1918 seems to be an interesting
year for vaccine research. Vaccine therapy was on its ebb, and development of
serious prophylactic vaccines was on the rise. At least that's how it seems
from the number of publications relating to each subject.
The topic of
today's post is a rudimentary clinical trial of a vaccine against pneumococcus1, now known as Streptococcus pneumoniae, a
bacterium that is one of the pathogens that cause pneumonia. Other causes can
be viral, fungal, or bacterial (from other species), but at the time, certain
bacterial pneumonias had been the cause of up to 80% of the pneumonial deaths
in US military training camps in winter.
Previous studies
had tried to test immunization against pneumococcus, but there are several
different strains (types I,II,III, and IV), and vaccination against one doesn't
necessarily protect against the others, and these studies did not discriminate.
Type IV is especially difficult because it has a number of sub-varieties,
according to this article.
This study1 focused on one particular
military camp, Camp Upton, at which 70% of their pneumonias were pneumococcal
(the other 30% were other kinds of Streptococcus).
Before the experiment or any vaccinations, cases of pneumonia had been spread
fairly evenly through the groups that would later make up the vaccinated and
unvaccinated groups, and 1/3 of those cases were types I to III, another 1/3
was type IV, and the last 1/3 was other bacteria.
The preparation
of vaccine was similar to previous studies: organisms (pneumococci of types I,
II, and III) were grown in broth culture, killed by heating, and the resulting
vaccine preserved with 0.3% tricresol. Those that worry about toxins might be
wary of tricresol, which apparently is harmful in high concentrations but not
in low, at least not acutely; not much is known about long-term effects of low
levels of exposure. But that's not super-relevant in this case.
The authors determined
the optimum total dose and dosing intervals using 42 volunteers, testing the
antibody levels of their serum (via agglutination and protection of mice
against the live bacteria), and concluded that the 6-9 billion cells was the
best dose, and spreading it over four separate injections (about a week apart)
reduced the severity of negative side effects. For these volunteers, at least,
there was hardly any negative reaction to this inoculation schedule.
Using this procedure, the authors then tested the
vaccine on 12,519 of the soldiers at Camp Upton, NY (about 40% of the men).
These were seasoned troops in stable positions at the camp. Out of that number,
25 of them (1 in 500) had an adverse reaction serious enough that they spent at
least a short time away from their duties. Some of these 25 only received one
or two of the scheduled 4 doses, due to the severity of their reactions. Those
that did react at all complained of malaise, chills, fever, and muscle pains;
some had something like a respiratory infection; others reported that
infections they had previously were worse.
One reaction the authors noted especially was, 152 individuals
(1 in 82 men) had strange reactions at the site of injection, with tenderness
and infiltration of fluid. It seemed to go away on its own before too long
though, but the authors determined that it was due to hypersensitivity to a
bacterial toxin.
So finally we get to the effectiveness results. The
authors were careful, as much as possible, to determine the true identity of
the organism causing pneumonia in each case, which is good.
As mentioned, there were 12519 vaccinated men, and
these were compared to about 19481 unvaccinated troops (the number fluctuated a
bit due to soldiers coming to and going away from the camp). About 75% (or
14610) of the unvaccinated group were seasoned, stable troops that were
probably less susceptible to pneumococcal infection, whereas the other 25%
(4871) were new recruits, presumably more susceptible.
These groups were followed for about 10 weeks, from
February to April. I made some graphs to represent the results, since it seems
like graphs were illegal to publish back then (or probably just difficult to
make for a printing press):
Figure 1. Cases per 10,000 men. “Unvax-resistant”
group is seasoned men, 75% of total unvaccinated; “Unvax-susceptible” is new
recruits; “Unvaccinated” is both combined. “Pneumo I-III” refers to
pneumococcus types I to III, against which the vaccinated group was vaccinated.
“Pneumo IV” is type IV, not vaccinated against. “Streptococcus” is other
streptococcal pneumonias, labeled as “S. haemolyticus” and “S.
viridans.” “Other” is pneumonias caused by other agents, including
something called “B. influenzae.”
Figure 2. Deaths per 10,000 men. Same labeling as
figure 1.
It’s worth noting that there was one case of types
I-III in the vaccinated group (you can see the small bar in figure 1), but this
case appeared 24 hours after the first dose, so it’s likely that guy was
already infected and there wasn’t time for the immunity to kick in yet. So it
was effectively zero cases in the vaccinated group, vs. 26 cases in the unvaccinated
(about 13 per 10,000 men, with 3 in 10,000 dying from types I-III).
However, a better comparison is between vaccinated
and the seasoned unvaccinated group, so it’s more like zero vs. 18 cases (12 per
10,000). Not much different, though I don’t know how many deaths were from the
more susceptible group.
Another important question is, how long would this
protection last? The study only went for about 2 months, so at least that long,
but one can’t really extrapolate from that.
Lastly, it’s curious that the vaccinated group
seemed to be significantly protected against things they weren’t vaccinated
against, such as the other types of pneumococcus and Streptococcus. Most
likely, either the vaccine conferred some cross-protection against other
bacteria (possible), or there was some confounding factor that differed between
the vaccinated and unvaccinated groups (also possible). Overall, I rate the
quality of this evidence as medium.
A number of other publications have cited this one,
for various reasons. Of those that commented on its clinical trial aspect, many
described its results favorably, though some had some criticisms, such as the
following:
“Their experiment is open to obvious criticisms, but the results at least indicate a degree of temporary immunity against the pneumococcal types used in the vaccine.”2
“The validity of the data is lessened by differences in the composition of the vaccinated and control groups, since the vaccinated group was made up entirely of seasoned troops, whereas in the control group approximately 25% were new recruits.”3
“Interpretation of the results was clouded by such variables as differences in the composition of the immunized and control groups; uncertainty as to whether the specific pneumococcal types included in the immunizing preparation were the same as those currently causing pneumonia; failure to determine whether the observed decline in cases in the immunized group was due to a decrease in cases caused by pneumococcal types included in the vaccine; and inadequate control of the antigenicity of the preparations used.”4
“However, since the incidence of other types of pneumonia—particularly those due to the streptococcus—was likewise greater in the controls than in the vaccinated, the validity of this experiment is open to question.”5
“Both trials [this and a similar], each including more than 10,000 recipients of vaccine, were suggestive of the prophylactic value of vaccination in reducing the incidence of pneumococcal pneumonia. Careful analysis of the data, however, failed to establish unequivocally such a conclusion.”6
The implication, I think, is that better studies have been
done after this one; I look forward to reading them.
1. Cecil,
R. L. & Austin, J. H. Results of prophylactic inoculation against pneumococcus in 12,519 men. J. Exp. Med. 28, 19–41 (1918).
2. Cruickshank, R. Pneumococcal Infections. The Lancet 221, 680–685 (1933).
3. MacLeod, C. M., Hodges, R. G.,
Heidelberger, M. & Bernhard, W. G. Prevention of Pneumococcal Pneumonia by Immunization with Specific Capsular Polysaccharides. J. Exp. Med. 82,
445–465 (1945).
4. B., W. H. Immunization with pneumococcus polysaccharide. Ann. Intern. Med. 24, 928–930
(1946).
5. Edsall, G. Active Immunization. N.
Engl. J. Med. 241, 60–70 (1949).
6. Austrian, R. The pneumococcus and some men who came to Yale: the Dorothy M. Horstmann Lecture. Yale J. Biol. Med.
66, 315–324 (1993).
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