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Active Immunization in Pediatrics
ACTIVE IMMUNIZATION IN PEDIATRICS PmLIP COHEN,
M.D.'"
Tms clinic will be concerned with the consideration of active immunization in children. By active immunzation I mean the generation of antibodies by an organism in response to the introduction of an antigen, no matter by what route. Active immunity results in antibodies which tend to persist for months or years. A cardinal and invaluable feature of active immunity is that years after the original immunization a single injection of the antigen will quickly reactivate the production of the antibodies. This stimulating, or booster, injection will raise the titer of protective antibodies, in a matter of days, from a low, inadequate level to a protective titer which is often higher than the original immune titer. In contradistinction, passive imlnunity, which consists of the injection of preformed antbodies, is of short duration and not susceptible to reactivation by a stimulating dose of antigen. In my opinion, we have not properly availed ourselves of the fact that booster injections can stimulate further production of antibodies long after the onset of active immunization. The past decade has witnessed important changes in the technic of active immunization. Preparations of antigens have been continually perfected, and the dosage and timing of the administration have changed for the better. These innovations were accelerated by the impact of war, which served as a vast laboratory for testing the efficacy of new methods. The lessons learned have been incorporated into civilian prophylaxis, with promise of further improvements. The pediatrist, who necessarily performs large scale routine immunization, should be in the van in the study of the efficacy and the innocuousness of the most recent prophylactic measures. DIPHTHERIA
Diphtheria remains a most important epidemiologic probleDl. It has been demonstrated by myself and collaborators! as well as by others,2 that the past generation has undergone a subtle change for the worse in· adult immunity to diphtheria. The mass of data collected by Schick3 (1914 to 1928) showed that about 85 per cent of adults were immune to diphtheria in this preimmunization period. The institution of routine diphtheria prophylaxis on a massive and widespread scale has resulted in a striking decline in the morbidity and mortality o
Attending Pediatrist, Beth Israel Hospital, New York City. 590
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of diphtheria. As a concomitant phenomenon, however, the carrier rate has declined to a proportionately low figure. The reduction of the carrier state in an artificially immunized community, with necessarily lessened exposure to toxigenic diphtheria bacilli, has resulted in a loss of the artificially acquired immunity in a high percentage of adults. It has already been noted that there is a trend to diphtheria increase in many sections, where outbreaks of diphtheria have been reported chiefly in adults, here and abroad, in civilian and in military life. 4 The New York City newspapers of October 17, 1946, publicized reports from the health commissioners of the state and city that diphtheria morbidity and mortality have noticeably increased throughout the nation, and stress the need of further immunization. Epidemiologists have commented that the diphtheria problem of the future is concerned with the immunity of the adult. 5 Epidemics of adult diphtheria should not occasion surprise, for studies have demonstrated that artificial diphtheria immunity confers sufficient but declining protection for a period of three years. After this period there is a perilous fall in the level of immune titer unless there is a stimulation of immunity by artificial or natural means, the latter normally through the medium of the vanishing carrier. My investigations at Beth Israel Hospital, in a large group of young women, indicate that as of today, about 50 per cent of adults are Schick positive. Important corollaries follow these observations. It was formerly confidently assumed that, since the adult is nearly always immune to diphtheria, the newborn baby is similarly immune, since he is endowed with his mother's antibodies at birth. Immunization of the infant had hence been postponed for six to nine months, after which period he presumably lost his passively acquired immunity. Indeed it was believed that in the presence of passive antibodies, active immunization would prove ineffective. Since proof has been adduced that in many areas 50 per cent or more of adults are susceptible, the immunity ascribed to the newborn baby often rests upon a false assumption. Recent tests by me on· a group of 100 babies substantiated this contention, for 50 per cent of infants below 6 months of age were Schick positive. These facts and findings should logically lead to a change in diphtheria prophylaxis. To guarantee the transfer of immunity from mother to baby, it is necessary to ascertain maternal immunity. If the mother is Schick positive, diphtheria toxoid should be administered during the seventh and eighth months of pregnancy at intervals of two to three weeks in doses of 0.1, 0.2, 0..5, and 1 cc. This conversion to a Schick negative state is transmitted to the baby to persist six to nine months. If the mother is Schick negative, a single stimulating dose of 0.2 cc. of diphtheria toxoid elevates her antitoxin titer to a highly effective level, to the benefit of her baby. The pediatrist has little
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opportunity to pursue this practice. It properly lies in the province of the obstetrician and general practitioner. Schick tests routinely performed on mothers before and after delivery and in newborn infants reveal that the mother is a better reactor and indicator than her baby. If the Schick test is positive in the mother or baby we begin to immunize the baby at 3 months of age. Since the period of prophylaxis and the attainment of an immune titer require three months the baby remains susceptible for its first six months of life. The only known way to remedy this undesirable situation is to immunize the mother during pregnancy.. Our method of diphtheria prophylaxis in infants is administration of three injections of diphtheria toxoid in doses of 0.5 cc., 1 cc. and 1 cc. at intervals of three to four weeks. Unlike alum toxoid, the plain toxoid rarely causes a reaction.., The Schick test is performed six months later. For years we have not seen a positive Schick test following this prophylaxis. Every three years a single inoculation of diphtheria toxoid is given, and continued as long as a state of immunity is desired, into adult life and the period of pregnancy, if so desired" TETANUS Tetanus, a dread disease also caused by a toxin, was characterized by a singularly low incidence in the last war. Routine tetanus toxoid prophylaxis was so effective in producing adequate immunity that not only was tetanus virtually absent in this war but there was seldom need of administering tetanus antitoxin.. The army employed the fluid formalized toxoid in three doses of 1 cc. each at intervals of four weeks. The navy favored alum toxoid, given in two doses, 0.5 cc. at four week intervals. A routine stimulating dose was given annually, with the additional precaution of an extra stimulating dose with every change of locale and before combat engagement. A point worth noting is that fluid toxoid should be given if there is need for a quick rise of the antitoxin content, for alum toxoid acts slowly, and is therefore less useful as a rapidly stimulating dose. In pediatric practise tetanus immunization procedure is the same as that employed by the army and navy. It is recommended routinely for children who spend their summers in camp, to avoid needless injections of tetanus antitoxin which are too often given for inevitable injuries, with the attendant risk of producing dangerous allergies. Children of the hyperkinetic type who frequently suffer trauma, and youngsters living in the country intimately in contact with soil, may also benefit by the administration of tetanus toxoid. The fluid toxoid is almost devoid of reactions except in the cases of a few children who develop allergy to the preparation as a result of repeated inoculation. The alum preparation causes more frequent reactions and nodule formation but spares the child an injection.
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Whooping cough is the most important contagious disease of childhood for which we employ bacterial vaccine prophylaxis. The vaccine developed by the Saner technic administered in adequate doses has materially reduced the incidence of pertussis in children above 1 year of age. Ample data has been accumulated to prove this point beyond reasonable dispute. It probably has also modified the course of the disease in many children in whom prophylaxis has not been entirely successful. As in diphtheria, the problem of protection of the infant has not yet been satisfactorily solved. Data has been accumulated proving that the majority of adults (80 per cent) are not immune to pertussis. 1 It follows that 80 per cent of babies are susceptible to whooping cough from birth, for they must lack immunity if their mothers do. It has been the custom to institute pertussis prophylaxis at 6 months of age. When vaccine therapy has been completed and immunity obtained, the infant is nearing 1 year of age. Here again is a dangerous gap in immunity against a disease which takes its highest toll in infancy. The only known method of conferring immunity upon the infant is immunization of the mother during the last trimester of pregnancy. The active maternal immunity is passively transferred to the baby. Since it is a passive immunity it lasts but a few months, after which period (at 4 to 5 months of age) active immunization of the infant should be initiated. There is much evidence pointing to the fact that a young organism, such as the infant, is a poor antibody producer, even if inoculated with potent antigens. Some years ago Sauer reported unsuccessful attempts to actively immunize infants below 6 months of age against pertussis. 6 The incidence of the disease was the same in the immunized as in the unimmunized group. Laboratory tests also demonstrated defective antibody formation in these young infants. A more recent attempt to immunize infants at 1 to 3 months of age against pertussis yielded more encouraging data. 7 Three injections of 0.2, 0.3, and 0.5 cc. of an alum preparation totaling 40 billion bacilli per cc. resulted in positive agglutination tests in about 80 per cent of the infants two to four months after the completon of prophylaxis. The morbidity and mortality of the vaccinated group (3,793 cases) was significantly lower than in a control group. It may be that the slowly operating alum preparation used was more effective in these young infants than the generally employed Sauer vaccine. Further observation by the New Opleans group and by other investigators employing a similar immunization procedure confirmed the growing opinion that very young infants may be capable antibody producers. 8 Nevertheless, Sauer, adopting a similar technic for this age group, reported that only 31 per cent of young infants so inoculated had a positive complement fixation
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test. Further data is needed to determine whether it is feasible to begin pertussis prophylaxis in babies so soon after birth. The usual procedure in pertussis immunization is to inject a Phase I vaccine at three to four week intervals until 90 to 120 billion organisms have been administered, the amount varying with the age and the size of the baby. This requires 6 to 8 cc. of a 15 billion per cc. preparation; 4.5 to 6 cc. of a 20 billion per cc. preparation. The entire procedure requires three to four inoculations, the number depending upon the presence or absence of reactions. It appears that alum preparations are equally effective in smaller doses. Studies upon similar groups of children are now in progress in my clinic upon the comparative immune titer obtained by alum preparations given in a dosage two-thirds that of fluid vaccine. Were it not for greater reaction and nodule formation, the alum preparation would undoubtedly be preferable. These reactions can be obviated to some extent by deep subcutaneous injections using a vaccine warmed and well shaken, followed by massage of the inoculated area. My present inclination regarding pertussis prophylaxis, as with diphtheria, is to begin immunization at an earlier age than heretofore. At three to four months of age immunization may be instituted in infants in good condition. If the infant is Schick positive a preparation of diphtheria toxoid combined with the pertussis vaccine is employed. This combination of antigens has previously not been included in the armamentarium of prophylaxis for very young infants. TYPHOID FEVER
Typhoid fever prophylaxis by vaccine inoculation has been admittedly effective for many years. The past war afforded another brilliant example of the efficacy of this vaccine, for again there was a very low morbIdity in those vaccinated. 9 It should be interpolated that all immunity is relative, be it natural or artificial immunity. An antibody titer effective under normal and ordinary circumstances may be insufficient and overwhelmed in the presence of a virulent infection or intensive exposure. Thus typhoid fever has been reported in individuals properly inoculated and with protective immune titers, but infections are much fewer than in unvaccinated individuals under the same conditions, and the course of the disease tends to be milder. 9 Many instances have been recorded (and observed by me) of two or more attacks of diseases like measles, scarlet fever, whooping cough, mumps, and other diseases which are known for their capacity to produce a lasting high level of immunity. This relativity of immunity applies to all immunity against disease. Innovations and improvements in typhoid prophylaxis have recently been introduced. Rawling's typhoid strain has been supplanted by the superior Panama 58 antigen, 9 which has been put to commercial
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use. The dosage remains the same; 0.5 cc., 1 cc. and 1 cc., but intervals longer than one week have proven superior. In pediatric, unlike military practice, there is seldom urgency of time, and an interval of two weeks is preferred. The dosage given to a child may be computed on the basis of weight ratio to the adult, or slightly more than this calculation calls for. Laboratory studies have shown that the former method of three inoculations every three years yields a titer of protective antibodies which sink to a low level long before the expiration of the three year interval. Only 20 to 25 per cent of individuals retain an adequate titer of protective antibodies two or more years after typhoid inoculation. lO A single injection of 0.5, cc. of typhoid vaccine given annually succeeds in elevating the protective antibodies to the optimum level in 100 per cent of cases. IO I consider the best practice to be administration of annual booster injections of 0.5 cc. of typhoid vaccine after the initial trio of inoculations. This practice should be adopted for children going to camp, for a constantly high level of immunity is thus obtained instead of the former uncertain fluctuating titer. The reactions incurred by this annual method are fewer and less severe than with the old three shot system. SMALLPOX
Smallpox vaccination is accomplished by the use of a preparation containing a live but attenuated virus. It is one of the few instances in which a live organism is used to induce active immunity in children. It has been established that there is no natural, probably not even passive immunity to smallpox. Donnally successfully vaccinated newborn infants thereby confirming that there is no immunity of the newborn to smallpox.!! A comparative study of the potency of culture and calf-grown virus was made in this group of vaccinated newboms. Revaccination two or three years later resulted in successful takes in 73 per cent of those vaccinated with the calf virus. Vaccination with a virus culture took in only two out of thirty-six cases. This study not only attested to the susceptibility of the newborn to smallpox and the superiority of the-calf-grown virus for vaccination, but also demonstrated that the immunity may wane as early as two to three years after successful vaccination. When smallpox is prevalent it is important to bear these facts in mind. Every infant should be vaccinated and failures should not be construed as indicating immunity. It is advisable, if possible, to wait an appreciable period, about a month after the unsuccessful vaccination, before revaccinating. If the interval is shorter, the site of the unsuccessful vaccination may light up and take as the second successful vaccination evolves. Thus two vaccinia will develop concomitantly with proportionately greater systemic effects, local reaction, and scar formation. In the presence of an epidemic or on the eve of travel to
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a state or country where smallpox occurs, previously vaccinated individuals should be revaccinated even if the interval is less than five years. I have several times observed successful revaccination without the expected modification in children vaccinated two or three years previously. My belief is that vaccination sh9Uld be repeated at the slightest indication, for if immunity persists, there is little or no reaction; if, however, immunity is lost or largely lost, the resulting take and immunity will be a source of satisfaction. The duration of immunity after vaccination is extremely variable, ranging from two years to many years, perhaps for the duration of life. Normally the initial vaccination is performed at 3 to 8 months of age at a time when the infant is in excellent health, the season favorable and the skin in normal condition. I try to avoid vaccination during uncomfortably hot weather and during seasons of rampant or endemic infections. The puncture method of vaccination yields a smaller area of reaction with a smaller scar and less systemic reaction. I have rarely used the intracutaneous method for lack of scar formation deprives one of definite proof of lack of immunity. I prefer the arm for the area of vaccination in both males and females. It is safer, less disfiguring and less prolninent than leg vaccinations. No dressing is used after the first day. A shield or a covering of any sort is strictly forbidden. I have been fortunate, aided by the insistence of the above precautions, never to have had any infection or ill effects from a smallpox vaccination. INFLUENZA
Influenza is another virus disease, for which an inactivated virus preparation has been invoked in the last few years. Because of newspaper predictions of epidemics, pediatrists are receiving numerous inquiries as to the efficacy and desirability of the new vaccine. From available data it may safely be assumed that nearly every adult has been infected at some time with pandemic influenza. 12 Hence, only one inoculation of I cc. of virus vaccine need be given since it acts as a reactivator or a booster injection of waning immunity. Within one or two weeks after inoculation over 90 per cent of subjects show a sharp increase in circulating antibodies,12 an effect comparable to that of booster injections for diphtheria, tetanus and other diseases in which an active immunity may be produced. One year later the antibody titer is still above the prevaccination leve1. 13 Nevertheless, the definite decrease of antibodies at the end of a year and the prompt, sharp response to a single injection .would indicate the need for annual booster injections. Surveys have shown that the rate of incidence in vaccinated groups is considerably lower than in control groups (25 per cent) .14 The technic for the preparation of the vaccine is quite different from the method ordinarily employed for vaccine preparations. The
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live virus is incubated on the extra-embryonic fluid of the developing hen's egg. As a result of processes of adsorption, diffusion and centrifugation, the final preparation of the virus contains little or no egg protein. Tests are being made by precipitin methods to determine whether egg protein has been completely eliminated to avoid allergic reactions in sensitive individuals. It may be the better part of wisdom~ at present, to test egg allergic individuals with the preparation, and if the reaction is positive, to proceed with caution. There is little avaliable data on influenza virus vaccination in chi!.. dren. 12 It may even be incorrect to assume that the very young child has been previously infected with the virus. If this assumption bE false, two inoculations at intervals of two weeks may offer better protection to the young child. The dose for children may best be gauged by weight ratio, as in other vaccine therapy. I have been inoculating children up to S years of age with 0.25 cc., up to 10 years with 0.5 cc., and the older group with 1 cc. of the vaccine. In my limited experience the reactions in children have been below expectation. Slight headache, transient chilliness and fever, and soreness of the arm for about a day have been observed by rue. Collective data is now needed to determine the efficacy of this vaccine in children in the presence of a proven epidemic. It must be emphasized that the· influenza virus vaccine protects only against influenza A and B. Parents are informed that other respiratory infections, virus or bacterial, will be unaffected by this prophylaxis. To protect against recurrent respiratory infections, often loosely called "colds," a bacterial vaccine, "catarrhal vaccine" has been employed for years parenterally and laterally orally. The genuine cold, a virus infection, must be uninfluenced by such measures. It is claimed, but not proved, that secondary respiratory infections may be influenced for the better by the use of a vaccine containing most of the common respiratory flora. Such a vaccine is not infrequently used for this purpose in pediatric practise, but its efficacy can only be conjectured through empirical observation. There is no scientific data demonstrating increased immune titers against respiratory disease after such inoculations. RICKETTSIAL DISEASES
Potent vaccines against rickettsial diseases have been recently developed, notably against typhus fever and other spotted fevers. 15 These vaccines are prepared on a yolk sac medium, and hence precaution must be 'taken when such vaccines are injected into egg allergic ind-ividuals. These vaccines are administered to children in amounts proportionate to. the adult dose of 1 cc. Two injections are given at intervals of two weeks. Typhus fever is not common in this country, but traveling to areas of infection is sufficient indication for such vaccination in children. The spotted fevers (Rocky Mountain fever) are
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indigenous to certain sections of this country. I have employed this vaccine for several children visiting infected sections. My cases are too few in number to warrant immunological conclusions, but there have been no untoward reactions. YELLOW FEVER, PLAGUE AND CHOLERA
The armed services us~d effective vaccines against yellow fever (a virus vaccine) and also vaccinated at times against plague and cholera. 15 Such vaccines are rarely given to children in this country as there is no need for them. I have never found occasion for such vaccination. Nevertheless, a trip to a section where these diseases are prevalent would be sufficient indication for the administration of such prophylaxis. Since the human serum component has been eliminated from the yellow fever vaccine, there has been a cessation of reports of jaundice following such vaccination. SCARLET FEVER
Scarlet fever active immunization has not proved popular in eastern United States. The frequency and severity of reactions after scarlet fever prophylaxis have been a distinct drawback. The injection of an unmodified toxin, generally five to seven times, in amounts varying from a few hundred to hundreds of thousands of skin test doses have caused in 10 to 15 per cent of cases such reactions as neausea, fever, vomiting and rash, comparable to a case of mild scarlet fever. 16 Infrequently, the alarming symptom of joint pains has been reported. On the other hand, such immunization has decidedly reduced the incidence of scarlet fever. This prophylaxis should be given for the protection of nurses and workers in contagious hospitals, and for those intensively exposed to scarlet fever. Because of reactions, the numerous injections, the often temporary nature of the" immunity, in conjunction with the fact that scarlet fever has for years been of a mild character in the East, I am not given to the use of scarlet fever prophylaxis. Should matters change and scarlet fever assume a more malignant form, I would advise prophylaxis in spite of its disadvantages. Perhaps newer preparations, (alum and tannic acid precipitation), now under investigation, will offer a happy solution. 16 If the precipitates prove effective, only three injections, provoking few reactions, will be necessary. Laboratory tests have demonstrated an immunity duration of four years after inoculations of these products. Other toxoids, previously tested in three doses at three week intervals, have not been as effective as the toxin preparation usually employed. COMBINED PROCEDURE; OTHER ROUTES
It should not be assumed that these immunization procedures must be given individually and in succession, necessitating much expendi-
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ture of time and inconvenience to the patient. Pediatricians have been leaders in proving the efficacy of combining immunization procedures. Even before tIle war investigations showed that each antigen combined in a mixture produced an immune titer equal to or greater than that effected by the antigen injected individually. Pediatric practice and the vast military immunization have yielded ample and convincing confirmation of the effectiveness of simultaneously injected vaccines. The infant and child, like the soldier, should have his prophylaxis completed in a brief period, for it is wiser to abbreviate as much as possible the period of absent immunity. The accepted and best practice today is to immunize the infant simultaneously against diphtheria, pertussis and, if desired, tetanus. I have also mixed toxoid with other vaccines, such as typhoid, with no ill effects. I have not yet ventured to mix vaccines or toxoid with rickettsial or live virus vaccine. Nevertheless, it may be entirely feasible to employ such mixtures, with the possible exception of the vaccine virus. Introduction of antigen by a route other than subcutaneous, intracutaneous or intramuscular has not been generally invoked in pediatric practice. It may well be that other forms of administration, notably by nebulization or aerosol technique, for direct immunization of localized regions, such as the respiratory tract, may yield better immunity against localized diseases. Experimental work along these lines has yielded promising results. Future studies may more emphatically prove this point and lead to a wider use of such methods in immunization practice. SUMMARY
In summary, it may be restated that modern active immunization favors the simultaneous adminisb'"ation of different antigens either in a mixture of two to three antigens, or by separate injections at different sites. The previous weekly interval between inoculations has been generally lengthened to two to four weeks. The active immunity, waning often to an inadequate and nonprotective level, should be stimulated by a booster injection every year, or every two or three years. This interval is determined by the need for immediate protection, and the desire for a constantly high immunity instead of an un.. certain and fluctuating one. The trend is also developing of maintaining a continually high level of immunity by giving annual injections instead of three injections every three years, as in typhoid fever prophylaxis. Vaccination against smallpox should be performed in the presence of outbreaks of this disase, unless the last successful vaccination was performed less than three years before exposure. By these methods safety is attained with a minimal expenditure of time and the omission of many painful injections to the child. I believe that active immunization of the infant will be given at
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an earlier age (3 to 4 months) than in the past (6 to 9 months). This still leaves the infant unprotected against some diseases (notably pertussis and often diphtheria) for the first six months of his life. Prenatal immunization by active immunization of the mother during pregnancy, can solve this important problem. REFERENCES 1. Cohen, Philip and Scadron, S. J.: The Effects of Active Immunization of the Mother Upon the Offspring. J. Pediat. In Press. Cohen, Philip, Shneck, H. and Cohlan, S. Q.: The Changed Status of Diphtheria Immunity. To be published. 2. Liebling, J., Youmans, G. P. and Schmitz, H. E.: Occurrence of Diphtheria Antitoxin in the Human Pregnant Mother, Newborn Infant, and Placenta. Am. J. Obst. & Gynec., 41:641 (April) 1941. Cameron, G. D. W.: The Schick Test in Adults. Canad. Pub. Health J., 32:414 (Aug.) 1941. Levy, A. J.: Susceptibility of Adult Population to Diphtheria. Illinois M. J., 82:390, 1942. Goldsworthy, N. E. and Wilson, H.: Schick Test in Young Adults. M. J. Australia, 2:349 (Oct. 30) 1943. Bull, U. S. Army Med. Dept., 76:104 (May) 1944. Wright, G. P. and Clarke, W. M.: Schick Reactions in Recently Confined Women and Their Infants. Brit. M. J., 2:146 (July 29) 1944. Karelitz, S. and Moloshok, R.: Immunity to Diphtheria in Anny Personnel. War Med., 6:232 (Oct.) 1944. Vogelsang, T. M. and Kryvi, B.O.: Schick Test During Diphtheria Epidemic. Nordisk Medicin, Gothenberg, 28:2021 (Oct. 5) 1945. 3. Schick, B.: Brennemann's Practice of Pediatrics, Vol. 11, Chapt. 4, pp. 4-6, Hagerstown. W. F. Preyor, 1944. 4. Campbell, P. S.: Occurrence of Diphtheria in Halifax from Oct., 1940, to Jan. 31, 1941. Canad. Pub. Health J., 32:404 (July) 1941. Diphtheria Mortality in Large Cities of U. S. in 1942. J.A.M.A., 122:1079 (Aug. 14) 1943; J.A.M.A., 131:1053, 1062 (July 27) 1946. Diphtheria in Soldiers: }.A.M.A., 131:1071 (July 27) 1946. Knipe, R. G.: Experiences in Diphtheria Control in Northern British Colunlbia. Canad. Pub. Health J., 35:349, 1943. Mattison, B. F.: Diphtheria in an Adequately Ilnmunized Community. New York State J. M., 44:2138 (Oct. 1) 1944. 5. Fleming, D.: Problem of Future. Canad. M.A.J., 50:46 (May) 1944. Fraser, D. T. and Brandon, K. F.: Duration of Schick Immunity. C:anau. Pub. Health J., 27:597 (Dec.) 1936. 6. Sauer, L. W.: Age Factor in Active Immunization Against Whooping Cough. Am. J. Path., 17:719, 1941. Whooping Cough, Preventive Treatment. M. CLIN. NORTH AMERICA, 45:,58 (Jan.) 1946. 7. Sako_ W., Treuting, W. L., Witt, O. B. and Nichamin: Early Inllllunization 1"lgalnst Pertussis with Alum Precipitated Vaccine. J.A.M.A., 127:379 (Feh. 17) 1945. 8. Waddell, W. W. and L Engle, C. S.: Immune Response to Early Administration of Pertussis Vaccine. J. Pediat., 29:847 (Oct.) 1946. 9. Callender, G. R. and Luippold, G. F.: Effectiveness of Typhoid Vaccine Prepared by U. S. Army. J.A.M.A., 123:319 (Oct.) 1943. 7
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10. Longfellow, D. and Luippold, G. F.: Typhoid Vaccine Studies: Revaccination and Duration of Immunity. Am. J. Pub. Health, 30:1311 (Nov.) 1940. 11. Donnally, H. H.: Smallpox Vaccination of Infants. J.A.M.A., 113:1796 (Nov. 11) 1939. 12. Andrews, C. H., Laidlaw, P. P. and Smith, W. W.: Observations on Recovery of Virus from Man and on Antibody Content of Human Serum. Brit. J. Exper. Path., 16:566, 1935. Francis, T. and Magill, T. P.: Incidence of Neutralizing Antibodies for Human Influenza Virus in Serum of Human Individuals of Various Ages. J. Exper. Med., 63:655, 1936. 13. Hirst, G. K., Rickard, E. R. and Friedewald, W. F.: Studies in Immunization Against Influenza; Duration of Immunity Induced by Inactive Virus. J. Exper. Med., 80:265, 1944. 14. Francis, T. F.: Influenza, Methods of Study and Control. Bull. New York Acad. Med., 21 :337 (July) 1945. 15. Dyer, R. E.: Role of Immunization in Advances of Medicine. Proc. Am. Soc., 88:182 (Sept. 8) 1944. 16. Edsall, G.: Active Immunization. New England J. Med., 235:256-298 (Aug 22 and 29) 1946.
M.D.'"
Tms clinic will be concerned with the consideration of active immunization in children. By active immunzation I mean the generation of antibodies by an organism in response to the introduction of an antigen, no matter by what route. Active immunity results in antibodies which tend to persist for months or years. A cardinal and invaluable feature of active immunity is that years after the original immunization a single injection of the antigen will quickly reactivate the production of the antibodies. This stimulating, or booster, injection will raise the titer of protective antibodies, in a matter of days, from a low, inadequate level to a protective titer which is often higher than the original immune titer. In contradistinction, passive imlnunity, which consists of the injection of preformed antbodies, is of short duration and not susceptible to reactivation by a stimulating dose of antigen. In my opinion, we have not properly availed ourselves of the fact that booster injections can stimulate further production of antibodies long after the onset of active immunization. The past decade has witnessed important changes in the technic of active immunization. Preparations of antigens have been continually perfected, and the dosage and timing of the administration have changed for the better. These innovations were accelerated by the impact of war, which served as a vast laboratory for testing the efficacy of new methods. The lessons learned have been incorporated into civilian prophylaxis, with promise of further improvements. The pediatrist, who necessarily performs large scale routine immunization, should be in the van in the study of the efficacy and the innocuousness of the most recent prophylactic measures. DIPHTHERIA
Diphtheria remains a most important epidemiologic probleDl. It has been demonstrated by myself and collaborators! as well as by others,2 that the past generation has undergone a subtle change for the worse in· adult immunity to diphtheria. The mass of data collected by Schick3 (1914 to 1928) showed that about 85 per cent of adults were immune to diphtheria in this preimmunization period. The institution of routine diphtheria prophylaxis on a massive and widespread scale has resulted in a striking decline in the morbidity and mortality o
Attending Pediatrist, Beth Israel Hospital, New York City. 590
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of diphtheria. As a concomitant phenomenon, however, the carrier rate has declined to a proportionately low figure. The reduction of the carrier state in an artificially immunized community, with necessarily lessened exposure to toxigenic diphtheria bacilli, has resulted in a loss of the artificially acquired immunity in a high percentage of adults. It has already been noted that there is a trend to diphtheria increase in many sections, where outbreaks of diphtheria have been reported chiefly in adults, here and abroad, in civilian and in military life. 4 The New York City newspapers of October 17, 1946, publicized reports from the health commissioners of the state and city that diphtheria morbidity and mortality have noticeably increased throughout the nation, and stress the need of further immunization. Epidemiologists have commented that the diphtheria problem of the future is concerned with the immunity of the adult. 5 Epidemics of adult diphtheria should not occasion surprise, for studies have demonstrated that artificial diphtheria immunity confers sufficient but declining protection for a period of three years. After this period there is a perilous fall in the level of immune titer unless there is a stimulation of immunity by artificial or natural means, the latter normally through the medium of the vanishing carrier. My investigations at Beth Israel Hospital, in a large group of young women, indicate that as of today, about 50 per cent of adults are Schick positive. Important corollaries follow these observations. It was formerly confidently assumed that, since the adult is nearly always immune to diphtheria, the newborn baby is similarly immune, since he is endowed with his mother's antibodies at birth. Immunization of the infant had hence been postponed for six to nine months, after which period he presumably lost his passively acquired immunity. Indeed it was believed that in the presence of passive antibodies, active immunization would prove ineffective. Since proof has been adduced that in many areas 50 per cent or more of adults are susceptible, the immunity ascribed to the newborn baby often rests upon a false assumption. Recent tests by me on· a group of 100 babies substantiated this contention, for 50 per cent of infants below 6 months of age were Schick positive. These facts and findings should logically lead to a change in diphtheria prophylaxis. To guarantee the transfer of immunity from mother to baby, it is necessary to ascertain maternal immunity. If the mother is Schick positive, diphtheria toxoid should be administered during the seventh and eighth months of pregnancy at intervals of two to three weeks in doses of 0.1, 0.2, 0..5, and 1 cc. This conversion to a Schick negative state is transmitted to the baby to persist six to nine months. If the mother is Schick negative, a single stimulating dose of 0.2 cc. of diphtheria toxoid elevates her antitoxin titer to a highly effective level, to the benefit of her baby. The pediatrist has little
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opportunity to pursue this practice. It properly lies in the province of the obstetrician and general practitioner. Schick tests routinely performed on mothers before and after delivery and in newborn infants reveal that the mother is a better reactor and indicator than her baby. If the Schick test is positive in the mother or baby we begin to immunize the baby at 3 months of age. Since the period of prophylaxis and the attainment of an immune titer require three months the baby remains susceptible for its first six months of life. The only known way to remedy this undesirable situation is to immunize the mother during pregnancy.. Our method of diphtheria prophylaxis in infants is administration of three injections of diphtheria toxoid in doses of 0.5 cc., 1 cc. and 1 cc. at intervals of three to four weeks. Unlike alum toxoid, the plain toxoid rarely causes a reaction.., The Schick test is performed six months later. For years we have not seen a positive Schick test following this prophylaxis. Every three years a single inoculation of diphtheria toxoid is given, and continued as long as a state of immunity is desired, into adult life and the period of pregnancy, if so desired" TETANUS Tetanus, a dread disease also caused by a toxin, was characterized by a singularly low incidence in the last war. Routine tetanus toxoid prophylaxis was so effective in producing adequate immunity that not only was tetanus virtually absent in this war but there was seldom need of administering tetanus antitoxin.. The army employed the fluid formalized toxoid in three doses of 1 cc. each at intervals of four weeks. The navy favored alum toxoid, given in two doses, 0.5 cc. at four week intervals. A routine stimulating dose was given annually, with the additional precaution of an extra stimulating dose with every change of locale and before combat engagement. A point worth noting is that fluid toxoid should be given if there is need for a quick rise of the antitoxin content, for alum toxoid acts slowly, and is therefore less useful as a rapidly stimulating dose. In pediatric practise tetanus immunization procedure is the same as that employed by the army and navy. It is recommended routinely for children who spend their summers in camp, to avoid needless injections of tetanus antitoxin which are too often given for inevitable injuries, with the attendant risk of producing dangerous allergies. Children of the hyperkinetic type who frequently suffer trauma, and youngsters living in the country intimately in contact with soil, may also benefit by the administration of tetanus toxoid. The fluid toxoid is almost devoid of reactions except in the cases of a few children who develop allergy to the preparation as a result of repeated inoculation. The alum preparation causes more frequent reactions and nodule formation but spares the child an injection.
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593
Whooping cough is the most important contagious disease of childhood for which we employ bacterial vaccine prophylaxis. The vaccine developed by the Saner technic administered in adequate doses has materially reduced the incidence of pertussis in children above 1 year of age. Ample data has been accumulated to prove this point beyond reasonable dispute. It probably has also modified the course of the disease in many children in whom prophylaxis has not been entirely successful. As in diphtheria, the problem of protection of the infant has not yet been satisfactorily solved. Data has been accumulated proving that the majority of adults (80 per cent) are not immune to pertussis. 1 It follows that 80 per cent of babies are susceptible to whooping cough from birth, for they must lack immunity if their mothers do. It has been the custom to institute pertussis prophylaxis at 6 months of age. When vaccine therapy has been completed and immunity obtained, the infant is nearing 1 year of age. Here again is a dangerous gap in immunity against a disease which takes its highest toll in infancy. The only known method of conferring immunity upon the infant is immunization of the mother during the last trimester of pregnancy. The active maternal immunity is passively transferred to the baby. Since it is a passive immunity it lasts but a few months, after which period (at 4 to 5 months of age) active immunization of the infant should be initiated. There is much evidence pointing to the fact that a young organism, such as the infant, is a poor antibody producer, even if inoculated with potent antigens. Some years ago Sauer reported unsuccessful attempts to actively immunize infants below 6 months of age against pertussis. 6 The incidence of the disease was the same in the immunized as in the unimmunized group. Laboratory tests also demonstrated defective antibody formation in these young infants. A more recent attempt to immunize infants at 1 to 3 months of age against pertussis yielded more encouraging data. 7 Three injections of 0.2, 0.3, and 0.5 cc. of an alum preparation totaling 40 billion bacilli per cc. resulted in positive agglutination tests in about 80 per cent of the infants two to four months after the completon of prophylaxis. The morbidity and mortality of the vaccinated group (3,793 cases) was significantly lower than in a control group. It may be that the slowly operating alum preparation used was more effective in these young infants than the generally employed Sauer vaccine. Further observation by the New Opleans group and by other investigators employing a similar immunization procedure confirmed the growing opinion that very young infants may be capable antibody producers. 8 Nevertheless, Sauer, adopting a similar technic for this age group, reported that only 31 per cent of young infants so inoculated had a positive complement fixation
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test. Further data is needed to determine whether it is feasible to begin pertussis prophylaxis in babies so soon after birth. The usual procedure in pertussis immunization is to inject a Phase I vaccine at three to four week intervals until 90 to 120 billion organisms have been administered, the amount varying with the age and the size of the baby. This requires 6 to 8 cc. of a 15 billion per cc. preparation; 4.5 to 6 cc. of a 20 billion per cc. preparation. The entire procedure requires three to four inoculations, the number depending upon the presence or absence of reactions. It appears that alum preparations are equally effective in smaller doses. Studies upon similar groups of children are now in progress in my clinic upon the comparative immune titer obtained by alum preparations given in a dosage two-thirds that of fluid vaccine. Were it not for greater reaction and nodule formation, the alum preparation would undoubtedly be preferable. These reactions can be obviated to some extent by deep subcutaneous injections using a vaccine warmed and well shaken, followed by massage of the inoculated area. My present inclination regarding pertussis prophylaxis, as with diphtheria, is to begin immunization at an earlier age than heretofore. At three to four months of age immunization may be instituted in infants in good condition. If the infant is Schick positive a preparation of diphtheria toxoid combined with the pertussis vaccine is employed. This combination of antigens has previously not been included in the armamentarium of prophylaxis for very young infants. TYPHOID FEVER
Typhoid fever prophylaxis by vaccine inoculation has been admittedly effective for many years. The past war afforded another brilliant example of the efficacy of this vaccine, for again there was a very low morbIdity in those vaccinated. 9 It should be interpolated that all immunity is relative, be it natural or artificial immunity. An antibody titer effective under normal and ordinary circumstances may be insufficient and overwhelmed in the presence of a virulent infection or intensive exposure. Thus typhoid fever has been reported in individuals properly inoculated and with protective immune titers, but infections are much fewer than in unvaccinated individuals under the same conditions, and the course of the disease tends to be milder. 9 Many instances have been recorded (and observed by me) of two or more attacks of diseases like measles, scarlet fever, whooping cough, mumps, and other diseases which are known for their capacity to produce a lasting high level of immunity. This relativity of immunity applies to all immunity against disease. Innovations and improvements in typhoid prophylaxis have recently been introduced. Rawling's typhoid strain has been supplanted by the superior Panama 58 antigen, 9 which has been put to commercial
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use. The dosage remains the same; 0.5 cc., 1 cc. and 1 cc., but intervals longer than one week have proven superior. In pediatric, unlike military practice, there is seldom urgency of time, and an interval of two weeks is preferred. The dosage given to a child may be computed on the basis of weight ratio to the adult, or slightly more than this calculation calls for. Laboratory studies have shown that the former method of three inoculations every three years yields a titer of protective antibodies which sink to a low level long before the expiration of the three year interval. Only 20 to 25 per cent of individuals retain an adequate titer of protective antibodies two or more years after typhoid inoculation. lO A single injection of 0.5, cc. of typhoid vaccine given annually succeeds in elevating the protective antibodies to the optimum level in 100 per cent of cases. IO I consider the best practice to be administration of annual booster injections of 0.5 cc. of typhoid vaccine after the initial trio of inoculations. This practice should be adopted for children going to camp, for a constantly high level of immunity is thus obtained instead of the former uncertain fluctuating titer. The reactions incurred by this annual method are fewer and less severe than with the old three shot system. SMALLPOX
Smallpox vaccination is accomplished by the use of a preparation containing a live but attenuated virus. It is one of the few instances in which a live organism is used to induce active immunity in children. It has been established that there is no natural, probably not even passive immunity to smallpox. Donnally successfully vaccinated newborn infants thereby confirming that there is no immunity of the newborn to smallpox.!! A comparative study of the potency of culture and calf-grown virus was made in this group of vaccinated newboms. Revaccination two or three years later resulted in successful takes in 73 per cent of those vaccinated with the calf virus. Vaccination with a virus culture took in only two out of thirty-six cases. This study not only attested to the susceptibility of the newborn to smallpox and the superiority of the-calf-grown virus for vaccination, but also demonstrated that the immunity may wane as early as two to three years after successful vaccination. When smallpox is prevalent it is important to bear these facts in mind. Every infant should be vaccinated and failures should not be construed as indicating immunity. It is advisable, if possible, to wait an appreciable period, about a month after the unsuccessful vaccination, before revaccinating. If the interval is shorter, the site of the unsuccessful vaccination may light up and take as the second successful vaccination evolves. Thus two vaccinia will develop concomitantly with proportionately greater systemic effects, local reaction, and scar formation. In the presence of an epidemic or on the eve of travel to
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PHILIP COHEN
a state or country where smallpox occurs, previously vaccinated individuals should be revaccinated even if the interval is less than five years. I have several times observed successful revaccination without the expected modification in children vaccinated two or three years previously. My belief is that vaccination sh9Uld be repeated at the slightest indication, for if immunity persists, there is little or no reaction; if, however, immunity is lost or largely lost, the resulting take and immunity will be a source of satisfaction. The duration of immunity after vaccination is extremely variable, ranging from two years to many years, perhaps for the duration of life. Normally the initial vaccination is performed at 3 to 8 months of age at a time when the infant is in excellent health, the season favorable and the skin in normal condition. I try to avoid vaccination during uncomfortably hot weather and during seasons of rampant or endemic infections. The puncture method of vaccination yields a smaller area of reaction with a smaller scar and less systemic reaction. I have rarely used the intracutaneous method for lack of scar formation deprives one of definite proof of lack of immunity. I prefer the arm for the area of vaccination in both males and females. It is safer, less disfiguring and less prolninent than leg vaccinations. No dressing is used after the first day. A shield or a covering of any sort is strictly forbidden. I have been fortunate, aided by the insistence of the above precautions, never to have had any infection or ill effects from a smallpox vaccination. INFLUENZA
Influenza is another virus disease, for which an inactivated virus preparation has been invoked in the last few years. Because of newspaper predictions of epidemics, pediatrists are receiving numerous inquiries as to the efficacy and desirability of the new vaccine. From available data it may safely be assumed that nearly every adult has been infected at some time with pandemic influenza. 12 Hence, only one inoculation of I cc. of virus vaccine need be given since it acts as a reactivator or a booster injection of waning immunity. Within one or two weeks after inoculation over 90 per cent of subjects show a sharp increase in circulating antibodies,12 an effect comparable to that of booster injections for diphtheria, tetanus and other diseases in which an active immunity may be produced. One year later the antibody titer is still above the prevaccination leve1. 13 Nevertheless, the definite decrease of antibodies at the end of a year and the prompt, sharp response to a single injection .would indicate the need for annual booster injections. Surveys have shown that the rate of incidence in vaccinated groups is considerably lower than in control groups (25 per cent) .14 The technic for the preparation of the vaccine is quite different from the method ordinarily employed for vaccine preparations. The
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live virus is incubated on the extra-embryonic fluid of the developing hen's egg. As a result of processes of adsorption, diffusion and centrifugation, the final preparation of the virus contains little or no egg protein. Tests are being made by precipitin methods to determine whether egg protein has been completely eliminated to avoid allergic reactions in sensitive individuals. It may be the better part of wisdom~ at present, to test egg allergic individuals with the preparation, and if the reaction is positive, to proceed with caution. There is little avaliable data on influenza virus vaccination in chi!.. dren. 12 It may even be incorrect to assume that the very young child has been previously infected with the virus. If this assumption bE false, two inoculations at intervals of two weeks may offer better protection to the young child. The dose for children may best be gauged by weight ratio, as in other vaccine therapy. I have been inoculating children up to S years of age with 0.25 cc., up to 10 years with 0.5 cc., and the older group with 1 cc. of the vaccine. In my limited experience the reactions in children have been below expectation. Slight headache, transient chilliness and fever, and soreness of the arm for about a day have been observed by rue. Collective data is now needed to determine the efficacy of this vaccine in children in the presence of a proven epidemic. It must be emphasized that the· influenza virus vaccine protects only against influenza A and B. Parents are informed that other respiratory infections, virus or bacterial, will be unaffected by this prophylaxis. To protect against recurrent respiratory infections, often loosely called "colds," a bacterial vaccine, "catarrhal vaccine" has been employed for years parenterally and laterally orally. The genuine cold, a virus infection, must be uninfluenced by such measures. It is claimed, but not proved, that secondary respiratory infections may be influenced for the better by the use of a vaccine containing most of the common respiratory flora. Such a vaccine is not infrequently used for this purpose in pediatric practise, but its efficacy can only be conjectured through empirical observation. There is no scientific data demonstrating increased immune titers against respiratory disease after such inoculations. RICKETTSIAL DISEASES
Potent vaccines against rickettsial diseases have been recently developed, notably against typhus fever and other spotted fevers. 15 These vaccines are prepared on a yolk sac medium, and hence precaution must be 'taken when such vaccines are injected into egg allergic ind-ividuals. These vaccines are administered to children in amounts proportionate to. the adult dose of 1 cc. Two injections are given at intervals of two weeks. Typhus fever is not common in this country, but traveling to areas of infection is sufficient indication for such vaccination in children. The spotted fevers (Rocky Mountain fever) are
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PlllLIP COHEN
indigenous to certain sections of this country. I have employed this vaccine for several children visiting infected sections. My cases are too few in number to warrant immunological conclusions, but there have been no untoward reactions. YELLOW FEVER, PLAGUE AND CHOLERA
The armed services us~d effective vaccines against yellow fever (a virus vaccine) and also vaccinated at times against plague and cholera. 15 Such vaccines are rarely given to children in this country as there is no need for them. I have never found occasion for such vaccination. Nevertheless, a trip to a section where these diseases are prevalent would be sufficient indication for the administration of such prophylaxis. Since the human serum component has been eliminated from the yellow fever vaccine, there has been a cessation of reports of jaundice following such vaccination. SCARLET FEVER
Scarlet fever active immunization has not proved popular in eastern United States. The frequency and severity of reactions after scarlet fever prophylaxis have been a distinct drawback. The injection of an unmodified toxin, generally five to seven times, in amounts varying from a few hundred to hundreds of thousands of skin test doses have caused in 10 to 15 per cent of cases such reactions as neausea, fever, vomiting and rash, comparable to a case of mild scarlet fever. 16 Infrequently, the alarming symptom of joint pains has been reported. On the other hand, such immunization has decidedly reduced the incidence of scarlet fever. This prophylaxis should be given for the protection of nurses and workers in contagious hospitals, and for those intensively exposed to scarlet fever. Because of reactions, the numerous injections, the often temporary nature of the" immunity, in conjunction with the fact that scarlet fever has for years been of a mild character in the East, I am not given to the use of scarlet fever prophylaxis. Should matters change and scarlet fever assume a more malignant form, I would advise prophylaxis in spite of its disadvantages. Perhaps newer preparations, (alum and tannic acid precipitation), now under investigation, will offer a happy solution. 16 If the precipitates prove effective, only three injections, provoking few reactions, will be necessary. Laboratory tests have demonstrated an immunity duration of four years after inoculations of these products. Other toxoids, previously tested in three doses at three week intervals, have not been as effective as the toxin preparation usually employed. COMBINED PROCEDURE; OTHER ROUTES
It should not be assumed that these immunization procedures must be given individually and in succession, necessitating much expendi-
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ture of time and inconvenience to the patient. Pediatricians have been leaders in proving the efficacy of combining immunization procedures. Even before tIle war investigations showed that each antigen combined in a mixture produced an immune titer equal to or greater than that effected by the antigen injected individually. Pediatric practice and the vast military immunization have yielded ample and convincing confirmation of the effectiveness of simultaneously injected vaccines. The infant and child, like the soldier, should have his prophylaxis completed in a brief period, for it is wiser to abbreviate as much as possible the period of absent immunity. The accepted and best practice today is to immunize the infant simultaneously against diphtheria, pertussis and, if desired, tetanus. I have also mixed toxoid with other vaccines, such as typhoid, with no ill effects. I have not yet ventured to mix vaccines or toxoid with rickettsial or live virus vaccine. Nevertheless, it may be entirely feasible to employ such mixtures, with the possible exception of the vaccine virus. Introduction of antigen by a route other than subcutaneous, intracutaneous or intramuscular has not been generally invoked in pediatric practice. It may well be that other forms of administration, notably by nebulization or aerosol technique, for direct immunization of localized regions, such as the respiratory tract, may yield better immunity against localized diseases. Experimental work along these lines has yielded promising results. Future studies may more emphatically prove this point and lead to a wider use of such methods in immunization practice. SUMMARY
In summary, it may be restated that modern active immunization favors the simultaneous adminisb'"ation of different antigens either in a mixture of two to three antigens, or by separate injections at different sites. The previous weekly interval between inoculations has been generally lengthened to two to four weeks. The active immunity, waning often to an inadequate and nonprotective level, should be stimulated by a booster injection every year, or every two or three years. This interval is determined by the need for immediate protection, and the desire for a constantly high immunity instead of an un.. certain and fluctuating one. The trend is also developing of maintaining a continually high level of immunity by giving annual injections instead of three injections every three years, as in typhoid fever prophylaxis. Vaccination against smallpox should be performed in the presence of outbreaks of this disase, unless the last successful vaccination was performed less than three years before exposure. By these methods safety is attained with a minimal expenditure of time and the omission of many painful injections to the child. I believe that active immunization of the infant will be given at
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an earlier age (3 to 4 months) than in the past (6 to 9 months). This still leaves the infant unprotected against some diseases (notably pertussis and often diphtheria) for the first six months of his life. Prenatal immunization by active immunization of the mother during pregnancy, can solve this important problem. REFERENCES 1. Cohen, Philip and Scadron, S. J.: The Effects of Active Immunization of the Mother Upon the Offspring. J. Pediat. In Press. Cohen, Philip, Shneck, H. and Cohlan, S. Q.: The Changed Status of Diphtheria Immunity. To be published. 2. Liebling, J., Youmans, G. P. and Schmitz, H. E.: Occurrence of Diphtheria Antitoxin in the Human Pregnant Mother, Newborn Infant, and Placenta. Am. J. Obst. & Gynec., 41:641 (April) 1941. Cameron, G. D. W.: The Schick Test in Adults. Canad. Pub. Health J., 32:414 (Aug.) 1941. Levy, A. J.: Susceptibility of Adult Population to Diphtheria. Illinois M. J., 82:390, 1942. Goldsworthy, N. E. and Wilson, H.: Schick Test in Young Adults. M. J. Australia, 2:349 (Oct. 30) 1943. Bull, U. S. Army Med. Dept., 76:104 (May) 1944. Wright, G. P. and Clarke, W. M.: Schick Reactions in Recently Confined Women and Their Infants. Brit. M. J., 2:146 (July 29) 1944. Karelitz, S. and Moloshok, R.: Immunity to Diphtheria in Anny Personnel. War Med., 6:232 (Oct.) 1944. Vogelsang, T. M. and Kryvi, B.O.: Schick Test During Diphtheria Epidemic. Nordisk Medicin, Gothenberg, 28:2021 (Oct. 5) 1945. 3. Schick, B.: Brennemann's Practice of Pediatrics, Vol. 11, Chapt. 4, pp. 4-6, Hagerstown. W. F. Preyor, 1944. 4. Campbell, P. S.: Occurrence of Diphtheria in Halifax from Oct., 1940, to Jan. 31, 1941. Canad. Pub. Health J., 32:404 (July) 1941. Diphtheria Mortality in Large Cities of U. S. in 1942. J.A.M.A., 122:1079 (Aug. 14) 1943; J.A.M.A., 131:1053, 1062 (July 27) 1946. Diphtheria in Soldiers: }.A.M.A., 131:1071 (July 27) 1946. Knipe, R. G.: Experiences in Diphtheria Control in Northern British Colunlbia. Canad. Pub. Health J., 35:349, 1943. Mattison, B. F.: Diphtheria in an Adequately Ilnmunized Community. New York State J. M., 44:2138 (Oct. 1) 1944. 5. Fleming, D.: Problem of Future. Canad. M.A.J., 50:46 (May) 1944. Fraser, D. T. and Brandon, K. F.: Duration of Schick Immunity. C:anau. Pub. Health J., 27:597 (Dec.) 1936. 6. Sauer, L. W.: Age Factor in Active Immunization Against Whooping Cough. Am. J. Path., 17:719, 1941. Whooping Cough, Preventive Treatment. M. CLIN. NORTH AMERICA, 45:,58 (Jan.) 1946. 7. Sako_ W., Treuting, W. L., Witt, O. B. and Nichamin: Early Inllllunization 1"lgalnst Pertussis with Alum Precipitated Vaccine. J.A.M.A., 127:379 (Feh. 17) 1945. 8. Waddell, W. W. and L Engle, C. S.: Immune Response to Early Administration of Pertussis Vaccine. J. Pediat., 29:847 (Oct.) 1946. 9. Callender, G. R. and Luippold, G. F.: Effectiveness of Typhoid Vaccine Prepared by U. S. Army. J.A.M.A., 123:319 (Oct.) 1943. 7
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10. Longfellow, D. and Luippold, G. F.: Typhoid Vaccine Studies: Revaccination and Duration of Immunity. Am. J. Pub. Health, 30:1311 (Nov.) 1940. 11. Donnally, H. H.: Smallpox Vaccination of Infants. J.A.M.A., 113:1796 (Nov. 11) 1939. 12. Andrews, C. H., Laidlaw, P. P. and Smith, W. W.: Observations on Recovery of Virus from Man and on Antibody Content of Human Serum. Brit. J. Exper. Path., 16:566, 1935. Francis, T. and Magill, T. P.: Incidence of Neutralizing Antibodies for Human Influenza Virus in Serum of Human Individuals of Various Ages. J. Exper. Med., 63:655, 1936. 13. Hirst, G. K., Rickard, E. R. and Friedewald, W. F.: Studies in Immunization Against Influenza; Duration of Immunity Induced by Inactive Virus. J. Exper. Med., 80:265, 1944. 14. Francis, T. F.: Influenza, Methods of Study and Control. Bull. New York Acad. Med., 21 :337 (July) 1945. 15. Dyer, R. E.: Role of Immunization in Advances of Medicine. Proc. Am. Soc., 88:182 (Sept. 8) 1944. 16. Edsall, G.: Active Immunization. New England J. Med., 235:256-298 (Aug 22 and 29) 1946.