, so I'll just cite some comments from later publications that cited this one, both positive and negative:

"There is ample evidence in the literature now that individuals inoculated with suitable doses of a proper vaccine have a high degree of immunity against whooping cough."²

"The Sargent-Merrell method of evaluating the success of an immunization program has been applied to data covering a 6-year period in the city of Grand Rapids...the proportion of cases prevented is 84%. The validity of the result has been verified on the basis of controlled field data."³

"The controversy dates back to the first trials of pertussis vaccines, which were carried out during the 1930s. These were criticized as biased in favor of the vaccines because they were not randomized; vaccinated volunteers were compared with unvaccinated 'nonvolunteers.'"⁴

"Methodologically, the original field trial design was flawed. The experimental group was self-selected and only control subjects were randomly chosen. Despite careful attention paid to case detection and diagnosis, 1603 observations from the study's early years had to be excluded from the final analysis. Several featuers of the trial nonetheless make it an important contribution, not simply to the development of an effective pertussis vaccine, but to the history of controlled trials: ... 2) The trial was unusual for the level of attention given to case diagnosis and follow-up, and to the discussion of unknown factors which might have biased the results; 3) a similar level of detail was given in reporting the analysis and the methodological limitations of the field trial"⁶

Also, if you want a really detailed historical account of this study and everything that went into it, before and after, check out Shapiro-Shapin 2007.⁵

References:

1.

Kendrick, P. & Eldering, G. A study in active immunization against pertussis. Am. J. Hyg. 29, 133–153 (1939).

2.

Cohen, P. & Scadron, S. J. The placental transmission of protective antibodies against whooping cough: By inoculation of the pregnant mother. JAMA 121, 656–662 (1943).

3.

Weiss, E. S. & Kendrick, P. L. The Effectiveness of Pertussis Vaccine: An Application of Sargent and Merrell’s Method of Measurement. Am. J. Epidemiol. 38, 306–309 (1943).

4.

Fine, P. E. M. & Clarkson, J. A. Reflections on the Efficacy of Pertussis Vaccines. Reviews of Infectious Diseases 9, 866–883 (1987).

5.

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).

6.

Marks, H. M. The Kendrick-Eldering-(Frost) pertussis vaccine field trial. J R Soc Med 100, 242–247 (2007).

074 - Influenza: Further Experiments on the Active Immunization of Mice

Andrewes and Smith were some of the researchers working on creating a flu vaccine, especially since people had discovered that influenza was caused by a virus, not bacteria.

The vaccine they were developing was made from infected mouse lungs, and mice were the model animal they focused on mostly, especially in this study. Mouse lungs produced a lot of virus, but it wasn't the cleanest, so what they were attempting in this study was to produce a cleaner version.

Actually there were three main goals:
1) Try to get as much virus as possible,
So less volume is needed for the same dose

2) Purify the virus as much as possible without reducing its immunizing ability,
So there aren't contaminants that could cause unnecessary reactions

3) and if possible, inactivate the virus (so it can't infect) without reducing its immunizing ability.
So that it can't possibly infect and cause disease.

For objective 1, they tried filtering the virus with membranes that the viruses were too large to pass through, but that didn't really seem to help. At some point though, their virus densities increased 10 to 100 times spontaneously, maybe through some mutation, so that worked out.

For objective 2, they wanted to remove mouse proteins from the preparation, so they tried adsorption/elution, in which they could stick the virus to something and wash everything else off, but they lost a lot of virus with this method too so it wasn't great. Filtering seemed to help though.

For objective 3, they tried inactivating the virus with formaldehyde. A solution of 0.01% could inactivate almost completely in 5 days at -2°C, and 0.02% could completely. This inactivated virus couldn't infect mice when put into their nose.

Immunization Experiments
Then they tested these preps in mice, to see which gave the best immunity against flu virus challenge. What they found was that washed live virus immunized about as well as unpurified virus (when inoculated into the skin or body cavity), and inactivated virus seemed almost as good, though it seemed like the dose they gave of this was higher than the dose of live. Even 0.1% formaldehyde-inactivated gave good immunity. Virus-free filtrate didn't help at all, so the antigen is not soluble.

They did find that virus that had been washed and then inactivated (or the reverse) didn't have much immunizing power in mice. That was unfortunate.

The immunity from each vaccine seemed to fade in mice after 6 weeks. However, this was similar to how long mice had immunity when they had gotten sick with the flu and recovered, so the vaccine was as long-lasting as natural immunity (especially considering that most of the infected mice died from the disease).

Preliminary Human Trial
Finally, they tested inactivated virus in a few human volunteers. They didn't want to use live virus, considering how others had seen what seemed like flu outbreaks from live virus vaccines (049). So 5 volunteers got washed and inactivated virus, and two more got inactivated unwashed virus. They also added 0.01% merthiolate (thimerosal) to prevent bacterial contamination just in case.

The first two had some pain, maybe from excess formaldehyde, so for the others Andrewes and Smith changed the pH to convert the formaldehyde to something else, which worked better. They didn't see any serious reactions to any version, though the ones getting unpurified virus had more tenderness (possibly sensitivity to mouse proteins).

What they saw was that in all but one volunteer, levels of antibodies against the virus rose after the first dose (not much after the second dose for some reason). This was heartening, especially with the washed+inactivated virus that hadn't worked well in mice. Even better, the levels seemed higher than in other people who had recently recovered from the flu! (Though I'm not sure the flu the people had would be the same antigenically as the virus used in this study.) And the levels still seemed high after 2.5 months. So they might be on the way to a good flu vaccine, but they weren't sure yet if antibody levels correlated well with immunity. More work to be done.

Citation: Andrewes, C. H. & Smith, W. Influenza: Further Experiments on the Active Immunization of Mice. Br J Exp Pathol 18, 43–55 (1937).

073 - Vaccination Against Acute Anterior Poliomyelitis

I've talked about John A. Kolmer and his polio vaccine before (047, 048, and 063), but I wanted to touch on it once more.¹

Kolmer's vaccine was a "live" but partially inactivated virus. He took infected monkey spinal cords, treated them with sodium ricinoleate, added some phenyl-mercuri-nitrate as a preservative to prevent bacterial contamination, and injected them subcutaneously. These things should prevent infectivity in humans, he thought. And it seemed to work well in monkeys, though it could still paralyze if injected into the brain. The reason he wanted it partially "alive" was that he thought completely inactivated virus was unable to immunize, for some reason.

By this point, more than 12,000 people had received Kolmer's vaccine. None seemed to have severe reactions, like encephalomyelitis, though some that received the version without preservative had abscesses temporarily.

However, there were 10 cases Kolmer knew of in which the subject seemed to get sick with polio soon after receiving the vaccine (soon meaning 1-6 days later). Usually it was after the second dose, never after the third, but five of the 10 (50%) actually died from their illness, from paralysis.

In this paper, Kolmer thought it unlikely that the polio had come from his vaccine, considering the many that received the same lot without getting sick, and how no one receiving all three doses got sick. However, he was unable to explain where the virus had come from for some of the cases, since there wasn't an outbreak in their areas. It was a mystery.

It seems like later, though, he does conclude that the vaccine is not safe enough to use in people, especially because he hadn't been able to establish its efficacy in preventing any disease.

"It was my hope that this strain of virus had lost infectivity for human beings by reason of its long adaptation to the monkey, and especially after treatment with sodium ricinoleate and when given by subcutaneous injection, but the occurrence of nine cases of poliomyelitis among 10,725 individuals given the vaccine in 1935 has indicated that the virus apparently possesses infectivity for human beings and that this vaccine as well as the formalized vaccine of Park and Brodie is too dangerous for use."²

So, I'm not sure whether it was the correct decision or not, but that's why we don't use Kolmer's vaccine these days.

References:
1. Kolmer, J. A. Vaccination Against Acute Anterior Poliomyelitis. Am J Public Health Nations Health 26, 126–135 (1936).
2. Kolmer, J. A. The Present Status of Methods for the Prophylaxis of Acute Anterior Poliomyelitis. Ann Intern Med 12, 95–105 (1938).

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).

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).

066 - Neurologic Complications Following the Administration of Vaccines and Serums: Report of a Case of Peripheral Paralysis Following the Injection of Typhoid Vaccine

NOTE TO READERS: Unfortunately, my free time this summer is very limited, so I won't be able to update VoT as frequently as I have been. I'll try to continue working on it as time permits though. It should pick back up in August.

So, now on to today's paper. It starts off with a case report (basically a well-documented anecdote) of a man who suffered a minor temporary nerve disorder after receiving a vaccine against typhoid. The man was admitted to a hospital with some problems of epilepsy, probably from alcoholism. While there, he was given the vaccine, as protection from hospital-acquired disease, I guess. Staff and patients there routinely received the vaccine with no problems.

At first there was no problem with this man, but then four days after getting the second dose, he had "foot drop." I guess this meant he wasn't able to move his foot as much as he should've been able to. They couldn't find any infection or anything, and tried treating it with different ways, but a month later it was still the same. After 3 and a half months though, it was almost completely recovered.

So the man's doctors diagnosed this as vaccine-induced peripheral paralysis. It seems a little post hoc, but no other explanation presented itself.

Then Robinson discusses nerve problems relating to vaccines and different kinds of serum in general. It seems like besides the rabies and smallpox vaccines, it's mostly sera that cause problems, which makes sense because I think at this time they were animal-derived (and thus liable to cause sensitivity reactions perhaps). But still somewhat a problem.

People weren't sure what caused the problems, though they had some suggestions: some kind of toxin, possible disruption of nerves somehow, or a contaminating pathogen like a virus. Robinson suggests that a virus would also be a problem in other kinds of injections, but it doesn't seem to be. And he adds one possibility: the preservatives used in these products.

Many of these products, and many of those producing them, used phenol-based preservatives, like phenol or tricresol, or others. Obviously preventing growth of bacteria in injectable products is a good thing, but some studies seemed to show similar serious nervous symptoms after injection with phenol-related compounds. Some seemed safer than others, though studies weren't entirely clear. So Robinson suggests recording whether each product contained a preservative when reporting this kind of side effect.

He concludes thusly:

"There is no way of knowing what patients may be unexpectedly affected by this unusual complication. The physician should not be held responsible for its occurrence, and the possibility of its happening is not a contraindication to the intended injection."

My conclusions: Not really sure. Doesn't seem especially relevant to the question of vaccine safety today, but worth paying attention in the future.

Citation: Robinson, L. J. Neurologic Complications Following the Administration of Vaccines and Serums: Report of a Case of Peripheral Paralysis Following the Injection of Typhoid Vaccine. New England Journal of Medicine 216, 831–837 (1937).

065 - Active Immunization Against Whooping Cough: Interim Report of the Cleveland Experience

Apparently there was a lot of interest in a vaccine against whooping cough around this time. Makes sense; it sounded pretty serious. People had recently discovered that when growing the pertussis bacteria in the lab, they started off with smooth-looking colonies that were virulent, which over time sometimes got more rough and less harmful. Some graded these from Phase I (smoothest, most virulent) to Phase IV (roughest, least virulent). Sauer and others thought the Phase I would make the best vaccine.

Studying vaccines of pertussis was tricky: the way the vaccine was made could influence things, obviously (as this study itself seems to show), and diagnosing the disease could be uncertain, and they weren’t even sure if having the bacteria in your body was even enough to make you sick; some might have the bacteria and not be sick, though there seemed to be some evidence against that idea.

Based on previous experience, James Doull, Gerald Shibley, and Joseph McClelland decided that a study of 200-300 children in each group (vaccinated and unvaccinated) could detect a difference in pertussis cases decently. But just to be safe, they decided to go with a higher number, around 500 per group.¹

They recruited these children at health stations in Cleveland that gave out free milk. The requirements were that the children must not have had pertussis before, and needed to have an older sibling who also had not had pertussis (to increase the likelihood of exposure), and had to be between 6-15 months old.

They started out planning to give every other child the vaccine they made, but a lot of parents refused to let their children be vaccinated, so they ended up counting some refusers as controls instead. So there ended up being 483 vaccinated (most with all three doses, a few with only one or two), 247 selected as controls, and 249 that refused. So almost 1000 total.

The vaccine was made with 5 recently isolated (and thus smooth and virulent) strains of bacteria, grown on agar, scraped off, washed with distilled water, and suspended in saline with 0.5% phenol. Standardized doses were given once a week for three weeks, subcutaneously in the buttocks. Sounds like fun.

They noticed some reactions to it, but not many. Some had a slight fever on the same day, or a local reaction lasting up to 3 days. It was claimed that 3 had convulsions, one of which was observed by a nurse.

After inoculation, the authors kept tabs on their subjects, sometimes sending someone to check on the families. If any reported a case, an epidemiologist or pediatrician obtained records and tests to confirm.

The distribution of race and sex in the groups seemed pretty even, though there might’ve been more white people refusing the vaccine than minorities. The age distribution was fairly even though too.

Ok, results: not great. 61 out of 483 vaccinated got whooping cough, or 12.6%. Of those not vaccinated, either from randomness or refusal, 71 of 496 (14.3%) got whooping cough. So at most, the vaccine was 11.6% effective, or prevented the disease in 11.6% of those who would’ve gotten it. Pretty awful.

They did mention that some thought the vaccinated cases might’ve been milder, but it seemed like a rather subjective judgment:

"The opinion of physicians who have seen representative attacks in both groups is that those in the inoculated have been milder. This is a difficult question to settle. There has been only 1 death, and that in a control child."

Overall, seems like pretty clear negative results. It wasn’t a great study (no placebo, no blinding, not even very good randomization), but usually one expects those problems to give more positive results, not less positive. So it’s somewhat interesting, considering the positive results others had observed with similar vaccines around that time.

Some people in later articles had some ideas about what the difference might be:

"In three field studies...favorable results were reported. In another very thorough study [this one] in which the method of preparation of vaccine was slightly different unequivocal evidence of immunization was not obtained."²

"The Cleveland vaccine [this study] was also a Phase I vaccine [freshly isolated organisms] containing 10 billion organisms per ml., but in its preparation the organisms had been washed once with distilled water, while the Michigan vaccine [showing a positive result] had been washed once with saline."³

"These varying estimates of vaccine performance had at least two possible explanations. They might have reflected either differing manufacturing processes, or variations in the methodological rigour of the studies."⁴

"In his pertussis studies, Doull relied on alternation, which in his view was sufficient to prevent bias in selecting which children would receive the vaccine. However, the actual allocations departed from this 'ideal' somewhat: in one recruiting location, Doull used children whose parents refused inoculation as the controls, while at a later point in the study, he assigned the vaccine in a 2:1 ratio, with every third child serving as a control."⁵

Citations:

1.  Doull, J. A., Shibley, G. S. & McClelland, J. E. Active Immunization Against Whooping Cough: Interim Report of the Cleveland Experience. Am J Public Health Nations Health 26, 1097 (1936).

2.  Singer-Brooks, C. & Miller, J. J. The Opsono-Cytophagic Test in Children with Pertussis and in Children Vaccinated with H. pertussis Antigens. J Clin Invest 16, 749–761 (1937).

3.  Perkins, J. E., Stebbins, E. L., Silverman, H. F., Lembcke, P. A. & Blum, B. M. Field Study of the Prophylactic Value of Pertussis Vaccine. Am J Public Health Nations Health 32, 63–72 (1942).

4.  Jefferson, T. Why the MRC randomized trials of whooping cough (pertussis) vaccines remain important more than half a century after they were done. J R Soc Med 100, 343–345 (2007).

5.  Marks, H. M. James Angus Doull and the well-controlled common cold. J R Soc Med 101, 517–519 (2008).

064 - Prophylactic pertussis immunization

Today's study is another test of whooping cough vaccines. Sauer's was the popular one at this time, showing 92% efficacy in some studies, but a Lucy Mishulow had created one that used a stock strain of pertussis instead of needing to isolate a new one with every outbreak, as the Sauer version called for. Also, it could be grown on animal blood instead of human blood. This made it more potentially useful.

So Eli Shorr selected preschool children with known histories of illness to vaccine or keep as controls. He tried to divide families up evenly between vaccinated and controls, to make things as equivalent as possible. Half the subjects attended the same nursery school.

They compared different methods of inoculation: intramuscular, intracutaneous, and subcutaneous. After, they looked at levels of agglutinins in the blood as a measure of antibody response.

In order to compare, they gave a few children the Sauer vaccine, and some of the controls got an injection of sterile diluted milk as a placebo.

They found that about 36% of the subjects were definitely exposed to pertussis over the next 30 months; probably more that they didn't notice. 16% of those receiving Mishulow's vaccine got pertussis, 10 out of 63, though 6 of the 10 were very mild cases (no whooping even), and also 6 of the 10 got sick within the period Sauer thought might be too soon for immunity to develop, and 4 of them had smaller doses of vaccine too. So it might be said that only 10% of well-vaccinated subjects got sick.

With the Sauer vaccine, 1 of 11 (9%) got sick, but that one had gotten a low dose too.

Whereas with controls, 26 of 72 (36%) got pertussis. Big difference. And they weren't even observed for as long a period.

In terms of inoculation route, intracutaneous was abandoned early because it was difficult to give an adequate dose and reactions to it were overly severe. Reactions to the other routes were never severe; most just had slight tenderness, some had redness or a low fever for a day or two.

The antibody measurements were as expected, pretty high soon after vaccination but none or very low in unvaccinated group. Levels fell after 2-3 months, but it wasn't clear if that meant immunity went away or anything.

So overall, it seemed like Mishulow's vaccine was pretty good, but it was too small a study to compare to Sauer's very well. Googling "Lucy Mishulow" doesn't bring up many results, so I wonder if the vaccine turned out badly somehow, such that this vaccine researcher got mostly lost to the sands of time somehow. Maybe I'll find out later.

Citation: Shorr, E. Y. Prophylactic pertussis immunization. The Journal of Pediatrics 9, 49–55 (1936).

062 - Virus—antivirus mixtures in smallpox vaccination

Immunization against smallpox using vaccinia or cowpox virus was not always a harmless procedure (though of course better than getting smallpox itself!): it often produced an unsightly scar at the inoculation site, and sometimes at other sites; a general reaction could be problematic, especially in infants; and at worst, post-vaccinal encephalitis.

So people were trying to find a safer way of doing it. One way that seemed successful in animal studies was mixing the vaccinia virus with serum containing anti-vaccinia antibodies and inoculating that. Similar to how people vaccinated against diphtheria toxin using mixtures of toxin and antitoxin antibodies. Some found that such antibodies could prevent potent vaccinia from producing generalized lesions in rabbits, without reducing immunity too much, and others found that completely neutralized virus could still induce immunity when introduced nasally.

So Frisch wanted to find out if this could work in human children, and how. So he took two groups of children, 39 in one and 47 in the other, and immunized them using mixtures of virus and antibody-containing serum, in various proportions between 3:1 and 1:20 virus:serum. The first group got serum from children that had been vaccinated 5 years before, and the second from children vaccinated only 4 weeks before. After a while, he revaccinated some of them with pure virus to see if they seemed immune to it.

In the first inoculation, the virus mixed with 5-year serum seemed much more potent than that in 4-week serum, causing typical vaccinia reactions in almost everyone getting a mix of as low as 11% virus. That mixed with 4-week serum didn't consistently cause reactions unless the ratio was 3:1 virus to serum.

Did either of these induce immunity despite lack of reaction? The answer seemed to be no; most of the revaccinated children showed a typical vaccinia infection, unless they had received enough undilute virus to cause a reaction the first time. And waiting up to 9 months for immunity to develop didn't seem to change anything.

So antibodies against vaccinia seem to inhibit all its effects, both reactions and immunity. Too bad. Well, even if the children had shown immunity, I'm not sure how much it would mean, since it'd be immunity to vaccinia rather than to smallpox, though there would probably be at least some overlap.

The other interesting thing is that it showed that levels of antibodies from vaccination did decrease over 5 years, so that the serum was less potent in neutralizing the virus. Did this mean the 5-year serum donors were no longer immune? Can't tell from this study: it might not take very much to protect against infection. It just shows their levels were relatively lower than the others, not necessarily inadequate.

Citation: Frisch, I. A. Virus—antivirus mixtures in smallpox vaccination. Am J Dis Child 49, 894–899 (1935).

059 - Small-Pox and Vaccination in the Light of Modern Knowledge

In this post, James McIntosh reviews some things about smallpox and vaccination against it.

Smallpox has been known to humanity since the 10th century, and to Europe since the 16th. People confused it with measles at first, and so thought it fairly mild, until it killed some royalty. Mostly it was only fatal in children (not that that's a good thing); 90% of deaths in epidemics were in children under 5. Mortality in people who caught it was typically 30-50%, which is very high for an infectious disease. And virulence seemed to be increasing through the 18th century, so people were excited about immunization.

Somewhat later, virulence seemed to shift toward older people and decrease over all, probably because of immunization, but also because another variety of the disease seemed to appear: called alastrim, or variola minor, the disease it causes is much milder than the original, even though they are almost histologically and serologically indistinguishable. Alastrim doesn't seem to make vaccination impossible (which it might if it induced an adequate immune response itself), but vaccination does prevent alastrim. But it did not replace smallpox, which still caused epidemics just as serious as before.

Regarding smallpox itself, McIntosh was uncertain whether Edward Jenner's original virus was really cowpox (vaccinia) or was rather an infection of cows with smallpox. I haven't read anything so far that does make a clear distinction between these possibilities. But in either case, it seemed safer than the practice at the time, which was called variolation: inoculating people with a little smallpox, which would cause disease but not as much as if they caught the disease unintentionally, and would induce good immunity. That practice sometimes didn't work out well, as you might expect.

So when Jenner's vaccination (from vaccinia) came along, the practice spread widely because it was safer and milder but just as good immunity-wise. Not completely safe though, as I mentioned before (040): post-vaccinal encephalitis was a serious side effect from vaccination, in which the immune system seemed to attack the nervous system, often causing paralysis and/or death. The incidence of this was 1 in 3555 recipients, or 1 in 31531 in children under 2, which isn't very many, but a lot more than would be preferable. McIntosh had some suggestions for avoiding this, but none he was very certain about: treating cases with serum from vaccinated people, maybe, or preventing it entirely by weakening the virus before vaccinating; this latter had the risk that it might be too weak to induce a good immune response. McIntosh thought it should be possible to standardize and minimize the dose as much as possible to let the body respond to it before it spread too much. I wonder how successful any attempts at that might have been.

Citation: Mcintosh, J. Small-Pox and Vaccination in the Light of Modern Knowledge. The Lancet 215, 618–621 (1930).

057 - The Progress of Work on Calmette's BCG Vaccine

The Lancet published an editorial in 1931 summarizing the different opinions about Calmette's BCG vaccine against tuberculosis. TB is a serious disease, so having a vaccine would be great, but not everyone agreed that the BCG was that great.

Calmette and those who supported him claimed the BCG was safe and effective. According to Calmette, 336,000 children in France and >1 million worldwide had been given the BCG over 5 years, and this had reduced mortalities from TB from 15.9% to 3.4% in children under 5. Even Calmette recognized that the BCG didn't provide permanent immunity, but he thought it was good enough to get children through the period of life where risk from TB is highest, in the early years.

Additionally, BCG supporters claimed that these bacteria, though still alive when used in vaccines, were safe and innocuous. They could produce lesions, sure, but no serious cases of tuberculosis. Many did animal studies that agreed with this claim.

On the other hand, many other medical practitioners and researchers found the claims more questionable. According to studies in cattle, guinea pigs, and monkeys, the BCG didn't seem that reliable in terms of safety or efficacy. Some of them thought they found animals dead from TB after inoculating with BCG, and some thought the BCG bacteria might increase in their virulence (ability to cause disease) after being grown in animals for long enough. And even previous studies on this blog found that Calmette's recommendations (feeding newborns BCG) didn't seem to work well, at least in animals (056).

So health professionals in Britain set up a special investigation of BCG, with not-great results. They decided that Calmette's good results could've been due to fallacies and biases and inadequate controls; for example, without blinding and placebo, it's possible that receiving the vaccine could've correlated with better care of the children in general, maybe because only cautious parents volunteered for the study or something. So hard to conclude anything. Also, some animal studies seemed to say it wasn't good, while others that it was.

Also there was a tragedy around this time in Lübeck, Germany. Many infants, 251, received BCG vaccine from the Pasteur Institute, but 67 of these soon died from tuberculosis. It turned out that what probably happened was some virulent Mycobacterium tuberculosis had been mixed with the BCG by accident. It was an awful thing that stresses the need for quality control. But it was interesting to see how different people interpreted it in different ways: some that BCG should not be used because of a risk of this kind of thing happening with any live attenuated vaccine (which makes some sense; if you don't have a good way to distinguish between strains, you can't test for contamination); and others (including Calmette) that this just shows that BCG was safe, because it was the fault of some contaminant, not the BCG itself.

But nevertheless, the Britain committee decided at this point that the BCG was still in the experimental phase, not ready for widespread use.

Citation: The Progress of Work on Calmette’s BCG Vaccine. The Lancet 218, 259–261 (1931).

053 - Minor Points in Diphtheria Immunisation

Previously on the Diphtheria Vaccine Show (or whatever), we saw that toxoid (or inactivated diphtheria toxin) had good potential for immunizing safely, since an immune response against the toxin effectively prevents serious disease. People had been using mixtures of toxin with antitoxin antibodies, but this was risky, so inactivating the toxin just enough that it didn't cause disease but still induced an immune response was better. Also, something called the Moloney test, in which a small amount of toxoid was put under a patient's skin, could detect if an individual was likely to have a severe reaction to toxoid immunization. If so, they could receive a modified dose or something safer, such as a mixture of toxoid and antitoxin serum.

So the current study by H.A. Raeburn examined this question somewhat. He compared results of Schick and Moloney tests for a number of patients. Recall that the Schick test, in which a small amount of intact toxin was placed just under the skin, to see how a patient reacted, was a measure of the patient's immunity: if there was a very positive reaction, the patient was not immune (because they couldn't neutralize the toxin), and if negative, the patient was immune. The Moloney test seemed rather opposite: a positive reaction showed immunity, because the patient's immune system was overreacting to it and causing the reaction. But there was a lot of overlap between the tests, so worth doing both.

Giving a full dose of straight toxoid to a sensitive individual could cause very unpleasant reactions, including headache, vomiting, fever, and overall illness for three days, though recovery was likely I think. So the Moloney test was important, and effective, for avoiding such reactions.

However, mixing toxoid with antitoxin was not risk-free either, since the antitoxin serum often came from horses, so there were other components in it that could induce an immune response. So a person injected more than once with horse serum often developed serum sensitivity, kind of like an allergy probably. And since some diseases at that time, such as scarlet fever, could be treated best only with serum, using up a person's chance at risk-free serum treatment on diphtheria immunization wasn't always the best idea. That is to say, a person could usually count on one serum treatment being okay, the next being more risky, the third even worse, etc. So if possible, it was good to avoid using serum in combination with diphtheria toxoid, because then if the person later needed serum to treat scarlet fever or something, the risk of negative reaction was lower.

Raeburn did a small experiment to test this hypothesis, that toxoid-antitoxin led to higher toxin sensitivity. He tested the serum sensitivity of a number of subjects (using similar methods as with the Schick and Moloney tests), then immunized them either with straight toxoid or toxoid-antitoxin mix, and then tested their serum sensitivity again. Sure enough, more of those immunized with a toxoid-antitoxin mix exhibited serum sensitivity afterwards.

Finally, the best part of this study! Most of the papers I've read about diphtheria toxoid immunization have been focused on whether it could turn Schick-positive (non-immune) patients into Schick-negative (immune); that is, could it effectively induce an immune response? Which is important, but I haven't seen where people correlated this test status to actual immunity by doing epidemiology with diphtheria epidemics or anything like that. Maybe toxoid makes people Schick-negative but for some reason doesn't actually make them immune! Who knows?

But in this study, Raeburn actually does report the effects of a diphtheria outbreak in an immunized population. There were 120 subjects in some sort of house (maybe a hospital or prison or orphanage, it doesn't say), all immunized with toxoid. And there was an outbreak of tonsillitis going around, showing that it was possible and likely that all the subjects were exposed to contagious diseases that spread by droplets through the air, the way diphtheria spreads. But among these 120 vaccinated subjects, only two of them came down with the disease.

This isn't super-great data, since there's no control group, so we have no idea just from this how many we would've expected to catch diphtheria if none of them had been immunized. It seems likely that it'd be more than two, and there's probably some other data from the time period to give some idea, but I don't know where it is. So I'll be on the lookout for better studies in the future.

Citation: Raeburn, H. A. Minor Points in Diphtheria Immunisation. The Lancet 230, 621–623 (1937).

048 - Poliomyelitis Following Vaccination Against This Disease

This one is pretty short, but important. And closely related to the previous two posts (046 and 047). In this short article, J.P. Leake of the U.S. Public Health Service lists twelve cases of paralytic polio in children, but not just any polio.¹

As you may recall from the previous posts, there were a couple of experimental polio vaccines being tested around this time, and more than 11,000 people had received them. Brodie’s was allegedly completely inactivated, and Kolmer’s was still alive, but chemically attenuated enough that it rarely caused problems in monkeys. But when it is uncertain whether a given person will ever encounter the virus, let alone have a serious reaction to it (such as paralysis or death), any vaccine must be extremely safe in order to be worth giving to the whole population.

Brodie and Kolmer claimed their vaccines were so safe, but Leake presents evidence to the contrary (though without naming names). His report of 12 cases come from children aged 5 months up to 20 years. Six of these children died from their polio, and at least four were still paralyzed at the time of this study. And more importantly, they all came down with symptoms one to two weeks after receiving a dose of experimental vaccine.

By itself, this wouldn’t mean much, since they could’ve been exposed to the virus soon before (or soon after) receiving the vaccine, such that they came down with symptoms before immunity set in. But in these cases, they weren’t in areas where polio epidemics were happening, and they hadn’t been exposed to people from known epidemic areas. Even worse, their paralysis tended to begin in the same area of the spine where they had received the dose of the vaccine (which in itself was pretty interesting, as it implied that the virus travels through nerves rather than other bodily networks).

So it seems like these unfortunate children were infected by an improperly-prepared product. As Leake concludes:

"Although any one of these cases may have been entirely unconnected with the vaccine, the implication of the series as a whole is clear."¹

Of the studies that cite this paper, almost none disagree with its conclusion, though a few try to propose an alternative explanation (that the vaccine interfered with an immune response to an already-ongoing polio infection, for example). But a couple reviews summarize the history well:

"The Kolmer vaccine was known to contain a small amount of live virus capable of infecting monkeys, but it was presumed to be safe for humans on the basis of the unproved assumption that serial passage in monkeys had reduced its pathogenicity for man. This vaccine was clearly implicated as the cause of a number of cases of poliomyelitis. The Brodie vaccine, believed to be completely inactivated, was also suspected of causing several cases of poliomyelitis, but the evidence is much less convincing. At a meeting of the American Public Health Association in November 1935, reports were given on both vaccines. During the discussion of these reports, both vaccines were roundly condemned, particularly by Rivers of the Rockefeller Foundation and by Leake of the U.S. Public Health Service. Shortly thereafter, Leake published a list of vaccine-associated cases, and the vaccines were withdrawn from use."²

"Undaunted, Brodie fooled himself and convinced Park that the vaccine was safe, attempting to prove it by inoculating himself, Park, and a few laboratory technicians, after he had done a group of monkeys. He presented and published papers, invoking Park's name and cajoling him to serve as cosponsor. The Brodie-Park vaccine was thereby launched and the press began to take notice. Their enthusiastic coverage of events aroused the hopes of parents and physicians anxious to believe that protection from the crippling scourge might at last be at hand.

"Meanwhile, a competitor, John A. Kolmer of Philadelpha, called a press conference to announce that he had successfully tested a vaccine, different from Brodie's in that the virus in his vaccine was "live but devitalized," the attenuation achieved by the addition of sodium ricinoleate. In addition, Kolmer's vaccine was carried one step further, having been tested not only in monkeys and on himself and his two children but also on 22 other children. Reporters asked Park whether his vaccine also was ready for human use. Brodie had assured him it was and that tests on children were planned. The press whipped up the rivalry to the point where newspapers carried frequent progress reports resulting in antics in which each tried to outdo the other.

"The pressure of public expectation, the lack of restraint, and poor judgment soon forced both Brodie and Kolmer to undertake the inoculation of several thousand children under the poorest of circumstances for such an experiemnt. The experiment resulted in at least 12 vaccine-associated cases and six deaths. Another tragic incident, another immediacy, and the U.S. Public Health Service stepped in, ordering that both of these vaccines be withdrawn and destroyed. With this were sown the seeds for the stringent legal requirements for vaccine safety and efficacy which were to sprout some years in the future."³

 Citations:

1. Leake, J. P. Poliomyelitis Following Vaccination Against This Disease. Cal West Med 44, 141–142 (1936).

2. Meier, P. Safety Testing of Poliomyelitis Vaccine. Science 125, 1067–1071 (1957).

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