082 - An Attempt to Increase Resistance to Pertussis in Newborn Infants by Immunizing Their Mothers During Pregnancy

With vaccine-preventable diseases, young children are often most at risk of serious health impacts or death; the younger, the higher the risk. At least, this is true of whooping cough, which had mortality rates of 26-55% in the 1930s among infants less than a year old.

However, some observed that newborns up to six months old seemed to have some resistance to some diseases—diphtheria, polio, measles, and scarlet fever, for example—especially when the mother had resistance of her own, such as immunity from having had the disease. So it seemed like the mother was transferring her immunity to the infant, probably through the placenta.

So John Lichty, Betty Slavin, and William Bradford thought it might be wise to take advantage of this transfer to give newborns more resistance until they could be vaccinated themselves around 6 months. In this study, they try immunizing mothers during pregnancy and then observing the immune response in mother and infant.¹ This was building on previous work in humans and animals with the same or other diseases, to some extent.

So they selected healthy women with normal pregnancies in obstetrics departments of Rochester hospitals, assigned them randomly to be immunized or be a control, using Sauer's whole-cell pertussis vaccine from Eli Lilly. No placebos, so no blinding of patients. They did separate observations of mothers and infants based on whether mothers had had pertussis before; i.e. history or no history. So they had four study groups: no history or vaccine, history but no vaccine, vaccine but no history, and both history and vaccine.

The way they measured immunity was a bit unusual: opsono-cytophagic index. They took blood from subjects, mixed it with dead pertussis bacteria, and observed how many dead cells the white blood cells gobbled up. They compared subjects based on the number of white cells that ate at least 20 dead bacteria; the "index" value. Presumably the immune status would affect how likely the white cells were to eat the bacteria. There was blinding in this test somewhat: the examiner counting the index didn't know the status of the subject from whom the blood was taken, so as not to be biased in counting.

Results

In total, there were 28 women immunized and 22 as controls. They observed in most groups, most infants had a lower index than their mothers; the exception was the vaccine+history group, in which a third of infants had a higher index.

I made a graph showing the values for the four groups, mothers and infants (in mothers' cases, after the vaccine, when relevant):

Opsono-cytophagic index for mothers (post-vaccine) and their infants; error bars are standard deviations reported in the study.

Overall, looking at the error bars, it doesn't seem like there's much significant difference anywhere. But looking at trends, two things stand out: infants from mothers with no history or vaccine seem lower than from mothers with either, and with both it's highest. Second, the difference between mothers and infants is largest with neither history nor vaccine, lower and similar for history or vaccine, and mothers and infants are closest with history plus vaccine.

The authors looked at a couple other things too. They observed some of the infants before they had nursed and then again after nursing for one week, to see if the colostrum affected the immunity at all. It didn't seem to make a difference.

Secondly, they looked at some clinical data for other patients; specifically, of 31 infants that died from pertussis. Eighteen of them died before 6 months of age, and 13 after. Of those that died younger, 28% of their mothers had had pertussis before giving birth; of those that died older, the number was at least 54%. Sample sizes were pretty small, but it suggests that mother's immunity does have a protective effect for the infant up to 6 months. Seems like just correlation though.

The authors concluded that vaccinating mothers seemed to help. Comparing each infant's index to mother's, the group with neither immunity had only 50% the index in infants compared to the mother; with either vaccine or history, that number went up to 75%; and with both, 100%, almost identical index. So perhaps an additive effect.

Overall, not a very rigorous study, but suggestive. Later articles were somewhat critical of the study, perhaps explaining the weak results:

"Lichty, Slavin, and Bradford attempted, as they put it, to increase resistance against pertussis in newborn infants by immunizing the mother during pregnancy. They confessed their failure. An analysis of the data revealed the following facts: The injections were given at two week intervals in the last six weeks of pregnancy. The total dose administered was 20-25 billion [cells]. Thus the dose was inadequate and too late for antibody formation which reaches its climax between one and two months after the last inoculation. The test for immunity which they employed, cytophagocytosis of the blood, has distinct limitations and has been abandoned by them in favor of mouse tests. Their figures showed no increase in cytophagocytosis of the inoculated mother's blood. Granted the validity of the test, they found no increased immunity in the mother, so that there were no antibodies transferable to the baby through the placenta."²

Even later, though, most studies citing this one seemed to focus on the safety aspect (which I forgot to mention above): of the mothers in the vaccinated group, almost the only side effect was a sore arm that wasn't bad enough to interfere with daily life. One woman had a systemic reaction with nausea and vomiting. Here's an example of a mention:

"Although phase 1 studies of maternal immunization with Tdap are in progress, studies many decades ago with whole-cell pertussis vaccine administration late in pregnancy resulted in high levels of pertussis-specific antibodies in infants and no safety concerns."³

Sometimes I wonder if people actually read old studies before citing them, but I guess usually it doesn't make much difference.

References:

1. Lichty, J. A., Slavin, B. & Bradford, W. L. An Attempt to Increase Resistance to Pertussis in Newborn Infants by Immunizing Their Mothers During Pregnancy. J Clin Invest 17, 613–621 (1938).

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. Healy, C. M., Rench, M. A. & Baker, C. J. Importance of Timing of Maternal Combined Tetanus, Diphtheria, and Acellular Pertussis (Tdap) Immunization and Protection of Young Infants. Clin Infect Dis. 56, 539–544 (2013).

081 - Measles in Detroit, 1935 I. Factors Influencing the Secondary Attack Rate Among Susceptibles at Risk

Before you can say much about a disease or treatments for it, it's useful to actually understand how it works. One aspect of that is attack rates: When a number of susceptible people are exposed to the disease, how many actually get it?

This was discussed for measles a bit in entry 060, concluding that about 95% of people in cities caught measles by age 15. Here, Franklin H. Top looked at attack rates on a smaller scale, following a number of families in Detroit that experienced one or more cases of measles and seeing how many other susceptible individuals in each family caught it.

Measles is one of the most contagious diseases we know about; this figure compares it to other diseases we know about:

Source: NPR

This is probably why it's showing up so much in the US, despite the very effective preventative measure we have (vaccination).

Franklin had observed high attack rates in Detroit, so much that he says, "parents often consider it unfortunate when all susceptible children in the family do not take the disease at one time, reasoning that it is more convenient to be done with it at once."

So he looked at more than 27,000 cases reported in Detroit in 1935, focusing on families that didn't have any kind of prophylaxis against measles (not that there was anything particularly effective, but we'll talk about that in a later post). He selected a fifth of these families for study, excluding those with no susceptible children or with difficulty in keeping records.

Then he looked at the influence of the sex and age of the primary case of measles, the sex and age of the susceptibles, the period in the seasonal measles cycle in which the case happened, the number of primary cases in a family, and the frequency and intensity of exposures, to see if any of these influenced the attack rate.

Some definitions: the primary case is the first case of measles in a family, so the exposure must've come from somewhere outside. Secondary cases presumably came from the primary case, infecting susceptible contacts in the family. It was assumed (based on previous study) that each case was contagious for 8 days: the exposure period.

There were 1,253 families in the study with one primary case, and 1,380 secondary cases resulting from them. The effect of the sex of the primary case was negligible: the attack rate from male cases was 84.3%, and 84.7% from females. Broken down by age groups, sometimes the male rate was slightly higher, sometimes female.

Looking at age groups of the primary case specifically, cases aged 5-9 years had by far the most susceptible contacts. Those under 1 year or over 15 had too few to make good conclusions. But in the middle, the attack rate was consistently 70-90%. So it didn't seem to matter much; if anything, 5-9 years was the highest, but not statistically significant.

For secondary cases, again sex didn't really matter (84.4% vs. 84.7%). In this case though, age did, a little: contacts between 1-9 years had significantly higher attack rates than those under 1 year, about 85% vs. 45%. I wonder if this is because of maternal antibodies.

Regarding time of year/period within seasonal disease cycle, rates stay constant from January through April at around 86%, then fall off by July until the next winter. Makes sense; measles might transmit better in cold weather, like influenza, or because people are huddled together inside more than when it's warm.

Now about intensity of exposure: comparing families with just one primary case to those with more than one, there didn't seem to be a significant difference in attack rate. It was all maxed out around 80-85%. If a second primary affected anything it would only be another 15%, and those are possibly already somewhat resistant somehow; otherwise they would've caught it from the first primary.

The same is mostly true for those exposed more than once: Not many who have been exposed once will escape, and the attack rate for them when exposed again is much lower. This makes sense; if they escaped the first time, they're more likely somewhat resistant (or records of past illness are incorrect, and they're immune). Still, the attack rate got up to 63% in contacts aged 1-4 exposed twice, so just being exposed once doesn't mean there isn't anything to worry about from later exposures.

Lastly, the influence of intensity of exposure: apparently exposure to multiple cases at the same time doesn't significantly increase the attack rate either.

So overall, it seems like time of year and age of the susceptible person matter the most, while sex and intensity of exposure don't affect much, though repeated exposures can increase the number of victims. And more than 80% of susceptible children exposed to a case of measles will catch it. Pretty hard to prevent.

Reference: Top, F. H. Measles in Detroit, 1935 I. Factors Influencing the Secondary Attack Rate Among Susceptibles at Risk. Am J Public Health Nations Health 28, 935–943 (1938).

080 - Whooping-Cough or Pertussis

As mentioned before, whooping cough can be pretty hard on children, especially young ones. In this article from 1938, Robert Cruickshank discusses whooping cough and how it compares to some other diseases in the UK at the time.

What Should We Call...

"Whooping cough" is the common term, referring to the shrill intake of air after a bout of intense coughing, but Cruickshank pointed out that even in severe cases of the infection, not all patients actually whoop. And since just "cough" or maybe "whooping and/or non-whooping cough" don't work too well, he suggests "pertussis" as a good alternative. On the other hand, as I discussed in 079, this could cause some confusion too, since not all cases of coughs with whooping are caused by B. pertussis. But obviously both names have stuck with us throughout the years.

Mortality

Different people had different estimates of how many people died from whooping cough. The case-fatality rate seemed to be between 1 and 8.5%, generally higher for younger patients. Though in Glasgow, the reported rate was 27%, and up to 44% for those less than a year old. Pretty bad.

For comparison, the rates for measles, diphtheria, and scarlet fever were 5%, 4%, and 0.4% respectively. So pertussis was the fourth leading cause of death in London ages 0-5 years, killing 434 people per year. The three leading causes were congenital causes, pneumonia, and diarrhea (presumably infections of unknown etiology). Measles was 5th.

Though despite these numbers, the death rates for these diseases had actually been decreasing over the past 70 years, at least for younger children. Cruickshank doesn't discuss why this might be. Could be better treatments, supportive care, immunization (at least for diphtheria), increasing public health in general... not clear.

Prevalence

Keeping track of cases of whooping cough wasn't mandatory throughout the UK at this time, though some areas did so. So it was only possible to estimate the prevalence. Some estimated that 44% of children in London got pertussis before age 5, and 60% by age 10. Measles was similar, diphtheria and scarlet fever less so.

In England, it seemed like pertussis came in two-year intervals, though it seemed different in other countries. This seemed to be because of the addition of susceptible people to the population (newborns), but could also because immunity after infection didn't last too long (possibly only a year; I wasn't clear on this part).

Lab Tests

It was pretty clear at this point that B. pertussis caused whooping cough (most of the time), not some virus. People infected with these bacteria developed antibodies, and antibodies produced from vaccination correlated with immunity to infection. Cruickshank discusses methods for diagnosis, those that work and those that don't.

Treatment and Prevention

Cruickshank says: "Pertussis is a disease of which it may be said that the multiplicity of remedies is an index of therapeutic failure." I think what he means is there a lot of suggestions but not many that actually seem to work. Probably like what I discussed in 078. Supportive care is good, of course, and anything that helps children breathe better. Some thought vaccine therapy or antiserum worked well, especially in the early stages of disease, but it didn't seem clear.

For controlling spread, Cruickshank mainly recommended keeping infected patients away from susceptible children, which makes sense. Pertussis isn't as contagious as measles or chickenpox, for example, so it wouldn't be too hard, even in hospitals. He thought that patients shouldn't be contagious anymore after the 4th week of disease.

If isolation of cases were impossible in any situation, he recommended vaccination as something that seemed effective. He cited Madsen's data (069) and Sauer's, showing effectiveness of their vaccines. But in the interest of more solid data, he recommends a more controlled study, and possibly a program similar to the one in place for diphtheria at the time.

Overall, not much new here, but an interesting perspective.

Reference: Cruickshank, R. Whooping-Cough or Pertussis. The Lancet 232, 33–37 (1938).

My Methods

It occurs to me that, if I were reading this blog instead of writing it, I would wonder, "how is this guy finding these studies and choosing which to blog about? And what isn't he telling me?" And these are good questions, worth asking of anyone who claims to be any kind of knowledgeable. So I thought it'd be worth going into my methods for this blog a little.

I started out by going to PubMed and searching for "vaccine", then saving all of the results as far back as they went, so far up to 1940. Each time I completed a decade of studies, I could go to PubMed for another. I save these studies in my favorite reference software, Zotero.

This method of searching is likely to miss out on a great deal, if not the majority, of potentially interesting studies: those that don't have "vaccine" in the title, for example, but instead say "immunization" or whatever. For this reason, I also gather studies from other sources on the web: pro-vaccine ones, like Science-Based Medicine, I Speak of Dreams, or this one; and also, perhaps more especially, anti-vaccine ones, like IMCV (now there's a place where it's important to ask yourself the questions mentioned above!). I also look at what the scientific journal Vaccine puts out, to see what's going on in that field.

And finally, for each study I blog, using Web of Science, I look up all the later studies that cite that study and save them, as well as any interesting studies cited by the blogged study. This helps give me an idea of what later scientists thought of the studies I'm reading, and also broadens my net to catch things that I might not otherwise encounter. With these methods, I've accumulated more than 2,000 articles I might someday blog about, and I'm sure I'll find many more as time passes.

How I Choose
You might've noticed that I don't blog about every study I've found. Part of this is practical: it takes a while to write a blog post, and I have a lot of other stuff going on.

The other part is that a lot of the studies just aren't that relevant to my purpose. I want to research vaccines' safety and effectiveness, and a lot of studies I've found are about basic bacteriology or virology, methods or vaccines that have been abandoned to history and thus aren't relevant today, or just don't add anything new to what I've already blogged about. For example, almost 400 articles cited reference 1 in 040, but the majority of those are about an experimental form of multiple sclerosis in animals, not very related to vaccine safety or effectiveness. So those I put aside.

I try to be careful not to be dismissive of articles that seem to show some problems with vaccines; I hope that's apparent. Those are the ones most likely to be interesting (aside from large, well-done trials of safety and efficacy, of course), so I give them some priority. So my goal for the answer to the question, "what isn't he telling me" is "not much."

I must reiterate, though, that I'm not an expert on this subject, so instead of telling you what is true, I'm trying to show you where to find that information. If anyone wants the full list of my references, blogged or not, shoot me an email and I'd be happy to share.

079 - Bacillus para-pertussis: A Species Resembling Both Bacillus pertussis and Bacillus bronchisepticus but Identical with Neither

This is a topic I've heard mentioned before as related to the effectiveness (or lack thereof) of the pertussis vaccine. And perhaps more distantly related to other vaccines. The idea is that there are other, rare, related pathogens or mutants of common pathogens that may take the place of pathogens made rare by vaccination, essentially refilling the niche. 

Or, in a more conspiracy-prone vein, that after a vaccine is widespread, cases of the vaccine-preventable disease are recorded instead as caused by a different strain, species, whatever; essentially changing the definition of disease so that artificially it looks like the rate of the disease declines drastically post-vaccine.

Personally I haven't found much evidence to bear out the latter idea yet. Definitions do change, a notable example being the broadening definition of autism artificially increasing the number of cases, but to say it's as simple to change a case rate as to reassign a set of symptoms to a different cause is to ignore the fairly modern ability to identify pathogens using very precise molecular techniques and such.

The former is an interesting idea, but I don't think it has borne out well in history. Though it may sometimes appear that there is a parallel increase in a parallel disease as one declines due to vaccination, often that's just because the vaccine-preventable was so common before, it masked instances of the parallel one, and now that's not so common, the parallel one becomes more apparent.

Anyway, the specific case today is infection with the bacterium Bordetella parapertussis as a rare alternative cause of whooping cough. Normally the disease is caused by Bordetella pertussis, which seems generally more severe than its cousin. Grace Eldering and Pearl Kendrick worked on pertussis a lot in the early 20th century, and in this study they identified B. parapertussis as similar but distinct from its cousins.¹

These researchers had collected almost 1500 isolates from whooping cough patients over 5 years. But 10 of them seemed unusual: on agar, colonies grew larger than expected over time, and could grow without blood in the medium. Another species, B. bronchisepticus, also caused disease, but was also different in some ways from this new isolate (chiefly, motility).

Of the cases from which these isolates came, half were less than moderately severe, but almost all of them whooped, so it seemed like regular whooping cough. Apparently at least one had a co-infection with this isolate and regular B. pertussis.

Then Eldering and Kendrick did a bunch of biochemical bacteriological tests on one of the isolates, called 309, and compared it to B. pertussis and B. bronchisepticus. This was neat because I remember learning about most of these in basic microbiology lab, and here I see them applied, many decades ago. Overall, 309 was similar to B. pertussis in some ways and similar to B. bronchisepticus in others, but to neither in all.

Finally they tested the immunological characteristics of the three strains. They found when antibodies were generated to any one of them, they cross-reacted somewhat with each of the others, but not completely. So they seem to share some antigens.

So apparently B. parapertussis is a separate agent, that occasionally (around 0.7% of cases) causes whooping cough in humans. One important question related to vaccines is the one raised at the beginning (if B. parapertussis could come fill a niche left if B. pertussis is eliminated by vaccines); more on that later, but J.J. Miller Jr. mentioned this in a study about a decade later:

"Some apparent failures of immunization in vaccinated children are due to infections with the Bacillus parapertussis. These infections will seldom be diagnosed correctly, as the cough is clinically indistinguishable from that of pertussis: in other words they are cases of whooping cough but not of pertussis."²

Another question, kind of on the other side, is whether a vaccine against B. pertussis could give cross-protection against B. parapertussis (or vice versa). Since they do share antigens, it's not unlikely. Today's study doesn't say much about this, but I think Eldering and Kendrick did address this question in later studies.

A final note on taxonomy: it seems like the taxonomy of Bordetella was pretty confused at least until the 1950s, so B. pertussis was referred to as Bacillus pertussis, Hemophilus pertussis, and probably others until people finally settled on Bordetella. So if you see those other names, you know.

References:

1.

Eldering, G. & Kendrick, P. Bacillus para-pertussis: A Species Resembling Both Bacillus pertussis and Bacillus bronchisepticus but Identical with Neither. J. Bacteriol. 35, 561–572 (1938).

2.

Miller, Jr., J. J. Immunization procedures in pediatrics. JAMA 134, 1064–1069 (1947).