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July 17, 1948

DIPHTHERIA IMMUNIZATION: Use of an Alum-Precipitated Mixture of Pertussis Vaccine and Diphtheria Toxoid

Author Affiliations


From the Division of Infectious Diseases, National Institute of Health, Bethesda, Md.; Medical Director J. P. Leake conducted this study in the author's absence during part of the years 1943 to 1945.

JAMA. 1948;137(12):1009-1016. doi:10.1001/jama.1948.02890460005002

There has been a downward trend in United States mortality from diphtheria and pertussis, but current reports show that several thousand young children continue to die every year from these diseases. Many deaths from these diseases will be prevented when effective prophylactic agents are extensively used. Such agents will be used more extensively when demonstrated improvements are made which increase their protective efficiency, decrease the number of reactions and simplify their method of administration.

To these ends considerable progress has been made in recent years. Diphtheria prophylactic agents have progressively improved from the old toxin-antitoxin mixtures to fluid toxoid and, now, alum-precipitated diphtheria toxoid. In 1938 Harrison and his associates1 introduced alum-precipitated pertussis vaccine and it became evident that the method for immunizing children might be simplified through mixing precipitated pertussis and diphtheria antigens for simultaneous administration. In 1940 Schutze concluded from animal experiments that the admixture of alum-precipitated

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Sako, W.; Treuting, W. L.; Witt, D. B., and Nichamin, S. J.:  Early Immunization Against Pertussis with Alum-Precipitated Vaccine ,  J. A. M. A. 127: 379, 1945.Crossref
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Public Health Nurses Anne Hodges and Ruth Sargent carried out the previous study 4 and were the mainstays of the present study through the period covered by this report. Most of the Schick tests were carried out by Public Health Nurse Edna McCaleb under my supervision and that of Dr. J. P. Leake, who read and interpreted the Schick reactions in all children having any reaction whatsoever.
Dr. D. R. Mathieson, under direction of Dr. Noble Ferry and the late Dr. L. T. Clark, all of Parke, Davis and Company laboratories, carried out a few laboratory tests with the mixed product. The results were: "A. 100 per cent of sixteen 270 Gm. guinea pigs survived six weeks when challenged in groups of 4 with 10, 20, 40 and 80 minimum lethal doses of Corynebacterium diphtheriae toxin, respectively. Three such guinea pigs out of 4 similarly survived 160 minimum lethal doses. All had previously received a 1 cc. subcutaneous dose of the mixed antigen. Five such guinea pigs, used as controls received no previous antigen and all died within six weeks after receiving only 1 minimum lethal dose of the same diphtheria toxin. B. Eighteen guinea pigs inoculated with the mixed antigen and then sacrificed fourteen days after receiving 10 to 160 minimum lethal doses of diphtheria toxin showed not the slightest vestige of reaction to the toxin, whereas the 1 control guinea pig given only 1 minimum lethal dose died in four days showing pleural effusion and massive hemorrhages of the adrenals, subcutaneous tissue, and abdominal muscles at the site of inoculation."
Edsall, G., and Wyman, L.:  Am. J. Pub. Health 34:365, 1944Crossref
Many of the Schick reactions were observed on the second, fourth and seventh day. Observation consisted of measuring and recording the transverse and longitudinal diameters of each zone of reaction at the test and control site and noting the presence of redness, edema, wrinkling and desquamation Reactions were classified according to the area of clear definite redness on the fourth to seventh day following injection. The area was computed by assuming it equivalent to a circle with a diameter equal to the mean of the vertical and transverse measurements. If the area of redness at the test site exceeded the area of redness (if any) at the control site by the area of a circle 10 mm. in diameter, the reaction was classified positive; otherwise the reaction was classified negative The reaction was classified negative in the few instances in which definite evidence existed that the maximum local reaction at the test site occurred within forty-eight hours after injection and the nature of the reaction was similar to that at the control site. The reaction was classified as positive in a few instances (particularly in the Negro where discolorations are less evident than in the white skin) in which, because of the intensity and duration of the reaction, the original observer (J.A.B. or J.P.L.) judged it to be positive even though the measured area of redness was slightly less than has been set forth. All reactions were observed and classified without knowledge as to what immunizations the child mayhave received.
These are the characteristics expected in groups of children who respond to routine public pleas for immunization and constitute the mass of children generally immunized.
Some of these attributes are known to be correlated with the Schick reaction in the general population; e.g., no. 11, age at time of Schick test. This study was designed to minimize the influence of attributes not pertinent to the questions propounded. For the vast majority of children the age spread at time of the Schick test was less than fourteen months, and thus no significant age correlation was to be expected.
This observation would appear to be incompatible with existing theories on the natural acquisition of diphtheria immunity. It is receiving further study,