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).

040 - Observations on Attempts to Produce Acute Disseminated Encephalomyelitis in Monkeys, and related studies

This entry will address a few issues relating to vaccines that were very serious, at least in their time. Not so much anymore, fortunately, but I’ll get into that later. A number of studies form the basis of this topic^1–9. Our understanding of the topic has changed over the years, but the fundamental issue is something called encephalomyelitis.

Encephalomyelitis comes in a number of forms, caused by different things, but it’s almost always a disorder of the brain and central nervous system in which the sheaths surrounding neurons/nerve cells, which are made of myelin, get broken down somehow, so the neurons stop working. In the worst cases, this leads to paralysis and sometimes death. One example of this is multiple sclerosis. It’s not pleasant.

How does this relate to vaccines though? Well, for a while it was suspected that the rabies vaccine, which was made from nervous system material of animals that had been infected with rabies, occasionally induced acute encephalomyelitis as a rare side effect⁹. But then in the 1920s, Turnbull and McIntosh observed several cases of encephalomyelitis after vaccinating people against smallpox⁴.

Post-Infectious Encephalomyelitis

The vaccine itself was a live virus, called vaccinia, or cowpox. This was inoculated into people’s arms, where it usually caused very little disease but induced enough of an immune response to protect the person from the much deadlier smallpox.

An article in the Lancet describes Turnbull’s and McIntosh’s observations. They saw 7 cases of post-vaccinal encephalomyelitis (or PVE) in 14 years of vaccinating people at their hospitals in London and Middlesex. The appearance of the disease, especially in autopsy, was distinct from poliomyelitis or other similar things². After this, others observed similar cases of encephalomyelitis in Holland, 35 cases of which 15 were fatal. The researchers didn’t find any vaccinia in the brain tissue though, but they all happened 10-13 days after vaccination. They speculated that there might be some latent infection activated by the vaccinia³.

Vaccinia wasn’t the only infection that could induce such a condition; smallpox itself could too, as well as other fever disorders, especially measles^6,7. Others included chickenpox, influenza, mumps, rubella, and possibly diphtheria, pertussis, and scarlet fever⁸.

According to Ricardo Jorge in the Lancet, the most common cause of encephalomyelitis was measles: one in 250 cases got it, though only 10% of the time was it fatal. More often than that, though, there were long-lasting sequelae, which could include partial paralysis or other impairments. Smallpox caused it in about 1 in 400 cases. Chickenpox-induced encephalomyelitis was relatively mild, while that induced by influenza (largely present in the 1918 pandemic) was variable in its severity. Encephalomyelitis from vaccinia was the most often fatal though⁸.

According to the CDC’s website, the vaccine for smallpox is still capable of inducing such reactions (though only in fewer than 14 to 52 out of a million people vaccinated); it’s not an entirely risk-free treatment. So it’s no wonder that it is not recommended for general use anymore; fortunately, smallpox has been essentially eliminated from the world, so it is no longer needed.

Somewhat puzzling was the frequency of post-vaccinal encephalomyelitis in the 1920s, which seemed to reach epidemic proportions, and then faded away to some extent, for no apparent reason:

"Attention may next be directed to the occurrence of encephalitis after vaccination (ordinary cow-pox), a sequel that has aroused some concern in the course of the last three years, over one hundred cases having been recorded in that time. There can be little doubt that such cases were formerly extremely infrequent, and the conclusion seems justifiable that they are somehow connected with the times through which we are passing."¹⁰

But this mystery, I think, remains unsolved.

Post-Rabies Vaccine Encephalomyelitis

Returning to the issue of encephalomyelitis induced by the rabies vaccine, that too was an unfortunate side effect, but better understood now. According to a paper from 2008,

"The susceptibility of humans to the induction of experimental allergic encephalomyelitis was discovered accidentally when patients were vaccinated against rabies with spinal cords from rabbits that were infected with the rabies virus."¹¹

What this means is that the injection of nervous system material induced an immune response against the myelin that surrounds the nerves. The patient’s own immune system then attacked the myelin, breaking it down, thus causing serious damage to the nervous system itself.

This was quite unfortunate, though rare; Stuart and Krikorian estimated that only 28 to 130 people per 100,000 vaccinated came down with the condition⁹. When you were bitten by a rabid animal, you could be virtually 100% certain that you would die from rabies before too long unless treated with the vaccine, so it was definitely worth the risk. The authors also suggested that adequate preparation of the vaccine material to denature and dilute out the myelin could significantly reduce the potential to cause encephalomyelitis, even in 1930⁹.

Since that time, of course, people have developed rabies vaccines with no myelin contaminating them at all, incapable of inducing an immune response against the recipient’s own brain¹².

Attempts to Induce Encephalomyelitis in Monkeys

All this brings me to the study that is the primary focus of this post¹. Thomas Rivers, Sprunt, and Berry had noted others’ previous observations of encephalomyelitis after vaccine or infection (as described above), though they called it “acute disseminated encephalomyelitis” (or ADE, or sometimes ADEM) instead of post-vaccinal encephalomyelitis or other names; I think ADE in later publications is something distinct from what I’m discussing here.

Anyway, the authors decided to try to induce encephalomyelitis in the lab, in rhesus monkeys, in several different ways, using vaccinia virus and some extracts or emulsions of virus-free body tissues.

First, eight monkeys were vaccinated with vaccinia the normal way, in their skin. Five negative controls were unvaccinated. Then at various intervals after vaccination, the monkeys received injections of live virus into their brains. The unvaccinated controls all died of meningitis from vaccinia multiplying in their brains; this was expected. The monkeys injected the soonest after vaccination died the same way, and the second-soonest survived a mild meningitis, but the rest proved immune and unharmed. None of them had encephalomyelitis though.

The authors weren’t satisfied with this, because the monkeys’ immune response was too quick somehow, so they tried again with more concentrated injections of virus. The results were pretty much the same though. Apparently vaccination protects the brain as much as other parts of the body, but even when the virus does get into a susceptible brain, it doesn’t cause encephalomyelitis, or at least not often enough to be detected in 21 monkeys (not very many).

The next hypothesis was that extracts from rabbit testicles might enhance the virus’s action, so they tried this with a few more monkeys. One got just testicle extract, but had no reaction. Another was vaccinated and then received extract, but also had no reaction. A couple more, one vaccinated and the other not, got virus combined with extract injected in their brains. They both had symptoms like stiff neck, lack of activity, etc, but when sacrificed and examined, their nervous system didn’t have the characteristic encephalomyelitis appearance. So testicle extract didn’t really seem to cause or enhance it either (at least not in 2-4 monkeys).

Next, the authors tested the hypothesis that injections of virus-free nervous material from rabbits, like in the rabies vaccine, could cause encephalomyelitis. So they made extracts or emulsions of rabbit brains and injected them into the muscles of eight monkeys, between 14 and 93 injections total, three per week (so over the course of up to 8 months). Five of these monkeys, including two with the fewest injections and two others with the most, had no symptoms or problems. One suddenly died after receiving 50 injections, for no apparent reason. But two had characteristic neurological and mobility problems, and their nervous tissue showed the loss of myelin and increased immune cell activity associated with encephalomyelitis. So that seemed like a positive result!

The four monkeys that hadn’t reacted to injections of brain at all were tested further with injections of vaccinia into their brains, after vaccination or not. The results here were the same as with those that hadn’t been injected with brain material, so the brain injections didn’t seem to affect the course of the vaccinia infection.

The two positive results in this study turned out to be a big deal, cited by almost 400 later papers and reviews; they were labeled “experimental allergic (or autoimmune) encephalomyelitis,” or EAE. This has been studied a lot as a (possibly controversial) model of multiple sclerosis. It was definitely decent evidence of the link between encephalomyelitis and brain-derived rabies vaccines though.

Here are some comments from later papers regarding this study:

 "Rivers and his associates were the first to succeed in producing, in the monkey, sterile, disseminated meningo-encephalomyelitis by often repeated injections of material from central nervous system tissue. Many of the observations made by these authors suggest that the disease induced was the result of an immunologic mechanism. Nevertheless, Rivers and his associates hesitated to express this view. Even 20 years later and after the accumulation of much new information—subsequent to the introduction of the use of adjuvants in the study of sterile experimental disseminated encephalomyelitis—conclusive evidence for its allergic nature is lacking."¹³

"Acute disseminated encephalomyelitis, which is essentially identical to the disease that occurs in patients receiving live or killed rabies virus vaccine, was produced in monkeys by Rivers and his colleagues in the 1930s by repeated injection of the animals with emulsions or extracts of normal nervous tissue from the central nervous system. These findings, together with increasing evidence that central nervous system tissue possesses organ-specific antigenic activity, provided strong evidence that the disseminated encephalomyelitis occurring in humans after rabies vaccination resulted from the host's immunologic responses. These responses, called forth by parenteral injections of nervous tissue, had the capacity to interact with antigenic components of the host's own central nervous system and thus to cause disease. It is important to note, however, that at about this same time there was increasing recognition that smallpox vaccination and some common exanthematous diseases of childhood such as rubeola were occasionally complicated by an acute encephalitic process. These cases of para- or postviral encephalitides had histopathological features that bore a striking similarity to those of the encephalomyelitis associated with rabies vaccine and the disseminated encephalomyelitis induced in monkeys by injections of nervous tissue."¹⁴

"Studies in the 1920s indicated that inoculation of rabbits with extracts of normal human spinal cord, or sheep brain, likewise resulted in occasional instances of post-vaccinal encephalomyelitis. The question was taken up by Thomas Rivers at the Rockefeller Institute, NY, perhaps because he himself had once been incapacited by progressive muscular atrophy and, being a virologist, he would be curious whether a virus could be implicated in post-vaccinal encephalomyelitis...Rivers concluded that the relation of the injections [of monkeys] to the central nervous system disease was 'not clear.'"¹⁵

"Experimental autoimmune encephalomyelitis is a well established model used to investigate the possible autoimmune etiology of multiple sclerosis. This model originated with Louis Pasteur's vaccinations with spinal cord from rabies-infected rabbits from 1885. This acute demyelinating disorder was later found to occur due to contamination of the inoculums by spinal cord components."¹⁶

Mackay and Anderson also provide a good overall history of Rivers’ and colleagues’ work¹⁷.

So overall, these were some legitimate problems with vaccines of old, though no longer. At the time, it was likely that, despite the risks, the vaccines were preferable to the diseases they prevented, on average. But for individual victims of encephalomyelitis, it probably was not worthwhile, so it’s good that those that study vaccines are constantly trying to improve them.

References:

1. Rivers, T. M., Sprunt, D. H. & Berry, G. P. Observations on Attempts to Produce Acute Disseminated Encephalomyelitis in Monkeys. J Exp Med 58, 39–53 (1933).

2. Encephalo-Myelitis Following Vaccination. The Lancet 208, 504–505 (1926).

3. Encephalo-Myelitis Following Vaccination. The Lancet 208, 764 (1926).

4. Turnbull, H. M. & McIntosh, J. Encephalo-Myelitis following Vaccination. Br J Exp Pathol 7, 181–222.19 (1926).

5. Turnbull, H. M. & Mcintosh, J. Encephalo-Myelitis Following Vaccination. The Lancet 211, 1094–1095 (1928).

6. Perdrau, J. R. Encephalo-Myelitis Following Vaccination. The Lancet 211, 1201 (1928).

7. Ward, G. Encephalomyelitis Following Vaccination. The Lancet 214, 1331–1332 (1929).

8. Jorge, R. Post-Vaccinal Encephalitis :: Its Association with Vaccination and with Post-Infectious and Acute Disseminated Encephalitis. The Lancet 219, 267–272 (1932).

9. Stuart, G. & Krikorian, K. S. A Fatal Neuro-Paralytic Accident of Antirabies Treatment. The Lancet 215, 1123–1125 (1930).

10. Wilson, S. A. K. A Lecture On Acute Cerebral Lesions At Different Ages. The British Medical Journal 1, 487–491 (1929).

11. Sampson, J. H., Archer, G. E., Mitchell, D. A., Heimberger, A. B. & Bigner, D. D. Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant glioma. Seminars in Immunology 20, 267–275 (2008).

12. Glück, R., Matthieu, J. M., Wegmann, A. & Méan, F. Absence of myelin basic protein in an improved purified duck embryo rabies vaccine. Neurochem Pathol 4, 69–75 (1986).

13. Lipton, M. M., Freund, J. & Brady, E. The Transfer of Experimental Allergic Encephalomyelitis in the Rat by Means of Parabiosis. J Immunol 71, 380–384 (1953).

14. Paterson, P. Y. Neuroimmunologic Diseases of Animals and Humans. Reviews of Infectious Diseases 1, 468–482 (1979).

15. Mackay, I. R. Travels and travails of autoimmunity: A historical journey from discovery to rediscovery. Autoimmunity Reviews 9, A251–A258 (2010).

16. Mecha, M., Carrillo-Salinas, F. J., Mestre, L., Feliú, A. & Guaza, C. Viral models of multiple sclerosis: Neurodegeneration and demyelination in mice infected with Theiler’s virus. Progress in Neurobiology 101–102, 46–64 (2013).

17. Mackay, I. R. & Anderson, W. H. What’s in a name? Experimental encephalomyelitis: ‘Allergic’ or ‘autoimmune’. Journal of Neuroimmunology 223, 1–4 (2010).

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

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

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

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

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

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

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

004 - Vaccine Lymph

This is another interesting piece of history, a review of vaccination from the time of Edward Jenner, and a discussion of the best places to get "vaccine lymph," or infectious material used for vaccination against smallpox.

Strangely, multiple people at the time (including a Mr. Badcock) had observed that infecting a cow with smallpox from a human, then using some of the lymph the cow produced from the infection to vaccinate humans, was remarkably effective and mild as a vaccine. From this, the author and his contemporaries conclude that smallpox and cowpox were identical. "This datum is irrefragible."

I'm not so sure, but I don't have a good explanation for this phenomenon. Attenuation, perhaps? I'll be on the lookout for an answer in future readings, and if anyone has any ideas, please comment or email about it.

The author explicitly recognized that vaccination was the lesser of two evils, the ideal situation being that no one would be exposed to either smallpox or the vaccine disease (an ideal fortunately realized in our time), but the latter was obviously preferable to the former.

Citation: Hingeston, J. A. Vaccine Lymph. Assoc Med J 1, 269–273 (1853).

002 - Observations on vaccination and small-pox, more especially with reference to the theory of vaccine influence, and the relations subsisting between the cicatrix and the character of the consecutive variola

Another old one, this time from 1841. These old publications are amazingly wordy and flowery! But now we get into some actual interesting data.

As in the previous article, the "vaccination" in this paper refers to inoculating patients with cowpox, also known as the vaccinia virus, pretty much by taking some infected pus from a previous patient and scraping it into a new patient's arm with a needle. This resulted in a mild infection that gave the immune system enough of a recognition of smallpox (variola virus) that it could respond and prevent the latter from being quite as deadly. Remember, smallpox could kill up to 80% of people it infected (I am happy here to be able to use the past tense when referring to it).

The author is a physician at the Smallpox Hospital in London, reporting on an epidemic of smallpox in 1840. Apparently between January 1839 and September 1840, there had only been about 16 cases each month, but then an outbreak started that resulted in almost 16 cases every four days. He gives some statistics about the cases he observed that year.

• 61% of cases had not been vaccinated
• Of these, 45% died
• 38% had been vaccinated previously
• Of these, 7% died
• 1% had had smallpox before

Here's a graph:

Seems like a big difference to me. But it is possible to question how many people of each group got sick enough after being infected to need to go to the hospital, and how many people in the general population of each group got infected at all. All we know is the case:fatality ratios.

Also potentially of interest are the effects on different age groups, of all patients (vaccinated or not):

• 15% were under 5 years old
• 60% of these died
• 14% were 5 to 15 years
• 20% of these died
• 71% were over 15
• 26% of these died
• Overall, 30% of patients died

What the author does report about vaccinated patients is the following: only 9% of those who had been vaccinated were under 16 years, and none were under 5 years (though occasionally a younger vaccinated child did catch it).

Other than that, the rest of the report is arguing that the appearance of the scars on the arms from vaccination  doesn't correlate well with how well-protected an individual is from smallpox. The author gives a series of cases in which nice-looking scars gave little protection and not-nice ones gave good protection.

Overall, it seems like good evidence, for what it's worth, that vaccination helped moderate the severity of smallpox.

Citation: Gregory, G. Observations on vaccination and small-pox, more especially with reference to the theory of vaccine influence, and the relations subsisting between the cicatrix and the character of the consecutive variola. Med Chir Trans 24, 15–29 (1841).

001 - Case of vaccine disease and measles, existing at the same time in the same individual

First, an introduction: there's so much controversy about vaccines, at least in some areas of society (not among scientists, as far as I've seen), so I was inspired to embark on a thorough investigation of the question, so I can promote the truth with more expertise and knowledge. Unfortunately, a Pubmed search for the word "vaccine" turns up more than 220,000 results, and that's just published research; it probably doesn't even cover all the historical, personal, political, and economic questions. But I have to start somewhere, so I'm going to start going through these results.

The first one is the oldest one, from 1823. It is a case report by one S. Gilder, describing his vaccination of a 14-month-old girl.

I wondered what "vaccination" meant in this context, since most of the vaccines we use these days were introduced in the 1950s. But from the context of the article, I figured out that it meant inoculation with cowpox (or in some cases, with smallpox itself) to prevent smallpox. That has been going on for a long time.

So anyway, he inoculated her with cowpox, and then a couple days later she caught measles from her brother. And he observed clear symptoms of measles, at the same time as she was showing clear symptoms of the cowpox inoculation. (Then he applied leeches to treat the measles; this was a while ago.)

The point of the report is to refute an idea present at the time, advocated by one John Hunter, that a person could only suffer from one disease at a time. He derived this theory from several observations of people who, after being vaccinated while ill, seemed to hold off on developing vaccine disease until they got over their illness. But Gilder had just observed two diseases present in the same girl.

It's an interesting piece of medical history, certainly, but I'm not sure it is very helpful for my quest, so I will continue.

Citation: Gilder, S. Case of vaccine disease and measles, existing at the same time in the same individual. Med Chir Trans 12, 186–189 (1823).