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

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

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

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

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

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

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

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

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

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

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

O469 - Advances in Vaccine Therapy

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Chart 1, Kneeland, 1934

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

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

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

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