U.S. Army Medical Department, Office of Medical History
Skip Navigation, go to content

HISTORY OF THE OFFICE OF MEDICAL HISTORY

AMEDD BIOGRAPHIES

AMEDD CORPS HISTORY

BOOKS AND DOCUMENTS

HISTORICAL ART WORK & IMAGES

MEDICAL MEMOIRS

AMEDD MEDAL OF HONOR RECIPIENTS

ORGANIZATIONAL HISTORIES

THE SURGEONS GENERAL

ANNUAL REPORTS OF THE SURGEON GENERAL

AMEDD UNIT PATCHES AND LINEAGE

THE AMEDD HISTORIAN NEWSLETTER

Chapter VIII

Contents

CHAPTER VIII

(From Preventive Medicine in World War II,
Vol III, Personal Health Measures and Immunization)

The Army Immunization Program

Colonel Arthur P. Long, MC, USA

The Army immunization program was a positive, direct, and specific approach to disease prevention and control. This program as it developed just before and during the war period represented a very considerable expansion of the application of immunization procedures in the Army. The pattern for the extended program was set at an informal meeting of representatives of the medical services of the Army, Navy, and the United States Public Health Service. At this meeting, called by Lt. Col. James S. Simmons (later Brig. Gen.), MC, in the spring of 1940, a general program considered desirable in the event of war was outlined. It was the consensus of the group that tetanus immunization in the Armed Forces should be instituted at the earliest possible date.

The Army immunization program, as it was evolved and applied, required not only the acquisition and application of the best available professional knowledge and techniques but also the rapid development of effective mechanisms to insure adequate administrative control and technical guidance. The general supervision of the Army immunization program was one of the major functions of the Epidemiology Division of the Preventive Medicine Service, Office of The Surgeon General. Many of the technical problems related to this program, as well as the administrative details, were handled by that division. The following is an outline of the activities of the Epidemiology Division in connection with that program:

1. Collection of the necessary information and establishment of policies governing the various immunization procedures.

2. Compilation and publication of general and specific instructions on various administrative and technical matters.

3. Investigation and evaluation of the development and improvement of materials and procedures.

4. Investigation and study of problems arising in connection with the immunization program such as the indications for special immunizations, occurrence of reactions, and efficacy and practicability of various procedures and methods.

5. Provision of technical advice and assistance to the Supply Service, Office of The Surgeon General, with respect to estimates of requirements, procurement, distribution, and storage of prophylactic biologicals.


272

6. Conduct of miscellaneous correspondence with both civilian and military personnel and agencies and with various governmental and civilian groups concerning the immunization program.

It is the purpose of this chapter to present a review of the entire program, to trace as accurately as possible the important steps in the development, adoption, and use of each of the various immunizing procedures authorized by the Army during the war, and to summarize and evaluate the experiences gained. In the interest of uniformity of presentation and to facilitate reference, discussion of the individual procedures will be presented under the general headings of development, and adoption of the immunizing agent, methods and requirements for immunization, and experience with the procedure. While emphasis is given to the developments arising from the demand of mobilization and conduct of the war, those procedures already practiced before the mobilization period are also discussed from the viewpoint of their application during the emergency. In addition to the discussion of the various immunizing agents and their use, an attempt is made to present the salient features of the general administration of the immunization program.

TYPHOID-PARATYPHOID VACCINATION

Development and Adoption

The full history of typhoid vaccination in the Army is a long one1 and need not be recounted here. It is sufficient to state that the regular administration of typhoid vaccine to all Army personnel had been routine since 1911 so that at the beginning of World War II, this practice was almost an Army tradition.

The Immunizing Agent

For many years, including the period of World War I, the typhoid or typhoid-paratyphoid vaccine used in the Army had been that prepared at the Army Medical School. This was continued throughout World War II. These vaccines had undergone changes as to content from time to time, and intensive research and investigation had been continuous. As a result, the production of typhoid vaccine for the expanding Army and such changes as were required to meet the new situation were not new projects, but represented rather expansion and intensification of previous efforts and existing facilities. In 1928 the paratyphoid B fraction contained in the vaccine during World War I was eliminated: the paratyphoid A fraction was discontinued in 1934. From that time until the World War II emergency period, a monovalent vaccine containing Salmonella typhosa organisms only was used.2

    1Siler, Joseph F., and others: Immunization to Typhoid Fever. Baltimore, Johns Hopkins Press, 1941.
    2Ibid.


273

In view of the anticipated increase in field service of troops and likelihood of exposure to enteric organisms, in early 1940 it was considered advisable to readopt a triple or typhoid-paratyphoid vaccine. This decision was reached after careful consideration by a committee representing the Army, Navy, and United States Public Health Service. Acting on the advice of this committee, The Surgeon General on 9 July 1940 instructed the Commandant of the Army Medical School to prepare a typhoid-paratyphoid vaccine for distribution to the Army.3 The triple vaccine was manufactured in September 1940 at which time official announcement of its readoption was made by Circular Letter 67, Office of The Surgeon General, 3 September 1940.

The vaccine contained in each cubic centimeter 1,000 million typhoid bacilli and 250 million each of the paratyphoid A and B components. The S. typhosa strain used was the Panama carrier strain 58 (Army Medical School culture collection No. 42-A-58); the Para B (S. schottmuelleri) organism (Army Medical School culture strain 41-H-6); and the Para A (S. paratyphi), originally Army Medical School strain 41-N-8, but replaced in 1942 by an English strain HA-6 (Army Medical School strain 41-N-22). Since the criteria for the selection of these strains is discussed at length elsewhere,4 as are their characteristics, these will not be presented here. It is enough to state that they represented the most highly immunogenic strains obtainable and were selected on the basis of their virulence, their biochemic behavior and productivity of agglutinins and protective substances, and their production of cross-immunity against other strains of homologous species. These strains were continued in the manufacture of the triple vaccine throughout the war.

On some occasions questions were raised as to the specificity of this vaccine for protection against infection with strains encountered in overseas areas. For example in 1942 the occurrence of three cases of typhoid fever among American troops in India occasioned the recommendation by the surgeon of that theater that typhoid vaccine produced locally be used there in place of the Army Medical School product.5 After study of strains isolated from cases in India and of the Indian-produced vaccine, it was determined that the United States Army vaccine was at least equal to the Indian vaccine in protection against the local strain of typhoid bacillus.

Methods and Requirements

At the beginning of the emergency, the vaccine was given in 3 subcutaneous doses administered at intervals of 7 to 10 days, the 1940 regulation reading ". . . intervals of not less than 5 nor more than 14 days between consecutive

    3Ltr, SG to Commandant Army Med School, 9 Ju1 40, sub: Change in the composition of typhoid vaccine manufactured for use in the U. S. Army. SG: 444.2-1 (AMS) GG.
    4Longfellow, D., and Luippold, G. F.: Immunization to typhoid and paratyphoid fevers. Am. J. Hygiene 38: 139-151, Sep 1943. Also see footnote 1, p. 272.
    5Ltr, Surg CBI Theater to SG, 12 Dec 42, sub: Typhoid fever. HD: 720.3.


274

doses; ordinarily the doses will be spaced at intervals ranging from 7 to 10 days. . . ." The dosage was 0.5 cc. for the first dose and 1 cc. each for the 2 subsequent doses. The interval between series was stipulated as 3 years, with only 2 such series being required under ordinary circumstances. A complete series of 3 injections was required within 1 year of departure for theaters of operations, and provisions were made for revaccination in face of a threatened outbreak (individuals over 45 years of age were exempted from typhoid vaccination except under these circumstances). The method for the accomplishment of the first series of typhoid vaccine injections (the basic immunization) remained unchanged throughout the war except for the required time interval between individual injections. It was soon learned that the requirement of an interval "not to exceed 14 days between doses" was undesirable and impractical when applied to large numbers of troops in a rapidly expanding Army. Frequently, when for one reason or another this interval was extended, literal-minded officers (medical and nonmedical, commissioned and noncommissioned) would require the repetition of the entire series. To correct this undesirable practice, Army regulations governing immunization were revised in 19426 and the circular letter implementing these regulations7 did not state a maximum allowable interval between individual doses, but indicated that the desired interval was 7 to 10 days. If this time were exceeded, the next dose was to be administered as early as possible and the entire series was not to be repeated.

The recommendation concerning the interval between individual injections was again changed in 1944.8 At that time the recommended interval was stated to be from 7 to 28 days. This policy was adopted largely for administrative reasons, chief among which was the desirability of simplifying the immunization schedules for individuals receiving the basic immunizations of typhoid and tetanus at the same time. Under the old system, with typhoid vaccination accomplished at weekly intervals and tetanus toxoid injections spaced every 3 weeks, at least 5 visits to the dispensary or other agency were required. By giving typhoid-paratyphoid vaccine and tetanus toxoid at the same time, a saving of 2 visits could be accomplished. This saving when translated into terms of hundreds of thousands of individuals was an extremely significant one. There was little hesitancy to accept this change of policy, from a technical point of view, since the 1-week interval was originally based on administrative grounds only and it is an accepted principle that in general and within reasonable limits the immunity response tends to increase rather than decrease with longer periods between the administration of individual doses of antigen in series. This hypothesis was borne out in part at least by the result of experimentation at the Army Medical School where it was determined that 3 doses

    6AR 40-210, 15 Sep 42.
    7SG Cir Ltr 162, 28 Nov 42, sub: Immunization.
    8TB Med 114, 9 Nov 44.


275

of typhoid-paratyphoid vaccine when administered to rabbits at intervals of 3 weeks were just as effective in the production of protective antibodies as were similar amounts of the antigen administered at intervals of 1 week.9

The only other changes effected in the typhoid-paratyphoid immunization practices were those in connection with revaccination methods and requirements. Following the demonstration by workers at the Army Medical School and elsewhere10 of the efficacy of 0.1 cc. of vaccine administered intradermally or of 0.5 cc. given subcutaneously as stimulating doses, serious consideration was given to the adoption of one or the other of these methods as routine practice in the Army. It was considered, however, that such a change in practice during the early phases of mobilization was not justified. This decision was based principally on the fact that prior to September 1940 the vaccine used by the Army for some years had been monovalent in type. Hence those who had received it rather than the triple vaccine had no basic protection against Para A or B, without which the effect of single small stimulating doses was questionable. Accordingly revaccination with the complete series of three injections of the triple vaccine was continued until 30 August 1943, at which time the practice of annual administration of 0.5 cc. of triple vaccine was adopted for reimmunization to the typhoid and paratyphoid fevers.11 The subcutaneous route rather than the intracutaneous one was chosen since the response was known to be at least as good with the former as with the latter, and it was considered that the intracutaneous technique when applied to large numbers of troops was considerably less certain of proper accomplishment than was the subcutaneous method of injection and would inevitably be more time consuming. At the time of the adoption of this method of reimmunization, the exemption from revaccination of those over 45 years of age was removed, the only exemption remaining being that of the presence of a medical contraindication to the procedure.

To recapitulate, the final policy for the administration of typhoid-paratyphoid vaccine was briefly as follows:12

1. Initial immunization: 3 doses of typhoid-paratyphoid vaccine, 0.5 cc., 1 cc., and 1.0 cc. respectively, administered subcutaneously at 7- to 28-day intervals without unnecessary delay after entry into the Federal service.

2. Revaccination: 0.5 cc. typhoid-paratyphoid vaccine administered subcutaneously annually or in the presence of danger from an outbreak of typhoid fever or the paratyphoid fevers, this revaccination procedure to be followed if an initial series as above had been received at any time in the military service.

    9Army Med School, "Comparative effectiveness of 1-week and 3-week intervals between doses of T. A. B. vaccine," 16 Oct 44. HD: 720.3 Typhoid and Paratyphoid.
    10See footnote 1, p. 272.
    11AR 40-210, C 6, 30 Aug 43.
    12(1) AR 40-210, 25 Apr 45. (2) See footnote 9.


276

3. Initial vaccination or revaccination required within the 12-month period prior to embarkation for overseas duty.

Experience

Effectiveness. The effectiveness of typhoid vaccination as employed in the Army over a period of approximately 35 years has been generally accepted and requires little exposition here. In the historical review, previously referred to, were presented the results obtained from the inception of the procedure in 1909 through the year 1939.13 These will not be repeated other than to recall that the incidence rates for typhoid and the paratyphoid fevers during World War I in a vaccinated Army were approximately one three-hundredths of those experiences in the Spanish-American War when no immunization was practiced, this difference being stated to be ". . . a result of the routine use of typhoid vaccine as a protective measure and improvement in methods of environmental sanitation."

A continuation of these excellent results is indicated by the fact that the combined average annual rates for these diseases during World War II was approximately 0.05 per thousand which is about one-eighth of the combined rate for World War I which was 0.42. Table 22 shows the cases and rates per thousand per annum for typhoid fever, paratyphoid fever, and the diarrheal diseases as they occurred in the Army during World War II, and Table 23 provides the same type of data as nearly comparable as possible for World War I.

    13See footnote 1, p. 272.

TABLE 22. TYPHOID, PARATYPHOID, AND DYSENTERY, DIARRHEA, AND ENTERITIS,
UNITED STATES ARMY, 1942-45

Rates Per 1,000 Troops Per Year

Typhoid

Paratyphoid

Dysentery, diarrhea, and enteritis*

Cases

Rates

Cases

Rates

Admissions

Rates

Total Army

505

0.02

839

0.03

785,164

30.82

    

United States

91

.01

125

.01

294,346

19.97

    

Overseas

414

.04

714

.07

490,818

45.72

    

     Europe only

64

.01

84

.02

92,304

20.98


*Relates to all dysenteries, enteritis, gastroenteritis, colitis, enterocolitis, and diarrhea (not elsewhere classified).
No vaccination is applicable to these groups of diseases.


277

TABLE 23. TYPHOID, PARATYPHOID, AND DYSENTERY, DIARRHEA, AND ENTERITIS, UNITED 
STATES ARMY, WORLD WAR I

Rates Per 1,000 Troops Per Year

Typhoid

Paratyphoid

Dysentery, diarrhea, and enteritis*

Cases

Rates

Cases

Rates

Admissions

Rates

Total Army

1,529

0.37

212

0.05

92,512

22.4

    

United States

546

.24

32

.01

39,854

17.8

    

Overseas (Europe only)

885

.53

151

.09

48,202

28.9


*Relates to all dysenteries, enteritis, gastroenteritis, colitis, enterocolitis, and diarrhea (not elsewhere classified).
No vaccination is applicable to these groups of diseases.

It will be seen that the rates for typhoid alone in the Army during the last war were only about one-twentieth of those experienced in the former conflict, while that for the paratyphoid fevers wins about three-fifths that encountered in the earlier experience. This difference seems to be particularly striking when considered in the light of the rates for the diarrheal diseases which were essentially the same for both periods. This single observation might suggest that the chances of acquiring an enteric infection were approximately the same in both wars, that the nonspecific protective measures were equally effective during the two periods, but that the protection from specific vaccination particularly that against typhoid fever was considerably improved over that afforded in World War I. If such were the case, however, it would be reasonable to have expected the rates for the diarrheal diseases to have increased at least as much as did typhoid under the unfavorable conditions met in overseas theaters of operations. This did not occur since typhoid fever among troops stationed overseas was approximately 4 times higher than for those in this country while the diarrheal disease rates showed an increase of about 2 times. A ratio approximating this held for all the major theaters despite wide variations in the actual incidence of the diseases in question. For example, the European Theater of Operations reported the lowest typhoid and diarrheal disease rates for any major theater and the China-Burma-India theater, the highest. The European theater typhoid rate was essentially twice that in the United States and the diarrheal disease rate about the same. The typhoid rate in the China-Burma-India theater was 30 times greater than that in this country and the diarrheal disease rate showed an increase of about 6 fold.

This situation also obtained in World War I when the rate in Europe for typhoid fever was just over twice as high as in this country and the diarrheal disease rate was slightly over 1½ times that experienced here. The experience with the paratyphoid fevers essentially paralleled that with typhoid in this


278

regard, the former showing a slightly greater increase in incidence in overseas theaters than did typhoid fever.

This view of the occurrence of typhoid and paratyphoid fevers does not bring forth evidence against the efficacy of vaccination for the prevention of these diseases nor does it gainsay the probability of a considerably improved typhoid vaccine. These observations do, however, emphasize again that the incidence of typhoid fever and the paratyphoid fevers, as well as of the other enteric infections, tends to be in proportion to the opportunities for infection existing in the environment and that specific protection through vaccination does not eliminate the necessity for proper application of sanitary measures for the control of these infections.

Histories were received by the Epidemiology Division, Office of The Surgeon General, of most of the cases of typhoid and paratyphoid fevers reported in the United States during the war. In a number of instances it was apparent from these histories that the diagnosis had been made on insufficient evidence. There were a few individuals in whom the clinical course and laboratory findings were such that a diagnosis of typhoid or paratyphoid fever could be made with reasonable assurance in spite of failure to obtain positive cultures of the organisms from stool, blood, or urine. These cases, however, were not included in the data presented in Table 24. There were 42 cases of typhoid fever in the 4-year period from whom the organism was recovered and on whom clinical and epidemiologic information was received. Eleven cases occurred in each of the years 1942 and 1943, and 10 in the years 1944 and 1945. Twelve cases had had not only a basic series of typhoid vaccine injections but 1 or more stimulating doses in addition. Eighteen had had the basic series but no stimulating doses. In 9, the basic series had been begun but not completed at the time of onset of typhoid, and in 3, no vaccination had been done, the individuals having just been inducted. Among the 12 who had had a basic series and 1 or more stimulating doses, there were 8 who had had 1 stimulating dose, 3 who had had 2, and 1 who had had 4. This last case was a result of a laboratory infection as was 1 other in the series. The intervals which had elapsed between the last dose of vaccine and the onset of typhoid were studied for those individuals who had completed a basic series with or without additional stimulating doses. The interval was less than a week in 2 cases, between 1 week and 1 month in 3, 1 month to 6 months in 9, from 6 months to 1 year in 9, and in excess of a year in 6. It is of interest that in 1942, when men were being inducted at a rapid rate, the majority of cases of typhoid occurred in those who had not received a complete basic series of typhoid vaccine whereas in subsequent years, particularly in 1945, most of the cases had had not only a complete basic series, but 1 or more stimulating doses. In summary, it may be stated that except for the year 1942, most cases of typhoid fever in the United States occurred in fully vaccinated personnel and that such cases as did occur during the war in unvac-


279

cinated individuals were not due to failure to carry out immunization. It is also apparent that most of the typhoid occurred through failure of immunization to protect against the dosage of the infecting organism received. Whether the important factor here was the strain of the infecting organism, against which standard Army vaccine might not have been adequate to protect whether it was the number of organisms ingested or whether it was some deficiency in the individuals ability to develop immunity after vaccination cannot be determined.

TABLE 24. IMMUNIZATION STATUS OF 42 CASES OF TYPHOID FEVER AMONG ARMY PERSONNEL IN THE UNITED STATES, 1942-45

CASES PROVEN BY POSITIVE CULTURES, ON WHOM HISTORIES WERE RECEIVED BY EPIDEMIOLOGY DIVISION, OFFICE OF THE SURGEON GENERAL

Immunization Record

1942

1943

1944

1945

Total

Typhoid Vaccine Received

Basic series completed, stimulating dose(s) given

---

1

5

6

12

Basic series completed, no stimulating doses

4

9

3

2

18

Basic series not completed

6

1

1

1

9

No vaccination

1

---

1

1

3

Total

11

11

10

10

42

Number of stimulating doses given

1 dose

---

1

5

2

8

2 doses

---

---

---

3

3

3 doses

---

---

---

---

---

4 doses

---

---

---

1

1

Interval From Last Dose to Onset of Disease (For Cases Who Had Completed Basic Series)

Less than 7 days

---

---

1

1

2

1 week to 1 month

1

---

1

1

3

1 to 6 months

2

4

2

1

9

6 months to 1 year

1

5

1

2

9

More than 1 year*

---

---

3

3

6

Not stated

---

1

---

---

1

Total

4

10

8

8

30


*Of the 6 cases in this group, the interval was 12 to 15 months in 3.

Reactions. As pointed out previously, typhoid-paratyphoid vaccination has for many years been an accepted, almost traditional procedure in the Army. That this procedure is attended by local and systematic reactions has also become more or less generally accepted. Accordingly, the proportion of such reactions


280

in those receiving the vaccine is not definitely known nor has it been considered to be of enough importance to initiate a study of sufficient magnitude to allow such definition.

During only one brief period of the war were reports received indicating an unusually high occurrence of untoward reactions following the administration of this vaccine. This was during the first half of the year 1942 and the reports indicated reactions to typhoid-paratyphoid vaccine unusual both in number and degree when the vaccine was administered within 5 to 10 days following yellow fever immunization.14 The occurrence of such reactions, however, was not sufficiently frequent nor were the reactions themselves of such severity as to warrant concern and the matter was automatically rectified with the discontinuance of routine vaccination against yellow fever. The matter was given considerable study, however, and it was considered that the apparent increase in reactions to typhoid-paratyphoid vaccine when this material was administered a short time after the yellow fever antigen were in the nature of a summation of reaction to the two agents (the febrile reaction to yellow fever vaccine having a usual incubation period of 5 to 7 days) rather than a true augmentation of the reaction from typhoid vaccine itself. This formed the basis for the recommendation that administration of typhoid-paratyphoid vaccine within a week following yellow fever immunization should be avoided whenever possible.15

Other than that just referred to, the experience with reactions from triple typhoid vaccine during World War II apparently differed little from that of previous years. A fairly high proportion of individuals receiving such vaccine will exhibit reactions, local or systemic or both. As previously indicated, the exact proportion of such reactors is not known. Previously published figures of 10 to 20 percent16 are probably safely conservative. The most common reaction is that of local redness, heat, and tenderness at the site of injection. The systemic reactions encountered are characterized by general malaise, headache, and elevation of temperature. The second injection of the basic series is the dose most likely to cause reaction but untoward effects from stimulating doses are not uncommon particularly in individuals who have received several "basic series" or stimulating doses in the past.

SMALLPOX VACCINATION

Development and Adoption

Smallpox vaccination may well be classified as one of the most important measures for disease prevention that has been applied in military as well as in civilian populations. It has long been recognized that vaccination is, for

    14Report of Conference on Yellow Fever, Typhoid Vaccine Reactions, SGO, 14 Mar 42. HD: 720.3.
    15See footnote 8, p. 274.
    16See footnote 1, p. 272.


281

all practical purposes, the only practicable effective procedure for the prevention of variola. The story of the recognition by Jenner of the effectiveness of cowpox inoculation for the prevention of smallpox and the subsequent development, refinement, and general application of this principle is one of the classics of medicine and has been recounted so often that its review here is not warranted.

Smallpox vaccination in the Army antedates the application of any other immunization procedure. The exact date of the adoption of this procedure for routine use in all Army personnel does not appear to be a matter of record. However, its first use is said to have been early in the last century. Its application was expanded somewhat during the Civil War period and its adoption as a routine measure was presumably at or near the turn of the century.17 Vaccination against smallpox has, of course, been continued since that time as a routine procedure and is applied on entry into the service and at intervals thereafter.

The Immunizing Agent

Glycerinated calf dermovaccine is the agent used in the Army. Army Medical Department specifications applicable to the purchase of this vaccine are quoted in part as follows:

Smallpox Vaccine, U. S. P.

General description.-Vaccine shall conform to the requirements of the National Institutes of Health.

Quantity.-Vaccine shall be supplied in capillary tubes, each tube sufficient for one vaccination. Ten such tubes shall he the unit of quantity, furnished with 10 sterile needles and one rubber bulb.

Packaging and Packing.-The unit of quantity shall be furnished in suitably sized and constructed individual containers. Shipment shall be made in a waterproof bag or envelope, in an insulated container, having enough dry ice to keep the vaccine at the proper temperature until it reaches destination.

Expiration date.-Shall not be less than 21/2 months after delivery date.

It will be noted that these specifications in stipulating refrigeration during shipping take cognizance of the fact that this vaccine, containing a living virus, loses its potency rapidly unless kept cold (preferably at freezing temperatures) at all times. This extreme lability and the short expiration date resulting therefrom were obvious obstacles to the maintenance of stocks of fully potent material in Army installations in the various theaters of operations and in this country as well. Continued emphasis was given to the necessity for proper shipment, storage, and care of this agent. In order that proper instructions in this regard might be disseminated to supply depots and other agencies concerned,

    17The Medical Department of the United States Army in the World War. Washington, Government Printing Office, 1928, vol. IX, pp. 357-386.


282

a memorandum outlining the proper procedure was forwarded to the Finance and Supply Division, Office of The Surgeon General, from the Epidemiology Branch, on 2 December 1941.18 In brief, this memorandum presented the following procedures as requirements:

    1. Shipment to be made by the most rapid and direct method and route

    2. Ordinary shipment by express, etc., or long distanced shipping by air, to be made by packing vaccine in dry ice and insulating the package properly

    3. For extended shipment such as by boat, the vaccine to be held at freezing temperatures

    4. Upon arrival at destination and thereafter until use, the vaccine to be kept at all times below 5° C., preferably below 0° C.

Essentially this same information was disseminated to all medical installations and medical officers in Circular Letter 162, Office of The Surgeon General, 28 November 1942, and again in November 1944 in War Department technical bulletin, TB MED 114. In addition, it was recommended in both of these publications that because of its perishable nature and the brevity of the period of expected potency, the amount requisitioned should not be in excess of the anticipated need for approximately 2 months. It was also recommended that for use overseas smallpox vaccine of acceptable quality be purchased locally whenever possible. This procedure was followed quite extensively in the United Kingdom for troops stationed there. Local procurement was also accomplished in India for a time but was discontinued upon the development of a more satisfactory system of air shipment with adequate dry ice refrigeration. Local procurement was also practiced in other areas but as a rule only to meet unusual needs.

The question of specificity of the action of American-made vaccine when used for the prevention of the virulent smallpox of the Far East and other areas was brought up from time to time. In view of the basic nonspecificity of the procedure (vaccinia virus being used for protection against variola virus) and the lack of evidence of noneffectiveness of American-made vaccines in these situations, this matter was not considered to present a problem. It was considered that vaccination properly performed and interpreted, using potent vaccine, would afford adequate protection.

Methods and Requirements

The method recommended for the performance of vaccination was the so-called "multiple pressure" method now generally accepted in this country to be the one of choice.19 The instructions issued with respect to this procedure em-

    18Memo, Chief Epidemiology Branch SGO for Dir Finance and Supply Div SGO, 2 Dec 41, sub: Shipping and storage of smallpox vaccine. HD: 720.3.
    19See footnotes 1, p. 272 and 11, p. 275.


283

phasized adequate care of the vaccine to insure its potency, careful attention to the vaccination procedure itself, and proper interpretation of the results obtained. It was stipulated that the procedure be repeated until a satisfactory result (vaccinia, vaccinoid, or immune reaction) was demonstrated.

Early in 1943 when large numbers of men were passing very rapidly through induction and reception centers, it became apparent that vaccinations performed at these centers could not always be properly interpreted, and hence it was thought that considerable value from the procedure was lost. Accordingly, a memorandum was published by The Adjutant General directing that smallpox vaccination should not be performed unless the personnel concerned were to remain at the center at least 1 week.20 It was thought that the results incurred by the postponement of this procedure for a short time were more than compensated for by the advantage which would accrue with the opportunity for observation and interpretation of the vaccination result.

Because of the occurrence of a certain number of cases of smallpox in overseas installations, it was found necessary in 1944 to emphasize once more to medical officers in the field the necessity for careful attention to the performance and interpretation of this simple procedure. To this end there was published in the Army Medical Bulletin, August 1944, a special article on smallpox vaccination.21 Unfortunately in some instances a lack of knowledge or failure to appreciate the importance of the development and maintenance of satisfactory immunity to smallpox resulted in failures to vaccinate troops properly. As will be seen, these failures led to a certain number of cases of smallpox, some of which were fatal.

The stated requirements for smallpox vaccination were such that had the vaccination been performed properly in each case the Army should have been essentially 100 percent immune to this disease. It was required that all personnel he vaccinated without unnecessary delay after entry on active duty and once every 3 years thereafter. In addition, provision was made for the vaccination or revaccination of all personnel ordered to duty beyond the continental limits of the United States unless such vaccination has been accomplished during the 12-month period prior to departure. Provision was also made for the revaccination of all personnel on the occurrence of the disease in a command or in the presence of a threat of such an outbreak. 22 In other words, smallpox vaccination at least once every 3 years was required for all personnel and more frequent vaccinations were authorized and recommended in the event of possible exposure to the disease.

    20WD AG Memo S40-6-43, 12 Apr 43, sub: Smallpox vaccination at induction and reception centers. AG: 720.3.
    21Smallpox vaccination. Bull. U. S. Army M. Dept. No. 79, Aug 1944, p. 2.
    22See footnote 6, p. 274.


284

Experience

Effectiveness. The Army experience with smallpox during the war years is further testimony to the effectiveness of vaccination in the prevention of this disease. There occurred during this period a total of 115 cases of which 10 were reported from the United States and 105 from overseas. This is in rather sharp contrast to the experience of the last war during which a total of 853 cases were reported, 780 from the United States and 73 from overseas stations.23 While the current record is an excellent one and shows a marked improvement over that of World War I, it appears profitable to inquire briefly into the reasons for the occurrence of even a few cases in a 100-percent vaccinated group. The review of the incidence figures reveals that almost half the cases reported occurred in the India-Burma theater and the Persian Gulf Command, the cases reported from these areas being 33 and 15 respectively. (See chapter on smallpox in another volume in this series.) Investigations conducted by the surgeons of these theaters led to the conclusions that failure to vaccinate properly was responsible.24 These conclusions were based on the fact that, with very few exceptions, the individuals who developed smallpox either presented no indication of a previous satisfactory vaccination as evidenced by a scar, or the scar present was the result of vaccination in infancy or childhood. The records of such individuals, however, almost invariably indicated immune reactions to vaccinations performed while in the military service. The fact that they then developed smallpox is clear indication of unsatisfactory performance of the vaccination procedure and failure to read and interpret the result properly. These findings were confirmed by study of the few cases which occurred in this country.25

Additional evidence pointing to unsatisfactory routine vaccination practice was found in the unusually high proportion of individuals presenting vaccinia or vaccinoid reactions when vaccinations were carefully performed in special situations and the results critically observed and analyzed. Two such instances are cited as examples.

In the Persian Gulf Command in 1944, 16,515 individuals were revaccinated with a fresh potent vaccine because of the occurrence of cases in the area and among military personnel. The result in reactions were as follows: vaccinia, 9.1 percent; vaccinoid, 35.5 percent; immune reactions, 55.4 percent.26 

In the face of an outbreak of smallpox among civilians employed in the 1155th Army Air Force Base Unit (Fortaleza, Brazil), all military personnel

    23See footnote 17, p. 281
    24(1) ETMD, CBI, 30 Apr 44. HD. (2) ETMD, Persian-Gulf Comd, 21 May 44. HD. (3) ETMD, India-Burma Theater, 1 Jun 45. HD.
    25File: Smallpox, Incidence, Treatment, and Control, ZI. HD: 710.
    26ETMD, Persian Gulf Comd, 17 Aug 44. HD.


285

subject to exposure were revaccinated in August 1944.27 Of the 155 individuals concerned, reactions of vaccinia resulted in 95, vaccinoid in 9, immune reactions in 39. Twelve were interpreted as being failures and repetition of the procedure was required.

In both instances the individuals concerned had all been vaccinated within 3 years and many within a considerably shorter period, obviously unsuccessfully in many cases. It was the consensus of the various observers that these failures were traceable to the use of outdated or improperly refrigerated vaccine or faulty technique. The basic fault, however, lay in the failure to observe and assign the proper interpretation to the reactions following vaccination. There was apparently a certain tendency to consider that all individuals not responding with a vaccinia or vaccinoid reaction were immune. This, of course, was fallacious and such individuals in many instances were in fact not immune at the time of vaccination, nor did they profit by the procedure if in fact it was an undetermined failure. As a result such individuals were unprotected.

Thus while the record with respect to the occurrence of smallpox among troops during the war period was probably the best ever achieved under kindred circumstances, the fact remains that failure of proper vaccination in individual cases did result in cases and death from this disease.

Reactions. Reactions, in the sense of untoward effects and complications following smallpox vaccination, were of little moment. A certain number of those vaccinated did require medical care because of fever, infection at the site of vaccination, et cetera. These incidents are not worthy of detailed study but an approximation of the extent of their occurrence is of some interest. For this purpose, the experience in the United States for the year 1943 may be taken as a representative sample. During that year there were admitted to Army hospitals in the continental United States, 5,260 individuals with admission diagnoses of reaction to smallpox vaccination. While there is no accurate method of determining the portion of total vaccinations thus represented, a figure for such reactions of approximately 1.7 per thousand vaccinations may be arrived at by considering that one vaccination was performed on each individual entering active service with the Army during the period. Since the total number of vaccinations performed was unquestionably greater than this, this ratio is undoubtedly high, but, even so, represents a small price to pay for the protection afforded. Of some interest is the fact that untoward reactions to vaccination tended to increase somewhat during the summer months. Applying the same method of calculation referred to above, it is estimated that the rates for such reactions were approximately 0.7 per thousand in January, and 3.3 per thousand during August. The only immediately available explanation

    27Ltr, Chief Surg USAF South Atlantic to SG, 8 Sep 44, sub: Epidemiological report on smallpox at Fortaleza, Brazil. HD: 710.


286

for this is that during the summer months there is a greater tendency toward maceration of the vaccinated area through increased skin warmth and perspiration, and thus a more favorable site for secondary infection is afforded. Also, in some areas the opportunity for contamination from outside sources, such as dust, is greater in summer than in winter.

The only other type of untoward reaction to smallpox vaccination reported was postvaccinal encephalitis. (See Table 25.) This condition was reported in

TABLE 25. POSTVACCINAL ENCEPHALITIS

Case

Date

Time between vaccination and onset of symptoms

Outcome

Remarks

1942

1

March

10 days

Fatal

Pathological diagnosis: meningo-encephalitis, cause undetermined.

2

May

31 days (?)

Recovery complete

Symptoms and signs more closely simulated those of peripheral neuritis than of encephalitis.

3

November

7 days

Recovery partial

4

November

(?) Onset nervous symptoms 17 days after induction

Fatal

Pathological diagnosis: infective polyneuronitis.

1943

5

February

3 days

Fatal

No specimens submitted to Army Medical Museum.

August

17 days

Recovered

1945

7

February

10 days

Recovered with some loss of vision.

8

March

2 days

Recovery complete.


8 individual instances, 4 such cases being reported in 1942, 2 in 1943, none in 1944, and 2 in 1945. Such study of these cases as it has been possible to make indicates that, while in fact they all occurred following smallpox vaccination, there is reason to doubt that some of them, at least, were in fact true postvaccinal encephalitis. The onset of central nervous system symptoms varied from 2 to 31 days following vaccination. Only 3 occurred after an interval of 7 to 10 days. Of the entire group of 8 cases, 3 were fatal. Post mortem specimens from 2 of


287

these were studied at the Army Medical Museum and the pathologic diagnoses arrived at were meningo-encephalitis, cause undetermined, in one case, and infective polyneuronitis in the other. Unfortunately, no specimens were available in the case of the third fatality. Of the remaining 5 cases, there were 3 who were reported to have recovered completely, and 2 with minor neurologic residuals. While the proof or disproof of true postvaccinal encephalitis in these reported cases cannot be made, it is considered that in at least half of them the only relationship between the presenting condition and vaccination was one of time and not of cause and result. The other 4 may have been encephalitis resulting from smallpox vaccination. Table 25 presents a résumé of these cases.

It is of some interest to note that no postvaccinal tetanus was reported among the many millions of vaccinations performed. Inasmuch as tetanus immunization was commonly not completed until some weeks after the smallpox vaccination in Army inductees, and hence could have afforded no protection for the majority of such individuals, freedom from this complication must be attributed to the high quality of vaccine used, the technique of application, and the avoidance of dressings over the site of vaccination.

TETANUS IMMUNIZATION

Development and Adoption

Administration of tetanus toxoid was the first new, generally applied immunization procedure to be adopted for the Army during the World War II emergency and this, added to typhoid and smallpox vaccination, became the third of the group of procedures referred to for administrative purposes as routine immunizations. Of all new procedures adopted during the war period, tetanus immunization was probably the most successful.

The use of the toxoid prepared from the toxin of Clostridium tetani for the production of active immunity to tetanus was not new at the time of its adoption by the Army. This prophylactic procedure was first applied in France prior to 1930.28 Following this pioneer work, extensive investigation of the usefulness of the procedure was carried on and numerous reports attesting to its efficacy were published both in this country and abroad.

Tetanus immunization using toxoid was adopted by the British, Canadian, and French Armies some time before its application in United States Forces.29

    28(1) Ramon, G., and Zoeller, C.: L'anatoxine tétanique et l'immunisation active de l'homme viś-a-vis du tétanos. Ann. de l'Inst. Pasteur 41: 803-833, Aug 1927. (2) Ramon, G., and Zoeller, C.: Sur la valeur et la durée de l'immunité conférée par l'anatoxine tétanique dana la vaccination de lhomme contre le tétanos. Compt. rend. Soc. de biol. 112: 347-350, 3 Feb 33.
    29(1) Rpt, Intelligence Div, Off of Chief Naval Opns, Navy Dept, 25 Sep 40, sub: Great Britain, immunization against tetanus and gas gangrene. (2) Ltr, Dr. R. D. Defries, Actg Dir Connaught Laboratories, to Dr. W. T. Harrison, Dir Div of Biological Control, Natl Inst of Health, 16 May 40. HD: 720.3 Tetanus Toxoid. (3) Ltr, Gaston Ramon, Institute Pasteur, France, to Dr. W. T. Harrison, Natl Inst of Health, 17 May 40. HD: 720.3 Tetanus Toxoid.


288

Toxoid was universally administered to personnel of the French Army as early as 1936. Information received from France in 1940 indicated that no cases of tetanus had occurred in immunized individuals up to that time. It was estimated that some 80 percent of the British Expeditionary Force in Flanders in the early phase of the war were protected from tetanus by toxoid. During this harrowing experience, the incidence of tetanus among British wounded was reported to have been but 0.45 per thousand, none occurring in any one previously immunized with toxoid. (Immunization to tetanus as well as other immunizations is on a voluntary basis in the British Army, and it was the policy to administer prophylactic antitoxin to all wounded including those known to have received toxoid previously.)

The first step toward the adoption of active immunization to tetanus in the United States Army was taken in the spring of 1940. At an informal meeting, representatives of the Army, Navy, and the Public Health Service agreed unanimously that such a procedure was desirable and should be adopted at once.30 A formal recommendation that all military personnel on active duty be actively immunized against tetanus was made by The Surgeon General on 28 May 1940 in a letter to The Adjutant General.3l In this letter it was pointed out that tetanus is one of the most serious complications of traumatic surgery and one that requires consideration in any skin perforating wound. The advantages of active immunization with toxoid over the administration of tetanus antitoxin for passive protection were emphasized and the necessity for early action as a means of preparedness was stressed. In addition an outline of the proposed method for the administration of the toxoid was presented. The War Department, while receptive to the proposal in general, was unwilling to adopt immediately this new immunization procedure. Accordingly, the correspondence between The Surgeon General and the War Department, initiated by the letter of 28 May 1940, was continued by 10 indorsements until 27 January 1941. Throughout this correspondence, The Surgeon General urged repeatedly that definite action be taken for the adoption of the procedure pointing out that, for effectiveness, early basic immunization of all military personnel was required and that this could not be accomplished on the eve of combat. He further indicated that the procurement of sufficient quantities of toxoid would require long-range definite commitments with the manufacturers. In support of his position, The Surgeon General referred in his indorsement of 3 December 1940 to the minutes of the meetings of three National Research Council committees in which each recommended strongly the adoption of this method for the prevention of tetanus in the Armed Forces. Reference was also made to a letter from the Surgeon General, United States Public Health Service (30 October

    30Memo, Lt Col J. S. Simmons, SGO, for Chief Prof Serv Div, SGO, 16 May 40. HD: 720.3 Tetanus Toxoid.
    31Ltr, SG to TAG, 28 May 40, sub: Active immunization military personnel against tetanus, with 10 inds, 7 incls. SG: 720.3-1.


289

1940), in which the procedure was strongly indorsed, and which pointed out the difficulties with respect to the procurement of adequate supplies of toxoid or of antitoxin, if toxoid were not to be used, unless definite and specific assurances could be given at an early date to the various manufacturers of biologics. At the termination of this series of indorsements, the proposal still lacked complete acceptance by the War Department. It had, however, been "approved in principle" and The Surgeon General had been instructed to "adopt a procedure which will provide for required immunizations with tetanus toxoid in event the War Department determines that the prospect of combat is imminent." Authority had also been given (8 January 1941) for the procurement and storage of sufficient toxoid to immunize the total armed force planned to be mobilized on 1 June 1941.

Before the administration of tetanus toxoid to all troops was directed, limited applications of this protective measure were made. In March 1941, the Commander of the Philippine Department requested advice by radio as to the advisability of the routine use of toxoid for all troops in that Department.32 Upon the recommendation of The Surgeon General, he was directed by the War Department to initiate the procedure immediately,33 and instructions for the method of administration of the toxoid were dispatched to him. Following this, it was recommended to the Assistant Chief of Staff, G-1, that a similar policy be adopted for the Panama Department, Atlantic bases, and the Hawaiian Department.34 On 11 April 1941, The Surgeon General was advised by The Adjutant General that the commanders of these departments and bases had been directed by radio to proceed with tetanus immunization of all military personnel under their command.35 A schedule for the accomplishment of this immunization was indicated, the Panama Canal Department being directed to accomplish the measure at once, the Atlantic bases to comply between 1 May and 1 July, and the Hawaiian Department between 1 June and 1 August 1941. In the light of subsequent events, these actions, particularly as they affected the Philippine and Hawaiian Departments, were most timely. As will be seen, this immunization afforded complete protection against tetanus, and undoubtedly through its application many lives were saved during the early phases of war in the Pacific.

In May 1941, the matter of the routine active immunization to tetanus of all military personnel was reopened by The Surgeon General.36 In a letter to The Adjutant General, the previous recommendations were reviewed, actions

    32Radio, Comdr Philippine Dept to SG, 13 Mar 41. AG: 720.3 (3-13-41) M-A.
    331st ind, SG to TAG, 13 Mar 41, and 2d ind. TAG to SG, 25 Mar 44, on basic radio cited in footnote 32.
    34Memo, SG for WD ACofS G-1, 27 Mar 41, sub: Immunization with tetanus toxoid. HD: 720.3.
    35Ltr, TAG to SG, 11 Apr 41, sub: Immunization of military personnel in overseas garrisons. AG: 720.3.
    36Ltr, SG to TAG, 27 May 41, sub: Active immunization of military personnel with tetanus toxoid. HD: 720.3.


290

taken with respect to the immunization of part of the Forces summarized, and the desirability for uniform policy for the entire Army stressed. On 11 June 1941, such a policy was adopted and it was directed by War Department Adjutant General's letter, that date, that all military personnel on active duty with the Army of the United States, regardless of location, be actively immunized against tetanus immediately.37

The Immunizing Agent

The agent chosen for administration to military personnel for the production of active immunity to tetanus was fluid or plain tetanus toxoid. The decision to adopt this form of toxoid rather than the alum precipitated product was made only after careful consideration of the known characteristics of each of these materials and study of the experiences accrued from their use and that of related agents.38 The satisfactory experience with the fluid preparation in the British and French Armies39 weighed heavily in the choice of a like preparation for administration to American troops. Relatively little experience had been had at that time with the administration of an alum precipitated agent to large numbers of adults. There seemed little choice between the materials from the point of view of satisfactory antigenic qualities. Both were known to be effective from the point of view of antitoxin production.40 In fact, if the experience with diphtheria toxoid in children could be taken as a criterion, two doses of the alum precipitated toxoid administered at intervals of several weeks might have been expected to accomplish the same end result as that derived from three doses of the fluid agent. It was appreciated, however, that alum precipitation of an antigen tends to increase its sensitizing powers thus leading to possible complications at the time of repeat doses. The choice between the two materials was a fine one, but the factors in favor of fluid toxoid were considered to outweigh those for the precipitated product and the former was decided upon. As will be seen, subsequent experience demonstrated that this agent was entirely satisfactory. Its effectiveness was complete and the only difficulty encountered following its administration was the occurrence of a limited number of reactions of sensitivity to certain peptone components of

    37Ltr, TAG to CGs all Armies, Army Corps, etc., 11 Jun 41, sub: Active immunization of military personnel with tetanus toxoid. AG: 720.3.
    38Memo, Drs. McCoy, Harrison, and Leake, USPHS, 17 May 40, sub: Concerning suggested program for the immunization of Army and Navy personnel. HD: 720.3 Tetanus Toxoid.
    39See footnote 29(1) and (2), p. 287.
    40(1) Lincoln, E. M., and Greenwald, C. K.: Active immunization of human beings with tetanus toxoid. Proc. Soc. Exper. Biol. & Med. 30: 1241-1243, 1933. (2) Sneath, P. A. T.: Development of tetanus antitoxin following administration of tetanus toxoid. J. A. M. A. 102: 1288-1289, 21 Apr 34. (3) Bergey, D. H., and Etris, S.: Immunization of humans with alum precipitated tetanus toxoid. Am. J. Pub. Health 24: 582-586, Jun 1934. (4) Jones, F. G., and Moss, J. M.: Studies on tetanus toxoid. I. The antitoxic titer of human subjects following immunization with tetanus toxoid and tetanus alum precipitated toxoid. J. Immunol. 30: 115-125, Feb 1936. (5) Cowles, P. B.: Tetanus immunization. Yale J. Biol. and Med. 9: 409-416, May 1937. (6) See also footnote 29(1), p. 287.


291

some of the material used. There is reason to believe that similar reactions might well have occurred with an alum precipitated agent containing the same peptones.

The toxoids used by the Army were procured from commercial biologic laboratories licensed by the Public Health Service for the production and sale of this material, and were required to conform in all respects to the requirements of the Biologics Control Division, National Institute (later Institutes) of Health.41 Because of the nature of tetanus toxoid, particular precautions were taken to insure the safety of the material distributed for use. Thus, in addition to special care on the part of the manufacturers to prevent contamination or adulteration which might render the product unfit for use and the routine checks made by the National Institute of Health, all such material used by the Army was required to pass satisfactorily an extra test to insure freedom from toxicity. This test was made on samples taken from toxoid lots delivered to Army depots and its completion was required before distribution was effected.

The only change in the toxoid used by the Army during the war period was that required when it was determined that certain reactions following the administration of some of the material were in all likelihood due to sensitivity to specific peptones. The worst offenders appeared to be those toxoids containing Witte's and Berna's peptone. Accordingly, it was necessary to discontinue procurement of toxoids of this type,42 and to recall from distribution certain lots of toxoid known to contain the reaction producing materials.43 When it was determined with reasonable surety that the peptone components of some of the toxoids were responsible for the reactions, it was suggested that toxoids produced on a peptone-free hydrolysate medium such as that devised by Mueller and Miller44 would be highly desirable. To this end, the Director, Biologics Control Division, National Institute of Health, forwarded to all tetanus toxoid manufacturers Mueller's formula for the hydrolysate medium and instructions for its use. He also recommended that it be given full trial in the production of tetanus toxoid.45 While it was shown that it was possible, in the experimental laboratory at least, to produce satisfactory toxoid from toxins made in this medium, these results were not consistently reproducible and were not achieved by the commercial manufacturers to the extent necessary

    41(1) Natl Inst of Health, "Minimum Requirements, Tetanus Toxoid," 17 Jun 38 and subsequent modifications. HD: 720.3. (2) Ltr, Chief Prev Med Serv SGO to Bureau Licensing of Biological Products, Natl Inst of Health, 3 Apr 41. HD: 720.3 Tetanus Toxoid.
    42Memos, Prev Med Div SGO for Chief Finance and Supply Div SGO, 17 Oct 41 and 15 Dec 41, sub: Purchase of tetanus toxoid. HD: 720.3.
    43Memo, Prev Med Div SGO for Chief Finance and Supply Div SGO, 19 Feb 42, sub: Recall of certain lots of tetanus toxoid. HD: 720.3.
    44Mueller, J. H., and Miller, P. A.: Tetanus toxin production on a simplified medium. Proc. Soc. Exper. Biol. & Med. 43: 389-390, Feb 1940.
    45Natl Inst of Health, Cir Ltr to Licensed Manufacturers of Tetanus Toxoid, 3 Oct 41. HD: 720.3.


292

for large-scale production.46 As a result, the toxoids used by the Army continued to be those made from toxins produced in media containing various types of peptones (other than Witte's or Berna's) and meat digests. As noted below, the reaction producing qualities of such toxoids were minimal.

Methods and Requirements

The basic administrative requirements for tetanus immunization have already been referred to; namely, the initial direction for the immunization of all troops in the Philippine, Hawaiian, Panama Departments and Atlantic bases, and later the adoption of the procedure as routine for the entire Army. This requirement was subsequently published as an Army regulation, in Section III, AR 40-210, September 1942. This regulation provided that all military personnel be actively immunized to tetanus without unnecessary delay after entry into Federal service, that they receive a single routine stimulating dose at the end of 1 year thereafter and a similar dose prior to embarkation for overseas duty if the initial series or the routine stimulating dose had not been received within 6 months prior to such embarkation. Further stimulating doses were, of course, authorized at the time of injury and the details covering such administration were published in technical directives. These basic requirements remained the same throughout the war except that the requirement for a stimulating dose within 6 months prior to embarkation for overseas travel was rescinded in September 1944.47 This rescission was based on the knowledge gained from experience that this added precaution was unnecessary.

The first formal technical directions for the administration of tetanus toxoid were published as Circular Letter 34, Office of The Surgeon General, 16 April 1941. These instructions called for a basic series of three subcutaneous injections of 1 cc. each of fluid tetanus toxoid to be administered at intervals of "not less than three or more than 4 weeks." Subsequent injections of 1 cc. each were prescribed as follows:

1. Under normal conditions, at the end of the first year only (after basic series), regardless of duration of service.

2. In time of war, during the months previous to departure for theater of operations unless such departure was within the 6-month period subsequent to the stimulating dose referred to above.

    46(1) Mueller, J. H.; Schoenbach, E. B.; Jezukawicz, J. J., and Miller, P. A.: Production of tetanus toxin on peptone-free media. J. Clin. Investigation 22: 315-318, Mar 1943. (2) Schoenbach, E.B.; Jezukawicz, J. J., and Mueller, J. H.: Conversion of hydrolysate tetanus toxin to toxoid. J. Clin. Investigation 22: 319-320, Mar 1943. (3) Mueller, J. H.; Seidman, L. R., and Miller, P. A.: A comparison of antigenicities of hydrolysate and peptone tetanus toxoids in the guinea pig. J. Clin. Investigation 22: 321-324, Mar 1943. (4) Mueller, J. H.; Seidman, L. R., and Miller, P. A.: Antitoxin response in man to tetanus toxoids. J. Clin. Investigation 22: 325-338, Mar 1943. (5) CMR Infection Disease Rpt No. 15 (Abstracted), "Tetanus," by Dr. J. Howard Mueller, 14 Jul 44. HD: 720.3.
    47Ltr, TAG to CGs POEs, COs POEs, CofTrans, 28 Sep 44, sub: Stimulating doses of tetanus toxoid. AG: 720.3.


293

3. As an emergency stimulating dose, to individuals incurring wounds or severe burns on the battle field, to patients undergoing secondary operations and manipulation of old wounds and to others with injuries which might be complicated by the introduction of Cl. tetani into the tissues.

Instructions were also given as to the proper recording of completed tetanus immunization. These included:

1. Recording on the immunization register (WD MD Form 81).

2. Stamping of the identification tag at the completion of the initial series with the letter "T" followed by figures indicating the year, and additional date to be stamped on the tag after the routine stimulating dose. "T 41-42" would indicate the completion of the basic series in 1941 and the routine stimulating dose in 1942.

The use of antitoxin for passive immunization was reserved for those with clinical tetanus, and for individuals with wounds or other conditions requiring protection against tetanus who presented no evidence of the previous administration of toxoid.

These instructions were supplemented on 10 November 1941 by the publication of additional information concerning the administration of tetanus toxoid in Circular Letter 110, Office of The Surgeon General. These additional instructions did not alter the basic procedures as outlined above but clarified certain points concerning which questions or misunderstanding had arisen. The most important among these were:

1. In order to avoid unnecessary repetition of injections, it was directed that if the prescribed intervals between doses were exceeded the missed dose or doses should be administered as soon as possible, but a new series should not be started.

2. It was stated that the stimulating dose to be administered prior to embarkation for a theater of operations should be given unless departure was to be within the 6-month period subsequent to the routine stimulating dose (1 year after the basic series) or within the same period after the basic series itself.

3. To avoid the undesirable use of prophylactic antitoxin it was pointed out that a satisfactory immunity producing mechanism is established at the time of completion of the basic three injections of toxoid and hence, toxoid and not antitoxin should be administered for emergency protection at any time after the completion of the basic series of injections. (This fact was not definitely known at the time of the publication of the original instructions but was established in October by a study carried on jointly at the Army Medical School and National Institute of Health,48 the details of which are summarized in the subsequent discussion of effectiveness of toxoid.)

    48Ltr, Dr. M. V. Veldee, Chief Div of Biologics Control, Natl Inst of Health, to Maj A. R. Driesbach, Army Med Center, 27 Oct 41. HD: 720.3 Tetanus-Toxoid, Experimental.


294

4. In view of the occurrence of some reactions of sensitivity, specific instructions were given with respect to the precautions to be taken in connection with such reactions. These included:

a. Have adrenalin at hand during immunization procedure.

b. Perform intradermal sensitivity tests using 0.1 cc. of 1 to 100 dilution of toxoid on those with a history of previous allergic manifestations, those who have exhibited untoward reactions to a previous dose of tetanus toxoid, and those who are to receive a dose of toxoid in the initial series after an interval of more than 4 weeks has elapsed.

5. If, in the opinion of the surgeon, previous reactions or positive sensitivity tests constituted definite contraindication to further immunization, the procedure was to be abandoned, care being taken to avoid stamping the identification tag to indicate completion of this procedure. If further immunization was not considered to be definitely contraindicated in such individuals, the 1 cc. dose was to be divided and 0.1 cc. administered cautiously. If an anaphylactic type reaction occurred, the immunization was to be discontinued. If not, the remainder of the cubic centimeter was to be administered in 3 or 4 portions at daily intervals.

Though the incidence of known sensitivity to tetanus toxoid was relatively low, the problem did arise of possible disqualification for overseas duty on the grounds of inability to complete immunization because of such sensitivity. The policy with respect to this matter was that sensitivity to tetanus toxoid should not be considered to be disqualifying for overseas duty. In such cases it was indicated that notation should be made on the service record of the individual concerned signifying the sensitivity and that the immunization to tetanus was not completed. In addition, the identification tag should not show complete immunization to tetanus.49

The instructions presented in these two circular letters (34 and 110) were subsequently combined with only minor changes and published in Circular Letter 162, November 1942, which represented a compilation of technical instructions covering all the immunization procedures authorized at that time. This circular letter was later replaced by TB MED 114, "Immunization," November 1944. Instructions in this bulletin concerning tetanus immunization were essentially unchanged from those reviewed above with the notable exception that, in conformance with the administrative change previously referred to,50 the stimulating dose of toxoid within 6 months of departure for a theater of operations was no longer required.

Despite these rather specific instructions, toxoid was not administered in a completely uniform manner. Perhaps the most outstanding deviation from

    49Ltr, CO Camp Crowder, Mo., to CG 7th SvC, 11 Aug 43, sub: Tetanus toxoid immunization of officers and enlisted men assigned to foreign service, with inds. HD: 720.3.
    50See footnote 47, p. 292.


295

the prescribed policy was the use of an annual stimulating dose in the European Theater of Operations. There was no clear indication for such a practice at the time and the evidence accumulated since indicates clearly that stimulating doses at such frequent intervals are not required and, hence, are undesirable.

Experience

Effectiveness. The administration of tetanus toxoid for the production of immunity to tetanus proved to be a completely successful procedure. A total of 12 cases of tetanus occurred among Army personnel between 7 December 1941 and 1 January 1946. There were 3 cases in 1942, 5 in 1943, 3 in 1944, and 1 in 1945. Four of the 12 occurred overseas but only 1 as a result of a battle wound. The immunization status of the individuals who developed the disease is shown in the tabulation below.
 

Fatal 
cases

Total 
cases 

No active immunization

2

6

Basic immunization (3 injections) accomplished but no booster injection given following injury

1

2

Basic immunization and booster injection following injury received

2

4

    Total

5

12


Of the 6 cases occurring in unimmunized persons, 4 resulted from injuries incurred prior to entry on active duty, 1 was in a soldier with 4 months of service, and 1 case occurred in a soldier who, though in the service for a year prior to the onset of the illness (January 1941 to February 1942), had received only 1 dose of toxoid. One of the 2 patients who had received the basic toxoid injections, but no booster dose at the time of injury, was first treated in a French hospital in North Africa and later transferred to an American installation. The other, who was injured while on furlough, was treated by a civilian physician.51 In the latter case, toxoid was administered after the onset of tetanus symptoms, some 48 hours after the injury. This injection is not considered to be a true emergency stimulating dose of toxoid.

Four patients in the series had received at least 1 booster dose of toxoid in addition to the basic series. One had had 3 such stimulating doses at yearly intervals. One of these did not receive a stimulating dose at the time of injury. All recovered. The other 2 individuals who had received the basic series of injections had been in the service less than 1 year thereafter at the time of injury.

The periods between the injury and the onset of symptoms of tetanus varied from 2 to 40 days. The median incubation period of the 6 immunized cases was 7.5 days, and of the 6 unimmunized, 13.5 days. The nature of the

    51Goehring, W. O.: Tetanus occurring in immunized individual. Am. J. Surg. 66: 123-125, Oct 1944.


296

injury resulting in tetanus with the number of cases in each category were: gunshot wound, 5; burn, 1; secondary to operation for osteomyelitis, 1; compound fracture, 2; miscellaneous injuries, 3. These injuries involved the foot in 5 instances, other extremities in 6, and the abdominal cavity in 1 case.

In summary, there were but 12 cases of tetanus in the Army during the war period. Six of these were in unimmunized individuals, including 4 resulting from injuries received prior to entry on active duty, and only 4 cases occurred in soldiers whose records indicated that they had received toxoid in complete accordance with Army requirements including the stimulating dose after injury. Tetanus occurred in only 1 battle casualty. There were 5 deaths from the disease, 2 in individuals who had received no toxoid and 1 in a person who though having had the basic immunization, did not receive a stimulating dose at the time of injury. Thus only 2 deaths from tetanus occurred in individuals immunized in complete accordance with requirements.

The contrast between this occurrence of tetanus and that experienced during World War I is not as striking as might be expected since but 70 cases were reported among Army personnel during the earlier conflict. It is likely, however, that this figure is low due to the incomplete reporting of the time. At that time specific protection was afforded by the administration of prophylactic tetanus antitoxin. There is no satisfactory estimate available as to the occurrence of serum sickness, anaphylaxis, et cetera, caused by this antitoxin, but it appears safe to assume that such reactions occurred to a significant extent. A total of 14 admissions for tetanus among Army personnel were reported to The Surgeon General during the period between the wars (1922-41), 2 more than the total number reported during World War II.

It is manifestly impossible to estimate the number of cases of tetanus actually prevented through immunization. There is, however, evidence to indicate the presence of potential hazards from this disease in areas where Army troops were in operation. In Hawaii, where no cases occurred among Pearl Harbor casualties, the annual incidence among the civilian population in peacetime is said to be about 5.7 per 100,000.52 No comprehensive data are available concerning the occurrence of tetanus among Japanese troops and natives in the various Pacific operations but sufficient information is at hand to indicate a relatively high incidence of the disease among this inadequately protected group. (Routine active immunization was not practiced in the Japanese Army. Selected personnel may have been immunized.) One Navy report indicated the occurrence of 14 cases of tetanus in a group of 284 Japanese wounded.53 Similarly, a report from Headquarters, Kwajalein, the Marshall Islands, reported 12 cases of tetanus among 266 wounded Japanese prisoners of war.54

    52Halford, F. J.: Gas gangrene and tetanus; their prevention and management in war wounds. Hawaii M. J. 1: 169-170, 13 Jan 42.
    53Navy Dept BUMED News Letter, vol. 4, No. 6, 15 Sep 44.
    54Monthly Sanitary Rpt, Surg APO 241 (Kwajalein Island), Jul 1944. SG: 721.5.


297

Tetanus among civilian casualties during the Manila operation was not uncommon, a total of at least 473 cases with 389 deaths having been reported.55 Also, at least 20 cases of tetanus are known to have occurred among civilians on Saipan.56 Probably the actual number was considerably greater than this. Of this known number, there were 14 fatalities.

Accurate data are likewise not available concerning tetanus among German troops. However, one report indicated that during the Normandy invasion, German ground troops (not immunized) suffered over 80 cases of tetanus but that there were no cases reported from the protected Luftwaffe.57 That this figure may be minimal is suggested by the fact that there were 53 cases of tetanus among American-held German prisoners of war in the United Kingdom during the period 7 September to 2 October 1944.58

The British have reported a total of 103 cases of tetanus from 1939 and 1940 to the end of the war.59 This total, however, included 34 German, 7 Italian, and 3 French cases. The remainder were in British, Dominion, or Colonial troops. Twenty-seven of the 103 were said to have been previously protected with 2 or more doses of toxoid.

From these rather fragmentary data concerning the occurrence of tetanus in other than American personnel, it is evident that without the benefit of toxoid appreciable numbers of cases of tetanus would have occurred in our troops. In addition, through the avoidance of the use of prophylactic antitoxin in the more than one-half million battle casualties an indefinite number of serious serum reactions and doubtless some fatalities were prevented.

In addition to the evidence of the actual protection reviewed above, certain experimental evidence was obtained in connection with various factors of the immunization processes. Early in the program, it became evident that there was at hand no factual evidence as to the rapidity with which a satisfactory immunity producing mechanism would be produced following the basic series of three injections of toxoid. This information was required for the basis for instructions regarding the administration of the emergency stimulating dose of toxoid after injury. Accordingly, serum specimens were obtained from each of nine individuals a week after the last injection of the initial series.60 At the same time, a fourth or stimulating dose of toxoid was administered in the same manner as if required by a potentially infected wound. A week after this fourth injection, blood specimens were obtained.

    55ETMD, USAFFE, 2 Jan 45. HD.
    56ETMD, POA, Nov 1944. HD.
    57OSS Rpt (Abstract), 27 Jul 45, sub: Medical installations in Munich area; new medical procedures. HD: 720.3 Tetanus Toxoid.
    58Ltr, Col J. H. McNinch, Off of Chief Surg ETO to Lt Col A. P. Long, SGO, 13 Dec 44. HD: 710 Tetanus.
    59Cope, Zachary, ed.: Medicine and Pathology. In Medical History of the Second World War. London, Her Majesty's Stationery Office, 1952, p. 446.
    60(1) Long, A. P.: Tetanus toxoid, its use in the United States Army. Am. J. Pub. Health 33: 53-57, Jan 1943. (2) See also footnote 48, p. 293.


298

All of the first specimens taken (1 week after the third dose) contained at least 0.1 unit of antitoxin per cubic centimeter of serum, and 3 contained 1 unit or more per cubic centimeter. Of the sera taken 1 week after the fourth or stimulating dose, two contained more than 0.1 unit but less than 0.5 unit; 3 contained more than 0.5 unit but less than 1 unit and the remainder contained at least 2 units of antitoxin per cubic centimeter. Since the amounts of circulating antitoxin necessary for protection had been stated by various workers to be 0.01 unit to 0.2 unit per cubic centimeter of serum, it was considered reasonable to assume that there was adequate protection based on active immunity after the completion of the initial series of three injections of tetanus toxoid, and that there was no indication for the use of prophylactic antitoxin after this immunity had been established.61

Late in 1942, in an effort to determine the antitoxin response to the stimulating dose of tetanus toxoid administered approximately 1 year after the initial series, serums for antitoxin titration were collected from 32 individuals. Stimulating doses of toxoid were then administered and a second serum specimen obtained 1 week later. Fifteen of these persons were stimulated with a regular commercial toxoid, while 17 were given a special peptone-free material, hydrolysate toxoid. Table 26 shows the results of these tests.62 It will be noted that while relatively small quantities of circulating antitoxin were present before the stimulating dose, 1 week thereafter adequate protective levels were reached in all but 1 individual who did not appear to respond well. These results compare favorably with those obtained by Mueller and his associates with a considerably larger sample.63 In their series of 103 individuals to whom stimulating doses were given 1 year after the basic series, titers from approximately 1 unit per cubic centimeter of serum to more than 50 were encountered. Approximately half of this group were given hydrolysate toxoids and the others, regular commercial products. No significant difference was noted between the responses from the two types of materials.

To extend further the knowledge on the immune response to stimulating doses of toxoid, a study was initiated early in 1945 to determine this response at least 2 years after the administration of the routine stimulating dose of toxoid. For this purpose, 22 volunteers were secured who had received their basic series of tetanus toxoid at least 3 years previously and the routine stimulating dose approximately 1 year thereafter with no subsequent doses of toxoid. Blood specimens for antitoxin titration were obtained from each of these men and a stimulating dose of toxoid was administered to 13. Blood specimens were obtained from the latter group on the third and seventh days following the injection of toxoid. Thus it was possible to determine the amount of

    61Ibid.
    62File: Tetanus Toxoid-Experimental. HD: 720.3.
    63See footnote 46(4). p. 292.


299

TABLE 26. RESULTS OF 1 CUBIC CENTIMETER OF STIMULATING DOSE OF TETANUS TOXOID APPROXIMATELY 1 YEAR AFTER BASIC SERIES

Before stimulation

After stimulation

Number

Units antitoxin per cc. serum1

Commercial toxoid

Experimental peptone-free toxoid

Number

Units antitoxin per cc. serum

Number

21

<0.1

---

<0.01

1

6

0.1

---

>0.01<.1

1

3

>0.1<.3

---

>0.1<.3

2

1

>0.1<1

---

>0.3<.6

3

1

Sample destroyed

---

0.3 or more2

4

15

0.6 or more3

6

32

15

17


1The antitoxin determinations were made at the National Institutes of Health and the Army Medical School.
2Tested for not more than 0.3 unit, actual value not known.
3Tested for not more than 0.6 unit, actual value not known.

circulating antitoxin present in all 22, and in 13, the increase in circulating antitoxin at the end of 3 and 7 days after the injection of 1 cc. of toxoid. The results of these determinations are shown in Table 27. It will be seen that only 2 of this group had less than 0.1 unit of antitoxin per cubic centimeter of serum before stimulation, and that 16 had 0.3 unit or more at that time. Thus, with the possible exception of the first 2, all were probably completely protected against tetanus in the event of an injury even though they were not to receive a booster dose. There was little increase in antitoxin level demonstrated at the end of 3 days following the booster dose but there was at least some indication of effect from the stimulus. At the end of 7 days, however, the rise was quite pronounced with only 1 of the 13 demonstrating less than 3 units, and 4 rising to a level of more than 10 units of antitoxin per cubic centimeter of serum.

In addition to the positive evidence of the practical efficiency of tetanus toxoid for the prevention of tetanus, there has been experimental evidence to indicate a protective response to a booster dose of tetanus toxoid administered as late as 3 to 4 years after the initial series, and 2 to 3 years after the routine stimulating dose as applied in the standard Army tetanus immunization regime. Continued investigation will be required to determine the full extent of this period of efficacy of the basic tetanus immunization as applied to adults in the Army.

Reactions. The administration of tetanus toxoid was attended by some reactions, a great majority of which occurred early in the program. At no time were these reactions of sufficient import to hamper seriously the practice


300

TABLE 27. SERUM ANTITOXIN LEVELS 2 YEARS OR MORE AFTER ROUTINE STIMULATING DOSE OR TOXOID AND EFFECT OF BOOSTER DOSE ADMINISTERED AT THAT TIME1

Case number

Prestimulation antitoxin units per cc. serum2

Interval since previous dose of toxoid

Poststimulation antitoxin units per cc. serum2

months

3 days

7 days

1

>0.01 <0.1

34

>0.03 <0.1 

>3 <10

2

>.01 <.1

26

>.03 <.1

>1 <3

3

>.1 <.3

28

.3

>30

4

>.1 <.3

28

>.1 <.3

>10 <30

5

>.1 <.3

27

.1

>3 <10

6

>.1 <.3

26

7

.3

33

.3

>3 <10

8

.3

26

>.3 <1

>3 <10

9

>.3 <1

33

>.3 <1

>3 <10

10

>.3 <1

27

>.3 <1

>3 <10

11

>.3 <1

27

>.3 <1

>3 <10

12

>.3 <1

26

>.3 <1

>10 <30

13

>.3 <1

26

14

>.3 <1

25

15

>.3 <1

27

16

>.3 <1

27

17

>.3 <1

27

18

>.3 <1

23

19

>.3 <1

26

20

>1   <3

27

21

>1   <3

26

>1   <3

>3   <10

22

>1   <3

26

>1   <3

>10   <30


1Antitoxin determinations performed in the laboratories of the Department of Bacteriology, Harvard Medical School.
2Arrangements made and specimens obtained by Lt. Col. Francis Cook, Medical Inspector, First Service Command.

of active immunization. Reactions encountered were classifiable to two main categories. Those in the first category caused no concern and were manifested by such symptoms as headache, weakness, general malaise, local soreness, and occasionally chills and fever. Such reactions were not unlike those experienced after typhoid vaccination but occurred much less frequently after tetanus toxoid than following the administration of triple typhoid vaccine.

The reactions of the second category occurred in a majority of instances within 30 minutes after the injection and were characterized in general by flushing and itching of the skin, local and generalized urticarial eruptions, and edema of the lips and eyelids. In some instances, edema of the glottis and dyspnea were observed. The nature of these reactions more than their frequency led to considerable study for the determination of their cause. It soon became apparent that they were manifestations of sensitivity to some constituent of the toxoid used. An early opportunity for the investigation of the occurrence of these reactions was afforded by their relatively high incidence in


301

the Newfoundland Base Command.64 During this investigation, it was determined that among 1,722 completed immunizations in that command in August 1941, there were 22 reactions of sensitivity among 18 individuals, 1 percent of those immunized presenting symptoms of sensitivity. All reactions followed the second or third dose. Skin sensitivity tests done on a limited number of those reacting, using a 1:100 dilution of the same type of toxoid used for the immunization, demonstrated definite local sensitivity of high degree, while the same type of test recorded on individuals who had experienced a reaction nonsensitive in nature were entirely negative. It was suggested by the investigator that these reactions were the result of sensitization by the first or second dose of toxoid, and that a study be made of the various culture media used in preparation of toxoid to determine the presence of a protein likely to cause such sensitization.

In view of these findings and the observations of Whittingham,65 Parish and Oakley,66 and Cooke and his associates,67 the reports of reactions received in the Surgeon General's Office were carefully scrutinized in an effort to determine the relationship between their occurrence and the use of particular lots or makes of toxoid. By early October 1941, sufficient evidence had been accumulated to indicate very strongly that those toxoids containing Witte's or Berna's peptone were responsible for a great majority of the reactions68 (toxoids containing Witte's or Berna's peptone had been used in about 75 percent of the injections reported and had been responsible for at least 90 percent of the reactions reported at that time). As a result, the action previously referred to was taken to discontinue the use of toxoids of this nature. This was followed by a significant decrease in the occurrence of these reactions.

An accurate figure as to the exact numbers of reactions of sensitivity which occurred and the proportion of injections resulting in such reactions was never obtained, the problem not having been considered worthy of the detailed investigation throughout the Army which would have been required for this purpose. However, a reasonably good sampling was achieved. Table 28 presents an estimate of the proportion of reactions of sensitivity to the number of injections given for various periods during the first 3 years of the tetanus immunization program.

64Memo, Dir Prev Med Div SGO for SG, 27 Aug 41, sub: Report by Capt. Long of tetanus toxoid reactions at Newfoundland Base Command. HD: 720.3.
65Whittingham, H. E.: Anaphylaxis following administration of tetanus toxoid. Brit. M. J. 1: 292-293, 24 Feb 40.
66Parish, H. J., and Oakley, C. L.: Anaphylaxis after injection of tetanus toxoid. Brit. M. J. 1:294-295, 24 Feb 40.
67Cooke, R. A.; Hampton, S.; Sherman, W. B., and Stull, A.: Allergy induced by immunization with tetanus toxoid. J. A. M. A. 114: 1854-1858, 11 May 40.
68Memo, Dir Prev Med Div SGO for SG, 7 Oct 41, sub: Reactions to tetanus toxoid, report of conference, Surgeon General's Office, 2 October 1941. HD: 720.3.


302

The highest proportion of reactions experienced, according to this estimate, was approximately 63 per 100,000 injections, and by the end of the year following discontinuation of the procurement of toxoids containing the offending peptones this had dropped to about 2 per 100,000. At this time, and certainly during subsequent periods, the actual proportion was in all likelihood considerably lower since negative reports were seldom received; that is, there was a tendency to report actual numbers of injections accomplished only when one or more reactions occurred. Following 15 July 1943, despite the steadily growing Army, the reports were so scattered and few as to make further computations entirely unsatisfactory.

TABLE 28. REACTIONS TO SENSITIVITY TO TOXOID*

Injections

Reactions

Reactions per 100,000 injections

To 1 October 1941

445,299

284

63

1 October 1941 to 1 March 1942

1,559,285

493

32

1 March 1942 to 15 October 1942

361,133

22

6

15 October 1942 to 31 December 1942

199,652

4

2

31 December 1942 to 15 July 1943

163,692

3

2


*These figures do not represent the total number of reactions during this period nor the total number of injections.

As the early experience indicates, the majority of reactions occurred after the second and third injections. Of these reactions reported in relation to the number of the injection causing the reaction, it was found that 16 percent followed the first injection and the remainder of the reactions were about equally divided between the second and third doses of the toxoid.

Earlier estimates of the proportion of reactions caused by the toxoids containing Witte's and Berna's peptone were also essentially borne out by the continued studies. By June 1942, just under one million injections of toxoid had been reported with indications of the name of the manufacturer and lot number of material used. From this information, it was possible to determine the type of peptone or other protein material contained in the product in question. This revealed that in this series, toxoids made with Witte's peptone had resulted in reactions of sensitivity in about 43 out of every 100,000 injections. Those containing Berna's peptone had caused similar reactions in 79 injections per 100,000, and other toxoids caused 16 such reactions in a similar number of injections.

Viewed in another way, toxoids with Witte's peptone tended to produce these reactions 3.3 times and those with Berna's peptone 5 times more frequently than did other toxoids.


303

These figures indicate that toxoids other than Witte's or Berna's peptone toxoid were at that time producing a higher proportion of reactions than was subsequently experienced. This may be explained in part on the basis of observations made in another study, described below, that individuals sensitized by one of the toxoids most commonly producing reactions may react in a sensitive manner to toxoids containing meat digests or similar substances, but no peptone. Thus, in late 1941 and early 1942, it was entirely likely that second or third injections of digest toxoid might have been administered to individuals already sensitized by a first injection of a peptone-containing material. Under such a circumstance, the toxoids other than Witte's and Berna's peptone toxoid might have precipitated a reaction based on earlier sensitization by a toxoid of another type.

In an effort to learn something of the duration of the state of sensitivity in individuals who had demonstrated such reactions and to observe the effect of nonpeptone toxoids on such persons, a study was conducted with 40 volunteers who had previously demonstrated reactions as subjects.69 Results of this study are summarized in Table 29. Of the total of 40 individuals studied, 33 were still positive to a material causing original reactions, 31 were positive to pig stomach digest toxoid, 27 were positive to the other digest toxoid used, and none gave positive reactions to hydrolysate toxoid (toxoid produced on Mueller's hydrolysate media). Of 16 people tested who had received peptone toxoid (Witte's or Berna's) but who had not responded with reactions of sensitivity, 5 were found to be positive to the material originally received, 3 to pig stomach digest, 6 to the other digest toxoid, and none reacted positively to the hydrolysate toxoid. These findings indicated that those individuals who had originally reacted in a sensitive manner to the peptone type of toxoids (approximately 1 year previously) were still sensitive to those materials. Since such toxoids were no longer available for use, this caused no concern. However, the fact that such individuals might react in a sensitive manner to digest toxoids on subsequent injections was viewed with some misgiving. Some effect from this conditioning probably was felt as indicated above. However, the fact that practically no reactions were reported following stimulating or booster doses during the later months or years indicated that this cross sensitivity was apparently of no great significance.

The entire experience with the reactions of sensitivity following tetanus toxoid served to emphasize the importance of great care in the selection of antigens for such widespread use as is practiced with immunizing agents in the Army. There can be no doubt but that in the production of materials of this type the greatest possible care should be taken to prepare materials with the least possible danger of the production of sensitivity consistent with a potent and stable product.

69Office memo, A. P. Long, 6 Aug 42, sub: Preliminary report of field study on reactions to sensitivity to tetanus toxoid. HD: 720.3.


304

TABLE 29. RESULTS OF SKIN SENSITIVITY TESTS ON INDIVIDUALS KNOWN TO BE SENSITIVE TO CERTAIN TOXOIDS1

Table A Tests

I. Skin Tests on Individuals Previously Sensitive to Witte Peptone Toxoid

Type of test toxoid

Hydrolysate

Digest2

Digest (Pig stomach)

Witte peptone

Reaction

Indefinite

Positive

Negative

Indefinite

Positive

Negative

Indefinite

Positive

Negative

Indefinite

Positive

Negative

Number

4

0

13

0

13

2

1

15

1

0

17

0

II. Skin Tests on Individuals Previously Sensitive to Berna Peptone Toxoid

Type of test toxoid

Hydrolysate

Digest2

Digest (Pig stomach)

Berna peptone

Reaction

Indefinite

Positive

Negative

Indefinite

Positive

Negative

Indefinite

Positive

Negative

Indefinite

Positive

Negative

Number

1

0

22

4

14

5

4

16

3

3

16

4

III. Summary

Type of toxoid

Hydrolysate

Digest2

Digest (Pig stomach)

Witte and Berna Peptone

Reaction

Indefinite

Positive

Negative

Indefinite

Positive

Negative

Indefinite

Positive

Negative

Indefinite

Positive

Negative

Number

5

0

35

4

27

7

5

31

4

3

33

4


305    

Table B

Controls

I. Skin Tests on Individuals Previously Receiving Peptone Toxoid but Exhibiting no Reactions

Type of toxoid

Hydrolysate

Digest2

Digest (Pig stomach)

Witte and Berna peptone

Reaction

Indefinite

Positive

Negative

Indefinite

Positive

Negative

Indefinite

Positive

Negative

Indefinite

Positive

Negative

Number

2

0

14

5

6

5

6

3

7

5

5

6


1Intradermal injections of 0.1 cc. of a 1:100 dilution of the toxoids were used for the tests.
2Two individuals not tested with this material.


306

VACCINATION AGAINST YELLOW FEVER

Development and Adoption

The development of a vaccine effective against yellow fever was begun in 1928 with the demonstration of the virus etiology of the disease.70 The various stages in this development have previously been traced and recorded and require no further review.71

Early in 1940 Lt. Col. James S. Simmons foresaw the need to determine Army policy on vaccination of troops against yellow fever. He referred the problem to the Advisory Committee on Tropical Diseases of the National Research Council, and on the basis of his suggestions the committee recommended, in June 1940, that military personnel going into areas where yellow fever was suspected to exist be immunized against that disease.72 In order that a supply of the vaccine might be available, this group requested the International Health Division of the Rockefeller Foundation to produce a supply of this vaccine for possible use by the Armed Forces. At a subsequent meeting held in October 1940, this committee made further specific recommendations that all military or civilian personnel dispersed to the American tropics or other areas where yellow fever was likely to be encountered should be immunized. It was recommended that the vaccination be done preferably before departure for such areas and that those individuals already in the areas should be vaccinated as early as possible.73

In January 1941, The Surgeon General recommended to The Adjutant General that all military personnel stationed in tropical regions of the Western Hemisphere, including Panama and Puerto Rico, be vaccinated against yellow fever.74 In this recommendation, it was pointed out that in the defense of the Western Hemisphere, it was anticipated that troops would be sent to certain South American countries where exposure to yellow fever was a likelihood. In addition, the possibility of the introduction of this disease into areas where it did not exist at the time was stressed. It was stated that the introduction of the disease into new areas might be accomplished through the increase in travel and exchange of troops between endemic and nonendemic areas or by the willful introduction by enemy action of the causative virus into areas where the vector was already established. Following this recommendation, the War Depart-

70Stokes, A.; Bauer, J. H., and Hudson, N. P.: The transmission of yellow fever to Macacus rhesus. J. A. M. A. 90: 253-254, 28 Jan 28.
71(1) Smith, H. H.; Penna, H. A., and Paoliello, A.: Yellow fever vaccination with cultured virus (17D) without immune serum. Am. J. Trop. Med. 18: 437-468, Sep 1938. (2) Gordon, J. E.: The preparation and use of yellow fever vaccine. In Virus and Rickettsial Diseases. Cambridge, Harvard University Press, 1940, p. 767-788. (3) Sawyer, W. A.: Yellow fever and its control. In Problems and Trends in Virus Research. Philadelphia, University of Pennsylvania Press, 1941, p. 27-39.
72Minutes of meeting, NRC Advisory Committee on Tropical Diseases, 19 Jun 40. SG: 040.9-10.
73Minutes of meeting, NRC Subcommittee on Tropical Diseases, 24 Oct 40. SG: 040.9-10
74Ltr, SG to TAG, 19 Jan 41, sub: Vaccination of troops against yellow fever. HD: 720.3.


307

ment, on 30 January 1941, directed vaccination against yellow fever of all military personnel stationed in the tropical regions of the Western Hemisphere, including Panama and Puerto Rico, and the preembarkation vaccination of personnel ordered to these areas.75 The requirements for vaccination as presented in the original directive were changed a number of times throughout the war period. These requirements will be reviewed below.

The Immunizing Agent

At the time of the adoption of yellow fever vaccination by the Army, the only producer of this vaccine in the United States was the laboratory of the International Health Division of the Rockefeller Foundation. Accordingly, arrangements were made for the procurement of vaccine from this laboratory in accordance with the recommendations of the National Research Council previously cited. This vaccine was a suspension of viable virus prepared from chick embryo cultures of the 17-D strain of yellow fever virus.76 This material was the Seitz or Berkefeldt filtrate of a 10-percent infected chick embryo emulsion in undiluted, inactivated human serum. The emulsion was placed in ampules and desiccated from the frozen state under vacuum. An immunizing dose was 0.5 cc. of a 1: 10 dilution of this material. Each lot was tested for sterility, virus content, and for evidence that the neurotropic virulence was low.

Shortly after the arrangements had been made for the procurement of vaccine from the Rockefeller Foundation, discussions were held with representatives of the Public Health Service in connection with the possibility of that agency also undertaking the manufacture of this agent with a view toward ultimately providing all necessary yellow fever vaccine to the Armed Forces. The initiation of this second source of supply was considered desirable inasmuch as the Rockefeller Foundation, while in a position to furnish the vaccine as an emergency measure, had recommended that its manufacture be assumed by some Governmental agency as soon as it was practicable to do so.77 Accordingly, the Surgeon General of the Public Health Service took the necessary action to establish facilities for yellow fever vaccine production. These facilities were established and, in September 1941, the Administrator of the Federal Security Agency notified the Secretary of War that the Rocky Mountain Laboratory of the Public Health Service was in a position to furnish yellow fever vaccine to the Army.78 During the intervening period, the Rockefeller laboratories had furnished large quantities of vaccine and the director of that organi-

75Ltr, TAG to CGs Armies, CAs, etc., 30 Jan 41, sub: Vaccination of troops against yellow fever. AG: 720.3.
76(1) Memo, Dr. W. A. Sawyer, International Health Div Rockefeller Foundation, to SG, 9 Jul 40, sub: Manufacture of yellow fever vaccine. HD: 720.3. (3) Memo, Dir Prev Med Div SGO for SG, 31Jul 40, sub: Conference with Director, Rockefeller International Health Board concerning yellow fever vaccine. HD: 720.3.
77Ltr, SG to Surg Gen USPHS, 17 Aug 40, and reply, 3 Sep 40. HD: 720.3. Yellow Fever.
78Ltr, Admin Fed Sec Agency to SecWar, 26 Sep 41. HD: 720.3 Yellow Fever.


308

zation stated his willingness to continue to furnish this material to the Army for the duration of the emergency. It was then mutually agreed by representatives of the Army, Navy, Public Health Service, and Rockefeller Foundation that the latter organization continue to furnish vaccine to the Armed Forces, the Public Health Service to manufacture such material as was considered necessary to meet any anticipated demands of the civilian population and thus also provide an emergency reserve of the agent to be available to the services if for any reason it should become impracticable to continue with the Rockefeller supply.79

This arrangement was continued until April 1942 when it became apparent that the outbreak of jaundice in the Army at that time was associated with yellow fever vaccination.80 While the role of yellow fever vaccine in the production of jaundice was not clearly understood at that time, it was considered advisable to discontinue, temporarily at least, the vaccine currently in use and to substitute an agent from another source. Accordingly, arrangements were made to obtain vaccine from the Public Health Service at least until the true nature of the vaccine-jaundice relationship could be established. In addition, stocks of the original material in this country were called in and supplies in installations outside the country were destroyed.81

The first vaccine received by the Army from the Public Health Service was prepared in much the same manner as that obtained from the Rockefeller Foundation and, like that material, contained as a stabilizing agent normal human serum.82 However, consideration was being given to the production of a vaccine containing no serum and in fact a small quantity of material of this type had been prepared previously and was furnished to the Army late in May 1942.83 Later in the same month, the decision was made that as soon as feasible all of the yellow fever vaccine used by the Army be made without human serum.84 In accordance with this decision the vaccine prepared for Army use by both producing laboratories, the Public Health Service and Rockefeller Foundation, was subsequently of the aqueous base, serum-free type. All of the yellow fever vaccine received by the Army after 1 June 1942 had been prepared in this manner.

79(1) Memo, Dir Prev Med Div SGO for SG, 21 Oct 41, sub: Yellow fever vaccine. HD: 720.3. (2) Ltr, TAG to Admin Fed Sec Agency, 29 Sep 41. HD: 720.3 Yellow Fever.
80Memo, Dir Prev Med Div SGO for SG. 15 Apr 42, sub: Report on jaundice and yellow fever vaccination. HD: 720.3 Yellow Fever.
81(1) Memo for file, Maj A. P. Long, Prev Med Serv SGO, 15 Apr 42, sub: Change of supply of yellow fever vaccine. HD: 720.3. (2) Memos, Asst Prev Med Serv SGO for Chief Prev Med Serv SGO, 10 and 18 Apr 42, sub: Recall of yellow fever vaccine. HD: 720.3.
82Memo, Dir Rocky Mountain Lab USPHS for Chief Prev Med Serv SGO, 5 May 42, sub: Preparation, et al., of yellow fever vaccine at the Rocky Mountain Laboratory. HD: 720.3.
83Ltr, Dir Rocky Mountain Lab USPHS to CO Army Med Supply Depot, Brooklyn, N. Y., 20 May 42. HD: 720.3 Yellow Fever.
84Memo, Prev Med Serv SGO for SG, 26 May 42, sub: Supply of yellow fever vaccine. HD: 720.3.


309

From this time, there were two sources of yellow fever vaccine. This allowed both for adequate amounts of the material for current use and for the maintenance of reserve stock piles both in this country and in overseas bases. The bulk of the vaccine used by the Army throughout the remainder of the war was that produced by the Public Health Service, while the Rockefeller Foundation also contributed large quantities of this immunizing agent and maintained large reserve stocks.

Methods and Requirements

The method of administration of yellow fever vaccine remained essentially unchanged throughout the war period. This procedure involved the subcutaneous administration of 0.5 cc. of a 1:10 dilution of the desiccated material. Sterile saline solution was furnished in bottles containing the proper amounts for making the desired dilutions. Thus with the 1 cc. vaccine ampule was furnished a bottle containing 10 cc. of saline, and with the 5 cc. ampule, a bottle containing 50 cc. of saline. Ten-fold dilutions yielded 10 cc. and 50 cc. of vaccine respectively, or 20 and 100 doses of 0.5 cc. each.

Detailed instructions for handling, storage, dilution, and administration of the vaccine were furnished in Circular Letter 9, Office of The Surgeon General, February 1941, and later in Circular Letter 162, Office of The Surgeon General, November 1942, and TB MED 114, November 1944. In addition, instructions for the dilution and administration of the vaccine were distributed with the material itself. The liability of this agent was stressed in all the instructions issued, and directions were given that it be shipped and stored at freezing temperatures and that diluted vaccine exposed to room temperatures for longer than 1 hour should not be used.

Possible contraindications to the administration of yellow fever vaccine at the same time as other antigens were considered. It was believed that since smallpox vaccine and yellow fever vaccine both contained living viruses, it was not desirable to administer them simultaneously. It was recommended that if both were to be administered, the yellow fever vaccine be given first and smallpox vaccination done at least 5 days later. Because of the apparent exaggerated reaction to typhoid vaccine when it was administered to individuals experiencing a febrile reaction from yellow fever vaccine, it was recommended that the administration of typhoid vaccine within a 7-day period following yellow fever vaccination be avoided whenever possible.

As previously indicated, the requirements for yellow fever vaccination were changed from time to time throughout the war period. These requirements and the various changes which were made were based on a number of considerations. The basic consideration was the provision for adequate protection against yellow fever of personnel stationed in or traveling through areas where the disease was known or reasonably suspected to exist. A second consideration was


310

the possibility of the introduction of yellow fever to areas where, while currently absent, the disease might spread rapidly due to the presence of the mosquito vector. Still a third consideration was the necessity for compliance with the quarantine regulations of certain foreign governments. Of all of these factors, the last-named was perhaps the most troublesome, since, unless these regulations were complied with, detention of individuals traveling by air resulted, thus interfering with military travel and the smooth operation of transportation systems, particularly air transport.

The various administrative requirements for yellow fever immunization which were in effect during the years 1941 through 1945 are shown in Appendix A. These requirements varied from that of selective vaccination of individuals stationed in the tropics, which was in effect early in the program, through the vaccination of all military personnel effected during the first half of 1942, to the final policy of the immunization of those individuals whose route of travel or place of station was considered to require this special protection. The areas where hazards from yellow fever were considered to exist were redefined from time to time. This was done for two principal reasons. One was consideration of possible infection in areas where it had hitherto not been considered. This, for example, was the basis for extending the requirement for yellow fever vaccination for those individuals stationed in or traveling to Panama and the Canal Zone. Changes in definition of the areas requiring yellow fever immunization which are found in War Department Circular 254, 1943, and Circular 187, 1944 (see Appendix A) are based on the definition of certain foreign governments, particularly India and Egypt. It was not until May 1944 that the accepted period of immunity following yellow fever vaccination was increased from 2 to 4 years. As will be seen later, it had been considered for some time prior to this that immunity produced by yellow fever vaccine was retained for longer than 2 years, but there was reluctance on the part of both Indian and Egyptian officials to consider individuals vaccinated longer than 2 years previously as immune, and hence incapable of introducing the infection into their respective countries. The solution of this problem, that is the reconciliation of what was considered in this country to be safe practice with the quarantine requirements and regulations of India, particularly, was a long slow process and involved voluminous correspondence and interchange of communications through State Department as well as military channels.85 The later phases of these negotiations are discussed in the chapter on Foreign Quarantine in Volume II of this series.

In addition to the War Department requirements for yellow fever vaccination as summarized and discussed above, there was a theater requirement for this vaccination for troops stationed in Hawaii and the Central Pacific Area

85"Résumé of the Controversy Regarding Yellow Fever Vaccination and Quarantine. India and the United States." HD: 720.3.


311

from September 1943 until June 1945.86 Hawaii was not considered to be a yellow fever endemic area and vaccination was not accomplished for individuals prior to their departure from the United States. Instead the vaccine was shipped to Hawaii and administered to troops after their arrival. The basis for the requirement for yellow fever vaccination in Hawaii and the Central Pacific was the concern in the War Department over the potential dangers of the introduction of yellow fever into Hawaii which, because of the presence of Aedes mosquitoes, was considered to be a fertile area for the rapid development of an epidemic. Such a situation did not develop and yellow fever was not identified in the area at any time during the war. Vaccination there was, therefore, entirely a precautionary measure taken against this potential hazard.

Experience

Effectiveness. The effectiveness of yellow fever vaccine for the prevention of yellow fever had been well demonstrated prior to its adoption by the Army.87 It was generally accepted in this country that satisfactory immunity developed within a week to 10 days following vaccination and lasted for an indefinite period beyond 2 years. In 1943, however, additional evidence became available which indicated clearly that the immunity following vaccination persisted for a period of at least 4 years.88 It was this evidence which, added to previous experiences, made it possible to adopt the 10-day, 4-year policy which was then accepted as meeting the quarantine requirements for unrestricted entry into Egypt and India from yellow fever endemic areas.

As far as the effectiveness of yellow fever vaccine in American troops is concerned, there is little that can be said. No cases of yellow fever occurred. Neither was there appreciable exposure to the disease. Yellow fever did occur sporadically in the general areas in which some troops were stationed both in South America and in Africa. However, it is not known that the disease actually occurred in sufficiently close proximity to Army installations so that exposure actually took place.

Laboratory evidence of the efficacy of the vaccination was, however, obtained. This was done in order to check on the potency of the vaccine as it was used in the field. It was accomplished by the procurement of blood specimens from representative groups vaccinated at various places throughout the country. The presence of protective antibodies in these serum specimens showed defi-

86(1) Ltr, Mr. J. W. McCloy, Asst Sec War, to CG Hawaiian Dept, 8 Jul 43, and reply, 20 Jul 43. AG: 720 Hawaii. (2) Memo, Chief Prev Med Serv SGO for Mr. J. W. McCloy, Asst Sec War, 13 Aug 43. AG: 720 Hawaii. (3) Ltr, CG Hawaiian Dept to Mr. J. W. McCloy, Asst SecWar, 6 Sep 43. AG: 720 Hawaii. (4) Ltr, CG USAFPOA to TAG, 5 Mar 45, sub: Immunization of personnel proceeding to this theater, with 5 inds. HD: 720.3 POA Reqmts.
87See footnote 71(1) and (2), p. 306.
88Fox, J. P., and Cabral, A. S.: The duration of immunity following vaccination with the 17D strain of yellow fever virus. Am. J. Hyg. 37: 93-119, Jan 1943.


312

nitely that the vaccines used were active and that the desired results were being obtained.89

Reactions. The relationship between apparently augmented reactions to typhoid vaccine in individuals recently vaccinated against yellow fever has been discussed. It is believed that this reaction occurred in those individuals expressing a febrile response to the yellow fever vaccine. Such a response had been anticipated, and in the first circular letter prescribing the use of yellow fever vaccine, it was pointed out that approximately 5 percent of vaccinated individuals could be expected to exhibit a slight general and febrile reaction between the fifth and the seventh day following vaccination. These reactions did occur but apparently not to the extent of 5 percent of the individuals vaccinated. Accurate figures of incidence are not available since complete reporting of reactions of this type was not required. In one series of approximately 125,000 vaccinations reported early in the program, febrile reactions were reported in just under 300 individuals; an incidence of approximately 0.2 percent.90 Essentially no reports of reactions were received subsequently but this figure is considered to be representative of the total experience. Reactions of this type were characterized in the main by variable degrees of malaise, elevation of temperature occasionally as high as 101º F. or higher, and occasional axillary adenitis. There was no indication that these reactions bore any relationship to the postvaccinal jaundice which made its appearance early in 1942.

In March of 1942 it became apparent that the jaundice then occurring among troops was likely to develop into an incidence of epidemic proportions. This in fact did occur and the peak of the epidemic among troops in the continental United States was reached in late June and in overseas contingents about 1 month later. A total of over 50,000 cases of jaundice believed to have occurred in relationship to yellow fever vaccination were reported.91

Exhaustive studies and investigations were instituted as soon as it was evident that an epidemic was imminent. Early results obtained from these studies indicated that a causal relationship existed between the occurrence of jaundice and the administration of at least certain lots of yellow fever vaccine 2 to 3 months previously. This relationship seemed to be in connection with the human serum used for the stabilization of the vaccine. Acting on this evidence The Surgeon General in April 1942 discontinued the vaccine in current use. Soon after this, a serum-free vaccine was introduced and no cases of

89File: Yellow Fever Vaccine-Tests. HD: 720.3.
90 File: Yellow Fever Vaccine-Reactions. HD: 720.3.
91(1) The outbreak of jaundice in the Army. Mil. Surgeon 94: 386-393, Oct 1942. (2) Sawyer, W.A.: Meyer, K. F.: Eaton, M. D.; Bauer, J. H.; Putnam, P., and Schwentker, F. F.: Jaundice in Army personnel in the western region of the United States and its relation to vaccination against yellow fever. Am. J. Hyg. 39: 337-430, May 1944: idem 40: 35-107, Jul 1944. (3) Walker, D. W.: Some epidemiological aspects of infectious hepatitis in the U. S. Army. Am. J. Trop. Med. 25: 75-82, Mar 1945.


313

jaundice were reported traceable to yellow fever vaccination with the new type of agent.

It was subsequently shown without question that jaundice could be transmitted to humans by the subcutaneous injection of very small amounts of human serum obtained from individuals developing the disease after yellow fever vaccination and that this jaundice resulted from infectious hepatitis.92 This and other evidence obtained from the jaundice epidemic experience demonstrated clearly that the jaundice after yellow fever vaccination was not associated directly with the yellow fever virus itself but that it was due to an extraneous or contaminating virus introduced into the vaccine with the human serum component.

Subsequent to this experience, many thousands of individuals were vaccinated successfully with a yellow fever vaccine not containing human serum. Thus the cause of an unanticipated complication of immunization was discovered and effective steps were taken for the prevention of its future occurrence.93

CHOLERA, PLAGUE, AND TYPHUS VACCINATIONS

Vaccinations against cholera, plague, and epidemic typhus fever were "special immunization procedures." That is, they were not applied routinely but only for the protection of troops stationed in or departing for areas where danger from the specific disease was considered to be a real or potential hazard and for troops traveling through such areas. Since these vaccinations were considered as a group in the adoption of policies and procedures for their use by the Army, they will be treated in a similar fashion here.

Action looking toward the specific protection of American troops against cholera, plague, and typhus, should such protection be indicated, was taken in the early autumn of 1941. At that time, no American troops were under actual threat of any of these diseases. However, the possibility of future assignment to or even action in areas where these diseases were present was becoming more and more likely. This first action was taken in preparation for the future rather than to meet an existing situation.

The first step taken was the presentation of a memorandum requesting recommendations concerning these immunization procedures to the Chairman of the Division of Medical Sciences, National Research Council.94 In this

92Oliphant, J. W.; Glllian, A.G., and Larson, C. L.: Jaundice following administration of human serum. Pub. Health Rep. 58: 1233-1242, 13 Aug 43.
93Jaundice following vaccination against yellow fever. J. A. M. A. 125: 1190-1191, 26 Aug 44.
94Memo, Col J. S. Simmons, SGO, for Dr. L. H. Weed, Div of Med Sciences NRC, 8 Sep 41, sub: Immunization against certain infectious diseases, notably plague, cholera, and typhus. HD: 720.3 Typhus.


314

memorandum, guidance was specifically requested with respect to the indications for vaccination and in connection with a definition of the agents to be employed and the methods for their use. In response to this request, a meeting of specialists in the various fields involved was arranged by the National Research Council and pertinent recommendations were made.95 In essence, these were to the effect that all individuals stationed in or about to enter areas where danger of exposure to typhus fever or cholera existed should be vaccinated with an appropriate vaccine. For typhus, the vaccine recommended was the Cox type, yolk-sac vaccine; and for cholera, a vaccine containing 8 billion killed vibrios per cubic centimeter. It was also recommended that all personnel under serious threat of exposure to bubonic plague be vaccinated with "killed plague bacilli of an approved strain."

Acting on these recommendations, after investigating the source of the supply of the agents involved, The Surgeon General, on 13 November 1941, recommended to The Adjutant General that these procedures be adopted for selective use in the Army.96 This recommendation was approved and these procedures were adopted on 6 January 1942 with the publication of War Department Circular 4 of that date. This circular stated that military personnel stationed in or traveling to certain areas should be vaccinated against typhus and/or cholera as prescribed by The Surgeon General, and that military personnel under serious threat of exposure to epidemics of plague should be immunized with plague vaccine as prescribed by The Surgeon General. This administrative directive was implemented on 14 January 1942 by technical instructions published in Circular Letter 3, Office of The Surgeon General, subject: Vaccination against typhus fever, cholera, and plague. In subsequent discussion of these procedures, each will be considered separately.

Cholera Vaccination

The Immunizing Agent. The cholera vaccine procured for use in military personnel was prepared by commercial manufacturers in accordance with the recommendations and requirements of the National Institutes of Health, United States Public Health Service.97 The organism strains chosen for the vaccine were Inaba and Ogawa strains which were agglutinable, smooth, motile, presented characteristic biochemical activities, and were apparently fully virulent and antigenic. A large number of freshly isolated strains obtained from India were studied both at the Army Medical School and at the National Institutes of Health and those chosen for inclusion in the vaccine were considered to be the

95Minutes of conference on immunization against typhus fever, cholera, and plague called by NRC Subcommittee on Tropical Diseases, 22 Oct 41. HD: 720.3 Typhus.
96Ltr, SG to TAG, 13 Nov 41, sub: Immunization against typhus, cholera, and plague. HD: 720.3 Plague.
97(1) Memo for file, 20 Feb 42, sub: Conference regarding cholera vaccine held at the Army Medical School. HD: 720.3. (2) Ltr, Dr. M. V. Veldee, Natl Inst of Health, to Lt Col A. P. Long, SGO, 4 Apr 44. HD: 720.3 Cholera.


315

best obtainable for vaccine production. The finished vaccine consisted of a suspension of phenol-killed cholera vibrios containing 8 billion organisms per cubic centimeter of the vaccine.

Methods and Requirements. The method prescribed for the administration of cholera vaccine was first presented in Circular Letter 3, Office of The Surgeon General, 1942, previously referred to, and was republished subsequently in Circular Letter 162, Office of The Surgeon General, 1942, and TB MED 114, 1944. The initial vaccination consisted of two subcutaneous injections of 0.5 cc. and 1 cc. respectively at 7- to 10-day intervals. Stimulating doses of 1 cc. each at intervals of 4 to 6 months were recommended in the presence of serious danger of infection. This procedure as originally adopted was continued without change throughout the war.

Cholera vaccination was required for troops who were stationed in or traveling to areas where danger from cholera was considered to exist. The requirements as stated in the original War Department directive of 6 January 1942 were as follows: "All military personnel stationed in or traveling through Asia or other regions where cholera is known to be present in endemic or epidemic form will be immunized with cholera vaccine as prescribed by The Surgeon General." The vaccine was administered in this country only after receipt of orders directing travel to one or another of the areas concerned. It was fully realized that such immunity as did accrue from cholera vaccination was in all likelihood incomplete and probably of short duration. It was therefore emphasized that this procedure should not in any way serve as a substitute for sanitary or other measures for prevention and control of the disease.

The official War Department requirements for this procedure are found in Appendix B. During certain periods of the war, cholera vaccination was required for travel to areas where in fact no cholera existed. This was made necessary on administrative grounds in view of the uncertainty of the actual destination of certain troop contingents in some instances, and because of the difficulty in accomplishing the vaccination in an active theater as a last minute procedure prior to an operational move. In a similar manner and for much the same reasons, cholera vaccination was required for all operational Army Air Force personnel including those assigned to the Air Transport Command. While this policy undoubtedly resulted in the vaccination of individuals for whom no danger of exposure ever existed, it was the only practicable method of accomplishing the protection of all of those for whom it was considered necessary.

Effectiveness. While there had been little experience in the Army with cholera vaccination prior to World War II, this procedure had been practiced for many years in those areas where cholera is more or less a constant threat. First among these areas were India, China, and the Malay States. The results of vaccination, however, were never clear-cut and had not clearly demonstrated


316

the value of the procedure. Strong, in reviewing this past experience, states that "While prophylactic inoculation in cholera has been very widely employed for many years no definite unanimity of opinion exists in regard to its value during an epidemic though in general the reports have been favorable regarding its use."98

An analysis of large scale experience with cholera vaccine was presented in a study of a cholera epidemic in the Province of Madras, India, in 1942 and 1943.99 In this epidemic, the study of two large groups, one vaccinated, the other unvaccinated, revealed that the incidence was 10.6 times more in the unvaccinated than in the "protected" group. From this and other supporting data, the authors drew the conclusion that 
". . . . there is definite proof that the protected persons are 10 to 14 times less susceptible to getting cholera than the uninoculated persons in the community." It was the feeling of the authors of this report that the protection afforded from vaccination persisted from 5 to 12 months.

The validity of these conclusions can neither be confirmed nor refuted by the experience with cholera among American troops during the war. The fact remains, however, that the occurrence of cholera among these troops was negligible. The disease was present in epidemic or semiepidemic form in a number of areas in which troops were stationed. These included China, India, and Burma. The only cases in American military personnel occurred in China in the summer of 1945 when 6 cases and 1 death were reported from the Liangshan area, and 7 cases and 1 death from Chihchiang.100 The source of the infections in the Liangshan group was considered to have been baked goods secured from a local bakery. The cases at Chihchiang were believed to have resulted from the drinking of contaminated water. All of those developing cholera at Liangshan had been vaccinated in August 1943 with American vaccine (just over 2 years before the onset of illness). Information concerning subsequent or stimulating doses was not complete. However, it was determined that 5 of the 6 individuals involved had received a stimulating dose of Chinese vaccine in April and May 1944. Five of the group also received stimulating doses of Chinese vaccine in October 1944 and the sixth was given a dose of American vaccine in September 1944. In April 1945, five of the individuals concerned received American vaccine and the remaining person was given a booster dose of Chinese vaccine in May of the same year. Two received stimulating doses as late as July 1945. This group then appeared to have been

98Strong, R. P.: Stitt's Diagnosis, Prevention and Treatment of Tropical Diseases. Philadelphia, The Blakiston Company, 1944, p. 634.
99Adisehan, R., Dir Pub Health Madras, India: Statistical evaluation of anti-cholera inoculation as a personal prophylactic against cholera and its efficacy in the prevention and control of cholera epidemics. HD: 710.
100ETMD, China theater, Aug 1945. HD.


317

reasonably well vaccinated although the exact nature of the Chinese vaccine used was not known.

Information on the original immunizations on the patients at Chihchiang was not obtained but all seven of the individuals had received a stimulating dose of vaccine as late as April and July 1945, the one man vaccinated in April having received Indian vaccine. These few cases of cholera in American personnel in China occurred at a time when there was a sharp outbreak among the Chinese in the Chungking area. Stringent precautionary measures were applied to safeguard the troops in that area from contaminated food and water. The relative effects of this procedure and of vaccination for the prevention of the disease in American personnel could not be determined. It was necessary to assume that the result obtained accrued from a summation of all the protective measures applied and that under similar circumstances, none of these measures may be omitted with safety.

No cases of cholera occurred in military personnel in the India-Burma theater although a sharp epidemic was experienced in the civilian population of Calcutta early in 1945.101 Some evidence of the efficacy of vaccination in the prevention of the disease in this situation was derived from the fact that cholera did occur in approximately 50 British and Indian troops in the area at that time.102 It was the practice of the British in this area to vaccinate only after the epidemic started, rather than to practice immunization before hand as was done for American personnel. The risk to which the British and American troops were exposed would appear to have been comparable although American sanitation may have been superior. As with experience in China, the only conclusion that could be drawn was that troops could be protected from cholera by the application of all the available preventive measures including vaccination.

Reactions. Almost no reports were received of untoward reactions following cholera vaccination. The vaccine used appeared to have been essentially free from reaction producing substances.

Plague Vaccination

The Immunizing Agent. The plague vaccine secured for use in the Army was commercially prepared in accordance with National Institute of Health requirements and standards.103 The first procured (approximately 100,000 cc.) was prepared from avirulent stock culture strains. The remainder of the material obtained was made from virulent plague bacilli. The original virulent strains used were the Ureka strain isolated from a human case of plague in 1941 and F8251 isolated from infected fleas in 1941.104 These strains were

101ETMD, India-Burma theater, 1 Jun 45. HD.
102Med Intel Rpt, U. S. Navy Liaison Off, Calcutta, 28 Jul 45, sub: Cholera. HD: 710.
103Natl Inst of Health, Minimum Requirements for Plague Vaccine, 20 Apr 45.
104Ltr, Dr. M. V. Veldee, Natl Inst of Health, to Maj A. P. Long, SGO, 8 Apr 42, with incls. HD: 720.3 Plague.


318

replaced in the latter part of 1942 by a virulent Indian strain (No. 337, Hooper Foundation, University of California).105 The finished vaccine was a suspension of formalin-killed plague bacilli containing 2,000 million organisms per cubic centimeter.

Methods and Requirements. Instructions for the use of plague vaccine were first published in Circular Letter 3, Office of The Surgeon General, 14 January 1942, and subsequently in Circular Letter 162, Office of The Surgeon General, 28 November 1942, and TB MED 114. Initial vaccination was accomplished by the subcutaneous administration of 2 doses of vaccine, 0.5 cc. and 1 cc. each, at intervals of 7 to 10 days. Subsequent doses of 1 cc. each were to be administered when stimulation of immunity was considered necessary. Under serious threat of exposure to plague infection, it was recommended that such doses be given as frequently as every 4 to 6 months.

Basic War Department policy for plague vaccination requirements contemplated administration of the vaccine to troops in areas where and when special danger from the disease was found to exist. Thus vaccination was not to be accomplished prior to embarkation for overseas but rather supplies of the vaccine were furnished to the theaters for use as indicated.106 This policy was adhered to throughout the war with but two exceptions.

In view of the endemicity of plague in the Azores and in accordance with the recommendation made by the Surgeon of the British Base at Lagens, those ordered to permanent duty in the Azores were vaccinated prior to departure.

The second exception was made in connection with troops departing for duty in the western part of the Pacific Ocean Areas. At the request of theater officials, personnel ordered to duty in those areas were given plague vaccine prior to embarkation during part of the year 1945.107 This practice was discontinued, however, shortly after the termination of hostilities.108

Effectiveness. The effectiveness of plague vaccination as practiced for American troops was not determined. No cases of plague were reported but neither was there indication that actual exposure occurred. The disease was present, however, in areas where American forces were stationed. These included the Azores where the disease smoulders in low endemic proportions, New Caledonia where two cases were reported in 1942, the Suez Area in Egypt where there was a brisk outbreak in late 1943 and early 1944, and the Dakar-Marrakech area where a moderate epidemic occurred in 1943 and 1944. Plague was also present in China and India in areas where American troops were

105Minutes of Conference on Plague Prevention and Therapy, Division of Medical Sciences, NRC, 15 Oct 42. HD: 720.3.
106WD Cir 4, 6 Jan 42.
107Ltr, TAG to CGs AAF, AGF, ASF, POEs, CofTrans, and SG, 20 Nov 44, sub: Immunization of troops moving overseas, and Amendment No. 2, 1 Feb 45. AG: 720.3.
108Memo, Troops Mvmts Branch Mobilization Div ASF to Opns Branch AGO, etc., 20 Aug 45, sub: Revised clothing and equipment chart for troops moving to all overseas commands (Change #11). HD: 720.3 Travel Rqmts, POA.


319

stationed. (See chapter on plague and plague control in another volume in this series.)

Vaccination of American troops was practiced in all these areas in addition to rodent and flea abatement programs and general protective measures. Credit for the protection of American personnel against plague must of necessity be given to all of the procedures applied. The true value of plague vaccination alone could not be determined from the situations encountered and the experiences obtained.

Reactions. Reactions reported in connection with the administration of plague vaccine were minimal and no difficulties developed from this aspect of the use of plague vaccine of the type applied in the Army during the war.

Typhus Vaccination

The Immunizing Agent. The first typhus vaccine recommended for use by the Army was the Cox vaccine. This consisted of a 2-percent formalinized yolk-sac suspension of louse-borne epidemic typhus rickettsiae, Breinl strain. The rickettsiae were cultivated in the yolk sac of fertile hens' eggs and extracted by centrifugation and then washed.109 As with all other biologic agents obtained commercially, acceptance for use in the Army was based on conformance with the minimum requirements of the National Institute of Health.

When the use of typhus vaccine was first contemplated it was being produced by only one commercial manufacturer and some time was required before large quantities of the agent could be made available. The supply situation was further clouded by the fact that sufficient funds were not available to purchase the quantities which would be needed soon after the procedure was officially adopted.110 During the period between the official adoption of typhus vaccination and the time adequate procurement from commercial sources was effected, considerable amounts of the vaccine were furnished by the laboratories of the United States Public Health Service.111 By March 1942, however, a number of commercial laboratories had accepted contracts for the production and supply of typhus vaccine and some 239,000 vials had been placed on order for delivery within the subsequent 6 months.112

The use of typhus vaccine for the protection of military personnel served as a stimulus to investigations aimed at improvement in the quality and effectiveness of this agent. Those most actively engaged in this work were investi-

109Cox, H. R.: Use of yolk sac of developing chick embryo as medium for growing rickettsiae of Rocky Mountain spotted fever and typhus groups. Pub. Health Rep. 53: 2241-2247, 23 Dec 38.
110Memo, Dir Finance and Supply Div for Dir Prev Med Div, 24 Nov 41. HD: 720.3 Typhus.
111Memo for file, 1 Jan 42, sub: Typhus vaccine. HD: 720.3.
112Table, Procurement status of typhus vaccine on order with manufacturers, 5 Mar 42. HD: 720.3.


320

gators at the National Institute of Health, the Connaught Laboratories of Toronto, Canada, and the Army Medical School.113

It was early recognized that the original Cox vaccine was deficient in antigen content. In December 1941, the workers at the Connaught Laboratories in Toronto demonstrated the ether method of extracting rickettsiae from yolk-sac suspensions. The vaccine recommended consisted of an ether extraction of the yolk-sac suspension followed by centrifugation and resuspension of the rickettsiae. Following this the Army Medical School initiated an experiment to compare the various typhus vaccines then available and susceptibility of being used by the Army. They consisted of the Cox vaccine described above, the ether extracted yolk-sac vaccine of the Connaught Laboratories, the French epidemic mouse-lung vaccine and the Mexican murine rat-lung vaccine. The results of these experiments showed the Cox vaccine and the Mexican murine rat-lung vaccine did not adequately protect guinea pigs against epidemic type of rickettsiae. The other two vaccines, however, did appear to afford good protection. A soluble antigen obtained from ether extracted yolk-sac suspension was demonstrated independently and at approximately the same time by two of the research laboratories (Army Medical School114 and National Institute of Health).115 A vaccine containing a greater concentration of rickettsiae and soluble antigen was prepared and tested in man and guinea pigs. This new method of processing eliminated centrifugation which in turn eliminated the loss of antigen in the form of minute rickettsiae and in the form of soluble antigenic material. On 25 May 1942, at a conference called by the Subcommittee on Tropical Diseases of the National Research Council, it was agreed that "Typhus vaccine should contain both the soluble antigen heretofore discarded and all of the available rickettsiae bodies," and that the "ether extraction method without centrifugation is at present the best method of preparation of vaccine. . . .116 On 26 August it was recommended that the Army, Navy, and Public Health Service use a typhus vaccine made from 10-percent yolk-sac suspension including the so-called soluble antigen formalin killed and prepared by ether extraction.117

By September 1942, all manufacturers of typhus vaccine for Army use had been instructed by the National Institute of Health to prepare this new type agent.118 However, in order to avoid a break in the supply, the new material

113(1) Memo, Col J. S. Simmons to SG, 26 Dec 41, sub: Report on conference on typhus vaccine attended at Connaught Laboratories, U. of Toronto. HD: 720.3. (2) Memo, Chief Virus Lab, Army Med School, for Dir Army Med School, 20 Mar 42, sub: Report on the testing of four different typhus vaccines in guinea pigs. HD: 720.3. (3) Natl Inst of Health Bull. No. 183, Studies on Typhus Fever, 1945. (4) "Outline of Methods Developed for the Preparation of a Concentrated Typhus Vaccine," Army Medical Center, 20 Nov 42. HD: 720.3 Typhus. (5) Connaught Laboratories Memos No.3 and 4, War Project Med 8 (NRC Canada), 13 Nov 42. HD: 720.3 Typhus.
114See footnote 113(2).
115See footnote 113(3).
116Minutes, NRC Conference on Immunization against Typhus Fever, 25 May 42. HD: 720.3.
117Minutes, NRC Conference on Typhus, Cholera, and Plague, 26 Aug 42. HD: 720.3 Typhus.
118Memo for file, 12 Sep 42, sub: Typhus vaccine. HD: 720.3.


321

was brought in gradually and a number of months passed before all the vaccine procured for Army use was being made by the improved methods. By late March 1943, however, sufficient supplies of this improved agent had been procured to allow the discontinuance of distribution of the "old" or original type of material.119

With the increase in experience in production and testing of the vaccine, it was possible to improve its quality still further. Such improvement was exemplified in May 1943 when the National Institute of Health increased the stringency of the antigenicity requirements which the vaccine was required to meet before it could be released for distribution.120 As a result of the efforts directed toward the preparation of an effective typhus vaccine and the continued supervision and control over its production by the Biologics Control Division, National Institute of Health, it was considered that this agent as supplied for the use in American troops was the most effective obtainable and certainly superior to any previously produced.

Methods and Requirements. The methods of use of typhus vaccine were first prescribed in Circular Letter 3, Office of The Surgeon General, 14 January 1942. The initial vaccination consisted of three 1 cc. doses administered subcutaneously at intervals of 7 to 10 days between doses. It was recommended that stimulating doses of 1 cc. each be administered in a similar fashion at 4 to 6 months intervals in the presence of serious danger from infection.

This method of administration of vaccine was followed until September 1944 when in accordance with the recommendation made by a National Research Council conference group, the basic immunization was limited to two 1 cc. injections of the vaccine.121 Instructions concerning this new method as well as the recommendation that stimulating doses be administered on a seasonal basis rather than at certain time intervals were published in TB MED 114, November 1944. No other changes in the methods of administering typhus vaccine were effected.

The administrative requirements for typhus vaccination as they obtained at various periods throughout the war are shown in Appendix C. The basic policy contemplated the protection of those troops likely to be exposed to disease. Vaccination of the entire Army against typhus was not done. At the end of the war, typhus vaccination was a requirement for travel to, or station in, virtually all overseas theater bases. This was necessary both because of the wide distribution of typhus throughout the world and because troops ordered to certain typhus-free areas were subject to movement to typhus areas on short notice. Since it was considered that the protection afforded from vaccination

119Memo, Chief Epidemiology Branch SGO for Dir Supply Serv SGO, 23 Mar 43, sub: Typhus vaccine. HD: 720.3.
120Natl Inst of Health, Memo for Manufacturers of Typhus Vaccine, 11 May 43. HD: 720.3.
121(1) Minutes, NRC Conference on Typhus, 22 Jun 44. HD: 720.3. (2) Ltr, TAG to CGs POEs, COs POEs, CofTrans, 8 Sep 44, sub: Inoculation for typhus fever. AG: 720.3


322

was considerably augmented by stimulation some months after the initial vaccination the value to such individuals was actually increased by having received the first doses of vaccine some time before actual danger from exposure occurred.

Effectiveness. As indicated, vaccination was practiced for all troops subjected to possible exposure to epidemic typhus fever. However, the prevention of typhus, like that of a number of other infectious diseases, was based not on vaccination alone but on the application of other protective procedures as well. First among there were the facilities, materials, and instructions provided for the prevention of louse infestation of troops and the performance of rapid and sure disinfestation should lousiness occur. The degree of louse infestation of American personnel was very low. For example in the European theater in December 1944, it was determined that only 0.5 percent of 1,800 troop units had experienced lousiness among their personnel, there being less than 25 individuals infested.122 The objective of the typhus prevention and control measures applied in the Army was the provision of the greatest degree of protection obtainable and not the determination of the comparative efficacy of the various procedures used. This objective was realized in the occurrence of less than 100 cases of epidemic typhus among Army personnel (see discussion on typhus fever in another volume in this series). Twenty-eight cases were reported from the European Theater of Operations, 19 from Africa and the Middle East, and 17 from the Mediterranean theater. In all of these areas, typhus fever was prevalent among civilians at one time or another during the occupation by American troops and the opportunities for exposure were undoubtedly numerous.

While the exact role played by vaccination in the prevention of typhus among troops could not be clearly defined, it was generally accepted that this measure was an effective one. Such cases of typhus as did occur among vaccinated individuals were apparently considerably milder than those experienced by unvaccinated individuals in the same area. This fact was first noted in North Africa in 1943 where about a dozen cases of the disease, all of which were mild, occurred among Americans who were vaccinated. Unvaccinated British troops on the other hand experienced about three times as many cases, one-third of which ended fatally.123 It was also the experience that when vaccinated laboratory workers contracted typhus the disease was modified considerably from that experienced under similar situations before specific protection was afforded by the type of vaccine used in the United States Army. In summarizing the efficacy of typhus vaccine, it was agreed by those present at the National Research Council conference on typhus, held in June 1944, that "The evidence is all in favor of the opinion that while vaccination against

122ETMD, ETO, Jan 1945. HD.
123(1) Ltr, Lt Col Y. Kneeland, and others, to Chief Surg ETOUSA, 2 Mar 44, sub: Report of mission on typhus, ETO. HD: 710. (2) NATOUSA Cir Ltr 43, 11 Nov 43, sub: Typhus fever control. HD.


323

epidemic louse-borne typhus fever does not always prevent infection, it causes the disease to be mild and appears thus far to prevent death from typhus."124 The experience subsequent to this meeting offered no evidence other than in corroboration of this opinion. By the end of the war, no reports of deaths from epidemic typhus fever in vaccinated Army personnel had been received in the Office of The Surgeon General.

Reactions. Untoward reactions to typhus vaccine were not significant either in number or severity and presented no interference with the vaccination program.125 Reports were received early in 1943 of reactions occurring immediately after injection of the vaccine and characterized by intense pain and burning. On investigation, these symptoms were determined to be the result of excess residual formalin in certain lots of vaccine. Following the discontinuation of use of these particular lots, no further reports of reactions of this type were received.

With the extensive use of vaccines produced in eggs, there arose the possibility of the occurrence of reactions of sensitivity to these agents. Such reactions, however, did not materialize in any appreciable number. From the few reports of reactions of allergic nature following typhus vaccination, it was shown, however, that this vaccine was capable of precipitating such a response. This was not entirely unexpected since it was known that approximately 10 percent of the typhus vaccine protein nitrogen was attributable to ovalbumen.126 Such allergic reactions as did occur appeared for the most part to have been on a basis of the presence of sensitivity to egg protein before the vaccination rather than the development of this sensitivity through the administration of vaccine containing the allergen. Two fatal anaphylactic reactions following the administration of typhus vaccine were reported. In both instances, investigation revealed the preexistence of a sensitivity to egg which was not detected prior to the injection of the vaccine. These occurrences led to the adoption of routine questioning of personnel who were to receive vaccines produced in eggs. A question usually used was "Do you eat eggs or chicken?" A negative answer required further study to determine the presence or absence of sensitivity.

INFLUENZA VACCINATION

Development and Adoption

The influenza vaccine adopted by the Army and the methods for its use were developed through the activities of the Commission on Influenza, Board for the Investigation and Control of Influenza and Other Epidemic Diseases

124See footnote 121(1), p. 321.
125File: Immunization, Reactions, Typhus Vaccine. HD: 720.3.
126(1) Memo, Chief Div of Virus and Rickettsial Diseases. Army Med School, for Dir Epidemiology Div SGO, 17 Jan 44. HD: 720.3 Typhus Vaccine. (2) Rpt of Joint Investigation, Div of Virus and Rickettsial Diseases, Army Med School, "Allergenic and anaphylactogenic properties of vaccines prepared from embryonic tissues of developing chicks," 1944. HD: 720.3 Egg Sensitivity, Reactions.


324

in the Army127 (later called Army Epidemiological Board), which was administered through the Preventive Medicine Service, Office of The Surgeon General.

Influenza vaccination was first adopted by the Army in the autumn of 1943.128 At that time the procedure was applied in certain Army Specialized Training Program units in the Second, Sixth, Seventh, and Ninth Service Commands. This selective vaccination was in accordance with provisions of AR 40-210, and was accomplished as a field trial of the procedure. Following the successful results of this trial, information was published stating that influenza vaccine had been approved for the Army but that it would be recommended for use only in the face of an outbreak or threatened outbreak of the disease.129 It was also pointed out that at that time the supply of vaccine was limited and that large quantities would not be available before the latter part of 1944. Because of this limitation of supply, the material that was available was stockpiled in a central depot in the United States so that the most judicious use could be made of it should the need arise.130

Some relatively small-scale influenza vaccination was accomplished in the Army in the late spring of 1945 but it was not until September of that year that vaccination of large numbers of military personnel was undertaken. At that time, in view of the possibility of an influenza outbreak during the coming winter, vaccination of the entire Army was directed.131 Because of the special nature of the procedure it was not adopted as routine but only for a one-time application to be accomplished, for personnel already in the Army, during the months of October and November and for recruits as they entered the service, from that time through 15 April 1946.132

The Immunizing Agent

The vaccine used was a suspension of killed (formalinized) influenza virus types A and B made from the growth of the virus in the allantoic fluid of the embryonated chicken egg. The vaccine was prepared commercially in accordance with the minimum requirements of the National Institute of Health and recommendations issued by the Office of The Surgeon General.133

127(1) Bayne-Jones, S.: Board for the Investigation and Control of Influenza and other Epidemic Diseases in the Army. Army M. Bull. No. 64, Oct 1942, pp. 1-22. (2) Francis, T.: The development of the 1943 vaccination study of the commission on influenza. Am. J. Hyg. 42: 1-11, Jul 1945.
128Book message 30-33, SG to CGs 2d, 6th, 7th, and 9th SvCs, 15 Oct 43. HD: 720.3 Influenza.
129TB MED 85, 15 Aug 44.
130Ltr, SG to CGs AGF, AAF, all theaters, etc., 12 Aug 44, sub: Influenza vaccine. HD: 720.3.
131WD Cir 267, 5 Sep 45.
132(1) WD Cir 381, 21 Dec 45. (2) Teletype message SPMDR, WD to CGs AAF, AGF, and ASF, 27 Feb 46. HD: 720.3 Influenza. (3) WD Cir 113, 18 Apr 46.
133(1) Natl Inst of Health, Minimum Requirements for Influenza Vaccine, 1 Jun 44 and subsequent revisions. (2) SGO, Recommendations for the Preparation of Influenza Virus Vaccine, Type, A and B, for the United States Army, 9 May 44; 2 Apr 45; Feb 1946. HD: 720.3.


325

The type A virus component consisted of equal quantities of the PR8 Strain and the Weiss Strain of influenza virus A. The type B component was made up entirely of the Lee Strain of virus B.

Methods and Requirements

The vaccine was administered in a single dose of 1 cc. given subcutaneously. Because the virus was grown in eggs it was emphasized that the vaccine should not be administered to individuals hypersensitive to egg protein.134

It was required that all Army personnel be vaccinated during the months of October and November 1945. Those who did not receive the vaccine during those periods were vaccinated as soon thereafter as possible. All military personnel embarking for overseas travel between 1 October 1945 and 15 April 1946 were required to have received influenza vaccine subsequent to 1 October 1945. No repetition of the vaccination was required although a booster dose of 1 cc. after an interval of approximately 30 days was contemplated if the situation warranted.

Experience

Effectiveness. The results of the 1943 trials of influenza vaccine in Army Specialized Training Program units were considered to be highly successful and have been amply described elsewhere.135 These trials were conducted in nine Army Specialized Training Program units in various sections of the country. The timing of the actual vaccinations was most fortunate since, in most instances, it was accomplished approximately 2 weeks before the outbreak of the 1943-44 epidemic of influenza type A. Over 12,000 individuals were included in the studies. This number was almost equally divided into a vaccinated group and a control group. The aggregate results showed the occurrence of approximately 3.5 cases among the controls for each case in the vaccinated group. The evidence gathered also strongly suggested that the protection from vaccination developed in about 1 week, thus indicating the probable value of the vaccine when given just before or even at the onset of an epidemic. As was expected, there was no significant difference between the vaccinated and the

134See footnote 131, p. 324.
135(1) Members of Commission on Influenza, Army Epidemiology Board: A clinical evaluation of vaccination against influenza. Preliminary report. J. A. M. A. 124: 982-985, 1 Apr 44. (2) Rickard, E. R.; Thigpen, M., and Crowley, J. H.: Vaccination against influenza at the University of Minnesota. Am. J. Hyg. 42: 12-20, Jul 1945. (3) Hale, W. M., and McKee, A. P.: The value of influenza vaccination when done at the beginning of an epidemic. Am. J. Hyg. 42: 21-27, Jul 1945. (4) Eaton, M. D., and Meiklejohn, G.: Vaccination against influenza: a study in California during the epidemic of 1943-44. Am. J. Hyg. 42: 28-44, Jul 1945. (5) Hirst, G. K.; Plummer, N., and Friedewald, W. F.: Human immunity following vaccination with formalinized influenza virus. Am. J. Hyg. 42: 45-56, Jul 1945. (6) Salk, J. E.; Menke, W. J., and Francis, T.: A clinical epidemiological and immunological evaluation of vaccination against epidemic influenza. Am. J. Hyg. 42: 57-93, Jul 1945. (7) See also footnote 127(2), p. 324.


326

unvaccinated group with respect to the occurrence of the so-called common respiratory infections or common cold.

The vaccination of all military personnel in the autumn of 1945 was also timely in that an outbreak of mild influenza type B occurred throughout the country during the month of December 1945.136 While this outbreak actually touched the Army very lightly, it was extremely difficult to arrive at a quantitative estimation of the part played by immunization in the prevention of the disease among troops. Unlike the situation in 1943-44, there were no unvaccinated control groups among military personnel for direct comparison. The only comparisons possible, therefore, were with other Service groups who were unvaccinated and with the civilian population. These comparisons, based on the relative experience of these groups in the 1943-44 influenza A epidemic as well as the current epidemic of influenza B, indicated strongly that the vaccination of military personnel was responsible for a considerable reduction in morbidity from that which could have been expected had this measure not been applied.137 The degree of this reduction could not be accurately measured for the Army as a whole but in two instances where direct comparison could be made between small groups of vaccinated and unvaccinated persons, the total incidence of the acute respiratory infections among the vaccinated as compared to that in the unvaccinated was 1.15 percent to 9.9 percent, and 1.9 percent to 16.9 percent respectively.

From all the evidence available from the 1945 experience it was concluded that vaccination played a significant role in the prevention of influenza B among military personnel in the United States during the epidemic period.

Reactions. Experience gathered during the trials of influenza vaccination in 1943 indicated the occurrence of systemic reactions following administration of the vaccine in 16 to 20 percent of those vaccinated. These reactions were characterized by generalized aching, chilliness, malaise, and mild fever. Only a small proportion of those experiencing reactions of this type required hospitalization.138 There were no anaphylactic reactions encountered in the groups studied at the time although there were reports of two instances of cutaneous eruption following vaccination.

Specific reports of reactions encountered following administration of the vaccine in 1945 were not required. However, some reports were forwarded to the Office of The Surgeon General in accordance with the general instructions regarding the reporting of reactions of unusual severity or number.139 These reports showed considerable variation in the occurrence of reactions. Some

136ASF Monthly Progress Report, Sec. 7, Health, 31 Dec 45.
137ASF Monthly Progress Report, Sec. 7, Health, 31 Mar 46.
138Rpt, Dir Influenza Commission, Army Epidemiology Bd, to President Army Epidemiology Bd, 8 Feb 44, sub: Preliminary report of the clinical evaluation of vaccination against influenza. HD: 720.3.
139File: Immunization Reactions-Influenza Vaccine. HD: 720.3.


327

organizations reported as few as 7 percent generalized reactions while others indicated that as many as 85 percent of those receiving the vaccine experienced generalized reactions of varying degrees of severity. The most common incidence was considered to be between 25 and 50 percent. These reactions were characterized in general by fatigue, aching muscles, headache, chilliness or slight actual chills, and fever. The onset was usually within 8 to 10 hours after vaccination. Only a small proportion of the reactions were of sufficient severity to require hospital care. Local reactions consisting of burning and stinging of the arm with some residual soreness and stiffness were not uncommon.

In addition to the local and generalized reactions referred to there were reported three reactions of an anaphylactic nature. Two of these were fatal. All were considered to have been allergic responses to the egg component of the vaccine in individuals previously sensitized to egg protein.

JAPANESE B ENCEPHALITIS VACCINATION

Development and Adoption

Large-scale vaccination of human beings against Japanese B encephalitis was first practiced by the Russians, but vaccines prepared in the United States according to their procedures were found to possess little or no immunogenic potency on assay in animals. In early 1943, however, a mouse brain vaccine with immunogenic potency measurable in animals and in human volunteers was developed in this country.140

Action was initiated in September 1944 to obtain a stock of this vaccine and to sponsor and encourage efforts toward the improvement of this agent.141 Because of the unique nature of the vaccine and the difficulties inherent in its preparation only limited supplies were available in the summer of 1945. Its use was officially adopted by the War Department in July 1945, however, and vaccine was sent to Okinawa as it became available.142

The Immunizing Agent

The vaccine adopted consisted of a 10-percent saline suspension of virus-infected mouse brain, the virus having been inactivated by formaldehyde. The Nakayama strain of Japanese B encephalitis virus was used.143 This material was procured from commercial biologic manufacturers and was prepared and

140Sabin, A. B., and others: The St. Louis and Japanese B types of epidemic encephalitis. Development of noninfective vaccines: report of basic data. J. A. M. A. 122: 477-486, 19 Jun 43.
141(1) Minutes of Conference on Japanese B Encephalitis Vaccine, SGO, 23 Sep 44. HD: 720.3. (2) Memo, Chief Prev Med Serv SGO for SG, 7 Oct 44, sub: Japanese B encephalitis vaccine. HD: 720.3.
142(1) TB MED 181, Jul 1945. (2) Memo, Dir Epidemiology Div SGO for Chief Supply Serv SGO, 13 Aug 45, sub: Japanese B encephalitis vaccine. HD: 720.3.
143See footnote 140.


328

tested for use in the Armed Forces in accordance with National Institute of Health Minimum Requirements for this agent.144

Subsequently, a vaccine prepared from infected embryonated eggs was developed in the Division of Virus and Rickettsial Diseases of the Army Medical School.145 This vaccine consisted of a 20-percent suspension of virus infected chick embryo tissue inactivated with formaldehyde. None of this material was available for use during the war. It was first produced in large quantities by the Army Medical School Laboratories in 1946, and used subsequently in Japan, Korea, and Okinawa.146

Methods and Requirements

The method of use of Japanese B vaccine as prescribed in TB MED 181, July 1945, was the "subcutaneous injection of two doses of 2 cc. each with an interval of 3 days between doses." The large individual doses were considered necessary in view of the apparent low antigenicity of the material and the short interval was considered desirable as a safeguard against reactions due to the establishment of a sensitive state following the first dose. In view of the low order of neutralizing antibody response among the vaccinated on Okinawa147 and the corroborating evidence obtained in the Virus and Rickettsial Disease Division of the Army Medical School,148 this method was later abandoned and the following procedure adopted for use in the preepidemic vaccination program on Okinawa and Japan in the summer of 1946. "Two doses of 1 cc. each mouse brain vaccine with 7 day intervals constitutes basic preepidemic course to be followed 1 month after first injection by one single 1 cc. booster dose of either mouse brain or preferably chick embryo vaccine. Booster dose may be given earlier in presence of threatened epidemic."149

Administrative requirements for this vaccination were limited sharply by the geographic distribution and the seasonal occurrence of the disease and in the first season of its use (1945) by the limited supply of vaccine. Thus the procedure was first limited to "the use of combat troops in areas where adequate mosquito control cannot be accomplished and not to be (applied) until cases of the disease have occurred."150 This requirement essentially limited the use

144Natl Inst of Health "Minimum Requirements Japanese B Encephalitis Vaccine for Use In Armed Forces," 8 Nov 44.
145Warren, J.: A vaccine against Japanese B Encephalitis prepared from chick embryos, 1945. HD: 720.3.
146Ltr, SG to CG Army Med Ctr, 21 Jan 46, sub: Production of Japanese B encephalitis vaccine. HD: 720.3.
147Rpt, W. McD Hammon, Consultant to SecWar, SGO, sub: Results of neutralization tests on sera of military personnel on Okinawa vaccinated by Japanese B mouse brain vaccine, 1946. HD: 720.3.
148Rpt, Chief Div of Virus and Rickettsial Diseases, Army Med School, Mar 1946, sub: Japanese B encephalitis vaccine. HD: 720.3.
149Radio SPMDR, CG ASF to CinC AFPAC, 29 Apr 46. HD: 720.3 Jap B Encephalitis.
150See footnote 142(1), p. 327.


329

of this vaccine to certain combat troops on Okinawa in the early summer of 1945. This policy was modified in August 1945 to the extent that the vaccine was authorized for all troops in the area where the disease was occurring. However, limitation of such general vaccination was necessary because of inadequacy of the supply of vaccine.151 This policy was still further modified in the spring of 1946 to allow for preepidemic vaccination of those troops considered to be at the greatest risk.

Experience

Effectiveness. A limited vaccination program was carried on in Okinawa in August 1945 in the face of an epidemic of the disease beginning among natives in July. A total of 53,139 individuals were known to have received the full course of vaccine and, in view of the limitations of reporting, it was considered that several thousand more may have been vaccinated.152 It was agreed by competent observers that the 1945 experience did not yield information from which conclusions concerning the efficacy of the vaccine could be drawn. The bulk of the vaccinations were accomplished as the epidemic was on the wane. Of the 38 reported cases of encephalitis among military personnel, 20 occurred before any troops in the area from which the cases originated were vaccinated. Twelve cases occurred subsequently in nonvaccinated persons and 6 in those who had received the vaccine. The fact that vaccination in Okinawa did not result in appreciable response in neutralizing antibody titers was suggestive of lack of protection but the state of knowledge concerning the significance of such a response precluded the complete acceptance of this finding as evidence of the immunogenic failure of the vaccine. As previously indicated, there was sufficient optimism concerning the value of the procedure to justify its use during the 1946 encephalitis season in Japan and the Ryukyu Islands, particularly Okinawa.

Reactions. In the preliminary studies carried out by the members of the Neurotropic Virus Commission some 1,000 persons (nonmilitary) were vaccinated with a noninfective mouse brain vaccine.153 Approximately 500 of these received Japanese B virus vaccine, the other 500, St. Louis virus vaccine. The majority of the subjects developed transitory local reactions at the site of the injection consisting of erythema, swelling, itching, and in some, pain and tenderness. However, these were not considered to be of consequence. Between 8 and 9 percent of the total group experienced what were considered to be significant untoward reactions. These were mild in all but one instance.

151Radio, WD to CinC AFPAC, 13 Aug 45. HD: 720.3 Jap B Encephalitis Vaccine.
152Med Bull 20, Hq Army SvC I (Okinawa), 6 Oct 45, sub: Report on immunization with Japanese B encephalitis vaccine. HD: 720.3.
153Rpt, Commission on Neurotropic Virus Diseases SGO, 24 Jun 43, sub: Preliminary report on the vaccination of man against the St. Louis and Japanese B types of epidemic encephalitis. HD:720.3.


330

The complaints most commonly expressed were those of headache, nausea, weakness, and drowsiness. Four persons receiving the St. Louis encephalitis vaccine experienced generalized urticaria. The one severe reaction followed administration of the St. Louis vaccine, and its onset was 5 days after the second dose. This patient developed unmistakable signs and symptoms of encephalitis, the etiologic diagnosis of which could not be made with certainty. It was considered to be either demyelination encephalitis from heterologous brain tissue or possibly true St. Louis encephalitis, the latter possibility being quite remote.

The true incidence of untoward reactions following the vaccinations on Okinawa could not be determined since the exact number of persons receiving the vaccine was not known. There were no stated criteria for the type of reactions to be reported, hence considerable variation in reporting was inevitable. The reactions reported appeared to have been those experienced among the 53,139 persons known to have been vaccinated with the full course and 2,274 who received one injection only.154 Sixty-one local reactions were recorded, including those with pain and swelling at the site of injection and occasionally axillary lymph node enlargement. Actual abscess formation requiring drainage was reported in 5 individuals in 2 small units, suggesting the possibility of a break in technique and the introduction of a microorganism other than the virus of the vaccine. Only 19 systemic reactions characterized by malaise, fever, headache, and nausea were reported. Nineteen allergic reactions were recorded. These consisted largely of urticarial manifestations and in some instances angioneurotic edema with moderate respiratory difficulties.

Eight instances of neurologic reactions were reported. None of these were suggestive of a demyelinizing process. Three were so mild and transitory that a diagnosis could not be established. There appeared to be little doubt that there was involvement of the nervous system in the remaining 5 cases but association with the vaccine was not clear in all. In 2 the relationship may have been temporal only, in that the symptoms and signs did occur after the vaccine was administered (2 days and 4 days respectively). The other 3 cases, polyneuritic in nature, occurred at such periods after vaccination as to make causal relationship possible.155

The allergic reactions and those of nervous system involvement were the most important encountered. The absence of symptoms or signs pointing to demyelination was reassuring. Nevertheless the development and use of a vaccine free from nervous system tissue were considered most desirable and it

154See footnote 152, p. 329.
155Ltr, Actg Dir Commission on Neurotropic Virus Diseases SGO to Chief Prev Med Serv SGO, 22 Apr 46, sub: Neurological "reactions" in military personnel inoculated with Japanese B encephalitis vaccine on Okinawa in 1945. HD: 720.3.


331

was planned to substitute such an agent for the original vaccine to the greatest extent possible during the 1946 season.

IMMUNIZATION FOR SPECIAL SITUATIONS

Immunization procedures other than those referred to in the foregoing paragraphs were authorized and applied occasionally to meet special situations. These included those for protection against diphtheria, Rocky Mountain spotted fever, measles, infectious hepatitis, and scarlet fever. The administration of rabies vaccine to persons bitten by animals known or suspected to be rabid was also practiced when indicated.

Diphtheria Immunization

This procedure was not practiced routinely for United States troops but was reserved for those situations where such protection was considered to be particularly indicated. This policy was based on the following considerations. First, it was felt that although the age distribution of diphtheria had been shifting somewhat in recent years and the disease was becoming more and more one of young adults, its incidence among the age group represented by military personnel had not yet become sufficiently high, in this country at least, to cause concern. In other words, it was considered that the proportion of troops possessing actual or latent active immunity to diphtheria was sufficiently high that a significant incidence of the disease among them would be unlikely except under unusual conditions. It was considered that at least 55 to 60 percent of American troops were immune to diphtheria. This conclusion was derived in part from a study involving approximately 3,000 personnel at the end of their training period in this country. Of this group 55.6 percent were immune as determined by the Schick test. Undoubtedly others possessed some degree of latent immunity not measurable by this method.156 A somewhat similar study was conducted in a general hospital in the North African theater where it was found that 71.5 percent of a group of 1,283 person were Schick negative.157 The difference in the results in these two groups was considered to be due to the possible stimulation of immunity in the overseas group through actual contact with the disease. Also the latter group was made up in part of hospital detachment personnel including nurses and medical officers, persons more likely to have had contact with the disease and hence, more opportunity for the development of immunity than had the group studied in this country.

The second consideration in the decision not to immunize troops routinely against diphtheria was based on the fact that while toxoid was believed to be

156Diphtheria susceptibility and immunization. Bull. U. S. Army M. Dept. No. 76, May 1944, pp. 104-108.
157Karelitz, S., and Moloshok, R. E.: Immunity to diphtheria in Army personnel. War Med. 6: 232-235, Oct 1944.


332

the immunizing agent of choice it was known that there would be an appreciable occurrence of reactions in adults following the use of this agent.

The first instructions issued concerning diphtheria immunization were those published in Circular Letter 162, Office of The Surgeon General, 1942. These instructions indicated that the fluid or plain diphtheria toxoid was the agent to be used. They also referred to the reactions to be expected and indicated that only Schick positive persons should be immunized and then only in the presence of a definite hazard from the disease. The dosage recommended was 0.5 cc., 1 cc., and 1 cc. to be administered subcutaneously at intervals of approximately 3 weeks.

In May 1944, these instructions were simplified somewhat in TB MED 47. In this publication, the Schick test was described in some detail and an explanation of the various reactions to this test was presented. It was recommended that in the persons demonstrating "combined" reactions to the test, immunizations not be accomplished or if done, that small divided doses be employed. In TB MED 114, published in 1944, these instructions were modified and it was recommended that the regular course of 3 doses referred to above be preceded by 48 hours by a dose of 0.1 cc. given subcutaneously and that the administration of the remaining doses be limited to those exhibiting no severe reactions to this test dose. (A severe reaction was considered to be local edema, induration more than 6 cm. in diameter, or a marked constitutional reaction with fever in excess of 101° F.) The occurrence of such a reaction after any of the subsequent doses was also considered to be a contraindication of further injections of the toxoid. This method of immunization was thought to be particularly applicable in those situations where the performance of mass Schick test surveys prior to immunization were not practicable. It was felt that such situations might not be uncommon in view of the time required and the difficulties surrounding the satisfactory conduct of such testing. As a part of one of the studies previously referred to,158 diphtheria immunizations were conducted in this manner without regard to the Schick test status of the personnel being immunized. In this study, reactions of considerably less severity than those described above were accepted as contraindications to further doses. It was determined that almost 60 percent of a group starting such a regime would complete the full series. Thus it was felt that the use of 0.1 cc. of toxoid subcutaneously as an initial test dose would exclude from subsequent treatment the majority of the reactors. No method was seen to eliminate entirely untoward reactions to diphtheria toxoid in adults, and it was realized that the regime described did not allow for the accomplishment of the complete immunization of any group of persons. It was believed, however, that such a program would raise the general level of immunity sufficiently to prevent a serious outbreak.

158See footnote 156, p. 331.


333

The first and only instance of the application in this country during the war of a diphtheria immunization program directed by the War Department was in the autumn of 1945. At that time, in view of the increase in diphtheria among general hospital personnel in the Zone of Interior, all such persons coming into contact with patients were Schick tested and the positives immunized.159 In April 1946 because of the rise in incidence of diphtheria in the European and Mediterranean theaters, all military personnel under the age of 35 and all civilian employees and dependents of similar age were required to be immunized or Schick negative before traveling to those theaters.160 At about the same time a program was undertaken to immunize personnel in the European theater most likely to be exposed to the disease.161 A short time later, all dependents between the ages of 6 months and 15 years departing for theaters other than those referred to were required to be immunized to diphtheria before departure.

Diphtheria immunization was practiced only rarely in overseas installations during the war and then usually for units or groups considered to be exposed to unusual opportunities for infection. For example, some immunizations were done in the North Africa-Mediterranean theater because of the high incidence of diphtheria among civilians.162 Also certain organizations in the Southwest Pacific area were Schick tested and the toxoid was administered in 1944.163 In some of these units diphtheria toxoid was administered in two doses of 0.3 cc. and 0.4 cc. given 1 month apart. This program resulted in generalized reactions in approximately 8 percent of those immunized, local reactions in about 17 percent. None of these was considered to be severe in nature. Immunization programs were also carried out in selected organizations in the Persian Gulf Command164 and the Alaskan Wing, Air Transport Command.165

Rocky Mountain Spotted Fever

Vaccination against Rocky Mountain spotted fever was practiced only to a limited extent. Early in the war the policy was established that mass vaccination of troops against this disease would not be undertaken. This policy was adopted in view of the general past experience with the disease which indicated a low attack rate even in those areas where it occurs with the greatest frequency. Consideration was given to the fact that protection by vaccination did not

159ASF Cir 415, 9 Nov 45.
160WD Cir 100, 3 Apr 46.
161ETMD, ETO, 27 Feb 46. HD.
162Monthly Sanitary Rpt, 51st Med Bn MTO, Nov 1943. SG: 721.5.
163(1) Ltr, SG to CG US Army Forces In South Pacific, 17 Feb 44, sub: Diphtheria. HD: 720.3 (2) Ltr, Surg POA to SG, 6 Dec 44, sub: Transmittal of report on diphtheria. SG: 710.
164Monthly Sanitary Rpt, Persian Gulf Comd, Feb 1944. SG: 721.5.
165Monthly Sanitary Rpt, Sta 3 ATC, APO 938, 3 Apr 44. SG: 721.5.


334

appear to be absolute and was apparently of short duration. For protection against Rocky Mountain spotted fever emphasis was placed on frequent inspection of individuals in tick-infested areas with prompt removal of ticks found on the body.166

This policy did not prohibit vaccination entirely but limited it to personnel located in regions where danger from the disease was particularly great and where prolonged contact with brush was inevitable. Thus vaccination was considered applicable to such groups as patrols and guards operating in areas highly infested by ticks where Rocky Mountain spotted fever was considered to be a definite hazard.

The vaccine used was furnished by the Rocky Mountain Laboratory of the National Institute of Health. Both the "tick vaccine" and that produced in embryonated eggs were used.167 During the year 1942 enough vaccine was supplied to vaccinate approximately 20,000 individuals. Vaccine was administered in 2 doses of 2 cc. each, with an interval of 5 to 7 days. This was considered somewhat excessive in view of the policy expressed above. Accordingly in subsequent years the National Institute of Health was requested to allot a total of 50,000 cc. of vaccine for use in the Army each year.168 From this quantity suballotments were made to the various service commands and instructions were issued emphasizing the desirability of limiting vaccination to the special situations previously described. As a result, the quantity of vaccine distributed was just over 40,000 cc. in 1943, and 13,000 cc. in 1944.169

In 1944 the dosage schedule was changed from a total of 4 cc. given in 2 doses to 3 doses of 1 cc. each.170 During the 1945 season, the National Institute of Health distributed to the Army enough vaccine for approximately 16,000 persons. The increase over 1944 being due largely to the vaccination of prisoners of war employed in areas of high tick infestation.

Only 81 cases of Rocky Mountain spotted fever were reported among troops during the war years. None of these were in vaccinated individuals. This was perhaps less of an indication of the efficacy of the vaccine than of the fact that the disease did not represent a problem of any magnitude among Army personnel. While the Army experience could not be taken as evidence of the protection offered by Rocky Mountain spotted fever vaccination, there was reason to believe that the protection was considerable. The total experience with the procedure over the years has suggested that it is probably comparable

166(1) Ltr, SG to Surg 9th CA, 2 Apr 42, sub: Vaccination against Rocky Mountain spotted fever. HD: 720.3. (2) Ltr, SG to CGs all SvCs, attn Surgs, 8 Jun 44, sub: Rocky Mountain spotted fever vaccine. HD: 720.3. (3) TB MED 114, 1944.
167See footnote 166(2).
168Ltr, Actg Dir Epidemiology Div SGO to Natl Inst of Health, 3 May 44. HD: 720.3 Rocky Mountain Spotted Fever.
169Ltr, Dir Rocky Mountain Lab, Natl Inst of Health, to Actg Dir Epidemiology Div SGO, 1 Jun 44, with incl. HD: 720.3 Rocky Mountain Spotted Fever.
170See footnote 166(3).


335

to typhus vaccination in effect and that, while prevention may not be complete in all cases, those that do occur in vaccinated individuals tend to be mild.

Reactions to Rocky Mountain spotted fever vaccines were of little consequence and hence little information is available concerning them. Both local and systemic reactions were somewhat more frequent following use of the early tick vaccines than after the yolk-sac egg vaccines used later. The latter type agents were prepared in the same manner as was epidemic typhus vaccine. As might be expected, reactions from these vaccines were very similar both in extent and nature. However, no reports were received of true anaphylactic reactions following Rocky Mountain spotted fever vaccine administration.

Measles Prophylaxis

Because of the problems presented by measles during World War I consideration was given to the provision of specific protection against this disease early in the recent war period. There being no agent available for the production of active immunity, the use of human immune serum globulin for passive protection was the only procedure available.171 In view of the short duration of this protection, the dose of globulin required, and the technique of its administration (10 cc. given intramuscularly), this method for the prevention of measles was reserved for debilitated persons and those whose protection was necessary for military reasons.172

Stocks of immune serum globulin were not available until early 1944 and at that time the quantity was limited. Accordingly this material was furnished routinely only to ports of embarkation for use in the protection of embarking troops.173 Arrangements were made to furnish this material to other installations on special request as a specific need arose.

In actual experience, globulin was used for the prevention of measles only very rarely, the main reason being that measles failed to become a serious problem among troops for whom specific protection was urgently needed. All instances of its use were not reported and there were only two reports received which contained indications of the efficacy of the procedure. One of these reported the administration of globulin to 610 enlisted men who were exposed to measles just before embarkation. None of the individuals so protected developed measles.174 The same procedure was applied to an Air Force unit under similar conditions and in this unit no measles developed subsequent to

171Cohn, E. J.; Onsley, J. L.; Strong, L. E.; Hughes, W. L., and Armstrong, S. H.; Chemical, clinical, and immunological studies on the products of human plasma fractionation. J. Clin. Investigation 23: 417-432, Jul 1944.
172(1) Memo, Chief Epidemiology Branch SGO for Chief Prof Serv SGO, 15 Dec 42. HD: 720.3 Measles. (2) See also footnote 166(3), p. 334.
173(1) Ltr, SG to CG Boston POE, attn Surg, 10 Mar 44, sub: Use of immune serum globulin, item No. 16055, for the prevention of measles. HD: 720.3 Measles. (2) Memo, Prev Med Serv SGO for Dir Supply Serv SGO, 25 Jul 44, sub: Item No. 1605500, immune serum globulin. HD: 720.3.
174Ltr, Surg Camp Kilmer, N. J., to SG, 10 Jun 44, sub: Immune serum globulin for prevention of measles. HD: 720.3 Measles.


336

the administration of the globulin and no reactions were reported in connection with the injections.175

Viral Hepatitis Prophylaxis

Evidence obtained from studies conducted in the Mediterranean Theater of Operations in 1944 and 1945 indicated the probable effectiveness of gamma globulin (immune serum globulin) for passive protection against naturally occurring viral hepatitis.176 However, the practical value of this procedure was somewhat limited due to the short duration of the protection afforded (probably not more than 2 or 3 months) and the dose and method of administration (10 cc. intramuscularly). These limitations militated against the application of the measure on a large scale and though recommended for use when the indications arose, passive immunization against hepatitis was practiced only rarely.177

Studies conducted in one of the general hospitals in this country in 1944 and 1945 indicated the possible value of globulin for the prevention of post-transfusion hepatitis (homologous serum hepatitis).178 This and other work led to the administration of globulin to general hospital patients in this country who had been wounded overseas and had received transfusions of blood or plasma.179 The globulin was administered intramuscularly to those whose wounds had occurred at least 4 weeks and not more than 16 weeks previously. It was also given to those who, though not wounded, had been given blood or plasma not more than 16 weeks prior to the opportunity for the administration of globulin.

Subsequent investigative work as well as results from the administration of globulin to returned casualties as outlined failed to corroborate the earlier findings and the practice was discontinued early in 1946.180

Scarlet Fever Immunization

It was recognized that the available methods for immunization against scarlet fever were of little value, at least for military personnel. However, the immunizing agent was supplied (scarlet fever streptococcus toxin) and provisions were made for its use for the protection of nurses, ward attendants, and others in close contact with cases of the disease. The probability of un-

175Hq Troop Carrier Comd, Stout Field, Ind., Prev Med Bull 7, 20 Apr 45. HD: 720.3 Immune Serum Globulin.
176(1) Gellis, S. S., and others: The use of human immune serum globulin (gamma globulin) in infectious (epidemic) hepatitis in the Mediterranean Theater of Operations. J. A. M. A. 128: 1062-1063, 11 Aug 45. (2) ETMD, MTO. Feb 1945. HD.
177TB MED 206, 3 Nov 45.
178Grossman, E. B.; Stewart, S. G., and Stokes, J. : Post-transfusion hepatitis in battle casualties and a study of its prophylaxis by means of human immune serum globulin. J. A. M. A. 129: 991-994, 8 Dec 45.
179ASF Cir 329, 31 Aug 45.
180(1) ASF Cir 24, 28 Jan 46. (2) Ltr, Surg 2d SvC to CG ASF, attn SG, 13 Aug 45, sub: Prevention of hepatitis. HD: 720.3 Immune Serum Globulin.


337

toward reactions following the administration of the toxin and the limitations of its value were stressed.181 As was anticipated, the procedure was seldom practiced.

Gas Gangrene

Throughout the war period, gas gangrene was a perplexing and to some extent an unsolved problem. While principally surgical in nature, this problem presented some aspects referable to preventive medicine. Among these were those matters relating to the prevention and to some extent treatment of the condition by immunological methods. At no time, however, were there established policies for the prophylaxis of gas gangrene through the routine use of antitoxin or toxoid. It was generally agreed that effective surgery plus the proper use of the new antimicrobial agents provided the most effective prophylactic and therapeutic procedures available.

An effective active immunizing agent was considered definitely indicated and desirable. Almost from the onset of hostilities, great efforts were made to develop such an agent. Numerous reports of the Committee on Medical Research of the Office of Scientific Research and Development and reports of the National Research Council attest to the diligence of these efforts. However, at the end of the war while much progress had been made no toxoid or other agent had been made available for active immunization to gas gangrene.

OTHER PROBLEMS OF THE IMMUNIZATION PROGRAM

Administrative Requirements for Immunizations in Overseas Theaters

The administrative requirements established by the War Department for the various immunizations have been presented in the foregoing paragraphs in the discussions of the individual procedures. In most of the overseas theaters or separate commands, local requirements were published in theater or command directives. In a number of instances, these included stipulations for the application of certain procedures in a manner particularly adapted to local needs. Appendix D shows these various overseas requirements.

Immunization Records

The proper preparation, maintenance, and forwarding of records of immunization presented some problems during the war period.

The designation of the completion of tetanus immunization by embossing the identification tag with the numerals of the years of completion of the basic series and single stimulating dose was mentioned in a discussion of tetanus immunization. This procedure appeared to be satisfactory and with a few

181(1) SG Cir Ltr 162, 1942. (2) Also see footnote 166(3), p. 334.

338

minor exceptions gave rise to no difficulties. None of the other immunizations were recorded in such a special manner.

It was required that records in duplicate be prepared showing all immunizations received by each person in the military service. These records were made on special forms known as immunization registers. The form employed from the beginning of the war until early 1945 was WD MD Form No. 81 (Immunization Register) and that employed after January 1945 was WD AGO Form 8-117 (Immunization Register and other Medical Data).

The greatest difficulty encountered with respect to these records was in connection with their ready availability when required. Early in the mobilization period particularly, appreciable numbers of immunizations were repeated unnecessarily because of the failure in forwarding adequate records of the immunization status of personnel being transferred to new stations. This was corrected in part by administrative action requiring the forwarding of information of all incompleted immunizations with such individuals. However, the fault was not satisfactorily corrected until early 1945 when the new form was adopted and provisions were made for each person to have a copy in his possession. Under this system the unnecessary repetition of immunizations was reduced to a minimum. The adoption of the new form and the improved methods for its handling and disposition made readily available information concerning the immunization status of each individual as well as that on allergic states, spectacles, dentures, et cetera. This was of considerable value to the person concerned as well as to those responsible for his medical care and processing.

Supply Problems

Although the matter of supply of the various immunizing agents was closely related to the immunization program, it will be discussed here only briefly since a general discussion of medical supplies is presented elsewhere in the history.

As already indicated, the number of immunization procedures used in the Army increased from 2 or 3 at the beginning of the war to a dozen or more which were applied at one time or another before its end. The success of these procedures was dependent upon the availability of adequate quantities of satisfactory immunizing agents of the various types required. Almost all of these agents were procured from commercial manufacturers of biologic products and were purchased for Army use subject to the conformance with the minimum requirements and standards of the Biologics Control Division, National Institute of Health, United States Public Health Service. The interest, efforts, and cooperation of the personnel of that agency in their assistance to the Medical Department of the Army were of the highest order. Without their expert


339

assistance, advice, and guidance, as well as their official actions, the program would have functioned poorly if at all.

The procurement, storage, and issue of biologicals consisted of two separate but closely related main aspects. One of these included the fiscal, contractual, business, and mechanical handling of the large quantities of materials required. The other aspect was the control over the many technical details connected with the supply of the various agents used. For the coordination of these two aspects of the problem, it was necessary that there be the closest cooperation between the Supply Service, Office of The Surgeon General, and the Preventive Medicine Service through which the immunization program was administered. By this cooperative effort it was possible to establish, for the purchasing office, estimates of requirements for the various biologicals in keeping with the overall anticipated needs and to effect judicious distribution of materials so that the maximum use could be obtained from the quantities available. Such distribution control was of particular importance in the early phases of the war when many immunizing agents were in short supply. In turn the establishment of immunization policies depended upon knowledge concerning the availability of the various agents required, and it was only through cooperative, long-range planning that it was possible to accomplish the desired procedures by having at hand the necessary materials.

Other matters requiring technical control were those dealing with physical conditions of storage and shipment of biologicals. Requirements for refrigeration were established as well as for methods of shipment for the various materials. For example, great emphasis was given to the necessity for maintaining smallpox and yellow fever vaccines at freezing temperatures while other agents could be shipped and stored under less carefully controlled conditions.

It was found that, in general, it was desirable that all technical matters relating to the nature, type, potency, safety, keeping qualities, et cetera, of the various prophylactic biologicals be the responsibility of the Preventive Medicine Service and that the office function as the liaison on all such matters with the manufacturers and with the National Institute of Health. This plan was effectively followed with but few exceptions throughout the war. It was materially aided by assignment to the Preventive Medicine Service of an officer experienced in the production and testing of biologicals.

Long-range planning for the procurement of biologicals was found to be a necessity. Many of the materials in this category required extended periods of time for their manufacture even if the equipment was available and the techniques perfected. Thus for large supplies it was necessary that contracts be let well before the time of anticipated use of the various agents. It was also found that because of the limited civilian outlet for many of the biologicals required by the Army the manufacturers were loath to expand their production


340

facilities until assurance would be given for definite quantity purchases by the Army.

In general, the supply of prophylactic biologicals was adequate to meet the needs. As indicated, there were shortages from time to time but through careful distribution planning the greatest use was made of the quantities available so that essentially no serious situation developed because of lack of the proper immunizing materials.

Antivaccination Activities

Throughout the war period, particularly during the early years, there was built up in the Office of The Surgeon General a considerable file of correspondence initiated by antivaccinationist individuals or groups.182 Many of the letters were from sincere but misinformed persons who expressed opposition to the principle of compulsory immunization of American soldiers. Other communications voicing opposition to the use of immunization procedures in the Army were from individuals obviously attempting to foster the cause of one or another of the groups of unorthodox or nonmedical so-called healing professions. Their efforts in this regard took the form of attacks on regular recognized medical practices such as the use of vaccines and other immunizing agents.

Considerable time and attention were given to the answering of these complaints and protests. Argument was avoided wherever possible and straightforward information was provided, whenever requested, concerning the immunization procedures followed for Army personnel. It was pointed out that Army practices followed the precepts of the best medical and scientific teaching in the country and that it was the intent of the War Department to continue to follow these teachings.

These antivaccinationist activities led to no real difficulties in the accomplishment of the immunization program and were reflected only to an extremely limited extent in the attitude of militarized personnel. The policy requiring certain immunizations for all personnel on active duty with the Army was clear. The only exceptions afforded were those based on definite medical contraindications. The legality of this policy was upheld by The Judge Advocate General and enforcement was accomplished in all instances.183

CONCLUSION

The World War II Army immunization program was in the main successful. Certainly, smallpox, typhoid and the paratyphoid fevers, tetanus, and typhus which were all real hazards occurred with very low frequencies. It is

182File, Antivaccination. HD: 720.3
183Ltr, JAG to TAG, 27 Nov 42, sub: Policy to be pursued in the event a soldier refuses to submit to preventive immunization. HD: 720.3 Legal Status.


341

fair to attribute at least some of this relative freedom from these infectious diseases to the immunizations practiced. There were but a few cases of cholera and none of either plague or yellow fever. There is no way to tell whether these diseases were, in fact, controlled in whole or in part by immunization since the degree and extent of exposure to them cannot be determined. The high degree of effectiveness of yellow fever vaccine had, of course, been well demonstrated previously. It must be remembered also that yellow fever vaccination for certain troops and forces was very necessary both because of potential exposure and to expedite their movement through the compliance with quarantine regulations of several countries.

The immunization program was large, comprehensive, and complicated. Some of the complications arose from its selective nature; that is, the requirement for specific immunizations for certain world areas. Though difficult to administer, this selective type of program was shown to be effective, and definitely to be preferred over the application of all procedures to all personnel.

This program demonstrated perhaps as well as any other of the Medical Service, the necessity for close coordination and cooperation between the professional and technical groups and administrative, fiscal, and logistic activities. Without this cooperation and coordination during World War II, the Army immunization program would undoubtedly have failed.

RETURN TO TABLE OF CONTENTS