Vaccines-related Podcast Episode - BacterioFiles 196

This blog is not my only project, nor even my primary: I also have a podcast, called BacterioFiles, which in some ways is sorta the opposite of this blog. It is about how microbes (bacteria, viruses, archaea, fungi) are awesome and useful, whereas this blog is more about how they are deadly and unpleasant.

But sometimes, in happy coincidence, they overlap, and the latest episode was one of those times:

BacterioFiles 196 - Flagellin Facilitates Flu-shot Function

Gut bacteria are important for a good immune response to unadjuvanted influenza vaccines!

It's a much more recent study than the ones on this blog have been so far, but interesting context to keep in mind while reading (or in my case, writing) the entries for this blog, so I thought I would share. Enjoy!

085 - The clinical severity of diphtheria in certain cities in Great Britain

So what is the reason all these people were trying to develop all these vaccines? This study is one that provides some justification, which is that these diseases can be pretty deadly. Hedley D. Wright looked at the clinical severity (that is, case-fatality rates, number of cases that ended in death) of diphtheria in seven cities of Great Britain over a number of years.¹

So Wright looked at the data of diphtheria cases and deaths in Liverpool, Birmingham, Manchester, Glasgow, Leeds, Hull, and Edinburgh from 1911 to 1935. Keep in mind that diphtheria antitoxin/serum treatment had been around at least 20 years in this case.

One difficulty in such a study is the issue of reporting: you don't really see things if you're not looking. And diagnostic criteria matter too: if something is not diagnosed as diphtheria, it's not reported as such, even if it should be (the same is true in reverse). Wright estimated that there could be as few as 40% of actual cases being reported, so more than half went unreported. Since deaths are more likely to be reported, this means the case-fatality rate appears higher than it actually is. But it's still possible to use it to compare cities, and also to get an idea of deadliness by death rates overall.

And this is how it seems: the average case-fatality rates ranged from 6% (Hull) to 10.1% (Manchester): this means that of 100 people who got diphtheria, 6-10 of them died. That's not great. On the other hand, looking at death rates per 100,000 people (based on 1931 census data), the rankings are almost reversed: Manchester is the lowest, with about 10 people out of each 100,000 dying (so in a population of about 800,000 that's 80 deaths), while Hull has a rate of almost 14 (so in 300,000, that's 42 deaths). The highest rate is Liverpool, with 17 (in 850,000, that's 144-145 deaths). So it seems like Hull might have a pathogen that spreads better between people but is not as deadly, compared with Manchester.

There was change over time though. Early in the data, around 1915, there was a pretty bad epidemic, and then cases and deaths fell off. But in the last five years of observation, cases and deaths picked up again. This trend was broadly similar over the seven cities, though not exactly. The new epidemic seemed to have a lot more cases but not as much death. Possibly the ability to diagnose had improved, though not everywhere.

Also important was the analysis of different age groups. In almost every case, death and case-fatality rates were worse in younger children than in older. This is consistent with what we've seen before; youth makes this disease deadlier. So ages 0-4 have case-fatalities from around 10-20%, 5-9 years have 5-10%, and 10-14 have 1-5%. 20% is a pretty high severity.

There's some good news though: the deadliness for the youngest age group went down over the period in question. It started out around 20%, and went down to about 10%. However, in the 5-9 years group, it dropped initially, after the 1915 epidemic, and then rose again. So it seemed like the later epidemic was worse for older children.

Wright and others speculated that this pattern could be due to children going to school together more, or better treatment for younger patients somehow, or changing sizes of families. Not sure. But this is the kind of disease that is why people were trying to develop vaccines.

There aren't really many studies citing this one that I can quote from, but here's one that's also by Wright, sort of an update on the Liverpool situation.²

References:
1. Wright, H. D. The clinical severity of diphtheria in certain cities in Great Britain. Journal of Pathology and Bacteriology 49, 135–155 (1939).
2. Wright, H. D. Diphtheria in Liverpool during the years 1937-40. Journal of Pathology and Bacteriology 52, 283–294 (1941).

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).

083 - Immunity and susceptibility to disease in early infancy

Similar to the last poat (082), this one is about how newborns are surprisingly immune to certain diseases, because they receive disease-targeting antibodies from their mothers. Charles McKhann and Israel Kapnick wrote this review, and sadly there's no new data, but it's a good summary of the topic (for the time).¹

So most interesting is that newborns are immune to several important diseases—measles, scarlet fever, polio, and diphtheria—for up to half a year after birth. This is especially true if their mothers had immunity to those diseases. The duration is impressive because when physicians attempted to produce immunity in people by injecting them with serum from recovered patients (so-called passive immunity, because it is not derived from the patient's own immune system), it only lasted a few weeks at most. Somehow the infant is able to maintain the passive immunity from the mother.

This is not the case with every disease though. Stuff that causes fevers or gut infections and diarrhea, and whooping cough, are not prevented in these newborns quite so well. Other things are intermediate, like chickenpox and pneumonia.

The duration of the immunity might seem to suggest that the antibodies are coming repeatedly from the mother, perhaps from breastmilk, but McKhann and Kapnick say that seems only to happen in cattle, not humans. The evidence seemed to show that infants' passive immunity came through the placenta in the womb. Though it's possible that some components of immunity come through breastmilk and others don't. But it seems possible that antibodies from the placenta get stored up somewhere in the infant.

So the importance of this study as pertains to vaccines is two-fold: first, as discussed in the last post, it may be possible to make the infant immune for some time by vaccinating the mother. Apparently this is pretty helpful with tetanus, as it prevents neonatal tetanus which is common in places in Africa.

Second, it is important for determining when the first vaccines should be given. With stuff like measles, which is an attenuated live virus, if there are already antibodies present, the vaccine won't produce as much of a good response. McKhann and Kapnick recognized this with certain things. So knowing when infants will become susceptible is important for immunizing them at the right time, not too early or too late. For some things, this may be late in the first year of life.

However, immunology is pretty complicated, with things we didn't understand until recently, and things we still don't understand. So it's not clear (to me, anyway) how much of this review is accurate. A later publication made these comments about older reviews, including this one:

"A large and useful part of the data bearing on the immunology of the newborn infant has come from clinical studies of immunizing schedules. There have been many careful reviews of this subject [like this one]...[But] quantitative interpretation of these studies and separation of the factors involved has often been difficult for reasons such as the following: 1. Antigen-antibody reactions may have been used for which there were no accurate methods of titration. Only rough, qualitative conclusions could be drawn. 2. Some studies used antigen-antibody reactions that require complement. The blood of the newborn infant has a low level of complement. This may have caused an undetermined error in the antibody estimation."²

I expect to have more to say in later posts.

References:
1. McKhann, C. F. & Kapnick, I. Immunity and susceptibility to disease in early infancy. The Journal of Pediatrics 13, 907–918 (1938).
2. Osborn, J. J., Dancis, J. & Julia, J. F. Studies of the Immunology of the Newborn Infant 1. Age and Antibody Production. Pediatrics 9, 736–744 (1952).