Current Concepts in Immunization

Current Concepts in Immunization HARRIS D. RILEY,

JR.,

M.D.

The object of immunization is to produce without harm a degree of resistance in persons as great as, or greater than, that which follows the natural infection. There are few more effective means of achieving this goal than the maintenance of an active and up-to-date immunization program. As Edsalll has stated: "Never in the history of human progress has a better and cheaper method of preventing illness been developed than immunization at its best." Immunization is a dynamic subject in need of constant evaluation. 73 This is emphasized by the introduction of effective new immunizing agents. Vaccines are particularly important in the protection against disease of viral origin, since at present there are no effective means of chemoprophylaxis against these infections. Even though antibiotics are available for the treatment of many bacterial infections, these drugs have definite limitations and disadvantages. Active immunization, in contrast to antimicrobial prophylaxis, converts a susceptible person into a resistant one, allowing him to travel where and when he wishes while carrying his protection with him, and without the necessity of taking a drug regularly. The administration of effective vaccines to as many people as possible on a private and community basis needs continued emphasis. Despite the accessibility of immunizing agents, recent surveys have revealed low rates of immunization. For example, in a large series of consecutive new patients referred to the outpatient clinic of the Children's Memorial Hospital, University of Oklahoma Medical Center, less than 11 per cent had received adequate primary and recall immunization against diphtheria, pertussis, tetanus, smallpox and poliomyelitis. The coverage was even poorer in their parents.2 In contrast, a survey of the immunization status of physicians in Oklahoma in 1963 revealed generally satisfactory From the Department of Pediatrics and the Children's Memorial Hospital, University of Oklahoma Medical Center, Oklahoma City, Oklahoma. Some of studies cited were supported in part by grant #8T1-HD-64-03 from the National Institute of Child Health and Human Development, United States Public Health Service, and in part by grants to the Pediatric Pharmacology Unit, Children's Memorial Hospital.

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coverage for the basic series, ranging from a low of 74 per cent for diphtheria toxoid to 99 per cent for smallpox vaccine. Nevertheless the maintenance of immunity through appropriately timed recall injections was not nearly as satisfactory.3 In Boston a survey of parents of children attending a pediatric clinic revealed that approximately two thirds had not been, or did not know whether they had been, immunized against diphtheria and tetanus. Sixty per cent of the fathers and 35 per cent of the mothers had not been immunized against poliomyelitis. 4 A similar level of immunization was found in a recent survey of Oklahoma County, Oklahoma. 5 In a nation-wide survey conducted by the Bureau of the Census in 1962, four million children under the age of five years, 20 per cent of those surveyed, had not received a single injection of diphtheria, tetanus or pertussis vaccine. Of the white children, 18 per cent were totally unprotected, whereas 31 per cent of Negro children had received no injections. 59 The purpose of this paper will be to review immunizing procedures which should be regarded as mandatory, i.e. against those diseases for which there is no satisfactory method of control other than by vaccination. No attempt will be made to cover immunizing procedures which are mandatory under certain circumstances, those which are advisable in certain areas or occupational groups, and those which are of passive value or are under study. For information on the less commonly used vaccines not included in this review, the reader is referred to the report of the Committee on the Control of Infectious Diseases of the American Academy of Pediatrics and other comprehensive reviews on immunization practices,23 from which much of this material has been derived. The public apathy toward immunization must be overcome, and the vaccines must be administered to the population groups who need them. It is a strange paradox that 95 per cent of the population of an area can be immunized with oral poliovaccine on a single day, and yet four million children under the age of five years have not been immunized against diphtheria, pertussis and tetanus, although vaccines of proved effectiveness against these diseases have been available for many years. In all probability the success of the oral poliovaccine program is due more to the participation of the medical profession at the local level than to the ease of administration. Another, most important factor is the need to record these data in the patient's permanent health record. It is important to emphasize in this age of jet travel that diseases formerly restricted to some remote country may be introduced into any other country in the world with relative ease. For example, the eight- to twelve-day incubation period of smallpox is easily overtaken by present-day air travel. Although the development of various immunizing agents is one of the most important health developments, it should be recalled that these agents are not without hazard. Katz 53 has recently reviewed the potential hazards of various vaccines.

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GENERAL IMMUNOLOGIC CONSIDERATIONS

In the establishment of basic immunity by vaccines and other antigenic agents two important principles deserve careful consideration: (1) the production of circulating antibody, and, what might be more important in the final analysis, (2) the establishment within the host of a capacity to respond when stimulated by a booster dose of antigenic agent or by invasion of the organism. These considerations are all-important in the selection of age, type of vaccine, and spacing in an immunization program. Factors Influencing Antibody Response The nature of the antibody response of an individual organism is the product of the interaction of a number of factors, including such host influences as age, strain differences, the presence of acquired antibodies, and various qualities of the antigen. Among the more important of the latter in determining its antigenicity are size of the antigen (larger molecules induce a more intense and earlier antibody response); complexity of the molecule; whether the antigen is living or not; dose; chemical state (purified diphtheria toxoid induces a greater antibody response than crude toxoid); physical state (including the enhancing effect of adjuvants); and solubility (particulate bacterial antigens elicit a better response when administered intravenously; soluble antigens are more effective when given by the subcutaneous route).6 In planning any program of immunization, of foremost consideration is the need to establish resistance to all possible infections as early in life as is reasonably possible. There is great variability in the protection of the young infant obtained by transplacental antibodies from the mother. Infants born to adequately immunized mothers receive passive humoral antibodies which protect for four to six months against diphtheria, tetanus, measles and poliomyelitis. The main reason for starting immunization in the first three months of life is that newborn infants do not receive such passive immunity against pertussis. Immunization against pertussis at the earliest possible time would be of particular value, since the mortality from pertussis is greatest in infancy. In addition to the fact that morbidity of poliomyelitis in infancy is significant, there is also need to begin immunization against this disease relatively early in infancy so that immunity will be established early in life in view of the changing tendency of the infection to attack primarily preschool children. When it is recalled that an effective immunization procedure (smallpox) has been known and available for 165 years, why is it that immunization of young infants is comparatively new? The chief reason for this has been the influence of the concept of immunologic immaturity. Baumgartner7 in 1934, in a paper which had great impact, sum-

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marized current concepts up to that time regarding the ability of young infants to produce antibodies. She concluded that the young animal responded differently than the older and that the ability to be actively immunized was quantitatively and qualitatively inferior in the young animal. This expressed the common belief of that time, that infants were incapable of forming antibody and that failure was due to a physiologic or immunologic immaturity. The concept of immunologic immaturity of infancy became so well ingrained that it was widely held that young infants could not be immunized successfully. These studies ignored, however, or overlooked the fact that infections in the young do produce immunity, and there is little question that the result to immunity is relatively as s"atisfactory as that developed in older persons by the same infection. In the early 1940's Peterson, Christie and their associates S at Vanderbilt University began to re-explore the fundamental question of whether young infants can produce antibody. In 1942 Peterson and coworkers 9 demonstrated that young infants could develop antibody after systemic injection with phase 1 pertussis vaccine, indicating that even the youngest infants could be protected against whooping cough. Peterson and ChristieS showed that approximately 71 per cent of infants less than three months of age given a total of 8 million absorbed phase 1 pertussis organisms divided into three injections at four-week intervals developed protective antibody levels. Although this was not quite as good a response as achieved in infants over the age of six months, the difference was slight and the response was essentially as good as that obtained in infants whose injections were started between three and six months of age. These and other workers found that infants immunized as young as two weeks of age against pertussis could develop antibodies to pertussis vaccine. Sako10. 11 reported that the attack rate of children immunized before three months of age who were subsequently exposed to pertussis was 13.2 per cent as compared with 89.7 per cent in a comparable nonimmunized group. No child with an agglutination titer of 1:320 or greater contracted the disease. That the young infant can produce antibodies to diphtheria toxoid has been well documented. It has been found that the very young infant is capable of responding to injections of diphtheria antigen even if this is given as early as the first few days after birth. Dancis and Osborne,12, 13 in 1952 and 1963, showed that infants less than two weeks old could manufacture antibodies to injections of diphtheria antigen. Subsequently the response to "booster" injections was found to be good regardless of either the age at which primary immunization had been carried out or the degree of response to the initial immunization. Di Sant'Agnese14 reported that 85 per cent of a group of infants in whom immunization was begun before one week of age showed "protective" antibody levels (0.03 microgram per milliliter) by 13 weeks of age, and almost all developed

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protective levels after a booster injection. Barr et al. 15 demonstrated that the antibody response in neonates first immunized between the sixth and tenth days of life was as good as in those injected at six weeks. Osborne and co-workers 13 showed that the response of premature infants given diphtheria toxoid a few days after birth was not significantly different from that of full-term infants immunized during the same period. If the premature infants were immunized at the estimated delivery time, their antibody response was better than that of newborn full-term infants, thus indicating that a change in antigenic environment may influence the maturation of the antibody-forming mechanism. Peterson and Christie8 also clearly showed that young infants were capable of producing a satisfactory antibody response to tetanus toxoid. Batson et al. 16, 17 also demonstrated that very young infants were capable of responding to poliomyelitis vaccine of either the inactivated or attenuated types. Another influence affecting the response of young infants to immunizing antigens is the presence or absence of transplacentally passed maternal antibodies. Perkins et aI.,18 Spigland and Goldbloom,19 Da Silva,20 Barrett et a1. 21. 24 and Gaisford22 showed that maternally transferred antibody exerted an inhibiting effect on antibody formation. This effect is not complete, and in most instances satisfactory active immunization can be achieved under the cover of maternal antibody if sufficiently potent antigen is used. From the available evidence it is apparent that, although the antibody response to primary immunization increases with increasing age (at the time of immunization), the human being is of such immunologic maturity by early infancy that he is able to produce antibodies at that time. It is likely that the greater responses in older persons result, at least in part, from cross-reactions with other antigens. Response to recall or booster injections is independent of the age of or response to original immunization or the presence of maternal antibody. This pattern, furthermore, is indicative of the infant's ability to be "sensitized" to antigen even from birth. Thus Gaisford22 has shown that the majority of very young infants immunized with diphtheria, pertussis and tetanus antigens in combination at one, five and nine weeks of age exhibit a satisfactory antibody level at 15 weeks (Fig. 16).

RECOMMENDED SCHEDULE FOR ACTIVE IMMUNIZATION

A proposed schedule for immunization of infants and children and certain recent developments concerning this schedule and certain of these immunizing agents will be reviewed. The schedule shown in Table 12 is modified from that recommended by the Committee on the Control of Infectious Diseases of the American Academy of Pedi-

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DIPHTHERIA

D.

RILEY, JR.

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Figure 16. Response of 31 infants 6 weeks after a primary course of 3 injections of 1 ml. of alum diphtheria-tetanus-pertussis combined antigens at 1, 5 and 9 weeks of age. Open circles denote infants in whom there was failure of response. (From Gaisford et a1. 22 ). (Reproduced by permission of author and J. Pediat.)

atrics. 23 It is to be emphasized that this is a flexible guide which may be modified within certain limits to fit individual situations. Physicians now generally accept the principle that combined vaccines should be used whenever possible. There are basic reasons why combined vaccination is preferable. Immunization programs are more successful when the number of injections, and thereby the number of physician or clinic visits, are reduced to a minimum. Emotional disturbances are reduced by decreasing the number of injections, and the period of time necessary to establish immunity is shortened. Thus, by use of modem schedules of combined vaccines administration, a significant degree of protection against several diseases may be established by the age of six months. 73 At present it is recommended that all infants be inoculated actively against diphtheria, pertussis and tetanus with a course of injections of combined antigens containing alum-precipitated aluminum hydroxide or aluminum phosphate-absorbed diphtheria and tetanus toxoid, and pertussis vaccines. These "depot" triple antigens combined with adjuvants are considered preferable to fluid mixtures for the following reasons: 23 1. They induce more prolonged antitoxic immunity to diphtheria and tetanus.

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CuRRENT CONCEPTS IN IMMUNIZATION

Table 12. Recommended Schedule for Active Immunization oj Infants and Children* (ALTERNATE POLIOVACGINE AGE

PREPARATION

1 monthl .... . Pertussis 2 months 1 . . . . DPT Type 1 OPV2 3 months ..... DPT Type 3 OPV 4 months ..... DPT Type 2 OPV 9 months .... . Measles vaccine Smallpox vaccine 12 months .. . Tuberculin test 15 months .. DPT Types 1, 2 and 3 Combined OPV 2 years. . . . Tuberculin test 5 years ....... DPT Tuberculin test 6 years. . . . . .. Smallpox vaccine Tuberculin test 8 years ....... DPT 10 years ...... . 12 years ....... TD6 Smallpox vaccine 14 years ...... . 16years 6 • • • • . • TD

SCHEDULE)

IPV IPV

IPV IPV IPV IPV IPV IPV IPV IPV IPV

1 Immunization may be started at any age. The immune response is limited in a number of young infants, and the recommended booster doses are designed to insure or maintain immunity. Protection of infants against pertussis should start early. The best protection of newborn infants against pertussis is avoidance of household contacts by adequate immunization of older siblings. 20PV; Oral poliovaccine of the Sabin type. 3 IPV; Inactivated poliovaccine of the Salk type. 'If IPV is used, injections of DPT and the poliovaccine may be given, separately or combined in same syringe, or one may use quadruple preparations. 5 TD; Tetanus-diphtheria toxoids, combined (adult type). 6 After 16 years of age, smallpox revaccination and tetanus toxoid booster doses should be repeated every 5 years. * Adapted from Reference 23. This schedule is intended as a flexible guide which may be modified within certain limits to fit individual situations.

2. They cause greater antigenic stimulation against pertussis in early infancy. 3. They are less likely to produce systemic reaction because of lower protein content and slower absorption. The preceding factors outweigh the two advantages of nonabsorbed (fluid or plain) mixtures, which are (1) possible greater speed in achieving antibody response; (2) freedom from causing draining cysts, sometimes called (incorrectly) sterile abscesses. The latter almost always can be avoided by adherence to sound principles of administration of antigens. Although it is frequently not followed, there can be little question

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that the recommendation initially made 40 years ago regarding the site of injection is still completely valid: "The region of the outer side of the thigh, where lies the great vastus externus muscle is as nearly as possible the ideal place for all types of intramuscular injections."6o This is particularly important in regard to injections in infants and young children. Serious nerve damage, especially in subjects in this age group, has been repeatedly observed following intragluteal injections. 61 The anterior aspect of the thigh and the deltoid areas are preferable to the gluteal region. Bacterial contamination of the skin is also less at these sites, and they, like the lateral aspect of the thigh, are not traversed by any major blood vessels or nerves. 28 Pertussis It cannot be emphasized strongly enough that the newborn is devoid of passively transferred antibodies and is highly susceptible to this infection from birth. Approximately 80 per cent of all deaths due to this disease occur in the first year, and almost 30 per cent occur within the :6.rst three months of life. Protection against pertussis by passively acquired maternal antibodies is insignificant. Although placental transmission of pertussis agglutinating antibodies can occur, the presence of this antibody in cord serums is usually negligible. When detectable levels of antibodies are present in the cord blood, they usually are lower than in maternal serum. When mothers are immunized during pregnancy, transplacental transfer of antibodies does occur, but the mean titer in cord blood is only half as high as in the maternal blood. The role of humoral antibody in affording immunity to pertussis is not clear. Young infants, for example, are usually susceptible to pertussis regardless of the presence or absence of passively transferred antibody. On the other hand, active immunization does afford a high degree of protection against pertussis. The value of maternal immunization in the last trimester of pregnancy in subsequently affording infants passive protection against pertussis is limited. The disadvantages of this procedure include not only a greater risk of neurologic complication to the mother, but also the decline of passively acquired antibodies in the infant at the time when they are needed most. Active pertussis immunization begun within a few days after birth could at least "sensitize" the infant's immune mechanism, thus priming this means of defense. Furthermore, as Gaisford22 has suggested, a booster response might be effected in such infants on contact with the organism (when known) by the administration of fluid vaccine at that time. Studies performed under the auspices of the British Research Council since 1951 have established that the present vaccines (purified antigenic phase 1 fraction of Bordetella pertussis) are potent and safe. With standardization of an acceptable level of potency of the vaccines by the

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intracerebral challenge mouse protection test and adoption of 12 antigenic units as a total immunizing dose, recent controlled field and laboratory trials with present vaccines have shown a considerable degree of protection. Twelve antigenic N.I.H. (National Institute of Health) units (1.5 mI.) of the fluid vaccine is not less in potency than 90,000 million bacteria of the N.I.H. standard pertussis vaccines. The alum-absorbed toxoid contains about 48,000 million organisms in 1.5 mI., since it produces a higher agglutinin titer than the plain vaccine, particularly when combined with diphtheria and tetanus toxoid. 29 It has been shown that infants given pertussis vaccine alone during the first six weeks of life are capable of satisfactory antibody response. 24 ,24a Under some circumstances an initial dose of pertussis vaccine may be given alone followed by three injections of combined diphtheria, pertussis and tetanus vaccine providing a total of 16 N.I.H. units (Table 12). This sensitizes the antibody mechanism against the disease to which the infant is so susceptible, starts the immunization schedule early with little possibility of a reaction, and sets the stage for the combined antigens to follow. 73 This schedule has been shown to be entirely satisfactory; however, in certain situations it may be more desirable to begin the immunization program with combined antigen as the first injection. Recall injections are given at intervals of two to three years after the first booster at 12 to 18 months of age. Although it is generally felt that there is probably little indication for maintaining active immunity to pertussis beyond six to eight years of age, older children and even adults may be susceptible to pertussis, though the infection at this age is not likely to be severe. Studies are in progress in this Clinic to determine whether the extracted pertussis antigen 25 will produce satisfactory protection with a lower incidence of untoward reactions than has been observed in susceptible older children after whole cell antigens. Fluid (plain, nonabsorbed) pertussis vaccine may be given any time after birth for the following circumstances: 29 1. To achieve rapid protection during the epidemics of pertussis; three equal doses of 4 N.I.H. units (0.5 mI.) each may be given subcutaneously at intervals of one week. Greater and more prolonged protection will result if the intervals are longer, i.e. three to four weeks. 2. For recall injections to obtain rapid protection after exposure to pertussis. 3. For the older infant or child who has already been immunized with tetanus-diphtheria toxoid, especially the child with cerebral dysfunction or a history of seizures. The incidence of postpertussis-vaccination encephalopathy varies

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widely between countries. A study from Sweden reported an incidence of 1:6000 with death or permanent defect in 1:17,000. In the United States this unfortunate reaction is much less frequent, and this is in all probability related to the ceiling or antigenic content of pertussis vaccine established by the National Institutes of Health. Neurologic reactions can be minimized if the contraindications to vaccination are observed and pertussis vaccine is eliminated from the immunization schedule, primary or booster, of children over the age of six to eight years of age. 26 An important recent development in pertussis immunization is the development of the extracted pertussis antigen. This vaccine is made from antigenic extract of Bordetella pertussis and has been combined with diphtheria and tetanus vaccines. Studies of infants receiving this new vaccine in comparison with those children immunized with the standard whole cell pertussis vaccine showed that the extracted antigen produced a high degree of antibody response and a significantly lower incidence of systemic and local reactions. The extracted antigen produced just as good, if not better, antibody response in infants less than three months of age. 25 Diphtheria Although, surprisingly enough, no adequately controlled field studies have been done, the evidence is fairly conclusive to justify the conclusion that a fivefold to tenfold degree of protection against diphtheria can be achieved by adequate immunization and that mortality is much lower in immunized cases. Despite the fact that almost 40 years have elapsed since diphtheria toxoid came into general use, diphtheria remains a constant menace, particularly in areas where the level of immunization is low. A natural decline in diphtheria has occurred during the past 30 years in many countries, but in no country is the decrease as noteworthy as that in Denmark, where the incidence fell from 23,000 cases to as few as one case per year. 29 Clinical experience has established the effectiveness of immunization in decreasing the morbidity and mortality from diphtheria. Some 900 cases occur annually in the United States. 27 In contrast to the over-all downward trend since 1927, a slight increase in cases occurred in the Southern states during 1958--1960. A recent outbreak in Oklahoma points up the importance of maintaining a satisfactory level of immunity.so The case fatality ratio has shown relatively little change, even with the availability of antibiotics, antitoxin and specialized medical care. Therefore it is obviously important that immunization against diphtheria be widely practiced. In the past, after a basic series of immunization, repeated natural exposure maintained the level of immunity. Because of the decrease of opportunity for natural exposure, at least in many parts of this country, a significant number of adolescents and adults successfully immunized in infancy and childhood have again

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become susceptible to diphtheritic infections. This decreasing immunity with increasing age probably explains the outbreaks of diphtheria among older age groups in institutions and in "skid row" populations which have been described recently.28 Yet of the cases occurring in the United States in 1960, 80 per cent were in children less than 15 years of age. 29 A study of 873 patients with diphtheria in the United States during 1960 revealed that 72 per cent had received no immunizations, 9 per cent had a primary series, but improperly spaced boosters, and only 10 per cent were fully immunized. A single death due to myocarditis occurred in the primary series group. Sixty-eight per cent of this group had mild cases compared to 54 per cent of persons with no history of immunization. Fifty-seven deaths occurred among persons without a primary series. About 80 per cent of the cases occurred in children under 15 years of age. Bacteriologic confirmation was obtained in 75 per cent of the patients. 29 Although diphtheria toxoid is one of our best antigens, it has never proved to be 100 per cent effective. The death of an eightyear-old who had received his booster 31f2 years previously has been reported. 29 Failure to immunize certain population groups may be the· focal point for an outbreak as shown by the 1956 Detroit epidemic. Most of the 30 cases were from one part of the city where the population consisted of large numbers of low-income persons from the South. In only one case had primary immunization with a booster dose been given. It is known that diphtheria can be brought under control in a community when some 70 per cent of the children (one to 15 years of age) are effectively immunized. It is generally recommended that in those areas where the natural disease has been markedly reduced, boosters should be given every four years, since the previous recurring antigenic stimulus has likely been removed. It may be necessary to revise these recommendations in view of the findings of Yolk et aJ.31 These workers reported that reinoculation with diphtheria tetanus toxoid containing 2 Lf. units of each toxoid of a group of young subjects initially immunized seven to 13 years previously resulted in excellent initial antitoxin levels which persisted for at least two years. The production of satisfactory immunity in very young infants is probably interfered with, to some degree, by the presence of passive maternally transmitted immunity. Nevertheless, as previously described, such subjects do respond, and, even more important, the ability to respond to booster doses is enhanced. Tetanus and diphtheria toxoid for adults' use has been available since 1958. This product contains no more than one tenth the amount of diphtheria toxoid contained in the standard pediatric preparation of DPT ( diphtheria, pertussis, tetanus) and DT (diphtheria, tetanus). It produces effective antibody levels and importantly carries practically no risk of significant systemic reactions. After three properly spaced doses of this

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material, 95 per cent or more of adults are found to be immune; after two doses of this material, 80 per cent are immune. This combination eliminates the necessity for separate diphtheria and tetanus immunizations unless sensitivity to the latter has been demonstrated. Adult DT can be given without prior or toxoid sensitivity (Moloney) testing. With the availability of adult tetanus-diphtheria toxoid the Schick test has been relegated to evaluation studies and is rarely used otherwise. If adult DT is not available, Schick testing must be done prior to inoculation of standard (10 to 20 Lf.) diphtheria toxoid. It is currently recommended that adult diphtheria-tetanus toxoid be used for primary and booster immunizations against diphtheria and tetanus in all adults and that for adequate protection a booster dose be given every four years. It is generally advised that it be utilized for recall immunization in children over eight years of age, but it is the author's feeling that the age in childhood for use of the more dilute toxoid should be individualized, depending on the experience which the childhood population has had with diphtheria. If the child resides in an area where the disease is endemic, it is more desirable and logical to use this dilute toxoid at an earlier age than if he resides in an area where clinical diphtheria has not been observed for many years. The findings of the committee on diphtheria toxoid of the British Medical Research Council demonstrate that very large doses of even the purified preparation of formal or "Huid" diphtheria toxoid are not as effective for basic immunization of children as toxoid with a mineral adjuvant. 82 With the effective and safe adult DT toxoid now generally available, there is no longer any justifiable reason for the family physician or internist to deny his adult patients the protection against diphtheria and tetanus which they enjoyed as children. Tetanus Immunization with tetanus toxoid should be universal. This is true because tetanus occurs at all ages and tetanus toxoid is among the most effective, yet innocuous immunizing agents available. When used properly, its effectiveness approaches 100 per cent, and the duration of immunity which it induces is strikingly lasting. That active immunization is effective seems clear from the experience in World War II among immunized United States and British personnel and the nonimmunized Japanese forces and from the comparison of immunized and nonimmunized German troops. Military personnel received only primary tetanus-toxoid immunization followed by boosters at the time of injury. During the war the United States Army reported more than 2,700,000 hospital admissions for wounds and injuries. Twelve cases of tetanus developed, of which six were in men not properly immunized, and two in troops who had not received boosters. 88 During the same period there were 2574 reported deaths due to tetanus

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among the civilian population in the United States. 26 In 1959, 283 deaths due to tetanus were reported. Of these, 99 occurred in children less than five years of age, and 32 in persons five to 19 years of age. The majority of these resided in the southern and southeastern parts of the United States.28 During the past 18 years a total of 72 cases of tetanus have been observed at the University of Oklahoma Medical Center.35 A plea for nation-wide tetanus toxoid immunization was recently made based upon a communication by Furste et al,39 It is a disturbing fact that 46 per cent of females and 28 per cent of males over 18 years of age have not had tetanus immunization, particularly with the availability since 1933 of tetanus toxoid, possibly our most satisfactory immunizing agent. In contrast, as a result of effective prophylactic programs carried on by pediatricians and general practitioners, only 8 per cent of females and 4 per cent of males under 18 years are not actively protected. A further appeal has been made to continue boosters and have the patient carry this information on his own health card. Approximately 50 per cent of cases in civilian practice arise from such insignificant wounds that medical attention would not be sought ordinarily. Furthermore, 50 to 70 per cent of all cases of tetanus occur in the pediatric age groupS.36 These seem adequate reasons for the routine use of tetanus toxoid. There is no evidence that previously immunized human beings develop antitoxin in response to tetanus infection: also, second attacks have been reported. These two observations indicate that in half of the cases prevention can be obtained only by maintaining an adequate protective level of antitoxin. It has been shown in guinea pigs that actively induced immunity (antitoxin titers of 0.01 antitoxic unit) affords tenfold greater protection than that passively given. The protective level produced actively in human beings is thought, without proof, to be 0.01 to 0.1 antitoxic unit.36 Recent studies have shown that a protective level occurred in 100 per cent of servicemen within three weeks after a booster though the last booster had been given 14 to 18 years previously. In many cases protective antibody levels developed within one to two weeks after a booster. In view of the frequency of various types of environmental injuries, it is important to maintain quadrennial recall immunization so that in the event of an accident, a booster will elicit protective antibodies within five to seven days, and thereby avoid the use of tetanus antitoxin. 29 Universal immunization with tetanus toxoid would eliminate the disease except in the rare person who cannot form antibodies. 1 Reactions to the alum-precipitated toxoid are minimal (1 to 2 per cent), especially if the injection is given intramuscularly and followed by injection from the syringe of 0.1 ml. of air. The use of tetanusdiphtheria toxoids combined, precipitated, absorbed (for adult use) has been previously discussed. Margileth, Shaul and Love29 have reviewed the use of tetanus im-

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munization in the immediate care of wounds. At the time of injury the wound should be thoroughly cleansed and debrided and a booster given, unless the patient had one in the previous 12 months and the wound was trivial. An extensive or heavily contaminated wound demands an immediate booster (0.5 mI.). For patients who have received proper primary tetanus immunization within the previous five to 10 years, a booster will produce an excellent antibody response within five daYS.44 In these patients, regardless of the kind of injury, the booster will provide ample protection if it is given within 24 hours, but if more than 24 hours have elapsed and the injury is extensive or heavily contaminated, then regardless of the age of the patient, 5000 units of tetanus antitoxin (or preferably human tetanus antitoxin) should be given at the same time in a different extremity. When the interval since the last toxoid booster is over 10 to 15 years, the physician must carefully weigh the facts: (1) a reliable history of primary tetanus immunization; (2) time elapse since injury; (3) kind of injury; (4) allergic past history; (5) previous tetanus antitoxin or other horse serum injection. Certainly, if a history of basic immunization is equivocal, if the wound is massive with the risk of tetanus self-evident, or if a delay of over 24 hours has occurred, then tetanus antitoxin must be administered. In the event that fluid toxoid is available, it is preferable to the depot toxoid, since it may induce a slightly faster response. If horse serum allergy is known or detected by skin testing, or tetanus antitoxin (equine) has been given previously, then bovine or preferably human tetanus antitoxin (see below) must be given. If 48 hours have elapsed, 10,000 to 20,000 units is recommended for all patients with massive wounds or those with potentially contaminated wounds over 24 hours in duration who have not previously had active immunization with tetanus toxoid. At the same time it is advisable to administer the first dose of toxoid in a different extremity. The heterologous antitoxin should be repeated within one week after sensitivity testing if the wound is not clean and healing. 29 One of the most significant recent advances in immunization against tetanus is the development of human hyperimmune tetanus gamma globulin. Certainly its use in the prophylaxis and treatment of tetanus is one of its most important. Even though it is at present very scarce, it offers promise for the immediate protection of persons sensitive to horse serum, including also the nonimmune, the partially immune and those whose status is unknown. It has been estimated that 2 million doses of tetanus horse antitoxin are used annually in the United States with an incidence of serum sickness of 15 to 30 per cent and of fatal anaphylaxis of one per 100,000.55 It also appears promising in the treatment of tetanus. It is relatively reaction-free and has a much longer half-life than horse serum. There is evidence that human antitoxin is retained in the circulation for a longer period than horse antitoxin and

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that protective levels of antitoxin are found in human patients for at least 21 days after administration of 5 units per kilogram of body weight of human antitetanus gamma globulin. The levels with this dose at seven days are equivalent to those produced with 1500 units of horse antitoxin. 56 This has important implications as regards combined immunization with tetanus antitoxin and toxoid (the latter to begin active immunization) at the time of injury. It has been shown that in combined simultaneous immunization the larger the dose of antitoxin administered, the less effective the active immunizing agent. The studies of Moloney and Mahoney57 suggest that the use of this smaller dose of human antitoxin in combination with alum-precipitated tetanus toxoid favors antibody stimulation by the toxoid. McComb,58 on the basis of recent studies, states that fluid rather than alum-precipitated tetanus toxoid should be used in combination with human antitoxin because it produces a higher antibody level. The use of homologous instead of heterologous antitoxin should eliminate the need for a second dose, since the half-life of the homologous antitoxin (gamma globulin) is four weeks, in contrast to one week for equine tetanus antitoxin. As this preparation becomes more regularly available it will eliminate the danger of serum sickness and anaphylactoid reactions, which varies from 5 to 15 per cent.29 When using equine tetanus antitoxin, the physician must inquire about sensitivity to horse serum and history of allergy and administer preliminary dermal and ophthalmic tests for sensitivity. A tourniquet and syringe with 1: 1000 epinephrine should be immediately available. The routine skin test dose is 0.1 ml. of a 1:100 saline dilution of the serum injected intracutaneously, but if a history of allergy is obtained, the dose must be reduced to 0.05 ml. of a 1: 1000 dilution of the serum. Fatal anaphylactic shock has occurred with a 1:10 dilution. 29 Bardenwerper's37 extensive review should convince every physician to maintain tetanus immunity actively in all patients. The indications for tetanus toxoid active immunization are· (1) routinely for all people at all ages; (2) to confer passive immunity against neonatal tetanus upon the infant through active immunization of the pregnant mother. Schofield et aP8 showed that three injections provided substantial protection against the risk of neonatal tetanus. Smallpox Inoculation with cowpox virus was the first successful immunization procedure and continues to be one of the most effective, in fact almost 100 per cent, yet protection of the population against this disease is far from complete. For example, a recent survey in Oklahoma City revealed that only 14 to 19 per cent of residents had been adequately immunized. 5 A similar level has been found in several other communities. 59 The control of smallpox has been so successful that physicians

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and patients have become complacent about maintenance of immunity, which must be assured by revaccination at appropriate intervals. Although Edward Jenner demonstrated the value of vaccination 165 years ago, routine vaccination is not practiced in England, and there is considerable controversy in that country at present as to the necessity of universal smallpox vaccination. 29 This is true in many other countries. The last reported case in the United States occurred in New York in 1949. Kempe 74 has recently evaluated the risk of smallpox vaccination in this country. He estimated the mortality rate to be between 1 and 1.5 per million primary or recall vaccinations and the over-all incidence of significant complications as in one in 4000. He recommended that current recommendations for routine vaccination be re-evaluated in view of the availability of the thiosemicarbazone agents and vaccinia hyperimmune globulin for prophylaxis after exposure to smallpox and the availability in the near future of less virulent vaccinia strains. The effectiveness of proper vaccination was shown during World War II by the occurrence of 105 cases of smallpox in the Armed Forces, most of which were in personnel in the Orient, where smallpox was prevalent. 42 The vaccination failures were due chiefly to faulty vaccination technique or intense sensitization reactions incorrectly interpreted as primary reactions. 43 Its protective efficacy was well demonstrated in 1960 with the swift control of a smallpox outbreak in Moscow when 9 million persons were immunized during one week, and previously in 1957 in an outbreak in New York City.40,41 The occurrence of outbreaks of smallpox in Great Britain and other countries points up the need for maintaining immunity against the disease. The importance of vaccination, proper interpretation and recording of the results of vaccination in this era of jet travel were emphasized when it was ascertained that a nine-year-old Pakistani girl who flew to England from Karachi two weeks before, and presumably transmitted the disease, had an apparent immediate reaction on revaccination. Having been vaccinated only once during infancy, her first booster (revaccination) had been given less than four weeks prior to her death. 29 The outbreak in Great Britain numbered 67 cases in a four-month period. . There is no universal agreement on the optimum age for primary smallpox vaccination, although it is generally agreed that the older the child the greater the risk of postvaccinal encephalitis. In Great Britain the risk from generalized vaccinia or encephalitis is higher in the first year of life than from one to four years of age. Although eczema vaccinatum, progressive vaccinia, and the like, are all more common under the age of one year, vaccinal encephalitis occurs more frequently after the age of two years in the United States. At present in this country, it is generally recommended that in the absence of contraindications, all children should have primary smallpox vaccination toward the end of the first year of life. Chick embryo vaccine, because it is at least theoretically less subject to bacterial and viral contamination, is perhaps

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preferable to calf lymph vaccine. Lyopholized vaccine is preferable to liquid vaccine, particularly in warm climates, because of its prolonged potency and simplicity of storage. The preferred site of vaccination is the skin near the insertion of the left deltoid muscle. Acetone or ether should be used for skin cleansing because alcohol inactivates the live virus and leads to failure of takes. A plastic, presterilized and disposable unit (Mono-Vacc, manufactured by Lincoln Laboratories, Inc.) has been useful in simplifying vaccination by the multiple pressure method. 26, 29 Although an attack of smallpox confers long-lasting protection, vaccination does so for a much shorter time. In order to maintain a high level of immunity among the general population and to avoid the discomfort of reactions that occur when the interval between vaccinations is long, revaccination should be repeated at least every five years. It is recommended before trav~l abroad and in the presence of an epidemic and required within three years before entry into the United States. In the United States Armed Forces the current practict. is to revaccinate at least every three years. In areas where the disease is epidemic, yearly vaccination is necessary. An important line of defense is to make certain that all hospital personnel are adequately protected. Methisazone (l-methylisalin ,8-thiosemicarbazone), an antiviral agent, is reported to be effective against smallpox in the incubation period and may protect close contacts of established cases when they are detected too late in the incubation period for vaccination to be of value. The agent, however, has significant side effects, and its role in the control of smallpox must await further evaluation. 62 , 63 The use of the fluorescent antibody technique for the rapid diagnosis of smallpox appears promising as a valuable surveillance aid. Interpretation of Response. Although smallpox vaccination is one of the commonest medical procedures performed, there is still widespreag confusion regarding the interpretation of response to vaccination.44, 29 The proper time to read the vaccination is between the seventh and ninth days, since differentiation of the three types of reaction is based on the time at which the areola reaches the maximum redness, and not upon the presence of a scab. Primary Reaction. A large area (lO to 12 cm.) of redness is expected between the eighth and twelfth days. A vesicle always occurs, followed by pustulation, crusting and scar formation. This reaction indicates complete absence of previous immunity. Fever, malaise and regional lymphadenopathy are expected at the height of the reaction, and occasionally erythema multiforme is observed. Vaccinoid (Accelerated) Reaction. This reaction occurs in those who are partially immune. Maximal erythema (4 to 6 cm.) is usually attained in four to seven days. A papule followed by a vesicle usually occurs within 24 to 48 hours. Scar formation is produced, but may be difficult to find later. Systemic manifestations are minimal. Early (Allergic) Reactions. This is seen in the immune person, or

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it may indicate nothing more than sensitization to viral protein from primary immunization or disease. This reaction may occur when deteriorated vaccine or poor technique is used. Therefore revaccination should be carried out and re-examined four to seven days later. The maximal area of erythema develops between eight and 72 hours and is only 1 to 2 cm. in diameter. A vesicle may appear with ultimate scabbing, but no scar formation. No Reaction. No reaction indicates an unsuccessful vaccination due to defects in technique or faulty vaccine, and repeat vaccination must be done. Repeated failures should direct one to vaccinate on the other arm or the Hexor surface of the forearm. Failure in very young infants may be due to interferences by parentally transmitted maternal antibodies. With the tremendous increase in international travel, every physician who has responsibility for international vaccination certificates is obligated before signing such a certificate to have actually seen the response eight to 10 days after primary vaccination or four to seven days after a revaccination, and to record this information on the certificate. Contraindications to Vaccination. Children or adults with eczema, impetigo or other forms of dermatitis (not diaper rash) should not be vaccinated because of the danger of eczema vaccinatum. Siblings of children with extensive dermatitis or eczema should not be vaccinated for the same reason unless the sibling to be vaccinated can reside in a separate building (and not just in a separate home in the same building) until the scab falls off. If a person with these conditions is accidentally exposed to vaccinia virus, then vaccinic immune gamma globulin'" should be administered intramuscularly in a dosage of 0.3 ml. per kilogram of body weight. Similar measures for passive protection of an eczematous person who must go to an area where smallpox is endemic can be used. The person can be vaccinated and 12 to 24 hours later hyperimmune gamma globulin given to abort the expected eczema vaccinatum.26. 29 Patients receiving therapy with adrenal steroids or immune-suppressing agents such as irradiation of antimetabolites and those with serious blood diseases such as leukemia should not be vaccinated under routine circumstances. During the first six months of pregnancy (unless an epidemic situation develops) vaccination should not be performed because of the danger of generalized vaccinia in the fetus followed by abortion. Vaccination should be delayed temporarily in other special situations. Patients with recent exposure to a contagious disease, conjunctival lesions or inHammation or an acute febrile illness, and those with agammaglobulinemia and related disorders should not be vaccinated. The physician should be aware of the availability and proper use of vaccinia immune globulin. 44 ... Available from regional blood centers of the American Red Cross. See reference 23 for addresses.

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These contraindications apply to the usual circumstances and, of course, are not absolute in the face of an epidemic. Complications. The incidence of adverse reactions is low in this country as compared to those in Great Britain, and there appears to be variation from country to country, depending upon the age at which primary vaccination is performed. In the United States the incidence of serious reactions to vaccination, based on the New York City experience of 1957, is less than 0.9 in 100,000. In association with the 1962 outbreak of smallpox in Great Britain approximately 5,500,000 doses of smallpox vaccine were administered. This experience provides further data on the risks and complications associated with this type of immunization. There were 125 cases of generalized vaccinia with one death, 72 cases of eczema vaccinatum with 10 deaths, and 54 cases of postvaccinal encephalomyelitis with four deaths-an over-all risk of complications of one per 22,000. 53 The two most serious complications of smallpox vaccination are postvaccinal encephalitis, which is rarely seen in the United States, and eczema vaccinatum. Eight cases of encephalitis were reported in troops during World War II, only four of which were proved subsequently to be vaccine-related. Encephalitis is much less frequent after revaccination unless more than 10 years have elapsed. Generalized vaccinia, a very serious complication, can be avoided if persons with skin disorders such as eczema are not vaccinated. Progressive vaccinia is rare and occurs chiefly in children with defects in gamma globulin synthesis. Acute renal failure, jnfectious polyneuritis, and myocarditis have been reported following vaccination. Secondary bacterial infection of the vaccination site can be reduced if dressings or tight clothing over the site is avoided. Occlusive shields or dressings should be avoided, but in the pustular stage a loosely attached dressing may be used. Poliomyelitis The safety and efficacy of both the killed, formalin-inactivated (IPV) (Salk) and the live attenuated oral (OPV) (Sabin) poliovirus vaccines have now been established. Statewide programs to immunize large segments of the population against poliomyelitis with OPV are important in establishing herd immunity. This does not provide continuing coverage for the new group of infants and children who are continuously entering the susceptible phase. Individual immunizations will be required for protection of such subjects. Each year over 4 million children are born, and if an adequate level of immunity is not maintained in this group so vulnerable to the disease, we will have in another five years some 10 million children who are not protected against poliomyelitis, creating another threat for epidemics of this disease. Inactivated poliovaccine has been effective in reducing the incidence of paralytic poliomyelitis by approximately 90 per cent. A progressive decrease from an average rate of 30 (1949-1954) to about 1.5 cases per 100,000 for 1960 in the United States, and from 27 to about 9.15 cases

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per 100,000 in Australia, Denmark and Sweden, attests to its effectiveness. 45 . 46 Since 1961 the incidence in the United States has further declined; the paralytic case rate for 1963 was 0.2. A further decrease in cases was observed in the first half of 1964.70 Yet paralytic disease has continued to occur in both immunized and unimmunized persons. Antibody levels fall rapidly in young infants and children; experience indicates that about 20 per cent of paralytic cases in the past few years occurred in patients who have had four or more injections of IPV, a few epidemic outbreaks have been observed in well inoculated populations, and antibody conversion of nonvaccinated children continues at a high rate in areas where IPV has been extensively used.23 In a type III epidemic in Massachusetts in 1959, 46 per cent of the patients with paralytic disease had had three or four injections of IPV. Furthermore, it has been shown that approximately 5 per cent of the population demonstrates no antibody rise to any of the three types of poliovirus after four injections of IPV.26 The results with IPV have been extensively reviewed. 46. 47. 48 Live oral poliovirus vaccine has been extensively tested and used. Approximately 100 million doses of each of the three types of OPV, as well as several million doses of the trivalent vaccine, had been distributed as of May, 1964.70 It appears that the inactivated vaccine will be superseded by the more easily acceptable attenuated live oral vaccine for the following reasons, as detailed by Margileth et al,29 and Taub and Haggerty.26 Antibody Response. Batson et al.17 have shown that 80 per cent serologic response occurred in six- to 18-week old infants fed OPV in the monovalent form at six-week intervals. High levels of passive antibody of maternal origin did not interfere with production of active antibody. Pagano et al. 26 noted that maternal antibodies in premature infants did not interfere with infection by CHAT type 1 live poliovirus vaccine, nor was there obvious inhibition of active immunologic response. Although the newborn infant is capable of responding satisfactorily to oral vaccine, the incidence of successful immunizations, based on antibody rises, is considerably less than at the age of two or three months, when full immunologic responsiveness occurs. In addition, the percentage of successful immunizations in newborn breast-fed infants is decreased, presumably owing to antibodies in the milk. These two factors suggest that it is not practical to undertake a widespread program of oral immunization in nurseries for newborn infants. It is generally recommended that immunization begin between six weeks and three months of age. One hundred per cent serologic response is possible if the vaccinees are over six months of age and are free from concurrent infections with other enteroviruses and the proper dose of vaccine and intervals are utilized. Rapidity of Immunity. After a single dose of any of the three

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types of OPV, immunity can be produced in about one week. This is most important in the young infant who may not respond to the killed vaccine. Ease of Administration. People do not accept injections readily, but will accept oral inoculations as evidenced by recent mass SOS (Sabin on Sunday) campaigns which resulted in the vaccination of 90 per cent of the populace of several cities. Oral administration has eliminated the need for syringes, needles and sterilization equipment, and has resulted in extensive coverage of all age groups, owing to the simplicity of inoculation. The basic principles of the methods successfully used are outlined by Sabin. Since there are variations in dosage, storage requirements, and length of stability after thawing or reconstitution, depending upon the manufacturer, it is important to follow the manufacturer's recommendations concerning administration. The complete oral immunization program should be carried out, regardless of how many injections of IPV previously have been given. It is known that immunity from injections of inactivated vaccine is not permanent, and furthermore, the intestinal multiplication of the virus will occur despite "serologic immunity." With "intestinal immunity" that develops in the orally immunized person, there will be a break in the cycle of fecaloral transmission of poliomyelitis. This last consideration is of great importance from a public health standpoint if the virus is eventually to be eliminated from the population. 26 Vaccine Effectiveness. The protection resulting from active immunity produced by the live vaccines has been well demonstrated in extensive field trials in Russia, Germany, Yugoslavia, South America, South Africa and in this country. In addition, these trials have shown how rapidly poliomyelitis can be eliminated from large populations. The immunity produced appears to be as good as after natural infections. The live vaccines probably induce cellular alterations in the intestinal mucosa similar to those of the natural disease, as predicted by Raffel. Resistance to Reinfection. The killed vaccine does not prevent enteric invasions by "wild" virus, whereas extensive multiplication of the live strains in the intestinal tract produces a local resistance to reinfection that is independent of the serum antibody. Thus "wild" virus dissemination in the community is prevented. It is estimated that if 70 to 80 per cent of the community is immunized, the "wild" strains would be unable to maintain themselves and, therefore, would be eradicated from the community. Immunization of the Unvaccinated (Herd Immunity). As a result of spread of the virus from vaccinated persons to nonimmune contacts, another means is provided for the indirect protection of those who are not themselves vaccinated. Thus many adults, particularly parents, become immune by contact with· vaccinated children.

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Safety. See also Addendum (p. 99). The occurrence of paralytic illness in temporal association with vaccine administration has been extensively reviewed53 • 64-68 and will not be repeated here. It should be noted that the task of the Special Advisory Committee on Oral Poliomyelitis Vaccine to the Surgeon General to determine whether each suspect case of illness similar to poliomyelitis was associated with oral vaccine ingestion or exposure has been a difficult one. A definitive answer was rarely possible even in the few cases in which complete clinical and laboratory data were available. Techniques to differentiate "wild" poliovirus from vaccine strains by the use of genetic markers in the laboratory proved of little assistance because passage through the human intestine rendered these markers unstable. 53 Critical analysis did not prove that any of the observed illnesses in 1962 could be attributed to the vaccine virus, and their true significance is still under study.23 Since approximately 15,000,000 doses of this vaccine had been administered in the time during which the cases occurred, epidemiologists interpreted the maximum potential risk as one case per 1,400,000 vaccinees; the age-adjusted risk for those 30 years of age or older was reported as one per 500,000. 67 There was no indication for risk of type II vaccine. The hazard of diagnosing poliomyelitis on clinical evidence alone is to be emphasized, since it has now been clearly shown that a number of enteroviruses other than poliovirus can produce paralytic diseases. 69 In comparison to smallpox vaccine, the risk for poliomyelitis vaccine seems highly acceptable. Nevertheless the considerably higher attack and mortality rates must be taken into consideration. 53 Katz 53 has reviewed the problems relating to Simian virus 40 (SV40) and poliomyelitis vaccines. To date there are no reports of any deleterious effects upon the mother or fetus. There is some evidence, however minimal, of genetic instability of the vaccine in that an increase in neurovirulence has occurred in monkeys after inoculation of isolates of the attenuated virus from human feces. Yet careful observation of contacts has not revealed any untoward reactions. Prevention of Epidemics. Because of an early onset of immunity, the ability to interfere with naturally occurring poliovirus infections, and the ease with which mass immunization can be carried out in a very short time, the OPV has proved most successful in aborting several large outbreaks, in Europe, Israel and several other countries. One of the most dramatic results occurred in New York state in 1961. An epidemic was aborted in two weeks' time after a massive three-day campaign with oral vaccine. In the face of an epidemic (defined as the occurrence of at least three cases of poliomyelitis within one month, two caused by the same virus type) Sabin advises (1) start early; do not wait until the epidemic is full blown; (2) give vaccine quickly within a few days, especially to children and their parents.

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Durable Immunity. Biennial doses of the killed vaccine are recommended, and some advise annual boosters, depending on the commercial vaccine used, whereas antibody levels are known to persist for at least eight years after basic OPV immunization. It is not unreasonable to believe that such immunity will persist for life. A disadvantage of OPV results from the intederence phenomenon. Certain enteric viruses, if actively multiplying in the intestinal tract at the same time that OPV is given, will intedere with the production of antibodies. If a mixture of all three types of poliovirus is given to nonimmune persons, infection with type I is readily suppressed by infection with the other types, and type II tend to proliferate in the presence of the other two. Thus each type should be administered separately at six- to eight-week intervals, with type II given last. (See Addendum.) Because of intederence phenomenon due to other enteric viruses it has been recognized that even during the off-season for these viruses, one or possibly more of the monovalent vaccine drinks may not lead to an immunologic response. For this reason it is currently recommended that a trivalent "booster drink" be given six months or more after the initial series.26 The vaccine is best given during the late fall, winter and spring months to avoid intederence by enteroviruses. Another disadvantage is that the vaccine must be stored in the frozen state, and the present shelf life after thawing is only one week. Reactions have not been reported, and there are no known contraindications to the attenuated vaccine, including specifically pregnancy, tonsillectomy, steroid therapy and penicillin sensitivity (see p. 99). The viruses of vaccinia, measles and poliomyelitis are all potentially neurotropic, and until data on combined use of live vaccines become available, it is recommended that live OPV should not be given within one month of other live vaccines, such as measles and smallpox vaccines. In order to avoid chance erroneous implication of the oral poliovaccine virus and to avoid intederence by enteroviruses, community programs with OPV should not be held in the natural poliomyelitis season. An exception to this general rule obtains when epidemic poliomyelitis appears in a community. This constitutes an indication for an emergency communitywide immunization program with OPV using the virus type demonstrated to be causing the epidemic. 23 The amounts of antibiotics in a dose of oral vaccine are so small that hypersensitivity is not a contraindication. The vaccines are propagated in monkey kidney tissue. Suggested Dosage.23 See also Addenum (p. 99). Mass Campaigns. OPV is given in three oral doses one to two months apart in the nonpolio season, type I, type III and type II in order, using the dose recommended on the package circular. The order of types III and I may be reversed for convenience. Emphasis should be placed on reaching the preschool age group. Other dosage schedules are under investigation in an attempt to reduce the number of feedings and thereby

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to achieve greater community participation. Equivalent antibody response and persistence of intestinal immunity for two years have been observed after a two-dose schedule to preschool children, in which type I virus was given initially followed by a single dose of types II and III combined. A trivalent vaccine containing virus types I, II and III combined in a carefully adjusted dosage has been licensed and is administered orally in two doses eight weeks apart. Data are not available to evaluate the need or frequency of booster doses for this vaccine. Seroconversion in the immediate postvaccination period for all three virus types has been demonstrated in 90 per cent of older children who received two doses of this preparation. Two doses of trivalent vaccine are satisfactory for community-wide prophylactic use, and one feeding of trivalent vaccine is recommended for booster doses when indicated. Thawed vaccine may be kept for one week at 4°C. In Infancy. See Table 12 for two alternate schedules based on the use of OPV and IPV in combination with routine inoculation schedules. DPV. Three oral doses of types I, III and II virus vaccine are given in order, spaced one month or more apart, at the time of DPT in young infants and followed approximately one year later by a single booster dose of a polyvalent preparation containing all three viruses. Trivalent poliovaccines are not advised for primary inoculation of infants. DPT-Poliomyelitis Combinations. Recent reports attest to the effectiveness of these preparations, provided the proper shelf life and other recommendations are observed. With the advent and success of oral poliovirus vaccine there does not appear to be any present need for the quadruple vaccines containing diphtheria and tetanus toxoids, pertussis and killed poliovirus vaccines. 26 Measles The importance of measles as a major problem in child health cannot be overemphasized. 51 There can be no question that safe and effective vaccines against measles are now available. At the time of writing, several schedules of administration and different types of vaccines are under investigation, and final recommendations must await further information from these studies. At present there are three logical methods of immunization against measles. Killed inactivated vaccines produce an antibody rise accompanied by a low incidence of untoward reactions, but require two or three injections at monthly intervals, as well as periodic recall injections to maintain immunity. Live attenuated virus vaccine, when given alone, produces an excellent antibody response and protective effect, both of which appear to be as durable as that occurring after natural infections. But administration is accompanied by a significant incidence (20 to 70 per cent of vaccinees) of febrile reac-

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tions (average 102°F.), and a measles-like rash. Both reactions may be reduced by the concurrent administration of gamma globulin, 0.01 ml. per pound of body weight, administered simultaneously with a separate syringe at a second site. There are many obvious disadvantages to this method. Studies with a highly attenuated live virus vaccine49 indicate that it is antigenic, results in a high degree of long-term protection and produces a much lower rate of fever and rash than the currently available live attenuated-virus vaccines. It does not require the concurrent administration of gamma globulin. Recent studies indicate that a satisfactory method of immunization against measles is to administer initially killed inactivated-virus measles vaccine and, after an appropriate interval, one injection of live attenuated-virus vaccine without the simultaneous administration of gamma globulin. This regimen has all the advantages of live attenuated-virus vaccine, without the high incidence of associated untoward reactions. 50 The reader is referred to recent publications for details concerning the present status of measles vaccine. 23 • 51. 52 Other Kinds of Immunizations Immunization against influenza and tuberculosis is not considered routine, mandatory immunization and is given only under certain circumstances or to certain selected groups. For details of immunizing procedures which are mandatory under certain circumstances, those which are advisable in certain areas or occupational groups and those which are of passive value or are under study, the reader is referred to comprehensive standard references on these subjects. 23 • 29 For travelers abroad, the United States Public Health Service has a useful guide to the immunizations desirable and recommended in different countries. 44

ADDENDUM

The Special Advisory Committee on Oral Poliomyelitis Vaccine to the Surgeon General of the United States Public Health Service met on July 17 and 18, 1964, and issued its report on September 23, 1964. 70 The total number of reports received by the Public Health Service through June, 1964, is 123. This number includes those cases reviewed by the Committee in 1962. Of this total, 36 cases occurred in epidemic areas where mass immunization programs were undertaken as emergency control measures. The Committee reviewed in detail 87 cases reported from nonepidemic areas since oral vaccine became available. Fifty-seven cases were adjudged to be clinically indistinguishable from paralytic poliomyelitis and considered "compatible." All had significant residual paralysis, the onsets occurred between four and 30 days after

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feeding, and laboratory data were not inconsistent with respect to multiplication of the vaccine fed. Twenty-one were excluded after careful consideration, and the data were insufficient in nine upon which to make a judgment. Of the 57 cases considered "compatible," 15 followed type I vaccine, two followed type II, 36 followed type III, and four followed trivalent vaccine administration. (By using the point binominal it is possible, according to Henderson et al.,71 to make an approximate test of statistical significance of these findings. Assuming independence of risk and recognizing that essentially equal amounts of oral vaccine of each type were distributed, the probability that 2 type II cases and 15 type I cases could have occurred by chance alone is 2.4 in a thousand [P=0.0024]; the probability of 2 type II cases and 36 type III cases is one in 185 million [P=0.000000005].) These "compatible" cases occurred chiefly among adults, 44 being 15 years of age or older and eight over 50 years of age. They included 46 males and 11 females. Fourteen of the group had received three or more doses of inactivated poliovaccine. There was no apparent association of cases with specific lots of vaccine or vaccines produced by a particular manufacturer. The report states: "The Committee recognizes that it is not possible to prove that any individual case was caused by the vaccines and that no laboratory tests available can provide a definitive answer. Nevertheless, considering the epidemiological evidence developed with respect to the total group of compatible cases, the Committee believes that at least some of these cases were caused by the vaccine." The 1962 report of the Committee recommended "that community plans for immunization be encouraged," but "because the need for immunization diminishes with advancing age and because potential risks of vaccine are believed by some to exist in adults, especially by the age of 30, vaccination should be used for adults only with the full recognition of the very small risk." According to the Committee, the extent of the risk can now be estimated more accurately from the incidence rates per million doses of the vaccine which have been distributed for use. It was small and differed by type of vaccine and age. For type III vaccine the over-all rate is 0.40 per million doses; for type I, 0.16; and for type II, 0.02. For trivalent vaccine the data available regarding amounts of vaccine distributed are limited and the rate cannot be estimated. In the age group under five, six cases followed type III vaccine administration, giving an estimated rate of 0.53 per million doses; two cases followed type I vaccine for a rate of 0.17. In the five- to 14-year age group the rates for both vaccines fell below 0.10. In older age groups the rates were higher, particularly for type III vaccine. In the age group from 20 to 39 it exceeded 0.50, or one case per 2,000,000 doses distributed. From this evidence it was inferred that the risk was highest for type III; the evidence of risk was less definite for type I vaccine. For type II vaccine the rate was so low as to suggest absence of risk.

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The Committee recognized that many additional factors enter into the appraisal of the extent of the risk in various population groups. For example, the risk following type III vaccine in adults was reported to be higher in males than in females. Furthermore, unimmunized adults who have lived in rural areas and those from upper socio-economic groups would appear to be at greater risk than those who have had more opportunity for prior exposure to naturally spreading polioviruses. The Committee's report stated that the age group to be immunized and the vaccine chosen for use should be determined locally. It further stated, however, that in its view the oral vaccination of persons over 18 should "generally be recommended only in those situations in which unusual exposure to poliomyelitis might be anticipated, such as epidemics, entry into military service, and travel to other countries." It recommended strongly immunization of infants during the first year of life, the routine immunization of all children on entering school and renewed effort to vaccinate those still susceptible, particularly poorly immunized children in economically depressed population groups. The extent of the assessed risk was considered to be sufficiently low relative to the risk of naturally occurring illness in children to warrant continuation and intensification of the poliomyelitis immunization program throughout the nation, although with some change in emphasis. It was recommended that communities which are not yet embarked upon mass immunization programs be encouraged to do so during the fall and winter of 1964-65. It recommended that the order of administration of the monovalent vaccines, previously given in the order of types I, III and II now be altered so that type II would be administered first. From serologic studies and epidemiologic evidence, the Committee reported that type II infection confers some heterologous immunity against types I and III infection and giving type II vaccine first should theoretically further diminish the slight risks associated with the other vaccine types. Furthermore, at present with poliomyelitis incidence rates at an all-time low and with epidemics rare, the Committee stated there is no longer an overriding need to give type I vaccine first as was believed to be important in the past. It also recommended that either monovalent or trivalent vaccines may be used for primary immunization of infants. If trivalent vaccine is used, it should be given at the time of the first and third DPT immunizations. In both instances a dose of trivalent vaccine at the end of the first year of life is recommended to complete the primary immunization series. The final dose in breast-fed infants should be delayed until cessation of breast feeding. It stated that monovalent vaccines are preferred for community immunization programs. When trivalent vaccine is used, it is recommended that at least eight weeks elapse between the first and second feedings. Doctor Albert B. Sabin, a member of the Special Advisory Com-

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mittee, disagreed with many of the conclusions of the Committee and filed a minority report. 72

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