In developing practical measures for the prevention or control of
influenza epidemics, preventive medicine faces one of the most difficult
problems of modern times. By means of quarantine, protective vaccination
and instructions in personal hygiene many of the diseases which formerly
ravaged the world have been brought under control. At first glance it
would seem to be a simple matter to apply the principles which we have
found successful against these diseases to influenza and let it go at
that, but in the recent epidemic many of the formerly successful
measures were tried and found to be either inefficient, inapplicable, or
at least of doubtful value.
During the pandemic there was little time to think collectedly, and no
time to analyze procedures, and even now it is far from easy to
determine what things were done wisely and what things were of no
practical value. There exists the greatest difference of opinion as to
what measures should again be used when the need arises, and what ones
should be discarded. For instance, there are confirmed exponents of
prophylactic vaccines, and equally able men who are convinced of their
uselessness; enthusiastic advocates of the face mask, and almost as many
objectors; those who would close schools, churches, theatres, etc., and
those who claim that such measures serve only to prolong the epidemic.
One naval officer is said to have stated that he had accumulated figures
either to prove or to disprove the usefulness of any preventive measure
yet recommended. There is, in short, a chaos of opinions with followers
who vary from the one extreme of believing there is “virtue in all
things” to those of the other extreme who state that every susceptible
person develops the disease in the degree of his susceptibility,
regardless of any and all preventive measures used. While there remain
so many points on which definite, concrete knowledge is lacking, and so
much controversy over the relative value of various measures, this paper
can do little more than state the facts and discuss their bearing on
prevention as impartially as possible.
Great progress has been made in controlling contagious diseases in
recent years—a fact which can be easily verified by anyone who will
compare the sick reports of the Great World War with those of any war
previous to the beginning of the present century. The diseases which
have been most easily controlled have been those against which
prophylactic vaccines or prophylactic sera have been developed.
Smallpox, dysentery and typhoid fever have lent themselves readily to
control by protective vaccination, while reliable temporary immunity can
be afforded by the administration of sera for protection against
diphtheria and tetanus. These are by no means all, but are probably the
most striking illustrations; and with such examples before us, the
greatest hope for the prevention of influenza apparently lies in the
development of a prophylactic vaccine against it.
_History of Prophylactic Vaccination in General_
The name vaccine came from “vacca,” or cow, and was originally applied
by Jenner (1796) to the virus taken from cowpox pustules for
prophylactic inoculation against smallpox. It has come to be loosely
applied to all forms of preventive inoculations except sera. We have,
therefore, a variety of vaccines which differ in their nature and method
of preparation. Some are produced by growing the virus in insusceptible
animals, some are composed of attenuated viruses, and most common of all
are the bacterial vaccines, sometimes called “bacterins,” which are
prepared from killed cultures of bacteria. Sera are used in prophylaxis,
as well as treatment, and are made by bleeding and separating off the
serum from animals which have been immunized against the cause of the
disease in question. Sera and vaccines are wholly different products,
and the distinction should be made in discussing them, although there is
a common tendency, particularly among lay writers, to use the words
interchangeably. Smallpox is the classical example of a disease which
can be completely controlled by universal vaccination. The parasite
causing smallpox has never been certainly demonstrated, but over a
century ago Jenner showed that cowpox, a localized, non-fatal disease,
protected against smallpox. Modern methods have proven that a cow
inoculated with smallpox virus develops cowpox, and that thereafter the
virus loses its power to produce smallpox when it is returned to man.
Instead, it causes a local pustule, and confers immunity to smallpox
over a considerable length of time. Rabies is another example in which
the exact cause of the disease is still in doubt, and in which a
protective vaccine has proven of great value. Rabies vaccine was
developed by Pasteur, and is prepared by drying the spinal cords of
rabbits that have been killed by a highly virulent rabies virus.
Typhoid, dysentery, pneumonia and several other diseases of known
etiology have been more or less controlled by the use of vaccines made
from their respective bacterial causes. These vaccines are of the
“killed bacteria” type of vaccines, and credit for their application to
human disease belongs to Sir Almroth Wright (1896). The preparation of
bacterial vaccines is very simple. Bacteria which are known to cause a
certain disease are isolated in pure culture, grown on artificial media,
killed either by chemicals or heat, standardized either by counting, or
drying and weighing, and suspended in salt solution for subcutaneous
injection. Salt suspension vaccines are usually given in three or four
increasing doses, about one week apart. Le Moignic and Pinoy (58) first
elaborated a lipovaccine for triple typhoid vaccination, which was used
extensively in France during the war. Whitmore, Fennel and Peterson have
recently also advised the drying of killed bacteria and the suspension
of them in oil. This method makes it possible to give a single massive
dose of bacteria which is sufficiently large to completely immunize the
individual against the disease, and which prolongs the immunizing period
by allowing slow absorption over a period of several weeks. These
vaccines are called lipovaccines, have been adopted in the United States
Army as the standard typhoid vaccine, and promise in time to supersede
the salt suspensions entirely from a commercial standpoint. Many other
modifications in the preparation of bacterial vaccines have been
advised, notably the class known as sensitized vaccines. These are
prepared by incubating bacterial vaccines for a time with the serum
taken from animals already immunized against them. The serum apparently
absorbs many of the toxic substances, and permits the injection of more
efficient doses. Besredka advised the use of living cultures which had
been incubated with immune sera, on the basis that vaccines so prepared
were very active and non-toxic. The sensitizing treatment, however, does
not stop the growing powers of the bacteria, and vaccines of the
Besredka type are generally considered dangerous and so are little used.
Sensitized killed bacterial vaccines, on the other hand, are quite
popular.
When a sufficiently large dose of vaccine is given to an individual
there is usually a transient rise in temperature for from 12 to 48
hours; the local focus of injection becomes sore and inflamed, and a
white count often shows an actual increase in the number of
polymorphonuclear leucocytes in the general circulation. A series of
doses are usually given. If after a few days blood is withdrawn from the
patient and immuniological tests made, it will generally be found that
the patient’s leucocytes take up bacteria, and particularly the type of
bacteria of which the vaccine was composed, more readily and in greater
numbers than the leucocytes of the ordinary individual. Wright and
Douglas (52) and Neufeld and Rimpau (53) have shown that this effect of
increased phagocytosis is brought about by the vaccine through the
production of substances which act specifically on the bacteria and
render them more susceptible to inclusion within the white cells. These
substances belong to the group of antibodies, and are known as
“opsonins” or “bacteriotropins,” and are specific for any given
bacteria. Moreover, the serum of the patient will, as a rule, be found
to have developed the faculty of agglutinating and bacteriolysing
suspensions of the specific organism injected and of fixing complement
in the presence of an antigen prepared from that organism. In animal
work it has been possible to go still farther, for it can be shown that
the resistance of the animal can be raised until it is no longer
possible to kill it with the same dose which is found to be fatal for
the unimmunized animals. Not only has animal work made it possible to
determine the protective powers of vaccines, but it has also served to
show the specific nature of the protective power and the relative extent
to which “group” or “crossed” protection can be conferred by vaccinating
with closely allied organisms—as, for instance, paratyphoid bacilli in
typhoid fever. The non-toxic nature of vaccines is also determined by
animal experiment before such preparations are injected into humans.
The most successful prophylactic bacterial vaccine which has been
developed so far is that for typhoid fever. A comparison of the
occurrence of typhoid fever in the United States Army before and since
the use of anti-typhoid vaccine is all that need be cited to convince
one of its value. At the time of the Spanish War there was no
vaccination against typhoid fever, and there were 20,738 cases, with
1,580 deaths, among 107,973 men who remained in the camps in the United
States during the war (54).
During the summer of 1911, the maneuver division of the United States
Army, having 12,801 men, all of whom had been vaccinated against typhoid
fever, were stationed at San Antonio, Texas. Two cases of typhoid fever
developed among them, and neither case died. Among the civilian
population of the city, living under usual conditions during the same
time, there were 49 cases of typhoid fever, with 19 deaths. Since 1912,
typhoid vaccination has been compulsory in the United States Army, and
the largest epidemic of typhoid fever which I have found reported so far
during the late war was that at Camp Greene (55), Charlotte, N. C.,
where 18 cases developed. Only 12 of these men had received the complete
series of immunizing doses. For a complete discussion of the value of
typhoid vaccine the interested reader is referred to Gay’s Monograph
(56) on typhoid fever.
_Prophylactic Vaccination Against Influenza_
The hope of finding an early solution to the vaccine problem in
influenza appeared to be in the development of a prophylactic “bacterial
vaccine” similar to that which proved so efficient for typhoid. In his
discussion of the vaccine problem in pneumonia, Fennel pointed out that,
theoretically, any disease of microbic origin in which spontaneous
recovery is at all possible should yield to specific prophylactic
measures. The difficulty, however, of preparing a bacterial vaccine for
influenza comparable to that for typhoid fever is that the unquestioned
cause of influenza has yet to be determined. The probable cause of
influenza is the Pfeiffer bacillus, but its relationship has not been
proven beyond question. On the other hand, the innocence has likewise
not been proven, as Dr. Holman in his article of this series has ably
shown. It is not my intention to go deeply into the question of
etiology, but simply to bring out a few points which _a priori_ seemed
to indicate that the reasonable solution of vaccine prophylaxis was in
the preparation of a pure Pfeiffer bacillus suspension.
The experiments in man lead to very surprising results. Rosenau, Keegan,
Goldberger and Lake, at Gallops Island, Boston, Mass., (1) inoculated
volunteers with pure culture of B. Pfeiffer, with secretions of the
upper air passages and with blood from typical cases of influenza.
Sixteen men, of whom 13 were supposedly non-immune, had Pfeiffer bacilli
installed into their nasal passages, and none of them developed the
disease. Secretions filtered and unfiltered also gave negative results.
Contact with well-developed early cases also failed. McCoy and Richey
(1a) conducted similar experiments in San Francisco, with negative
results. The men of the latter group had been vaccinated with a mixed
streptococcic vaccine, which may have played some part. Had the
experiments with the Pfeiffer bacillus been negative and the other
experiments positive, they would have shown that the bacillus of
Pfeiffer was not the cause of influenza; but since all attempts were
negative, it merely brought out the fact that there had been a change,
due probably to some immune factor, which seemed to have acted alike on
the Pfeiffer bacillus and all other types of virus present, and to have
made them all innocuous. These experiments still leave the cause of
influenza in question.
Those who are opposed to the Pfeiffer bacillus being the cause of
influenza in its epidemic form base their position on the points that
the common finding of the bacillus might be accounted for on the grounds
of its being a secondary rather than a primary invader; that while it is
not so common at ordinary times, it does occur with other organisms in
whooping cough and sometimes in chronic diseases of the air passages,
and that the rules of Koch have not been complied with in that the
organism has not been found in every case of the disease; that where it
has been grown in pure culture and inoculated into man and animals, it
has either produced no disease, or the lesions which followed have not
been typical of epidemic influenza. On the side of those who believe
that the Pfeiffer bacillus is the chief cause, or, at any rate, that it
is partly responsible for epidemic influenza, are the facts of its
fairly constant presence in the purulent bronchial secretion of patients
suffering from epidemic influenza; its relatively uncommon occurrence at
other times; its known pathogenicity in occasional cases of meningitis,
and in the inflammation of the bony sinuses of the head and face; the
relative immunity of nearly all common laboratory animals and the fact
that the attempts to transfer epidemic influenza from man to man failed
not only when Pfeiffer bacilli were used, but also when direct contact
and direct coughing by the patient into the face of the volunteer were
tried. The argument that many cantonment laboratories failed to find the
organisms loses weight when we find that the percentage of positives
increased where the material examined was removed directly from the
lungs at autopsy, where special cultural methods were in use and where
the laboratory personnel was large enough to devote a sufficient amount
of time to each individual culture. All of these points indicate that
the organism was overlooked in a great many instances. In our laboratory
we found the examination of sputa very unsatisfactory because of the
great amount of contamination, and because the bacillus seemed to lose
its ability to grow after a relatively short time in the sputum in
vitro. Moreover, I am convinced that the bacillus changes its morphology
to such an extent under varying conditions as to make it impossible of
identification when present among other organisms in sputum smears. The
failure of animal inoculations is also not conclusive evidence against
the Pfeiffer organism, because guinea pigs, rats and mice have a natural
immunity for them. Rabbits are only slightly susceptible, and then only
to intravenous injections. The mixture of the Pfeiffer bacillus with any
one of several other pathogenic organisms will increase the
pathogenicity of both. Monkeys inoculated intracranially develop a
typical Pfeiffer bacillus meningitis.
Whatever the ultimate outcome of the investigations as to the parasitic
cause of epidemic influenza, the Pfeiffer bacillus was the generally
accepted cause at the beginning of the 1918 epidemic, though it was at
once realized that most of the deaths were due to complicating
pneumonias and to secondary infections with other organisms. Under the
circumstances, one of two courses was open: (a) the acceptance of the
Pfeiffer bacillus as the presumptive cause of influenza and the
preparation of a specific prophylactic vaccine against infections with
that organism; or (b) the use of a mixed bacterial vaccine containing
the common and most deadly secondary infecting organisms, designed to
increase the patient’s general resistance by decreasing his
susceptibility to the allied, collateral and secondary infecting agents.
Attempts were made along both lines, with more or less unsatisfactory
results.
_The Attempt to Develop a Specific Prophylactic Vaccine by the Use of
Pure Pfeiffer Strains_
By a specific prophylactic vaccine for any given disease, we mean a
material which when inoculated into an individual will actively protect
that individual against the given disease. In infectious diseases, the
immunizing material is usually of microparasitic origin (in contrast to
desensitizing substances used in pollen diseases and those due to
unusual sensitiveness to foreign proteins), and is specific only for the
disease caused by the microparasite from which the material was
prepared. With the knowledge in hand during the epidemic, the logical
plan seemed to be to prepare a pure Pfeiffer bacillus vaccine, the
object of which was to eliminate primary infection with that organism
and thus prevent the secondary invaders from obtaining a fertile soil.
While specific Pfeiffer bacillus vaccines had been tried in treatment,
the field was a comparatively new one so far as prevention was
concerned. Many of the biological products companies had so-called
influenza vaccines on the market for treatment purposes, and many of
these contained Pfeiffer bacilli. A few preparations of pure strains of
the bacilli were also available, but I was unable to find any records of
their use for prophylaxis. Lacy (2) reported two cases of sinusitis
treated with autogenous vaccines made from pure Pfeiffer strains—one
patient improved rapidly and the other showed no change. Investigation
of several of the other references on influenza vaccines showed that
mixed vaccines had been used in each instance. The work of Flexner and
Wolstein (3, 4 and 5) indicated that active immunizing substances could
be prepared from the Pfeiffer bacillus, although they worked with serum
instead of vaccines. They prepared an anti-influenza-meningitis serum by
immunizing goats and horses. These sera cured monkeys of experimentally
produced influenzal meningitis. The sera showed agglutinins and
bacteriotropins for Pfeiffer bacilli, as well as positive fixation tests
in dilutions of 1 in 100, but they contained no lysins. The serum was
offered for intradural use in treating influenzal meningitis, but was
found to have no value when used in human cases.
The first references which we have found on the use of pure Pfeiffer
bacillus vaccines for the prevention of epidemic influenza were those of
Leary (6), (7), and of Rosenau (8). Shortly after the appearance of the
first influenza cases in Boston, Leary used a vaccine prepared from
several strains of Pfeiffer bacilli both for the treatment of influenza
and for its prevention. The vaccine for the latter purpose was given to
medical students and nurses, and the first results were apparently very
encouraging. Continued use has not been convincing. Barnes (9) reported
an attempt to protect the employees and patients of an institution near
Woonsocket. On October 9 a case of influenza developed in the female
ward, and was followed five days later by another. On October 22 the
disease appeared in the male ward, and the same day 172 employees and
patients were given their first inoculation with Leary’s vaccine. Doses
of 400, 800 and 1,200 million bacilli were given at 24–hour intervals.
All persons who had developed influenza before the three doses had been
completed were excluded from the computation of the disease incidence,
which was found to be 20 per cent. both among vaccinated and
unvaccinated individuals. The mortality rate was 16 per cent. for the 25
cases among the vaccinated, and 15.8 per cent. among 57 unvaccinated
patients. The result failed to show any protective qualities for the
vaccine.
The best controlled vaccine experiment in which Leary’s vaccine was used
was that reported by Hinton and Kane (10), and was carried out at the
Monson State Hospital for epileptics. The hospital had a population of
979 inmates, ranging from 4 years of age to senility; of these 461 were
vaccinated and 518 were not. Vaccination was begun on October 6, and
three doses of 400, 800 and 1,200 million were given at 24–hour
intervals. The first case of influenza developed a few hours after
vaccination was completed, but there were no more cases before October
12, when five cases developed. The table shows the result of the work,
and that the vaccine failed to protect.
Population. No. of % of No. of % of
Cases. Cases. Deaths. Deaths.
Vaccinated 461 163 35.4% 28 17.1%
Unvaccinated 518 178 32.4% 24 13.4%
Attempts to protect by the use of Leary’s influenza vaccine were made in
11 other Massachusetts institutions, but the results cannot be used to
compare the incidence and mortality rates between the vaccinated and
unvaccinated, because the epidemic was either on the wane, or at least
well advanced when the vaccinations were begun. The reports are of great
interest in showing the large number of vaccinations which failed to
protect.
In the Taunton State Hospital about 800 were vaccinated, and among them
there were 81 cases of influenza and 17 deaths from pneumonia, even
though the epidemic was on the wane when vaccinations were begun.
In the Gardner State Colony 834 were vaccinated after the peak of the
epidemic had passed. This number included all but 15 of the inmates who
had not contracted influenza up to that time. Out of this group, 62
vaccinated individuals developed the disease.
At the Massachusetts School for Feeble-Minded 457 inmates were selected
for vaccination and controls. Of the 234 vaccinated, 56 developed
influenza. Of the 223 unvaccinated, 185 developed influenza, with 16
pneumonias and 12 deaths. The vaccinated group, however, were a more
vigorous group of individuals to begin with, and represented a higher
mental grade than the unvaccinated group, so that the evidence was
considered of questionable value.
At the Wrentham State School the influenza epidemic was well under way
before vaccinations were begun, and hence the susceptible individuals
were in a large part either affected or infected with the disease. Of
1,198 unvaccinated persons, 758 developed influenza, giving a morbidity
rate of 63 per cent. Of 128 vaccinated, 13 developed influenza and 1
died. Physicians in this institution believe that the vaccinated were
not as ill as the unvaccinated patients.
In the Medfield State Hospital, having a total population of 1,940,421
cases of influenza, with 63 deaths, had occurred before vaccinations
were begun. Of the remaining unattacked inmates 902 were vaccinated.
After the completion of vaccination one new case appeared among the
unvaccinated, and there were none among the vaccinated.
At the North Hampton State Hospital there were 9 cases of influenza, 4
of whom died, among 444 unvaccinated individuals, and 9 cases, with 1
death, among 563 vaccinated patients.
Among 506 patients vaccinated at the Westborough State Hospital there
developed 15 cases of influenza, 2 of which terminated fatally. Of the
415 unvaccinated controls, 25 developed influenza and there were no
deaths. At the time vaccinations were completed only 13 had developed
influenza.
In the Worcester State Hospital vaccination was carried out after the
epidemic had entirely subsided.
At the Bridgewater State Hospital no vaccines were used, but the
morbidity rate was 29.9 per cent., as contrasted with 32.9 per cent.
among the unvaccinated at Monson.
At the Danvers State Hospital the population of 853 adults was divided
into three sections. One section was vaccinated with the Leary vaccine,
one section with an unheated influenza vaccine prepared by Dr. Rosenau
at the Chelsea Naval Hospital, and one section held as controls. The
epidemic had, however, reached its height before vaccination was begun,
and no information as to the relative value of the vaccines could be
determined.
In Hinton’s (11) report the analysis covered the studies on about 6,000
vaccinated individuals, which represented slightly less than half of the
population of 12 Massachusetts State institutions. Hinton’s conclusions
were as follows: “The heated suspension of influenza bacilli used as a
prophylactic vaccine did not prevent influenza, lessen its severity nor
its complications, and, as far as could be ascertained, resulted in no
harm.”
About the same time that Leary was working on his vaccine, Rosenau
prepared an unheated suspension of Pfeiffer bacilli, isolated from cases
of influenza of the existing epidemic, which he used at the Chelsea
Naval Hospital and in an experiment at the Pelham Bay Naval Training
Station. The writer is indebted to Surgeon-General of the Navy W. C.
Braisted for the data from which this report was compiled—the report of
the Sanitary Officer of the station not having been completed at the
time the information was furnished. The vaccine experiment was made in
the isolation regiment, which had remained practically free of
influenza. Inoculations were begun on September 30, when 638 men were
given the first dose of vaccine, 833 men being held as controls. On
October 4 the second dose was given to 589 men, and vaccination was
completed on October 8, when 565 men were inoculated. This group
comprised the total number who received three inoculations. On October
14 practically all of these men were transferred, so that it was very
difficult to get a complete record. Those cases which developed
influenza prior to October 10 have been omitted by the writer, both from
the control and vaccinated groups, because it is unfair to consider the
incidence of influenza among controls which developed prior to the time
the inoculations were completed in the vaccinated group. Between October
10 and October 24 there were 27 cases of influenza which developed among
the vaccinated, and 30 among the controls, giving a morbidity rate of
3.6 per cent. among the 833 controls, as compared to 4.7 per cent. among
the 565 vaccinated men. Emphasis is laid on the fact that these
morbidity rates were calculated for both groups on the number of cases
that appeared after vaccination had been completed. The result failed to
show protective qualities in the vaccine.
Influenza vaccines for prophylaxis were also prepared in great
quantities by the New York City Board of Health, and were made under the
direction of W. H. Parke. No reports on the value of their vaccines have
as yet appeared, and the writer has been unsuccessful in obtaining any
data on the matter. The Parke vaccine was made in the following way: A
large number of strains of Pfeiffer bacilli were isolated from cases of
influenza during the epidemic. These were grown on a veal infusion agar
containing 1 per cent. peptone, 0.5 per cent. of sodium chloride, 5 per
cent. chemically pure glycerin, and the reaction of which was made
neutral to phenolthalein in the cold. The agar was melted, and from 3
per cent. to 5 per cent. of citrated horse blood was added to it at a
temperature above 95° C. The media was then slanted and cooled in 6 × 1
inch test tubes. Most of the vaccines contained about 17 different
strains of Pfeiffer bacilli. The strains were inoculated separately on a
series of slants, and at the end of 24 hours the cultures were washed
off with sterile water and the washings from each series were placed in
a separate bottle. Smears were then made to determine whether or not
gram positive organisms were present, and as soon as each bottle was
found to be free from contamination the contents were pipetted off into
a 1,000 c.c. flask, and the dilution with sterile salt solution
containing 0.25 per cent. phenol made. All of the strains were mixed
together in the large flask. A sample was then removed for
standardization by Wright’s method, and the flask was submerged for one
hour in water at 53° C. Transplants for sterility were made and watched
for 48 hours. The vaccine was then diluted so that each cubic centimeter
contained 1,000,000,000 Pfeiffer bacilli. Prophylactic vaccination was
carried out by giving ½ c.c., 1 c.c. and 1½ c.c. doses at seven-day
intervals.
_Author’s Vaccine_
At the request of the Department of Public Health of the city of
Pittsburgh, the writer undertook to prepare Parke’s vaccine in large
quantities. The vaccine was to be prepared under the direction of a
committee consisting of Drs. Oskar Klotz, W. L. Holman, E. W. Willetts,
George L. Hoffman and the writer, and the vaccine was to be turned over
to the City Health authorities for distribution in the community. The
work was carried out at the Singer Memorial Laboratory, and was begun
the same day that the committee was appointed. Thirteen strains of
Pfeiffer bacilli were used. Holman contributed six strains, isolated at
autopsies done by Klotz at the Magee Hospital. Other fresh cultures were
furnished by Willetts; Wiese, of the City Laboratory, and by the Singer
Laboratory. The media used was that recommended by the New York Board of
Health, save that sheep’s blood was used instead of horse blood because
of convenience. The same technique was employed, with the exception that
a modification of the Hopkins method of standardization was used instead
of the Wright method. This was done because Pfeiffer bacilli are
extremely small, tend to form unbreakable clumps and tangles, and so
increase the difficulties of making satisfactory counts, either by means
of the Wright method or with the Helber-Glynn counting chamber, that the
methods are independable. Opalescent standards permit of such enormous
variations that it was decided to use the Hopkins method, or a slight
modification which we found so satisfactory that we will give our method
here in detail.
_Method of Standardization_
When the sample was removed for standardization it contained not only a
thick suspension of Pfeiffer bacilli, but also bits of agar and
blood-stained debris. It was necessary to rid the suspension of the
gross contamination, and this was done at first by filtering it through
sterile glass wool filters, and later by centrifuging it at slow speed
for about 10 minutes. The suspension then contained little but the
Pfeiffer bacilli, and was placed in the Hopkins tube and centrifuged for
½ hour on the sixth contact of the rheostat. This gave the per cent. of
Pfeiffer bacilli in the suspension, and the necessary dilutions to make
1,000,000,000 per cubic centimeter were readily determined. The Hopkins
tube consists of a centrifuge tube, with a capillary tube sealed on at
the smaller end. The centrifuge tube is graduated in 10 c.c., 5 c.c. and
1 c.c. amounts, and the capillary portion is graduated in 0.01, 0.02,
0.03, 0.04 and 0.05 c.c. amounts. To standardize the vaccine, 10 c.c. of
the sample was centrifuged in the tube and the amount of sediment read
on the capillary scale. If the amount of bacilli fell between the
graduations, an additional amount of sample was added, so that the
sediment reached one of the graduated lines, the exact amount of sample
added being noted. The percentage of the suspension could thus be
determined by dividing the number of c.c. of sample used into the amount
of the sediment obtained, and the number of bacteria calculated
according to Hopkins table. The table available to us did not list the
Pfeiffer bacillus, but according to it a 1 per cent. suspension of
staphylococcus contains 10 billion organisms to the cubic centimeter,
and we estimated that Pfeiffer bacilli were about half the size of
staphylococci. This assumption was borne out by a number of Wright’s
method counts on standardized suspension of bacilli. We, therefore,
calculated that a 1 per cent. suspension of Pfeiffer bacilli should
contain about 20 million organisms. Then, if 10 c.c. contain 0.02 c.c.
of bacterial sediment, the per cent. was calculated by taking 0.02/10 =
0.2 per cent., the strength of the suspension. If 1 per cent. contains
20 billion, then 0.2 per cent. contains 4 billion per c.c. In order to
get a 100 million per c.c. suspension, it would be necessary to dilute
the original suspension 40 times.
Every method of standardization is more or less inaccurate, but the
above described method gave a fairly uniform product. Drying and
weighing is claimed by many to be more accurate, but even with this
procedure a fair amount of non-bacterial sediment is present in the
material to be weighed.
After the vaccine was completed, cultures were made from the final
dilutions and were watched for 48 hours. Mice and guinea pigs were
injected with the first samples to make certain that the material was
non-toxic. Two laboratory employees also volunteered and received full
doses before the first batch of vaccine was released. The first five
litres were turned over to the Red Cross on October 31, one week from
the day the work was begun. In three more days the laboratory reached a
capacity of 10 litres a day, and on the fifth day the order was received
to discontinue preparation of the vaccine.
Relatively little of our vaccine was given out, and in the rush it was
not possible to determine which physicians had been given our vaccine
and which had received commercial mixed products, so there is no data on
its protective powers.
As soon as we found that there was no call for prophylactic vaccines, we
planned some animal experiments; but inasmuch as we were unable to get
our cultures of Pfeiffer bacilli virulent enough to kill mice or guinea
pigs, the minimum lethal dose could not be determined, and without it it
was impossible to determine the protective value of the vaccine. Mr.
Purwin, in our laboratory, injected a 25–gram mouse intravenously with 2
c.c. of a milk thick suspension of Pfeiffer bacilli without killing the
animal. He was successful in getting a small needle into the tail vein
and in slowly injecting the whole amount. The mouse was sick for about
36 hours, but entirely recovered. Guinea pigs were insusceptible to very
large doses. Had we succeeded by means of a vaccine in completely
immunizing a man against Pfeiffer bacilli, we still would have been
uncertain that he was immune to influenza in its “epidemic” form.
The absence of virulence in our laboratory strains may not mean that the
cultures were non-virulent when first isolated, but it suggests the
uselessness of attempting to make active vaccines from strains kept on
artificial media for months or years, such as those commonly offered for
sale by commercial houses.
The loss of virulence in strains that have been isolated for some time
is interesting in the light of Parker’s (12) work upon toxine production
by Pfeiffer bacilli. She found that toxic filtrates appeared in infusion
broth cultures in from 6 to 8 hours, and that 2 c.c. of a 20–hour
filtrate would kill a medium-sized rabbit in from 1 to 3 hours. It was
also found that the poison deteriorated so rapidly that, in order to
determine its toxicity, the tests had to be made on the same day that
the filtrate was obtained. Parker succeeded in making an anti-serum
against the poison, which appeared to be antitoxic for it both in vitro
and in vivo. This work is interesting, and may be a step toward the
development of a practical prophylactic serum.
_Conclusion_
From the above data, it is apparent that there is very little to
indicate that an immunity to epidemic influenza is conferred by the use
of a prophylactic vaccine composed of inert Pfeiffer bacilli alone. If a
desirable vaccine is to be obtained through the use of these organisms,
there must be radical changes in the mode of preparation of the vaccine
or in the size of the doses given.
_The Attempt to Protect Against Epidemic Influenza by the Use of Mixed
Vaccines_
For some years commercial houses have been carrying mixed vaccines for
the treatment of colds, which they called influenza vaccines. These
preparations were made up usually of six or more different varieties of
bacteria, and all of them were of similar composition. There was more or
less variation in the doses, both as far as the total number of bacteria
and the relative number of the different types were concerned. A typical
example of a so-called “mixed influenza vaccine” may be given about as
follows:
B. Influenza (Pfeiffer) 25 to 400 million per c.c.
M. Catarrhalis 25 to 400 million per c.c.
B. Friedlander 25 to 400 million per c.c.
Pneumococci 25 to 400 million per c.c.
Streptococci 25 to 400 million per c.c.
Staph. Albus-Aureus 50 to 800 million per c.c.
——— ————
Totals 175 to 2800 million per c.c.
These vaccines were recommended in the various catalogues for use either
alone or together with other vaccines in the prophylaxis and treatment
of common colds, and in acute and chronic diseases of the respiratory
tract. As a matter of fact, they had been used very little in
prophylaxis, and had failed to show very much value in treatment. In
discussing these vaccines from the standpoint of treatment, R. M. Pearce
(13) had the following to say: “A mixed vaccine for common ‘colds’
containing several organisms (staphylococcus, streptococcus,
pneumococcus, micrococcus catarrhalis group, bacillus of Friedlander
group, diphtheroid group, bacillus influenza) is one of the most recent
bacterial ‘shotgun’ mixtures, which takes the chance of one lucky
bull’s-eye in seven shots.” “No one can claim a scientific or even a
common-sense basis for the treatment of a cold by such a mixture.”
Catarrhal mixed vaccines of a similar kind were refused acceptance by
the committee on “New and Non-efficial Remedies” of the American Medical
Association, in June, 1918 (14), on the grounds that insufficient
evidence of their therapeutic value had been furnished by their
manufacturers.
While the above illustrates the status of “mixed vaccine” for
therapeutic purposes, it is a well-recognized fact that it is possible
to produce an immunity for most of the bacteria composing such vaccines,
if killed cultures of the various strains are injected in sufficiently
large doses. Again referring to Pearce’s article, we find the statement:
“Prophylactic vaccination rests on a sound, scientific basis of
experimental studies and clinical observation.”
The attempt to protect against epidemic influenza by the use of mixed
vaccines was based largely on the following points. The medical
profession was confronted by a rapidly approaching deadly epidemic,
against which ordinary measures of control had failed. The epidemic was
supposed to be due to a primary infection with Pfeiffer’s bacillus, but
all of the fatal cases were found to have profound secondary or
symbiotic infections, with one or more of the strains contained in the
“mixed vaccines.” It was known that mixed bacterial proteins, even
though they were not actually specific, possessed certain qualities of
producing reactions unfavorable to infections in general, which were
characterized by a temporary rise in temperature, by an increase in the
number of leucocytes, and by a more or less demonstrable amount of
active immunity against each one of the contained bacterial toxins. The
artificial production of a leucocytosis was especially desirable,
because a characteristic of epidemic influenza was the failure of
leucocytosis on the part of the infected individual. In other words,
mixed vaccines were used because they were the only available substances
which offered the hope of creating a reaction against the secondary
invaders which were so commonly the cause of death in influenza.
Since Pittsburgh’s experience with prophylactic vaccination had chiefly
to do with the use of commercially prepared mixed vaccines, a brief
history of the local experience with them may be of interest.
About the time that the first cases of influenza were being reported
from the Pittsburgh district, articles on preventive vaccines as used in
Boston and at some of the camps began to appear in the daily papers,
shortly after which came the announcement that the Carnegie Steel
Company was offering free vaccination to their employees and to the
families of their employees. Dr. W. O. Sherman, chief surgeon for the
company, advocated the use of the vaccine because he hoped to increase
the immunity to secondary infection and to produce an active
leucocytosis in the vaccinated individuals, and at the same time to
allay panic among the employees at a time when an interruption of
manufacturing and mining pursuits might be disastrous to the entire
country; and he did it with the assurance that if the vaccine did no
good, it would at least do no harm. He took steps to arrange for the
collection of data by which he hoped to determine whether or not the
vaccine as used by their company did any good. His report has not yet
appeared. Other large corporations at once instituted prophylactic
vaccinations with commercial “mixed vaccines.”
In contrast to the altogether laudable efforts of these companies to
protect their employees, a complete history of the vaccine episode in
this community necessitates the recounting of a very different phase in
the matter. When it became known that corporations were vaccinating
their employees, people in general naturally began to investigate.
Physicians’ offices were besieged by persons who either demanded
vaccination at once or wanted to know whether or not there was “anything
in it.” Conscientious physicians in their turn called up the offices of
the medical societies, the various laboratories, and telegraphed
everywhere trying to get some definite data before recommending the
vaccine to their patients. It was impossible to answer the question
definitely, because it was a new procedure and purely in the
experimental stage. On the whole, the medical profession handled the
situation in a competent and dignified manner, for the great majority
gave vaccines only after a full explanation to the effect that its value
was in doubt, or else refused to give it altogether. There were some,
however, who were not conscientious, and the unscrupulous practitioner
seldom had a better chance to impose upon the public. The demand for
vaccine soon exceeded the supply, and it is claimed that there were
doctors who gave any type of vaccine they could obtain without regard to
its bacterial make-up or intended purpose. Anti-diphtheritic serum was
given in many instances, and it is said that even normal salt was used.
Statements to the effect that exorbitant sums were being charged and
that guarantees of prevention were being made resulted in the Red Cross
Society undertaking the distribution of the vaccine. To protect itself,
the Medical Society issued the following notice in the weekly bulletin
for October 26, 1918:
The Society wishes it understood that at present there is no vaccine,
serum or inoculation which will secure anyone against influenza. It is
desirable that everyone should avoid hysteria and consider only the
reports which are officially given out by the Health Department, since
of late various methods of prophylaxis and treatment have found their
way into the daily newspapers, and these may prove harmful rather than
do good.
Almost simultaneously the daily papers published the report of
Surgeon-General Blue, of the United States Bureau of Public Health,
which expressed practically the same opinion. It was not the intention
of either of these articles to criticise the practice of vaccination,
but merely to warn the public against profiteering and fraudulent
guarantees. They had the unexpected effect, however, of causing people
to completely lose faith in prophylactic vaccines, and in many instances
to become actually antagonistic to them. It was during this period that
the preparation of vaccines from pure influenza strains was undertaken,
under supervision of the County Society and for distribution through the
Department of Public Health. Two days after the first supply of this
vaccine was ready the Red Cross authorities telephoned that there was no
further call for vaccine. The man in charge of the distribution stated
concretely that “the bottom had dropped out of the vaccine business.” A
few days later the Department of Health issued an order to stop the
preparation of the vaccine.
Many pharmacies, having small supplies of vaccines, realized the great
call for it and the difficulty of obtaining a new supply, and were also
guilty of commercialism. Certain of the large biological product
companies were no exception. One house issued a hand-bill, printed in
red on a yellow background, which stated: “Epidemic influenza is due to
the influenza bacillus. The present epidemic of influenza has a tendency
to develop pneumonia. The use of our influenza bacillus vaccine No. ——
will abort the influenza and avoid pneumonia and other sequelæ. When
pneumonia has developed, it can be reduced to less than one-third the
mortality and duration usual with other methods of treatment,” etc.
Practically all of the above statements are still unproven, and probably
will never be shown to be true. Such a bulletin undoubtedly lays this
firm of vaccine manufacturers open to prosecution under the law
protecting against false and fraudulent advertising. Several fairly
well-authenticated incidents occurred in which the representatives of
vaccine houses offered factory managers and others share and share alike
in the profits, if the brand of vaccine made by them was used. It is on
such happenings as the above that the writer advocates legal measures,
allowing Boards of Health to control the advertising of remedies and
distribution of biological products during epidemics.
How much Pittsburgh will learn from the experience with vaccines will
depend on the numerous analyses of data which were acquired during the
epidemic.
_Data on the Prophylactic Value of Mixed Vaccines_
Proof of the prophylactic value of mixed vaccines for epidemic influenza
depends entirely upon the results of its practical application to human
subjects in times when the disease is prevalent. Animal determinations
are out of the question, because it has not been possible to produce the
epidemic form of influenza experimentally. If all people were equally
susceptible and were equally exposed, it would be a simple matter to
compare the number of vaccinated persons who developed the disease with
the number of unvaccinated persons who contracted it; but since many
thousands were vaccinated and some of them contracted the disease in
spite of it, and a greater number of persons who were not vaccinated
entirely escaped, the analysis is extremely difficult.
The time element is a big factor. In instances where vaccination was
completed in a community before the epidemic appeared there, the figures
are worth more than those in which vaccination was undertaken after the
epidemic had become established. This is true, because the most
susceptible persons in a community developed the disease as soon as they
were exposed, the less susceptible ones were not attacked until later,
and the insusceptible ones escaped altogether. Whenever vaccination is
begun during an epidemic, the persons vaccinated for prophylactic
purposes are necessarily chosen from those who have not yet developed an
attack. The later in the epidemic that vaccination is begun, the greater
will be the number of persons selected for vaccination from among those
more or less naturally immune. Then, if the total number of cases among
the vaccinated is compared with the total number of cases among the
unvaccinated, the apparent value of the vaccine is increased; but the
estimation is not a fair one, because the vaccinated group is
unavoidably selected from among relatively immune persons, while the
controls include all of the very susceptible people who were suffering
from the disease at the time vaccination was begun. Where vaccination is
begun after the epidemic is advanced, the only figures worth while are
those obtained by a day-by-day or a week-by-week comparison between the
number of cases developing among controls and the number of cases
appearing among those vaccinated, and by beginning that comparison at a
time subsequent to the day on which the prophylactic inoculations were
completed.
Aside from the interpretation of the results there is possibly a more
serious reason for objecting to the beginning of vaccination during an
epidemic. This lies in the danger of producing a temporary negative
phase in the patient, which makes him somewhat more susceptible to
natural infection for a few hours immediately following each
administration.
McCoy (15) outlined the requirements necessary for an ideal vaccine
experiment as follows: 1. The community should be as large as possible,
and should number at least 10,000 persons. 2. The conditions under which
they live should be as nearly equal as possible. 3. The turnover, or
rather the change in population, should be as small as possible. 4. The
social service should be efficient and reliable, so that it can be
definitely ascertained when anyone becomes sick and what the disease is
from which he is suffering. 5. Fifty per cent. should be vaccinated
before the epidemic arrives, and the other 50 per cent. should be held
as controls.
No examples were found which came up to the above requirements, but
there were some instances in which vaccination was completed before the
epidemic appeared, and some in which we were able to get a week-by-week
comparison between vaccinated and unvaccinated groups. Most of the data
which has been reported shows that vaccination was begun about the last
of the second or the first of the third week of the epidemic, and in
some instances not until after the peak was passed. Add to this the fact
that the vaccine was given in from three to four doses, at from three to
seven day intervals—a course which required in the neighborhood of two
weeks for completion—and it is obvious that the full protective powers
of the vaccine were not acquired by the individual until the worst of
the epidemic was over and the number of cases were rapidly subsiding.
In order to get the best understanding from these experiments, the data
will be presented in three series: I. Those instances in which
vaccination was completed before the epidemic appeared. II. Those
instances in which it is possible to compare the relative occurrence of
influenza in both the vaccinated and unvaccinated groups after
vaccination was completed. III. Those instances in which vaccination was
begun after the epidemic appeared and in which comparisons of total
figures only are available.
_Series I. Those Instances in Which Vaccination Was Completed Before the
Epidemic Appeared_
1. The only instance in the Pittsburgh community in which vaccination
was completed before the epidemic appeared is that reported from the
Dixmont Hospital, Dixmont, Pa., and furnished me through the courtesy of
Dr. Hutchinson (16). The institution had a population of about 1,000
patients and 300 employees. Prophylactic vaccination was begun on
October 20, and was completed about November 6. Each c.c. of the vaccine
used contained 200,000,000 each of B. Pfeiffer, Micrococcus Catarrhalis,
B. Friedlander, Pneumococci, Streptococci and Staphylococci, both Aureus
and Albus. Four doses were given of 4 minims, 8 minims, 12 minims and 16
minims, respectively. Inoculations were carried out at four-day
intervals. Owing to the isolation of the institution from the general
community, the first case did not appear until two weeks later—namely,
on November 20. The results are shown by the table.
Population. No. of % of No. of % of
Cases. Cases. Deaths. Deaths.
Vaccinated 600 44 7.3% 0 0%
Unvaccinated 700 69 9.8% 9 1.2%
None of the vaccinated patients developed pneumonia, though there were
15 cases among the unvaccinated.
This experiment shows a slight percentage in favor of vaccination, and
indicates that there was some decrease in the severity of the secondary
infections.
2. The experiment reported by McCoy, Murray and Teeter (17) showed quite
opposite results from the above, and was an excellent example of a small
though completely controlled test. In an asylum for the insane in San
Francisco all of the patients under 41 years of age were divided into
two groups—one group was kept as controls and the other was given a
vaccine furnished by F. O. Tonney, of the Chicago Health Department. The
vaccine contained 500,000,000 each of B. Influenza, Pneumococcus I, II
and III, 1,500,000,000 Pneumococcus IV, 1,000,000,000 Streptococcus
Hæmolyticus and 500,000,000 Staphylococci. Doses of 0.5 c.c., 1 c.c. and
1½ c.c., which were given at 48–hour intervals. Inoculation was
completed on November 15, and the first case of influenza appeared on
November 26. The table shows the result.
Vaccinated. Not Vaccinated.
Persons in group 390 390
Cases of influenza 119 103
Cases of pneumonia 23 17
Number of deaths 10 7
3. The report of Minaker and Irvine (18) included several groups of men,
the first two of which apparently belonged in our first series. They
used a vaccine, each c.c. of which contained 5,000,000,000 B. Pfeiffer,
3,000,000,000 each of Pneumococcus I and II, 1,000,000,000 Pneumococcus
III, 100,000,000 Streptococcus Hæmolyticus. In all, they vaccinated
11,179 persons.
(a) Their first group numbered 4,950 persons in quarantine at the Naval
Training Station. The quarantine was maintained for 24 days, and no
influenza appeared during that time. Three thousand five hundred and
fourteen of them were released at a time when there were still 200 to
300 cases of influenza being reported daily in San Francisco. Out of the
3,514 men, 15 had influenza, and there were no deaths.
(b) At the Mare Island Navy Yards 1,950 marines were released
immediately after completion of the inoculation. They were turned into
Valejo and San Francisco, where influenza was at its height. Only 35
cases, with 1 death, occurred, and these developed shortly after the men
were released in San Francisco. This group was controlled with an
unvaccinated group of 8,232 persons who remained at Mare Island, and
1,296 cases of influenza, with 65 deaths, occurred among the controls.
(c) At San Pedro 3,100 were vaccinated, and of these 53 had influenza,
and there were no deaths. The occurrence among these was compared with
the prevalence of the disease in Los Angeles, but this part of the
report leaves much to be desired in the way of the relative dates, etc.
(d) The fourth group, consisting of 1,080 civilians, developed 14 cases,
with no deaths. However, vaccination of this group was not completed
until 21 days after the pandemic had appeared in the community.
Minaker’s and Irvine’s analyses show a favorable percentage for
vaccination in the first two groups, but their groups three and four
were not sufficiently well controlled to be of much help.
4. In a report which appeared during October, 1918, Eyer and Lowe (29)
published the results of prophylactic inoculation of 1,000 New Zealand
troops with a mixed catarrhal vaccine. They controlled their experiments
with 19,000 New Zealand troops who were not inoculated. A comparison of
the incidence of acute respiratory disease and influenza during the
primary wave of the epidemic as it appeared during June and July, gave
two cases among the vaccinated troops and an average of 43.2 cases per
thousand among the controls.
Later they reported (58) the results of much larger experiments as
carried out at 17 different camps and hospitals. The vaccine which they
used was a typical “mixed” vaccine, save that the authors emphasized the
advantage of using strains not more than three generations removed from
the body. At some of the camps their reports were unfavorable, but upon
the whole their results, as summarized below, were most encouraging. In
most instances inoculations were completed just prior to the arrival of
the autumn epidemic.
Out of a total average strength of 21,759, approximately 16,104 men
received full prophylactic vaccination, and approximately 5,700 were
uninoculated, or had received only 1 dose; 3,366 cases of influenza
developed—15 per cent.; 1.3 per cent. occurred among the vaccinated,
while 4.1 per cent. developed in the uninoculated; 8 per cent. of the
severe cases among the protected died, as compared to 23 per cent. among
the uninoculated. The death rate for all infected cases was 0.26 per
cent. among the inoculated and 2.2 per cent. among the uninoculated.
NOTANDA.—All of the above reports, comprising the “Series I”
experiments, indicate that mixed vaccines reduced the number of severe
illnesses and lowered the death rate to some extent.
_Series II. Those Instances in Which It Is Possible to Compare the
Relative Occurrence in Both Vaccinated and Unvaccinated Groups After
Vaccination Was Completed_
1. The report on prophylactic vaccination at the Hospital for the Insane
at Retreat, Pa., was very kindly furnished by Dr. Charles B. Maberry
(20). When the epidemic approached, the institution was placed in
quarantine and remained free from influenza until October 28, when two
cases appeared in nurses who had broken quarantine. Influenza spread in
the male ward, but the female wards were kept free during the whole of
the epidemic. There were 370 male patients, but 60 were in the infirmary
and were not included in the calculation. Out of 310 patients, 210
received vaccines. Ordinary commercial mixed vaccine was used, and
vaccination was begun two days after influenza appeared. During the
first week there were 40 cases of influenza, 6 of which occurred among
those who had received a single dose of the vaccine. After the first
week there were 38 cases of influenza, with 10 pneumonias and 5 deaths,
among the unvaccinated, giving a morbidity rate of 38 per cent. and a
mortality rate of 5 per cent. In the vaccinated group there were no
cases after vaccination was completed. Maberry states further that in
ward III the only cases which appeared subsequent to vaccination were in
six patients who refused preventive inoculations. This appears to be the
most favorable of any of the reports.
2. Nurses on duty in hospitals everywhere suffered greatly from
influenza, and those of Pittsburgh were no exception. Some of the
hospitals vaccinated the nurses during the epidemic and some did not,
and it was hoped that by getting a week-by-week comparison of the number
of cases among vaccinated and non-vaccinated nurses some reliable data
would be obtained. A circular letter sent to all of the hospitals in the
community contained a blank asking for the number of nurses, date of
appearance of the epidemic, use of vaccine, dates of inoculations, and
for a week-by-week occurrence of influenza in each group. Only 7
hospitals complied with the request, and of them only 5 sent complete
data. Complete reports were received from the Allegheny General,
Columbia, Presbyterian, South Side and St. Francis Hospitals. Of a total
of 336 nurses in these 5 institutions, 38 developed influenza in the
first week, 48 in the second, 39 in the third, 43 in the fourth, and 45
subsequent to the fourth week, making a total of 213—a morbidity of 63
per cent. The Mercy and St. Margaret’s Hospitals reported the total
number of nurses and the occurrence of influenza among them, and adding
in their reports there were 521 nurses on duty in 7 hospitals, with 257
cases of influenza, giving a morbidity rate of 50 per cent.; 28 cases of
pneumonia and 11 deaths, giving a 2 per cent. mortality rate. The total
figures from hospitals where vaccines were used are against vaccination,
due partly to the fact that vaccination was started late. In these
hospitals the morbidity was 66 per cent. and the death rate 3 per cent.
In the hospitals where vaccines were not used the morbidity rate was 20
per cent. and the death rate 1.2 per cent. No dependable data was
obtained, but the report from the South Side Hospital was interesting.
Of 60 nurses on duty, 36 had influenza and 2 died. Of this number 19
were stricken the first week. Three days after the first cases were
admitted to the hospital vaccination was begun, and was given to most of
the nurses still on duty. Of those taking vaccines 20 developed
influenza and 1 died during the period of immunization, but after the
inoculations were completed there were no more cases in either group.
During the epidemic it was said that benefit was derived from the use of
vaccines on nurses at the West Penn Hospital, but the writer was unable
to obtain a report from this institution. The collected data on nurses
was useless, though it is interesting, in that it shows the possibility
of making figures prove almost anything you want them to prove.
_Series III. Those Instances in Which Vaccination Was Begun After the
Epidemic Appeared, and in Which Comparisons of Total Figures Only Are
Available_
Undoubtedly the largest attempt at prophylaxis against epidemic
influenza through the use of “mixed vaccines” was that made under the
direction of Dr. W. O. Sherman for the Carnegie Steel and H. C. Frick
Coke Companies. The results which Dr. Sherman hoped to attain when he
planned using the vaccine and collecting the data have already been
given. Commercial mixed vaccines similar to those described under the
“Series I” experiment were used, and four doses, three days apart, were
given. Inoculations were begun on October 20, 1918, and were completed
during the first week of November. Vaccine was administered to the
employees and their families without charge. Later cards were given to
all employees, and they were made to fill them out and return them. On
the cards were blanks calling for the name, age, sex, color, number of
inoculations, whether or not the employee himself or any member of his
family had had influenza, and how many days the sick individuals had
been in bed. Each mill and mine was then supplied with a set of blank
forms providing for a complete statistical record of the number of
inoculations and the total incidence of influenza, pneumonia and death.
From the reports of the respective mills and mines the total figures
given in the charts were compiled.
Difficulties were encountered in every part of the work. The vaccine
demand was so great that the products of three different firms were
used. So many doctors were in service that most of the vaccine had to be
given by carefully coached nurses. The bulletins of the United States
Bureau of Public Health and of the Allegheny County Medical Society,
with their warnings about influenza vaccines being only in the
experimental stage, appeared just at the time the work was begun and
caused a great many to refuse to complete vaccination after one or two
doses had been given. So few medical men were left that it was
impossible to have them see all cases and so determine the nature of
many of the illnesses which were occurring. It was assumed, therefore,
that any employee who had fever and was sick for a period of three days
had influenza, and that any who were confined to bed for seven days or
more had pneumonia. The figures of the central offices were made up from
the reports of 14 steel mills, 1 cement factory, 4 warehouses and 57
mining districts. The accuracy of data depended on the careful work of a
great many local statistical workers, which made individual variations
hard to control. The greatest difficulty of all, however, lay in finding
a common basis for comparisons of the incidence of influenza, pneumonia
and death in the vaccinated and non-vaccinated groups, since the data on
the former group included the occurrence only after the peak of the
epidemic had been passed, and that of the latter group included the
occurrence for the entire epidemic.
The total figures are given in the three charts.