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).

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).

054 - The Effect of Hemophilus influenzae suis Vaccines on Swine Influenza

Richard Shope and others already knew that it was possible to vaccinate against influenza using the influenza virus, in animals at least (049). But an important part of typical swine influenza was an infection with bacteria called H. influenzae suis, which often caused a secondary infectious pneumonia that could be fatal. Immunizing with this bacterium intranasally doesn't prevent the flu, but it seems to help when combined with the virus. It seemed like the bacteria needed help from the virus to get into the body and infect. So Shope wanted to know if it would help on its own when inoculated intramuscularly, into muscle.

So he took H. influenzae suis (henceforth "H.suis" for ease of typing) cultures, killed some of them with heat, and kept the rest alive as a live vaccine. He inoculated 8 pigs with the former, heat-killed ones, and 6 with the live, 3 injections each. He didn't see any side effects from the killed vaccine, but the live consistently caused a fever after the second injection.

After a week or two, Shope tested their immunity with flu virus plus bacteria. He observed them for a few days, and then killed and autopsied them.

All of them got the regular, virus-caused flu, of course. Of those that received the killed vaccine, only one seemed completely protected from the bacterial infection, with no H.suis found anywhere in its body. Another two had bacteria only in their upper respiratory tract, not their lungs, and the remaining 4 had bacteria in the lungs, but their pneumonia was not as severe as that of the 3 unvaccinated control pigs.

The live results were a big weirder. The 6 pigs got very sick when infected with flu, but recovered remarkably after only a day and then had no more than mild illness, compared to controls that had typical flu. All the pigs had bacteria in their respiratory tract, but only one had them in the lungs.

Shope also tested the antibodies in the pigs' serum before infecting them, and none of them had inactivating antibodies against flu or bacteria. Which doesn't necessarily mean they weren't immune.

So in conclusion, intramuscular H.suis, either killed or live, seems to affect the course of the flu but doesn't prevent it. The live seems slightly better at protecting after the initial severe reaction, but the reaction does make it seem less appealing, so it's not clear which is better.

Shope speculates that the severe reaction could be due to an allergic-type reaction to H.suis naturally in the lungs being quickly cleared out, but it's not clear why the killed vaccine wouldn't induce this also.

And he says that this study is just interesting, not practically very useful because there's already a virus-based vaccine that can prevent the whole flu, not just the bacterial part. This is not quite true, as we know, because H. influenzae in humans was a common cause of secondary pneumonia after the flu, so a vaccine against it is quite useful, especially because even today our flu virus vaccine is not super-great enough to depend on.

Citation: Shope, R. E. The Effect of Hemophilus influenzae suis Vaccines on Swine Influenza. J Exp Med 66, 169–175 (1937).

O469 - Advances in Vaccine Therapy

This isn't a full post, but I really liked this quote (whole section, really) from a review written by Alexander Fleming (who you'll recall is credited with discovering penicillin, not that it's particularly relevant here).

"The question whether or not an individual can be protected against epidemic influenza by means of a vaccine is one which is of the greatest importance in medical practice. This question leads to another, What is epidemic influenza? Before the great war we were quite content to think that it was infection by the influenza bacillus of Pfeiffer, and there is no doubt that in the 1918-19 pandemic this bacillus was present in practically 100 per cent of cases in England and France, and that it was responsible for much of the mortality. However, more recent work, especially at the Medical Research Council laboratires, has definitely established that the primary infective agent in epidemic influenza is a virus. This virus can be passed on in ferrets and mice, and can be cultivated in the incubator in chicken embryos still in the shell. It appears likely that mild influenza, such as the first wave of 1918 or the more recent epidemics, is to all intents and purposes a pure infection of the virus and that the serious and deadly epidemic of 1918-19 was due to a combination of this virus with a bacterium, especially the influenza bacillus.

"A very interesting influenza story comes from America. During and following the 1918 pandemic an epidemic of swine influenza appeared among the pigs in that country. This swine influenza is a serious and fatal disease, and has been investigated by Shope (1937) [054] more thoroughly than was possible in any human disease. Shope discovered that swine influenza was due to a combined infection with a virus and a bacillus practically identical with the influenza bacillus of Pfeiffer. If he infected pigs with a pure virus without the bacillus a transient fever resulted and all the pigs recovered; if he infected them with the bacillus alone practically nothing happened; but if he infected pigs with both the virus and the bacillus typical swine influenza resulted and the pigs died with pneumonia. Shope found that the pigs which had been given the pure virus and had recovered from the trifling infection that resulted were completely immune to fresh infection with the virus. He also found that inoculation of the pigs with vaccines made from the influenza bacillus gave some degree of protection against swine influenza, although it was not so complete as the protection with the virus.

"Here it will be seen that all the animals receiving the vaccine of the influenza bacillus suffered from a much milder disease than the controls, which had not been protected. This observation is of the greatest interest in view of the attempts made to prevent influenza in man with bacterial vaccines, especially those of the influenza bacillus. After the 1918 pandemic many papers appeared stating that such vaccines had conferred a degree of protection against influenza, but none of the figures given have satisfied statisticians. In view, however, of Shope's experimental results with pigs it appears that these claims were justified and that protection can be obtained by such bacterial vaccines.

"Attempts are at present being made to protect man against influenza by means of a vaccine of the influenza virus. The results on experimental animals have been successful, but the opportunity has not yet arisen for the final proof that it can protect man during an epidemic. It seems likely that in the near future it will be possible to obtain a virus vaccine which will give, either alone or in combination with the older bacterial vaccine, complete protection against epidemic influenza in the majority of the inoculated individuals."

Citation: Fleming, A. Advances in Vaccine Therapy. Br Med J 2, 99–104 (1939).

047 - An Improved Method of Preparing the Kolmer Poliomyelitis Vaccine

Now for another attempt at a polio vaccine: first there was Brodie’s (046), and now Kolmer’s.¹ It is prepared from monkey spinal cords infected with the virus, but the virus is attenuated with glycerin and sodium ricinoleate (a fatty acid from castor oil that has some antimicrobial activity), which reduces its infectivity enough to make it relatively safe but good for immunizing.

But this method isn’t good for keeping bacteria from growing in the preparation, so this study looks into potential preservatives that could keep bacterial contamination down without reducing the effectiveness. The candidates were formalin (diluted formaldehyde), phenol, mercurophen, merthiolate (aka thiomersal or thimerosal) and phenyl-mercuri-nitrate.

John Kolmer tested some vaccine intentionally contaminated with a few different kinds of Gram-positive or Gram-negative bacteria (Staphylococcus aureus, Escherichia coli, Bacillus subtilis, etc), to see what concentrations of those chemicals would work. He found that phenyl-mercuri-nitrate (PMN) worked at the lowest concentrations for all of them, followed by the other mercury-containing compounds, then formalin, then phenol. E. coli was more resistant than Gram-positives. So PMN seemed best.

Then Kolmer tried making vaccines the normal way except with these preservatives at twice the minimum killing concentration, to see if they damaged the immunizing ability of the virus. He tested this by injecting rhesus monkeys and then infecting them with polio, six monkeys for each compound plus six with no preservative and four with no vaccine at all, just virus. He also tried three different doses in each group.

Results:

• The non-immune monkeys all became paralyzed within 7-8 days.
• None of them got sick from the vaccine alone.
• The preservative-free vaccine was the most effective, protecting four of the six monkeys completely, though the lowest-dose recipients got paralyzed after 11-14 days.
• PMN was second-best, with 3 of them completely protected. The others were paralyzed after 8-21 days.
• The worst was formalin, which was pretty much useless even at the highest dose; all monkeys were paralyzed after 7-8 days.
• The others were intermediate.

So Kolmer decided to start using PMN as a preservative. He also found that it didn’t cause any extra reactions in the monkeys; with or without, there were only slight local reactions. Actually it was better, because there was less chance of a bacterial infection from the injection.

The other thing he did was test his vaccine preparations for the presence of something called lymphocytic choriomeningitis virus, which others had found could be present in the monkeys, and could cause problems in humans injected with monkey spinal cords. The way to test for this was to inject some vaccine into mice and guinea pigs, in which the LCV also causes problems (makes sense since apparently it’s primarily a rodent virus anyway). But he didn’t see any sign of its presence in his vaccines.

So this all sounds pretty promising, though those preservatives do sound intimidating and would be harmful in large amounts at least. But apparently this vaccine was not a good one, as history bears out: 

"In the United States during 1935, cases of poliomyelitis followed the use of two experimental vaccines, developed by Kolmer and Brodie, respectively. These preparations were subsequently withdrawn from human use.
"Kolmer explicitly states that the virus was not killed, and his papers document the highly paralytogenic activity of the vaccine when given to monkeys by the intracerebral route. Subcutaneous injection of vaccine paralyzed 3 of 124 monkeys, while untreated virus brought down 1 of 20 animals by this route."²

 "None of these necessarily implies provocation linked to virus contained in the vaccine. The vaccine contained three components which could have provoked: 4% monkey spinal cord, 1% sodium ricinoleate, and 1:80,000 phenyl-mercuri-nitrate and in addition, some batches were contaminated with bacteria."³

So it’s not surprising we don’t use this version of the vaccine today either.

Citations:

1. Kolmer, J. A. An Improved Method of Preparing the Kolmer Poliomyelitis Vaccine. Am J Public Health Nations Health 26, 149–157 (1936).

2. Nathanson, N. & Langmuir, A. D. The Cutter Incident: Poliomyelitis Following Formaldehyde-Inactivated Poliovirus Vaccination in the United States During the Spring of 1955: I. Background. American Journal of Hygiene 78, 16–28 (1963).

3. Wyatt, H. V. Provocation poliomyelitis: neglected clinical observations from 1914 to 1950. Bull Hist Med 55, 543–557 (1981).

041 - The Protection Afforded by Vaccination Against Secondary Invaders During Colds in Infancy

Compared to the previous post, this story is nice and simple and straightforward, and positive.

Previous studies had tried to prevent the common cold, sometimes in combination with other respiratory infections (026 and 031). Obviously these attempts didn't work (especially since they contained only bacteria, and colds are viral infections), though they helped with pneumonia sometimes.

With this in mind, Yale Kneeland, Jr. observed that in the fall, respiratory infections were usually mild and viral (common colds), but that later in the winter, there were more and more complications and secondary infections with dangerous bacteria, causing pneumonia, fevers, etc. And if vaccines couldn't prevent the colds themselves, maybe they could reduce the severity of the illness overall?

A previous study in Norway, in which 500 infants were vaccinated against bacteria and 500 were not, showed a 5-fold reduction in fevers and a smaller number of serious complications of colds.

So Kneeland enrolled 46 infants, averaging half a year old, in the Home for Hebrew Infants in New York City, 23 as controls and 23 to receive vaccinations. The vaccines consisted of three species of pathogen: pneumococcus, hemolytic streptococcus (the kinds that caused scarlet fever, rheumatic fever, and some other things), and Haemophilus influenzae, which causes pneumonia. These bacteria were all grown up, killed (with heat and phenol), and injected whole.

There were two courses of weekly injections for the vaccinated group: the first in October, 9 injections, and the second the following February, 7 injections. Seems like way more than would be acceptable these days. Three of the subjects had fevers in February, so they missed much of the second course of injections. They were still included in the study though.

In terms of side effects, they were mild. Larger doses of vaccine caused local redness and such, but there were no fevers or anything more serious.

So now, the results: first, the two groups of subjects were no different in terms of the mild "common cold" infections they experienced. Which makes sense.

The real difference was in the number of days each group suffered a fever of more than 100°. Here is the graph from the paper:

Chart 1, Kneeland, 1934

Not much difference between groups until after the first course of vaccinations, but then the control group had many more days than the vaccinated (3 times more in January, almost 2 times more in February). Pretty striking.

The actual number of infections per subject was not much different: 5.4 in vaccinated vs. 5.8 in controls. But the severity was the big difference. The controls had 5 cases of pneumonia and the vaccinated only 2 (one of which started early in the first course of injections, probably before immunity had taken effect).

Overall, these are good results, but there are a number of problems. First, the number of subjects and infections are pretty small, so it's difficult to make good comparisons. There didn't seem to be any placebo for the controls, or any blinding, or much indication that the two groups were matched very well. Also, the number of injections is pretty high and the benefit not super great (2-3 days of high fever per infant in a given month? Seems like there's room for improvement. Also, the immunity from the first course seemed to drop after only a few months). Not quite ready for prime time, but seems like a step in the right direction.

Citation: Kneeland, Y. The Protection Afforded by Vaccination Against Secondary Invaders During Colds in Infancy. J Exp Med 60, 655–660 (1934).

027 - Experimental Studies of the Nasopharyngeal Secretions from Influenza Patients X. the Immunizing Effects in Rabbits of Subcutaneous Injections of Killed Cultures of Bacterium pneumosintes

This study,¹ and those accompanying it (parts I-IX) seemed like a particularly exciting step forward in the understanding of influenza. Published about 4 years after the worst known epidemic of flu in history (1918 Spanish flu), people were understandably keen on discovering the cause and ways to prevent this disease.

Previous research had suggested bacterial pathogens as the culprit, such as Pfeiffer's bacillus (aka Bacillus influenzae, later named Haemophilus influenzae) or others, but these could not be reliably found in flu patients, nor did serum from patients always contain antibodies against the bacteria. Vaccines made from them (such as in 019 or 026) didn't reliably protect against the flu, though they may have helped with secondary pneumonia infections. It didn't help that research during the 1918 epidemic was mostly rushed and sloppy.

But then, four years later, two researchers at the Rockefeller Institute for Medical Research made an important discovery about influenza.

Experimenting on nasal washings from patients from the 1918 epidemic, they found that the disease could be transmitted to rabbits effectively, but no bacteria need be consistently present in the washings for the transmission to occur.² In addition, the washings could be filtered through a filter small enough to remove all known bacteria, and the resulting filtered product could still cause disease.³ This showed that the infectious agent was something smaller than known bacteria, but still capable of replication and spreading to new hosts.

These researchers isolated a tiny rod-shaped organism, often small enough to fit through the filter, that they could grow in the lab; they named it Bacterium pneumosintes.⁴ Unfortunately, many other researchers could not replicate the results of Olitsky and Gates,^5-7 though B. pneumosintes was later found to be a bacterial inhabitant of the human mouth and renamed Dialister pneumosintes,8,9 but the true agent of influenza was not discovered until the 1930s.

However, Olitsky and Gates went ahead and tried making a vaccine using this organism they discovered. They grew up two strains of it, one isolated from a patient in 1918 and one from a patient in a flu epidemic in 1922, killed these cultures with heat, and injected them into rabbits. The rabbits tolerated the vaccines pretty well, having some redness and swelling after the second of three doses.

When challenged with infectious bacteria, the results were as follows: two vaccinated rabbits and two controls were challenged with samples from rabbits previously infected with B. pneumosintes from previous experiments. The two controls got sick, while the two vaccinated did not.

Then another 17 vaccinated rabbits and 17 controls were challenged with cultures of B. pneumosintes, and 15 of the vaccinated rabbits did not get sick while the others did. So 88% effective. The two vaccinated rabbits that did get sick, and 10 of the ones that didn't, were also challenged with bacteria that cause secondary infections in flu patients (pneumococcus, Streptococcus haemolyticus, etc), and the 10 that didn't get sick were also protected against infection with these organisms, while the 2 that did were not, and succumbed.

So this shows, perhaps, that B. pneumosintes is indeed a pathogen, in rabbits at least, and a vaccine made from it protects rabbits from infection with it. Too bad it's not actually influenza.

Citations:
1. Olitsky, P. K. & Gates, F. L. Experimental Studies of the Nasopharyngeal Secretions from Influenza Patients X. the Immunizing Effects in Rabbits of Subcutaneous Injections of Killed Cultures of Bacterium pneumosintes. J Exp Med 36, 685–696 (1922).
2. Olitsky, P. K. & Gates, F. L. J Exp Med. 1921 January 31; 33(2): 125–145.
3. Olitsky, P. K. & Gates, F. L. J Exp Med. 1921 February 28; 33(3): 361-372.
4. Olitsky, P. K. & Gates, F. L. Experimental Studies of the Nasopharyngeal Secretions from Influenza Patients IV. Anaerobic Cultivation. J Exp Med 33, 713 (1921).
5. Andrewes, C. H., Laidlaw, P. P. & Smith, W. Influenza: Observations on the Recovery of Virus from Man and on the Antibody Content of Human Sera. Br J Exp Pathol 16, 566–582 (1935).
6. Garrod, L. P. Filter-Passing Anaerobes in the Upper Respiratory Tract. Br J Exp Pathol 9, 155–160.1 (1928).
7. Wilson, G. S. An Attempt to Isolate Bacterium pneumosintes from Patients Suffering from Influenza. The Lancet 209, 1123–1124 (1927).
8. Willems, A. & Collins, M. D. Phylogenetic Placement of Dialister pneumosintes (formerly Bacteroides pneumosintes) within the Sporomusa Subbranch of the Clostridium Subphylum of the Gram-Positive Bacteria. Int J Syst Bacteriol 45, 403–405 (1995).
9. Ghayoumi, N., Chen, C. & Slots, J. Dialister pneumosintes, a new putative periodontal pathogen. Journal of Periodontal Research 37, 75–78 (2002).

020 and 021 - Results of Prophylactic Vaccination Against Pneumonia at Camp Wheeler

In terms of time, people, and purpose, this post is a continuation of 017: published a year later, performed by at least one of the same authors, and as a follow-up to the previous. Also subject to many of the same comments and criticisms.

So, the Cecil & Vaughan article is the study itself, and the other is basically a review of it with some policy recommendations. While 017 took place in Camp Upton, NY, this took place at Camp Wheeler, Georgia. This camp had been having serious trouble with pneumonia, and 34% of it was from pneumococcus types I-III, against which Cecil & Co could vaccinate. And they did.

The vaccine in the previous study was a suspension of killed bacteria in salt solution, which seemed to cause more irritation and side effects than the authors felt it should, so in this study they tried to improve it by instead suspending the bacteria in vegetable oil. Apparently others had good results with this method, decreasing the dose volume and number of injections while maintaining good immune response, with lower irritation to the recipient.

So Cecil and Vaughan gave this vaccine to a total of about 13460 men in the camp, leaving 3415 unvaccinated. It did seem to be less mild, with only 37 out of 100,000 recipients suffering the strange infiltrations that were common with the saline vaccine (1214 of 100,000). Only 7 in 1000 men had to stay in the hospital for a few days, and 77% of these had received another bacterial vaccine at the same time as the pneumococcal one. Still, this seemed more severe than it needed to be.

Now the results. I'm going to share the graph they put in the paper, since I can:

This shows that the vaccination rate rose over time (as they vaccinated more of the troops), and partway through they got a surge of new recruits. Then there was a spike of pneumonia in the unvaccinated troops, but much less in the vaccinated.

Here are graphs I made, similar to those in 017 except without a breakdown of different causative agents:

There were many fewer cases of both pneumococcus and overall pneumonia. Actual numbers were 42 of types I-III in the 3415 unvaccinated troops, vs. 8 in the 13460 vaccinated (actually there were 32 cases, but 24 of those happened within a week after vaccination, and work by another author showed that immunity is not present until 8 days after vaccination, so those were excluded).

Overall, for all types of pneumonia, there were 327 cases in 3415 unvaccinated, and 155 in 13460 vaccinated.

Death rates are proportionally similar:

Numbers for types I-III are 1 in 13460 vaccinated vs. 14 in 3415 unvaccinated.

This study was complicated by a few things, though, which make the results more difficult to interpret. Most importantly, the 1918 flu pandemic arrived about the middle of this study, making the risk of secondary pneumonia much greater. Second, the number of men in the camp was changing, with new recruits (more susceptible to pneumonia) coming in and other troops leaving, so it was difficult to say how much effect vaccination had on each group. Still, the populations did seem decently equivalent.

And so, like in 017, it's difficult to explain why the vaccinated troops seemed to be well-protected even from types of pneumonia against which they weren't vaccinated. The authors speculate there could be cross-protection, providing some protection against multiple different pathogens, but it is not clear. And again, how long the protection against pneumococcus might last after vaccination was not determined, so it might not be very long. So again, medium quality (relative to other studies I've written about so far, at least).

Russell Cecil seems to agree, acknowledging that his pneumococcus vaccine was not good enough for a population-wide vaccination effort (because of its limited cross-protection, still-too-unpleasant side effects, and the fact that pneumonia doesn't really cause awful outbreaks like smallpox did). But he did recommend it for certain high-risk populations, such as soldiers, miners, people in institutions, and those individuals that seemed especially susceptible. But I believe there is more improvement to be made.

Citations:
Cecil, R. L. Present Status of Pneumococcus Vaccine. Am J Public Health (N Y) 9, 589–592 (1919).

Cecil, R. L. & Vaughan, H. F. Results of Prophylactic Vaccination Against Pneumonia at Camp Wheeler. J Exp Med 29, 457–483 (1919).

019 - The Use of a Vaccine in the recent Epidemic of Influenza

Another interesting thing that was going on in 1918 is something you might have heard of: the worst influenza pandemic in recorded history, sometimes called Spanish flu, which killed up to 100 million people (~5% of the world’s population) in all parts of the world.³

It doesn't seem like the influenza virus had been discovered at the time, not until the 30s, but it did seem like health officials at the time understood that the nature of the disease was not bacterial. Nevertheless, they recognized that a bacterial respiratory infection and pneumonia often accompanied cases of influenza, and that such an infection was responsible for much of the mortality associated with flu.

So today’s study describes the arrival of 1918 flu in Winnipeg, Canada in October of 1918, and the attempt to create a vaccine against the bacteria that caused secondary pneumonia in patients.¹

After swabbing and sampling more than 100 cases, they determined which bacteria seemed most closely associated with the disease: some kinds of streptococcus, pneumococcus, and something called “Bacillus influenzae.” So they made a vaccine in the typical way at the time: grow these up, kill them with tricresol and heat, and inject people.

Then they inoculated soldiers in Winnipeg, 4842 of the 7600 present, leaving 2578 unvaccinated.

Of the vaccinated, about 6% were hospitalized with flu, 0.35% got pneumonia, and 0.1% died. Though of the 5 deaths, 3 had only been vaccinated after being admitted to the hospital, and the other two had been vaccinated 3 or 10 days before, so it might've been too late for them anyway.

Of the unvaccinated, about 9% were hospitalized with flu, 1.5% got pneumonia, and 0.62% died. The average hospital stay of the unvaccinated was twice as long as the vaccinated, and the captain of the soldiers said it seemed like the unvaccinated had more severe cases.

So that’s a 33% reduction in flu, 77% reduction in pneumonia, and 84% (or probably more) reduction in deaths from vaccination.

It seemed like the populations were mostly equivalent in exposure, except for some of the flu cases being from troops coming in on trains, rather than being in the camp, so that complicates things a bit.

Then there was another experiment, this time with civilians: 52,999 were vaccinated and another 85,941 not. About half who were received one dose, while the rest received two.

Number of doses didn’t affect number of flu cases much (9.7% for 2 vs. 9.8% for 1), but pneumonia cases decreased 18% and deaths 57%. Not super impressive.

But compared to unvaccinated, there seemed to be up to 61% reduction in flu cases, 77% in pneumonia, and 86% in deaths. And of doctors surveyed, 93% said the vaccine seemed to have an effect, and 86% said it seemed to help prevent fatalities in pregnant women. However, precautions were not taken to make sure these populations were equivalent, and the types of bacteria infecting people seemed to vary between different places and/or times, so it’s not a very good study overall.

"Contemporary medical opinion generally agreed that while the right vaccine would be invaluable, it probably had not been found yet...the consensus was that vaccine should only be used on an experimental basis, its results being unknown and perhaps dangerous."²

References:

1. Cadham, F. T. The Use of a Vaccine in the recent Epidemic of Influenza. Can. Med. Assoc. J. 9, 519–527 (1919).

2. McGinnis, J. P. D. The Impact of Epidemic Influenza: Canada, 1918-1919. Hist. Pap. 12, 120 (1977).

3. Wikipedia.

006 - Vaccine and Vaccination:--Observations and Bacteriological Investigations

This was another paper concerned with the success rate of vaccination. The author is concerned with refining the material used to vaccinate so that it is as pure as possible; that is, free from foreign and unnecessary entities. At that time, people were developing the field of microbiology, enough that they had named some of the bacteria they had discovered (some of which retain the same names today).

Unfortunately, they hadn't figured out what the microbe responsible for vaccination was. They thought it might be a kind of coccus, but this wasn't consistently associated with vaccine material. (Makes sense; they hadn't yet realized there were infectious particles even smaller than bacteria.)

However, they did know enough to realize that there could be contamination of the material with pathogens, and the author recommends trying to avoid this.

He reports a study he did with a group of vaccination patients, in which some of them washed the spot to be vaccinated and others did not. Those that washed had lower rates of excessive swelling, only 14% compared to 32% of those that did not wash. Makes sense.

Most importantly, the author speculates that, at least in some cases, ignorant vaccinators mistook the signs of a bacterial infection for the signs that the vaccination was working (i.e. vaccine disease), and so they thought a patient had been effectively vaccinated when actually they were just infected with bacteria. Then when smallpox came along, of course they weren't protected. Hard to know how much of an effect that might have had, but it seems plausible.

Citation: Paquin, P. Vaccine and Vaccination:--Observations and Bacteriological Investigations. Public Health Pap Rep 17, 171–179 (1891).