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).

068 - Fatality Rates of Small-Pox in the Vaccinated and Unvaccinated

This is more a series of studies than a single one, all with the same title. A sort of discussion between physicians, regarding the value of vaccination against smallpox.

It started with a letter in the British Medical Journal from R.P. Garrow, which presented some data over 4 years of deaths from smallpox in Britain, comparing vaccinated and unvaccinated cases.¹ As Garrow says, it should be expected (assuming vaccination is helpful) that there be more deaths among unvaccinated than among vaccinated, but in these data the case-fatality rates (proportion of people with the disease who died from it) was higher among the vaccinated, 30 in 10000 vs. 6 in 10000. The number of cases of smallpox is higher in the unvaccinated (almost 7000 vs. 4000 in vaccinated), but we don’t know what proportion of these populations these numbers represent. All these cases are in subjects over 15 years old. Garrow remarks that the cause of death may sometimes be questionable, and this might explain the discrepancy, but he’s not sure.

This letter is followed by another collection of letters from other physicians, in the same journal.² First, Dr. Percy Stocks tries to explain the strange data by pointing out that the age distributions of the two groups are pretty different. Check out the number of cases:

It appears there are a lot more cases in unvaccinated in general, though again the proportion is unknown, but most of the cases are in the young, decreasing with age. Compared with this is the vaccinated population, where the median age seems to be around 40-50 years. Similar results are seen with the number of deaths from smallpox by agegroup:

 This seems to indicate a limited duration of immunity from vaccination, such that those vaccinated as children are no longer as well-protected as they used to be, and thus get sick again in old age. And the number of deaths in any group is so small that it’s hard to compare the groups.

Dr. Fred Wynne repeats the explanation of waning immunity in his letter, though I’m not sure why this makes everything okay. He also admonishes Dr. Garrow for giving support to antivaccinationist arguments, which apparently was a problem even then.

Dr. C. Killick Millard points out that smallpox comes in two forms: variola major, the serious, deadly form, and variola minor (AKA alastrim), which is much milder. Cases of the latter are much more common, but Dr. Garrow didn’t distinguish between the two, so it’s hard to say what exactly is going on. Thousands of minor cases with a few major ones just makes for a complicated situation.

Finally, L.A. Parry comes in with a bunch more questions, about how supposedly less vaccination means fewer deaths and cases from smallpox, etc, without providing reference to any such data, prompting the BMJ editor to admonish Parry for introducing “assumptions of fact into framework of his questions.”

I tried to figure out who this Parry guy is, but everything else he published (judging by titles, at least) didn’t seem that different from what I would expect from a typical medical doctor. Weird.

In the third letter, this one in the Lancet, Dr. Duncan Forbes provides more data from the early 1900s in Britain.³ This data is purely serious smallpox, variola major, as far as he knew, excluding all variola minor. The number of cases was much smaller, about 500 total, but the case-fatality rates are very different. For the unvaccinated, 19.2% who caught the disease died (10 of 52), vs. 1.9% of the well-vaccinated (more than one vaccination scar) (7 of 362). In between were those who were said to be vaccinated but had no scar, or had only one scar: with no scars, the rate was 17.1%; with one scar, 10.8% (combined 13%). From this, Dr. Forbes points out the importance of good vaccination.

Finally, Stallybrass wrote to the Lancet to point out differences in smallpox between northern and southern Britain.⁴ Apparently many people in the north were unvaccinated, and variola minor (the mild kind) was rampant there, but in the south, where most people were vaccinated, variola major occasionally came in from visitors from France or Spain. Stallybrass tracked down all the deaths from smallpox and discovered that among the vaccinated, almost all deaths were in the south in people over 30, whereas almost all deaths in unvaccinated were in the north in people under 15. Overall, case-fatality rates were lower for vaccinated (10 in 10000 compared to 11.2 in 10000), and lower in age groups under 15 and over 30. In the middle, there was just one death in either group, so it’s hard to compare; could be just due to chance.

He also points out that older people may be more susceptible to smallpox, especially the worse version in the south, and indeed most deaths in the vaccinated are in the south in older people. In contrast, even the mild version is dangerous for the very young when unvaccinated.

Summary

It’s tricky to say what’s really going on exactly with these data. What it does show is how a complicated question like this can be confused more and more by a lack of details. It’s all too easy to distort the data to show what you want to show, if you have an agenda, simply by leaving out certain details, like age or geographical distributions.

Citations:

1.  Garrow, R. P. Fatality Rates of Small-Pox in the Vaccinated and Unvaccinated. British Medical Journal 1, 74–74 (1928).

2.  Stocks, P., Wynne, F. E., Millard, C. K. & Parry, L. A. Fatality Rates of Small-Pox in the Vaccinated and Unvaccinated. British Medical Journal 1, 115 (1928).

3.  Forbes, D. Fatality-Rates of Small-Pox in the Vaccinated and Unvaccinated. The Lancet 211, 208 (1928).

4.  Stallybrass, C. O. Fatality-Rates of Small-Pox in the Vaccinated and Unvaccinated. The Lancet 211, 313–314 (1928).

067 - Active immunization of tuberculous children against whooping cough with Sauer's vaccine

It seems to be the age of whooping cough vaccine testing, at least in this blog. This is another.

Given other questionable results (065), though not with Sauer's vaccine exactly, Siegel and Goldberger decided to do a more controlled trial, in the Sea View Hospital for people with tuberculosis. This place had a bunch of children with TB that were kept together by age and sex (after a certain age), with limited contact with the outside world. Since they were monitored and isolated, pertussis would be easier to track among them.

So Siegel and Goldberger got vaccine from Sauer and Eli Lilly, and vaccinated a total of 101 children over 2 years, keeping a second group as controls. They stopped vaccinating when an outbreak of pertussis occurred in the hospital. Sixty-four children in total were exposed over 3.5 months, and there were 27 definite cases of characteristic whooping cough. The staff isolated each child when they started having symptoms of course, but symptoms don't show up until after the child starts being able to spread the bacteria to their playmates. Another 5 children got sick but didn't have the characteristic whoop, so they were counted as probable cases.

At the time of the outbreak, the average age of vaccinated children was 4.2 years, vs. 2.3 years average for controls. This is a big difference, and could affect the results. The groups didn't have significantly different severity of tuberculosis though.

There were only 36 children in the final study, too: 17 vaccinated and 19 controls. The others either had left the hospital, or had certainly or possibly encountered pertussis previously (and thus maybe had some natural immunity). They only considered those with no known history.

So now for results: considering only definite cases, vaccinated did better, 29% (5 of 17) getting sick, vs. controls with 53% (10 of 19). 44% decrease. Not very good at all. Especially when adding in probable cases, which brought the numbers up to 53% vs. 58%.

Most of these cases were mild; there was one moderately severe case among the vaccinated, and four more in the controls. Pertussis didn't seem to aggravate TB in either group. The average durations of whoop and severe period in the vaccinated group were 21 and 2.8 days, vs. 32.5 and 7.5 days in controls. And considering more of the cases in the vaccinated group weren't even certainly whooping cough, it seemed like the disease was less severe in those vaccinated. However, these children were older too, so it's possible the age might've contributed more than the vaccine to this effect.

So these aren't great results for the vaccine, especially considering the lack of blinding or placebo. It's possible some things complicated the results: having tuberculosis may have increased the children's susceptibility, but according to studies of antibodies, they seemed to respond to the vaccine as well as normal children do. Also, being so closely intimate in the hospital setting, there might've been just too heavy an exposure to the pathogen for the vaccine to be adequate. But it seems like if it were a good vaccine, that shouldn't be an issue. So, more work to do perhaps.

Citation: Siegel, M. & Goldberger, E. W. Active immunization of tuberculous children against whooping cough with Sauer’s vaccine. JAMA 109, 1088–1092 (1937).

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).

About Me - Who is this guy anyway?

I'm a PhD student studying microbiology, though not specifically the health-related kind at this point. I don't claim expertise in vaccines or immunology or toxicology or any of that, so I don't want you to accept what I say because of who is saying it; I try to reference my claims well and make it accessible so you can check my work and make sure I get it right.

The reason I started this blog is that I had always thought vaccines were pretty neat, giving people immunity to diseases without having to actually go through the disease process, but some people think this is not a good thing. So I decided to do a thorough investigation of vaccines: their history, safety, and effectiveness, to make sure I have good reasons for what I believe, or change my belief if it turns out I'm wrong. That's how science works. Not that it'll be the final word on the subject for anyone but me, I expect. I started this blog for my own benefit, to try to motivate me to keep up work at this project, but it's public, so if anyone else benefits too, that's great.

Other than that... I like making science interesting to people, especially microbiology, so I have a podcast (BacterioFiles). I like growing my own food (gardening, chickens). I like fermenting my food too (yay microbes!): sauerkraut, pickles, sourdough, kombucha, yogurt... all very tasty, and if there's any health benefit that's good too, though I'm not completely convinced.

So overall... I enjoy nature, health, and science.

Conflicts of interest: I don't work for a vaccine manufacturer and don't have any friends or family who benefit financially from vaccines. I think I may have a few stocks in pharmaceutical companies that were given to me as a child, but I don't know how much they're worth. That's it. But like I said, regardless, don't take my word for anything I say; check my work.

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).

063 - Susceptibility and immunity: In relation to vaccination in acute anterior poliomyelitis

As discussed before, John Kolmer's version of a polio vaccine failed the test of safety (048). But that doesn't mean we can't learn anything from him, especially about polio in general. Keeping in mind that he did have a conflict of interest, being a vaccine inventor.

In this article, he speculated that polio would make a good target for vaccine prevention, because 1) it was scary, killing at least 73 in 1000 victims and even up to 43 in 100 in some epidemics, and paralyzing another 25-45%; 2) those who survived seemed to be immune and have anti-polio antibodies throughout life.

He also noted that, although infants under 1 year old seemed to have temporary immunity transferred from their mothers, this faded over time, such that a large proportion of children under 10 were susceptible to the disease. So they'd be good candidates for a vaccine.

He discusses a bunch of other stuff, especially his own vaccine-making efforts, but nothing that seems particularly important.

Citation: Kolmer, J. A. Susceptibility and immunity: In relation to vaccination in acute anterior poliomyelitis. JAMA 105, 1956–1963 (1935).

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).

061 - Experimental Pertussis

This is a pretty neat study, though it kinda makes me cringe. You’ll see why.

Whooping cough is a respiratory infection caused by the bacterium Bordetella pertussis, though apparently there was a lot of debate about the pathogen (bacteria or virus?) in the first half of last century. This study was designed in part to test that.

The other part was testing whether Louis Sauer’s vaccine made from B. pertussis could protect against the disease (which would be another indication of its bacterial cause). So how did it go?

H. and E.J. Macdonald, a physician husband and nurse wife team, intentionally exposed four healthy brothers aged 6 to 9 years to cultures from a separate whooping cough patient. These boys, it turns out, were their own sons. Now that’s dedication to science!¹

Two of the boys, the 9-year-old and one of the 8-year-old twins, had been vaccinated by Sauer 5 months before, and the other two (8 and 6 years) had not. None had any previous exposure to pertussis.

The team took a cough plate culture from someone with typical whooping cough and grew cultures from it on agar, checking under a microscope to make sure it was a pure culture. Half of the growth on this plate they suspended in saline solution, and then filtered it through a filter with pores small enough to remove bacteria from the solution, presumably leaving only viruses, if there were any. The other half of the growth they suspended in saline without filtering.

To start, they squirted a little of the filtered solution into the boys’ nose and throat, then quarantined them in a rural apartment with their mother (the nurse) for 8 weeks. They didn’t come down with any symptoms within 18 days, long enough for whooping cough to show up, so it didn’t seem to be some virus present in the culture.

So then after the 18 days, the team squirted some of the unfiltered suspension into the boys’ nose and throat. They aimed for about 140 bacteria total per boy. First the vaccinated results: neither of the two vaccinated boys had any symptoms or sign of whooping cough in the whole period of 38 days. Cultures from their throats and such were consistently negative.

On the other hand, the unvaccinated boys started coughing after only 7 days. Cultures were rated as ++++, which seems very positive, even from the beginning. Over the next few weeks, their fever and coughing increased in severity, they started whooping and vomiting food and mucus, stopped eating much, and had headaches. Seems pretty miserable. Then they got better, fortunately.

After recovering, the team tested the antibodies of all four boys, as well as two others each that were known to be immune or non-immune, and found that all were positive except the two known non-immunes.

So what could be concluded from this: as few as 140 cells is enough to cause an infection. B. pertussis is the agent that causes whooping cough. Seven days is the incubation period (at least here). Possibly also that the vaccine works pretty well.

On the other hand, it’s definitely a small sample size (2 patients in each group), and there was no blinding or placebo, but it gave very distinct results in a very controlled situation. All of them were known to have been exposed to enough pathogen to cause disease, and none could’ve been exposed from somewhere else. The populations were pretty matched too: two of the boys were twins, one vaccinated and one not. But one could argue that it’s not good enough.

As a minor question, I’m not even sure why they would’ve thought there would be any virus on the culture plate, unless they thought it were stuck to and replicating along with the bacteria or something…

And finally, the cringe-y part: this seems so unethical based on my understanding of standards for medical research these days, exposing children to a potentially deadly disease, but at least we can benefit somewhat from the results.

Some others agree with me in some ways and make observations:

"In...1933 the Macdonald husband-and-wife team performed an experiment on their four sons, from which they concluded that 'a filter-passing virus plays no role in the etiology of pertussis.' The wife, a nurse, sequestered herself with the boys in a rural apartment for eight weeks...Aside from proving that there are hazards in being born into a physician's family, and that B. pertussis could cause whooping cough, the findings did not really exclude the possibility of a direct or indirect role for viruses in the disease. It would have been a hardy virus to survive through two subcultures on agar medium."² [Though later studies confirm the result.]

"In 1933, Sauer vaccinated 2 of 4 brothers; all 4 brothers were then inoculated in the nose and throat with whooping cough bacillus. The 2 hapless controls (sons of a local physician) developed classic cases of whooping cough while their vaccinated siblings remained healthy."³

The four boys.
Source: National Library of Medicine, and Baker 2000³

Citations:

1. MacDonald, H. & MacDonald, E. J. Experimental Pertussis. The Journal of Infectious Diseases 53, 328–330 (1933).

2. Nelson, J. D. Whooping Cough — Viral or Bacterial Disease? New England Journal of Medicine 283, 428–429 (1970).

3. Baker, J. P. Immunization and the American Way: 4 Childhood Vaccines. American Journal of Public Health 90, 199 (2000).

A Note on Researching Vaccines (or anything else)

A lesson from my own experience: I've been looking at a lot of vaccine-related websites from both sides recently, for this blog and in general. Some provide lists of allegedly research publications that allegedly show some kind of problem with vaccines, some go through all those publications and allege that they are worthless and/or unrelated, and some are the same kinds of lists from the other side (that vaccines are safe and awesome).

And I've found that my feeling of the weight of the evidence depends on which kind of site I'm going through at the moment. If it's a list of allegedly anti-vaccine research, I feel the weight of the evidence is on that side. And vice versa.

Fortunately I recognize that making judgments and conclusions from such feelings would be highly biased and susceptible to error. It's not the number of studies that matters, but rather the quality and relevance, to make a fair, rational judgment of the evidence, one must go through it all and evaluate it all as objectively as possible.

Basically my point is, don't rely on feelings of which side has more evidence, because those feelings depend on what you have been exposed to (or even just been exposed to more recently), and you might've missed something. So instead of relying on feelings: compile, catalogue, and calculate, whenever possible.

060 - The Corrected Average Attack Rate from Measles Among City Children

Today’s post is not directly related to vaccines, but indirectly: it’s about measles epidemiology, or the observation of patterns of measles in populations over time; how many cases, in which ages, when it’s fatal, etc.¹

Specifically, A.W. Hedrich suspected that reports of measles cases in cities didn't always indicate the true level of measles that existed; the reports were incomplete. So he calculated a correction factor that should help health workers determine if their reports were complete, or estimate what the true rate might be.

The rate of measles varies seasonally, attacking more in winter than in summer (like the flu I guess), but it also cycles up and down in what’s called “epidemic swing,” as you can see in Figure 1 from the paper. Sometimes there could be 13 times more cases in one year than in the next.

Figure 1: Reported measles case rates. Baltimore, MD. 1897-1927. Hedrich 1930.

This is because in a high year, many people are infected and become immune naturally, so there aren’t as many susceptible people to be infected the next year. Levels of immunity might even be high enough to produce some herd immunity effect, where the virus can’t transmit from infected people to susceptible people, because the only contact between those groups is via immune people (who block the transmission). So that’s a low year. But as more people are born, the proportion of susceptible people rises until there’s another epidemic. That’s the natural cycle of measles, in cities at least.

This cycle made it difficult to compare between cities though, because obviously comparing a low year in one city to a high year in another would be inaccurate. So it’d be better to compare averages, say over ten years, to even out the variation.

Measles is pretty much a disease of childhood, or at least it was in pre-vaccine days in cities, because hardly anyone avoided it for that long, and generally one time is enough to be immune for life. (Not to say it can’t infect adults if they’re susceptible; see Panum's report on measles in the Faroes to see what the disease could do to a completely susceptible population.²) But in these days, almost everyone in cities had been exposed by age 15, so Hedrich decided that comparing case rates in people under 15 would be the best strategy. This was especially true because including those over 15 could introduce bias in cities that had a lot of immigrants from the countryside, who were often over 15 but still susceptible (since measles didn't spread as well in rural settings due to low population density), so that could inflate the case rate.

Hedrich compared some surveys of different cities, figuring out what proportion of the population had ever been exposed to measles by their 15^th birthday. It was pretty consistent between cities, countries, and over time that this proportion was about 95%.

Figure 2: Measles history rates by age. Hedrich 1930

So one might think, if reports of measles cases over different ages up to 15 don’t add up to 95%, they’re incomplete, and one can calculate a correction factor from that! But one thing this doesn't take into account is the children that have died before reaching age 15, either from measles or from other causes. The 95% figure is based on surveys of living children. So Hedrich looked at some data to see what measles mortality was and if it could affect the correction factor.

He found that in Baltimore from 1906 to 1915, measles killed about 4 out of every 1000 children under 15. The deadliest age was around 1 year old, with about 14 in 10000 dying from measles. This isn't necessarily indicating severity at these ages; it could be that the longer one lived, the more likely one had already survived measles.

Figure 3: Data from paper, figure I made. Deaths from measles per million people in Baltimore at a given age.

But anyway, this allowed calculation of the correction factor, and it turned out that fatal cases of measles didn't really affect it much. Though this wouldn't be the case with diseases that had higher mortality, or even sometimes measles epidemics that were especially deadly (like in Aberdeen, Scotland from 1883 to 1902, where the estimated death rate from measles was 2 of every 100 people; pretty scary).

Using this correction factor, Hedrich calculated with remarkable consistency that on average, 6.5% of city children under 15 get measles each year. He discusses a number of potential confounding factors that could introduce error but decides they don’t change the results significantly. So this could be useful for further study of measles epidemiology.

A number of later papers cite this one as important for later epidemiology, but I think some may have confused this paper with another of Hedrich's, since I didn't find what they say is there in it. Still, it’s interesting:

"Hedrick [sic] demonstrated, in Baltimore, that measles epidemics did not develop when the level of immunity was above 55 per cent. Though all the figures do not necessarily apply to urban areas, his findings do point out that considerably less than 100 per cent of the population need become immune before an epidemic is prevented or halted."³

"Based on the study of Hedrich (1930), Sencer et al. (1967) estimated that in Baltimore during the period 1897-1927 a level of immunity of 55 per cent was sufficient to prevent the development of epidemics."⁴

"The meticulous studies by A.W. Hedrich of measles diffusion in Baltimore from 1897 to 1927 formed the basis for epidemiological studies of measles for nearly 35 years. By carefully tabulating monthly measles rates and correlating them with the proportion of the population under fifteen years of age, Hedrich was able to develop a ratio of susceptible to immune children and thus account for fluctuations in the incidence of measles. It was determined that when the level of natural immunity exceeded 55 percent, the diffusion rate decreased. However, children escaping epidemics were still susceptible, and as more children were born, the number of susceptibles was augmented. Increased numbers of susceptibles led, in turn, to further epidemic fluctuations in measles."⁵

Citations:

1. Hedrich, A. W. The Corrected Average Attack Rate from Measles Among City Children. Am. J. Epidemiol. 11, 576–600 (1930).

2. Panum, P. Observations made during the epidemic of measles on the Faroe Islands in the year 1846. Bibiliothek for Laeger, Copenhagen 3R, 270–344 (1847).

3. Kogan, B. A. et al. Mass measles immunization in Los Angeles County. Am J Public Health Nations Health 58, 1883–1890 (1968).

4. Griffiths, D. A. The Effect of Measles Vaccination on the Incidence of Measles in the Community. Journal of the Royal Statistical Society. Series A (General) 136, 441–449 (1973).

5. Pyle, G. F. Measles as an Urban Health Problem: The Akron Example. Economic Geography 49, 344–356 (1973).

O723 - The Neurotropic Virus Diseases

Quote of interest:

"By comparison with the ephemeral effects of antiserum, the protection afforded by vaccination is relatively long-lived. The chief disadvantage of all methods of producing active immunity is the comparatively long time they require to lead to results. While the long incubation period of rabies permits the adoption of such procedure, in acute diseases such as poliomyelitis it is useless to think of vaccination when the patient or animal is already infected. It must be carried out beforehand in anticipation of the coming epidemic. And this means that in the case of a disease like poliomyelitis, which in this country [England] relatively seldom causes serious epidemics, it is very improbable that public opinion will ever be educated to the point of wholesale vaccination. But looking to the future and speaking quite generally, one would be inclined to forecast that in both human and animal medicine vaccination will ultimately prove of greater value than serum therapy."

Citation: Hurst, E. W. The Neurotropic Virus Diseases. The Lancet 226, 758–762 (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).