Part 16

───────────────────────────────┬────────────┬───────────┬─────────── EMPLOYEES │ MORBIDITY │ PNEUMONIA │ MORTALITY ───────────────────────────────┼──────┬─────┼─────┬─────┼─────┬───── │ No. │ % │ No. │ % │ No. │ % ───────────────────────────────┼──────┼─────┼─────┼─────┼─────┼───── Received only one dose 3,895│ 511│13.13│ 31│ 0.8│ 28│ 0.72 Received only two doses 3,329│ 414│12.44│ 40│ 1.2│ 19│ 0.57 Received all three doses 9,897│ 468│ 4.75│ 46│ 0.46│ 32│ 0.32 ───────────────────────────────┼──────┼─────┼─────┼─────┼─────┼───── Total of above 17,119│ 1393│ 8.14│ 117│ 0.68│ 79│ 0.46 Received no doses 10,036│ 1522│15.17│ 154│ 1.53│ 106│ 1.06 ───────────────────────────────┼──────┼─────┼─────┼─────┼─────┼───── Total for both groups 27,155│ 2915│11.66│ 271│ 1.10│ 185│ 0.76 ───────────────────────────────┴──────┴─────┴─────┴─────┴─────┴─────

Before satisfactory conclusions can be drawn from these figures it is necessary to know how many of the 10,036 persons became sick before vaccination, and whether or not the rate of decrease in this group was not similar to that shown by the number of patients who developed influenza during the intervals between their doses of vaccine. The relatively high percentage of cases following the first and second doses are capable of explanation on one, or perhaps on all, of the three following grounds: (a) the general subsidence of the epidemic, which showed a rapid decrease by the time the third dose was given; (b) the increased protection afforded by the three doses of vaccine, and (c) the broken resistance of the patient following sudden sensitization by the vaccine.

3. Rosenow (21) prepared a mixed vaccine by growing the various bacteria in glucose broth, for from 18 hours to 36 hours, centrifuging and suspending the sediment in salt solution and making up the vaccine on a percentage basis.

FORMULA OF VACCINE

Pneumococci, Types I (10 per cent.), II (14 per cent.) and III (6 per cent.) 30 per cent. Pneumococci Group IV and the allied green-producingdiplostreptococci described 30 per cent. Hemolytic Streptococci 20 per cent. Staphylococcus Aureus 10 per cent. Influenza bacillus 10 per cent.

Most of the vaccine was distributed within a radius of 200 miles of Rochester, Minn., but samples were furnished to physicians all over the country, who agreed to return statistics on its use. No evidence was found that this vaccine caused a temporary break in the resistance of the user. Out of a total of 20,972 persons vaccinated, 14.6 cases of influenza, 1.8 cases of pneumonia, with 1.8 mortality, occurred per thousand in the six weeks following vaccination. As controls, he took “such persons in institutions, colleges, factories and communities where vaccine was used, and included only those reports which contained accurate data as to the incidence and mortality among them.” Among 61,753 such controls he found 229 cases of influenza, 15.7 cases of pneumonia and 3.4 deaths per thousand. He concluded from his results that “it appears possible to afford a definite degree of immunity by prophylactic inoculations to persons against the more serious respiratory infections during the present epidemic.” It is quite difficult to agree with Rosenow in his interpretation of the figures as presented by him, inasmuch as he made no allowance for the stage of the epidemic at which vaccination was carried out, either among the vaccinated or the non-vaccinated. Such a comparison would be well nigh impossible where the vaccine was sent in varying quantities to such a large number of places.

4. League Island Report (22). Vaccines were used as a preventive in 50 persons, most of whom were hospital apprentices and in the wards 12 to 15 hours a day. Other precautions were used, such as masks, but not a single case developed in the group. The vaccine was used as a curative agent in 50 uncomplicated cases; none of the patients injected early developed pneumonia.

5. Puget Sound Navy Yards Report (23). The vaccine used at this station was made from hæmolytic streptococci, no other organisms being used; 4,212 men were vaccinated, and not one died from influenza. Among 111 Philippinos isolated and vaccinated there occurred only 2 cases. Among 361 marines vaccinated early there occurred 2 cases. Among 62 marines at the ammunition depot who were vaccinated early there occurred 3 cases, only 1 of which occurred after completion of vaccination. Among 662 bluejackets at Seattle Training Camp only 10 men developed the disease. Among 83 at the aviation corps there were 32 cases—31 of them developed the disease within a few hours after the first injection. There were no deaths in any of the above groups. The period of observation was closed on October 21, and so few cases of influenza appeared subsequent to that date that it seemed that the epidemic was practically over at the time the data was obtained.

6. Kitano (24) used a vaccine for prophylaxis containing 0.2 m.g. of Pfeiffer bacilli per c.c. on 10,300 persons with encouraging results. He used vaccine for treatment on 87 patients, without any deaths. In the same group were 270 cases treated in the usual way, with 23 per cent. mortality. The vaccine lessened the severity, shortened the period of illness, and lowered the mortality.

7. Wynn (25) used mixed vaccines in the treatment of influenza, and believed they aborted the disease if given early.

8. Norman White (26) states that vaccination in India would be impractical, because the disease is so brief and severe that it would be over before innumerable doctors could complete inoculations.

9. Whitingham and Sims (27) reported the use of a mixed vaccine in an institution where 156 were inoculated and 149 were not. The case incidence was 5 per cent. among the vaccinated and 12 per cent. among the controls. No statement of the stage of the epidemic at which vaccination was done is mentioned in the report.

10. Cadham (28) reported on inoculations in a military hospital and in the civilian population near Winnipeg. Of 282 vaccinated soldiers admitted to the hospital, 17 had pneumonia and 5 died. Of 238 not vaccinated, 41 had pneumonia and 17 died. Among 24,184 civilians given two doses, 9.7 per cent. had influenza and 0.5 per cent. had pneumonia and 0.09 per cent. died. Among 85,941 controls, 24.8 per cent. had influenza, 2.2 per cent. pneumonia and 0.66 per cent. died. Cadham states that most of the inoculations were made early in the epidemic, but no accurate statistics were kept on the point.

11. A conference was held at the British War Office on October 14, 1918 (30), to discuss prophylactic vaccination and vaccines for treatment of influenza. Elaborate plans regarding dosage and gathering of statistics were made.

NOTANDA.—For reasons already given, the reports in Series III fail to give very reliable data on which to base a knowledge of the value of preventive vaccination against epidemic influenza.

The Attempt to Prevent Pneumonia as a Complication of Influenza Through the Use of Lipovaccine

Whitmore, Fennel and Peterson (31) developed a method of preparing an oily suspension of killed bacteria which they called “lipovaccine.” The method was used at first in making typhoid and dysentery vaccines. The advantages of lipovaccines (32) over salt suspensions are: the prevention of autolysis of the bacteria, thus increasing the length of time during which the vaccine remains active; the slow absorption of the dose, allowing the patient to continue to absorb immunity-producing substances over a period of days or weeks; the administration of a single massive dose, which does away with the three doses necessary when salt suspensions are used; and perhaps, also, the direct reduction in the toxicity of the dose by the lipoid material.

Based upon the classification of pneumococci by Dochez and Gillespie (33) in this country, and by Lister (34), (35), (36) in South Africa, and upon the latter’s successful use of anti-pneumonia vaccine on the Rand, an anti-pneumonia lipovaccine was prepared at the Army Medical School which contained approximately 10,000,000,000 each of types I, II and III pneumococci. The vaccine was made by growing the pneumococci in dextrose broth, centrifuging them out of the broth with a sharpless milk centrifuge, drying the sediment at 55° C., weighing it out so that each cubic centimeter of the finished vaccine contains 0.83 m.g. of each type, and making a suspension of them in olive oil. More recently cotton-seed oil has been used.

The result of the use of a salt suspension pneumococcus vaccine at Camp Upton was published by Cecil and Austin (37). A study of the agglutination and protective power of the serum of 42 persons vaccinated against pneumococcus types I, II and III demonstrated that a definite immune response could be secured to types I and II but not to type III. Twelve thousand five hundred and nineteen men were vaccinated at the camp, and most of the men received three or four inoculations at intervals of from five to seven days. The men were under observation for ten weeks, and during that time no cases of pneumonia of the three fixed types occurred among those who had received two or more injections. In a control of approximately 20,000 men there were 26 cases of pneumonia of types I, II and III. The incidence of pneumococcus type IV pneumonia was less among the vaccinated than among the unvaccinated groups. There were, however, 17 cases of pneumonia among the vaccinated men, compared to 173 cases of pneumonia among the controls. The annual pneumonia death rate for vaccinated groups in the army was 0.83 per one thousand, and for unvaccinated groups was 12.8.

Fennell reported the use of pneumo-lipovaccine in Washington during the influenza epidemic, but the number of cases cited by him were too small to permit of definite conclusions. His results appeared favorable.

Cecil and Vaughan (37a) reported on the results of vaccination with pneumo-lipovaccine at Camp Wheeler; 13,460 men, comprising 80 per cent. of the camp, were inoculated. Most of these men were under observation for 2 or 3 months after vaccination, and there occurred among them 32 cases of pneumococcus types I, II and III pneumonia. In one-fifth of the camp which was not vaccinated there occurred 43 cases of pneumonia. They observed that influenza caused a marked reduction in the resistance to pneumonia among vaccinated as well as non-vaccinated men. Of 155 cases of pneumonia of all types, which developed one week or more after vaccination, 133 were secondary to influenza. The death rate among vaccinated men one week or more after vaccination was 12.2 per cent., whereas the death rate for 327 cases of all types of pneumonia which occurred among unvaccinated groups was 22.3 per cent. The death rate for primary pneumonia among vaccinated groups was 11.9 per cent., and among unvaccinated 31.8 per cent. It was found that protective bodies do not begin to appear in the serum after lipovaccines are given until the eighth day after the injection. Twenty-four cases of pneumonia occurred in the first week after vaccination. In their conclusions Cecil and Vaughan state that there was no evidence whatever that pneumococcus vaccine predisposed the individual, even temporarily, toward either pneumococcus or streptococcus pneumonia. Most of the reactions after vaccination were mild, but one disagreeable feature was that in a certain percentage there persisted a small fluctuating mass at the site of the injection. Lacy saw a number of these cysts aspirated, and the contents were found to be a sterile, oily fluid, with many leucocytes present. In one instance the primary reaction disappeared within a few days after vaccination, but recurred after four months and persisted for several weeks.

NOTANDA.—The army lipovaccine apparently offers a certain definite amount of protection against pneumonia, which was the most dangerous complication of influenza. The protective substances do not appear in the serum until eight days have elapsed after the vaccination, and while no definite evidence has appeared to show that there is a temporary increase in susceptibility immediately after vaccination, the best results would undoubtedly be obtained where the dose is given something more than eight days before the appearance of the epidemic. The indications are that the vaccine will not protect against influenza, but that the complication of pneumonia is less likely to occur in the vaccinated than in the unvaccinated individual.

Summary

Records of attempts to confer immunity to influenza by the use of vaccines have been separated into related groups and studied. Those where pure Pfeiffer strains were used have been considered in one group. Those where mixed vaccines were used have been analyzed in three sub-groups or series, depending on the relation between the times of vaccination and of the advent of the epidemic, upon whether or not a week-by-week comparison of the occurrence of influenza among vaccinated and unvaccinated groups was made, and upon whether or not statistics for total comparison alone were available. The third group included the reports of the use of army pneumo-lipovaccines for the prevention of the secondary pneumonia complications of influenza.

Conclusions

From our statistics we conclude that:

1. There is as yet no evidence that vaccines composed purely of strains of Pfeiffer bacilli will confer immunity to epidemic influenza.

2. The only data which can be used as a basis for estimating the value of mixed vaccines as a preventive for epidemic influenza must be obtained from experiments in which vaccination was either completed before the epidemic appeared, or in which week-by-week comparisons between the number of cases occurring in the vaccinated and unvaccinated groups can be made.