Current and Future Vaccines for the Prevention of Bacterial Diseases

Symposium on Recent Clinical Advances

Current and Future Vaccines for the Prevention of Bacterial Diseases David H. Smith, MD.,* and Georges Peter, M.D.**

The ultimate goal in the control of infectious diseases is their prevention by methods that can be effectively and widely distributed, that are economically feasible, and that are not deleterious to the host. Active immunization with effective, non-toxic vaccines is one of the primary means by which that goal can be attained. Antibacterial drugs have been a significant advance in the therapy of infectious diseases but, with rare exceptions, they cannot be used successfully to prevent bacterial diseases. Furthermore, 30 years of experience have revealed that therapy with antibacterial drugs is costly, may have significant hazards, may retard or limit the development of infection-induced immunity, and may be unsuccessful. Indeed, the mortality and morbidity of certain serious bacterial diseases of children, such as meningitis, have remained unchanged for the past 15 to 20 years despite the availability of antibiotics to which the causative bacteria are susceptible. These considerations and recent advances in laboratory technology and understanding of host immunity have renewed interest in the development of new bacterial vaccines. Currently, new vaccines against pneumococci, meningococci, Hemophilus influenzae b, group A streptococci, shigella, and pseudomonas are being developed and tested. These recent advances have also prompted review of current bacterial vaccines with respect to the relative importance of toxicity and protective benefit, basis of efficacy and adverse reactions, and optimal timing and number of booster injections. In this review we have summarized the current status of most of the available and potential vaccines for the prevention of bacterial diseases.

IMMUNOLOGIC CONSIDERATIONS The timing of active immunization with a given vaccine is determined by the frequency of contacts between the child and the health care ·"Associate Professor of Pediatrics, Harvard Medical School; Chief, Division of Infectious Diseases, Children's Hospital Medical Center, Boston, Massachusetts ':":'Instructor, Department of Pediatrics, Harvard Medical School; Fellow, Division of Infectious Diseases, Children's Hospital Medical Center, Boston, Massachusetts Supported in part by training grant TOI-AI-00350 from the National Institute of Allergy and Infectious Diseases.

Pediatric Clinics of North America- Vol. 19, No.

~,

May 1972

387

388

DAVID

H.

SMITH AND GEORGES PETER

delivery system, the age-related susceptibility to the disease, and certain immunologic considerations. The factors that primarily influence the immune response of children to bacterial vaccines include the age of the individual, his previous experience with the immunogen, the dose and chemical nature of the immunogen, and the composition of the vaccine in which the immunogen is administered. That age influences the primary antibody response to certain immunogens was appreciated before the basis for the synthesis and regulation of immunoglobulins was defined. Figures 1 and 2 depict the results of a typical early study that sought to answer the question whether newborn infants could produce antibody. Approximately 100 units (which is about 14 times greater than the dose in a single DPT injection) of diphtheria and tetanus toxoids were administered as individual vaccines to infants who had no passively acquired antitoxins. Infants as young as 7 days produced antitoxin, but peak titers and the lag between immunization and detection of circulating antitoxin differed significantly between younger and older infants. It was also evident that the responses to tetanus and diphtheria toxoids differed with age. 40 Results of studies on the ability of pertussis vaccine to protect young infants are contradictory, but considerable evidence indicates that the initiation of a primary series of DPT injections in 7 day old infants having no passively acquired antibody produces no, or low, levels of antibody and also deleteriously affects the response to a booster dose given at 10 to 14 months. 42 • 47 Certain antibacterial and antitoxin antibodies cross the placenta and could potentially affect the antibody response of infants immunized subsequently. However, most bacterial vaccines contain relatively high concentrations of antigen, and available evidence indicates that imI.

2-6 month old infants

.5

\ mon\-" o\d infants ndnts under 2 weeks

.Olt Immunized

J~ Months after immunization

2

6

Figure 1. Age-related response of infants to tetanus toxoid. (From Osborn, J. J., Dancis, J., and Julia, J. F.: Pediatrics, 9:736,1952, reproduced with permission.)

389

VACCINES FOR BACTERIAL DISEASES

I.

.~

2

6

Months after immunization Figure 2. Age·related response of infants to diphtheria toxoid. (From Osborn, J. J., Dancis, J., and Julia, J. F.: Pediatrics, 9:736,1952, reproduced with permission.)

munization of infants with passively acquired antibody produces "protective" levels of antibody, although peak titers may not be so high as in infants without maternal antibody. Thus, the age of the child and the "potency" of the individual bacterial vaccine play major roles in the antibody response of young infants to the tested bacterial vaccines, while passively acquired antibody appears to be less important. The effects of these factors on responses to diphtheria and tetanus toxoids have subsequently been found to be insufficient to negate the initiation of successful immunization to diphtheria and tetanus in the newborn nursery. However, the lack of urgency in starting immunization against diphtheria and tetanus in very young infants, the desire to combine diphtheria and tetanus toxoids and pertussis vaccine, and the noted effects of the latter vaccine when administered to newborn infants have led to the current recommendations that DPT injections should be started at 2 months of age. Early studies in animals and man suggested that the host can respond only to a certain finite (yet undefined) antigen load and that vaccines containing multiple antigens may be associated with a "crowding-out" phenomenon. More recent experiences indicate, however, that the immune system can respond simultaneously to several antigens and that the response to all components of a multi-valent vaccine can be satisfactory. Unfortunately, the composition and concentration of antigens that produce a satisfactory combined vaccine cannot be predicted; rather, they must be determined by appropriate clinical studies. DPT is the combined vaccine best known in the United States, but combined DPT-killed polio vaccine is used widely in Canada and Western Europe, and a com-

390

DAVID

H.

SMITH AND GEORGES PETER

bined DPT-typhoid vaccine is recommended by the World Health Organization in developing countries. 22 Substances that are relatively insoluble in vivo and to which antigens "adsorb" reversibly are often used in vaccines to slow the uptake of the injected immunogen. Aluminum compounds, such as the hydroxide or the phosphate, are commonly used for this purpose. "Adsorbed" vaccines generally produce higher and more prolonged antibody titers than "fluid" vaccines containing comparable doses of antigen. Although reported experiences are conflicting, most indicate that "adsorbed" vaccines are also less toxic than their fluid counterparts, presumably because of slower rate of immunogen uptake. The most recent comparison of fluid and adsorbed tetanus toxoid was conducted among an immunologically virgin population of adult females in New Guinea. 2o ,33 Mean peak titers following 2 doses, containing 10 units of absorbed toxoid, produced antitoxin titers that were 3 times greater than those obtained after 3 doses of fluid toxoid containing 15 units of vaccine; mean titers approximately 1 year after immunization were 5 times greater in those who received adsorbed vaccine. Booster responses were consistently higher if adsorbed toxoid was used as the primary vaccine, regardless of the vaccine used as booster. Furthermore, the booster effect of adsorbed toxoid was 1.7 times that of plain toxoid. The length of time between doses of immunogen markedly affects antibody response and must be empirically evaluated. During early studies with diphtheria and tetanus toxoids, peak titers and the duration of detectable antitoxins following second injections were found to be greater when the first and second doses were given to infants at 6 month rather than 1 or 2 month intervals.lO Wilkins et al. 58 recently demonstrated that 2 doses of DPT given at intervals of 60 or more days produces peak pertussis agglutinin titers that are comparable to those obtained following 3 monthly doses. However, the levels of antibody produced in infants by a single dose of DPT are generally inadequate to produce immunity to pertussis. Since there is marked age-related susceptibility to pertussis (see Pertussis Vaccine) it would be unwise to leave young infants susceptible to pertussis in order to produce better antibody levels in older infants. Thus, a primary series of 3 DPT injections, given at monthly or bimonthly intervals, is still recommended. There is no need, however, to reinitiate a primary series if the child has missed a single injection. Many of the potential bacterial vaccines now under development are purified polysaccharides, and experiences with the pneumococcal, meningococcal and H. influenzae b vaccines so far indicate that the kinetics of antibody response to polysaccharides differ from those observed with protein immunogens. Protein vaccines generally produce relatively short-lived, rapidly recallable, and boostable antibody responses. On the other hand, antibody is generally not detected for 1 to 2 weeks after immunization of immune adults with polysaccharides. Available data do not support the suggestion that these dissimilarities result from differences in sensitivity of the antibody assays for protein and polysaccharide vaccines. Secondly, the antibody activity produced by polysaccharide vaccines remains relatively constant for prolonged periods: the activity of antipneumococcal antibody produced in adult man following a single 50

VACCINES FOR BACTERIAL DISEASES

391

microgram dose of polysaccharide declined only slightly over 8 yearsP Finally, polysaccharide vaccines generally do not enhance antibody titers above certain apparently age-determined levels. The basis for this phenomenon has not been defined, but it has been suggested that polysaccharides, while capable of stimulating antibody production, are less potent than proteins in stimulating the replication of cells involved in the immune response. The effect of mixing polysaccharide vaccines with adjuvants, or of linking them to protein immunogens, has not yet been evaluated. The question of the responsiveness of young infants to polysaccharide vaccines is not yet resolved, but it is being studied with great care because of the potential state of immunologic tolerance that might be produced. This phenomenon was first observed in mice given doses of pneumococcal polysaccharide that were several times larger than an immunizing dose; they failed to form antibodies and were susceptible to subsequent experimental challenge with the respective pneumococcus. Recent studies have indicated that this phenomenon is associated with no antibody synthesis and that it is antigen specific and more readily established in young than in old animals. However, the establishment of tolerance requires large doses of antigen and it is not uniquely associated with polysaccharide antigens: proteins, polypeptides, and haptens can also produce tolerance. Furthermore, with the possible exception of the results reported with pertussis immunization of 7 day old infants, no evidence that tolerance can be produced in humans has emerged from the years of study and practice of immunization. It seems reasonable to predict, therefore, that properly selected doses of polysaccharide vaccines will not produce immunologic nonresponsiveness. The resistance to certain bacterial diseases (e.g., pertussis and typhoid fever) is not correlated with measured antibody activities. Such findings suggest either that other factors playa role in immunity to these diseases or that the "wrong" antibodies are being assayed. The possibility of stimulating secretory antibody or cellular immunity or both by bacterial vaccines, other than BCG, has not been studied; but the role of these parameters of the immune system in host resistance to bacterial diseases should be examined.

AVAILABLE BACTERIAL VACCINES Tetanus Immunization against tetanus is a universal requirement regardless of age because the disease is produced by a potent toxin and thus by the time symptoms are appreciated, antibiotics cannot alter the course of the disease; no natural immunity to tetanus toxin exists; Clostridium tetani is ubiquitous; and the case fatality rate in the United States remains at about 65 per cent.30 Tetanus toxoid is prepared by treatment of purified toxin with formaldehyde by methods that alter its virulence but not its immunogenicity. Antibodies produced by the toxoid neutralize circulating toxin but have no antibacterial effect. The efficacy of tetanus toxoid is

392

DAVID

H.

SMITH AND GEORGES PETER

truly remarkable: only 8 cases of tetanus occurred during World War II among United States military personnel with histOries of complete immunizations, an incidence of less than 0.5 per 100,000."2 The attack rate among allegedly immunized children under 10 years of age in the United States"O is no more than 3.8 per 100,000,000. This record surpasses that of all other immunizing agents, and is all the more impressive since the natural reservoirs of Clostridium tetani are soil and natural wastes, and since tetanus toxoid cannot reduce the potential for infection. Tetanus toxoid rarely causes toxic reactions among infants and young children, but reactions among adults are being appreciated with increasing frequency. Urticaria may occur, although sore and swollen injection sites, fever, and malaise, which have a delayed onset and may last one to several days, are more common. These reactions have generally been observed in individuals with high levels of circulating antitoxin,50 and the delayed local reactions may be an Arthus phenomenon involving antigen-antibody interaction. However, they may also be mediated by cellular factors, in which case the observed antitoxin titers reflect only one aspect of the individual's sensitization. These observations and the demonstrated potency of booster injections of tetanus toxoid in recalling antitoxin-a single booster injection given to individuals who received primary immunization as long as 21 years previously may raise nondetectable titers of antitoxin to more than 1000 times the protective level-have prompted recent study of the need for and timing of booster injections. By analyzing the sera of 143 normal children who received a primary series of DPT injections, Peebles et al. found that 3 doses produce 16 times, and 4 doses, 150 times, the protective level of tetanus antitoxin. When the observed antitoxin levels were analyzed in relation to post injection intervals, protective levels of antitoxin were found to be present for more than 12 years following the last of 4 or more doses.41 These authors concluded that a primary series of DPT injections need be routinely boosted only on admission to school, and at 10 year intervals thereafter. The Committee on Infectious Diseases of the American Academy.of Pediatrics has recently (October 17, 1971) recommended this policy (see Table 1). Table 1. Recommended Schedule for Routine DTP Immunization. Committee of Infectious Diseases, American Academy of Pediatrics, October 17, 1971 2 mo. 4 mo. 6 mo. PI. yr. 4-6 yr. 14-16 yr.

DTP'" DTP DTP DTP DTP Td"'*

"Diphtheria and tetanus toxoids combined with pertussis vaccine. "·Combined tetanus and diphtheria toxoids (adult type)

393

VACCINES FOR BACTERIAL DISEASES

Table 2.

Guide to Tetanus Prophylaxis in Wound Management

HISTORY OF TETANUS IMMUNIZATION

CLEAN, MINOR WOUNDS

(Doses)

Tetanus Toxoid

Uncertain 0-1

Yes Yes Yes Not

2

3 or more

TIG* No No No No

ALL OTHER WOUNDS

Tetanus Toxoid Yes Yes Yes No!

TIG" Yes Yes No''':' No

':'Tetanus immune globulin. ''':'Unless wound is more than 24 hours old. tUnless more than 10 years since last dose. ~ Unless more than 5 years since last dose.

Table 2 is the latest United States Public Health "conservative guide to active and passive tetanus immunization" at the time of wound management, which is based on "a reliable knowledge of the patient's immunization history. "57 A booster dose should be given if there is an uncertain history or an incomplete series of tetanus immunizations. However, such data has prompted a change in the recommendations for individuals with adequate primary immunization. "In wound management, it is unnecessary to use booster injections more than every 5 years. "57 Tetanus toxoid containing diphtheria toxoid (Td), at a concentration 15 to 20 per cent of that in DPT, is considered the agent of choice for booster immunizations in older children and adults. Hyperimmune globulin is also recommended in unimmunized individuals with extensive wounds. Human tetanus immune globulin (TIG) is preferable to animal antitoxin for passive immunization and should be used at a dosage of 5 units per kg. of body weight, up to 250 units for wounds of average severity and up to 500 units for more severe wounds. If human TIG is not available, equine antitoxin is given in a dose of 3000 to 10,000 units, but only after screening for hypersensitivity. Since passively administered antitoxin does not interfere with induction of active immunity by toxoid, both preparations, administered in different syringes at different sites, are recommended under certain circumstances. Antiserum does not provide long-lived immunity and tetanus confers no immunity; thus, survivors of disease or recipients of antiserum with incomplete primary immunizations should have that series completed. Neonatal tetanus represents a special problem in tetanus prophylaxis, particularly in certain areas of the world. The potential for elimination of this disease has been emphasized by the findings of Newell et al. 39 Proceeding from the observation that the ratio of antitoxin in maternal to cord blood is 1, the effect of immunization of pregnant women on subsequent neonatal tetanus was evaluated in a double-blind trial involving 1618 women in a rural area of Columbia. The death rate from tetanus neonatorum was 7.8 per 100 births in the control group and none among women who received 2 or 3 doses of tetanus toxoid. 39 Clearly, those charged with the health of infants and children in this and developing countries should take the lead in identifying and immunizing pregnant women with incomplete tetanus immunity.

394

DAVID

H.

SMITH AND GEORGES PETER

Diphtheria Inflammation at a site of infection, myocarditis~, and neuritis are the most important pathologic lesions of diphtheria. The toxin elaborated by the causative organism plays a role in the production of the local inflammation and is solely responsible for the systemic lesions. Antibiotics can eliminate the local infection; however, the disease has no pathognomonic features during its early stages, and the patient is often toxemic before an accurate diagnosis is made. Thus, antibiotics provide incomplete therapy. The current low incidence of diphtheria in the United States makes naturally acquired immunity unlikely. Since only a fraction of young adults, including few women, now receive diphtheria toxoid as part of a military experience, adults comprise a potentially large reservoir of susceptible individuals in the United States. For these reasons, active immunization, directed toward neutralization of the toxin, should be universally practiced at all ages. Mixtures of toxin and antitoxin (T-A) were employed as the initial vaccine for diphtheria, but they were not generally used after a catastrophe in Austria in which several children who received T-A died of toxin poisoning. Diphtheria toxoid was developed in 1923, and has been used widely in this country since the 1940's. The production of toxoid from toxin-rich culture filtrate involves several purification procedures, followed by treatment with formaldehyde. The basis for the toxin-neutralizing effect produced by formaldehyde treatment is not well understood, but the configurational changes produced in the toxin must be subtle, since toxicity is removed without affecting antigenicity. The purity of current diphtheria and tetanus toxoids is much improved over those formerly employed, but considerable, and variable, amounts of impurities remain in available toxoid preparations. Impurities may promote either of two effects: adjuvant action or adversereactions. Indeed, reduction in protein impurities reduced the prevalence of hypersensitivity reactions to earlier preparations of diphtheria toxoid. It is not apparent that further efforts are being made to evaluate the role of impurities in reactions to currently used diphtheria or tetanus toxoids. The efficacy of diphtheria toxoid has not been subjected to controlled study, but its ability to raise human antitoxin titers to, or above, 0.01 antitoxin units per mI., a level often described as "protective," has been thoroughly documented. Unfortunately, few studies have been reported of attack rates among individuals whose pre-infection antitoxin titers were known. Furthermore, the often quoted analysis by Ipsen of individuals admitted to hospital with clinically and bacteriologically proven diphtheria indicated that no admission antitoxin level correlated with susceptibility, but that the more antitoxin above 0.01 units per mI., the better the protection. 25 There is no question, however, that immunization with diphtheria toxoid markedly reduces the attack rate and the severity of the disease, although it does not produce "absolute" immunity. Only 16 per cent of those in a national survey of 1959 to 1968 with disease caused by toxigenic strains of Corynebacterium diphtheriae had had 3 or more doses of toxoid, and disease was milder in the immunized group: 2 per cent of those with 3 or more toxoid injections, and 15 per cent of the

395

VACCINES FOR BACTERIAL DISEASES

unimmunized, died. 9 On the other hand, the incidence of the disease was decreasing prior to thQ routine use of diphtheria toxoid (Fig. 3); thus, factors other than immunization (such as improved housing) must have also played a role in the reduction of diphtheria in the United States. It has been widely held that immunization of at least 70 per cent of individuals in a given environment will eradicate diphtheria. 50 This

400 200 100 80 60

GENERAL USE OF TOXOID

40 20

MORTALITY RATE

Z

0

::>

10 8 6

0

4

!i ..J

Q.

11.

0 0 0

....z

w

u

a:

w

2

20

en

I .8 .6

10 8 6

u

:'l

4

....>-

.2

2

«

c5

~

0

'en w

e::(

Q.

CASE - FATALITY RATIO

I

0

!;i a:

:::i

.... e::(

u. I

.1 .08 .06

w

en

«

u

.04 .02 .01 .008 .006 .004 .002 .001 1920

1930

1940

1950

1960

1970

YEAR Figure 3. Reported experience with diphtheria in the United States, 1920 to 1968. (From Brooks, G. F.: J. Infect. Dis., 120:500, 1969, reproduced with permission.)

396

DAVID

H.

SMITH AND GEORGES PETER

thesis is based on the proposals that circulating antitoxin decreases the incidence of infection by altering the effect of toxin at the site of infection, and that the reduction in the number of active cases, the most contagious source of the organism, will reduce the level of environmental contamination by C. diphtheriae below some undefined danger value. Thus, "herd" immunity, in which nonimmune individuals have been protected from exposure because of the effects of immunizing a critical percentage of individuals, was held to exist for diphtheria. There is no question that individuals with symptomatic disease are the most contagious sources of diphtheria. However, the disease has been observed in highly immunized populations: new cases continued to develop in the recent epidemic in Austin, Texas, although the rate of immunization among school children was raised from 68 to 89 per cent.60 Indeed, epidemiologic analysis of the Austin epidemic suggested that immunized individuals might be asymptomatic carriers and the source of infection of susceptible individuals. This question was recently studied during an outbreak in an elementary school in Elgin, Texas in which 67 per cent of the children and staff were fully immunized against diphtheria, and 97 per cent had had at least one dose of toxoid. The rate of nasopharyngeal infection among the students and their teachers was nearly identical (30 to 35.6 per 100), regardless of immunization status. However, the rate of symptomatic disease among those with organisms in their nasopharynx was 37 times greater for the nonimmunized individuals than those fully immunized. 9 The observation that immune individuals may be asymptomatic carriers of toxigenic C. diphtheriae has important implications for those involved in eradicating an outbreak of the disease. Immune as well as nonimmune individuals must be screened in order to fulfill the recommendations that, in addition to immunizing susceptibles, carriers should be identified, isolated and treated. Primary immunization of infants with diphtheria toxoid has relatively little risk of toxicity, but unacceptable local reactions with fever are often observed in older children and adults who receive standard doses (7.5 units) of toxoid. One unit of diphtheria toxoid given to adults less often produces a toxic response, but it is generally immunogenic: "protective" titers are produced in all adults by this dose when used as a booster and in most adults when it is used as a single, primary injection. Thus, "adult" Td, which contains 1 unit of diphtheria toxoid and the usual dose of tetanus toxoid, is recommended for all immunizations of individuals older than 6 years of age. The latest recommended schedule for booster and primary immunizations against diphtheria is listed in Table l. "Antitoxin should be administered on the basis of clinical diagnosis even before culture results are available."2 The dose is empirically determined by the degree of toxicity, duration of illness, and site of membrane: 20,000 to 40,000 units in mild or pharyngeal or laryngeal disease; 40,000 to 60,000 units in moderately severe or nasopharyngeal disease; and 80,000 to 120,000 units in severe disease. Sensitivity to the antitoxin (equine) should be tested before its administration. Intravenous administration is preferred in order to neutralize the toxin as rapidly as possible.

VACCINES FOR BACTERIAL DISEASES

397

Pertussis The case for uni\rersal immunization of infants against pertussis is quite strong. This is one of the most contagious of all infectious diseases, and approximately 90 per cent of exposed susceptible children develop symptomatic disease. Newborn infants apparently derive no immunity to Bordetella pertussis from their mothers. This lack of immunity, coupled with the pathophysiology of the disease and the anatomic characteristics of their lower airway make infants particularly vulnerable to pertussis. Although the disease has certain characteristic symptoms and laboratory findings, these may not be recognized until infection is well established and pathologic changes have been produced in the lower respiratory tract, at which time even appropriate antibacterial therapy does not alter the course of the disease. The age-related susceptibility is emphasized by mortality statistics: at least one-fourth of the deaths from pertussis occur in children under 3 months, and 75 per cent occur before 1 year. 12 All pertussis vaccines are homogenates or extracts of killed whole bacteria. The results of multiple, early trials with different vaccine preparations were contradictory. However, the controlled study of Kendrick and Elderling in Grand Rapids, Michigan28 left little doubt that immunization could prevent or reduce the severity of pertussis. The approximately 2300 children in the vaccinated and control groups were followed by special nurses and physicians who documented the clinical and bacteriologic diagnosis. Pertussis vaccine reduced by 6.5 tiines the overall incidence of the disease and by more than 5 fold that among exposed children. "Severe" disease was 4 times more common among the unvaccinated children. Subsequent studies demonstrated that different vaccines may differ greatly in ability to prevent disease; the "critical antigen" for protective action is not known, but it probably does not depend on serotype; antibodies directed against certain of the studied antigens of B. pertussis correlated with, but were not critical for, immunity; and the protective action of pertussis vaccine mixed with diphtheria and tetanus toxoids was similar to that of pertussis vaccine alone.37 Since the introduction of immunization the incidence and mortality of pertussis has fallen dramatically in the United States (Fig. 4). Recently, similar attack rates and severity of disease were observed among immunized and nonimmunized children in Great Britain. These results could not be attributed to immunization in early infancy, absence of booster doses, or long intervals between immunization and exposure. The vaccine employed was deficient in certain antigens possessed by currently prevalent strains, but a similar situation pertains in the United States and elsewhere where no evidence of the loss of vaccine efficacy has been observed. Furthermore, the problem in Great Britain was eliminated following an increase in the concentration of (the original) antigens in the vaccine. Local erythema, swelling, pain and tenderness, fever, abnormal screaming, prolonged loss of consciousness, and convulsions have been observed following pertussis immunization. The incidence of these reactions depends on the vaccine and the host. Local reactions of from 6 to about 80 per cent were reported in extensive field trialS. 37 The results

398

DAVID

H. SMITH AND GEORGES PETER

400.0 200.0 100.0 80.0 60.0 40.0 20.0 0 0 0 0

10.0 8.0 6.0

a: w

4.0

0

INCIDENCE

Q.

en :x: I-

'"w

2.0

0 0

z

'"enw en '"u

1.0 0.8 0.6 0.4

0.2 0.1 0.08 0.06 0.04 0.02 0.01 1920

1930

1940

·1950

1960

1970

Figure 4. Reported experience with pertussis in the United States, 1922 to 1968. (From Brooks, G. F., and Buchanan, T. M.: J. Infect. Dis., 122:123, 1970, reproduced with permission.)

of studies evaluating the incidence of reactions in relation to the number of injections have been contradictory. The report by Byers and Moll in 1948 of 15 children with severe encephalopathy which the authors associated with pertussis vaccination, raised the question of the incidence of this reactionP In certain British studies, "no definite evidence that convulsions or encephalopathy were directly related to vaccination was observed in over 30,000 immunized children."36 However, the data col-

VACCINES FOR BACTERIAL DISEASES

399

lected by Strom from 516,276 children immunized with DPT in Sweden from 1959 to 1965 suggested that 1 of 3600 vaccinated children had a neurological reaction. 53 The local toxicity of pertussis vaccines has been correlated with an effect of the vaccine on the weight gain of mice,37 and thus this test is now applied prior to commercial release of vaccine. Furthermore, an antigenic ceiling, based on international potency units which are determined by mouse protection potency, has been placed on primary immunization in the United States. Thus, while no adequate surveillance exists to provide an accurate estimate of vaccine-associated reactions in the United States, the United States Public Health Service states that "severe central nervous system reactions ... occur very rarely after ... pertussis vaccine," and "their incidence ... is much lower than the incidence of similar serious reactions following the disease itself."55 Current recommendations are those cited for DPT (Table 1). As indicated in the section on immunological considerations, the recommended age for administration of DPT injections is due in large part to the lack of reactivity of very young infants to pertussis vaccine. In an epidemic area, where protection is desired at an earlier age, immunization can be begun at 2 to 4 weeks of age. The low incidence and mildness of pertussis in older individuals and the increased incidence of febrile reactions after administration of pertussis vaccine to older children and adults are the basis for the recommendation that vaccine not be given after 6 years of age. There is no indication that the incidence of neurologic complications of the vaccine is increased among adults. A history of convulsions or brain damage was formerly held to be a contraindication to pertussis vaccination. The American Academy of Pediatrics Committee on Infectious Diseases2 has more recently stated that no clear-cut evidence exists that children with brain damage or convulsive disorders have a higher incidence of significant reactions from routine immunization procedures than do normal children, and has recommended that immunization of children with neurologic disorders be initiated with 0.05 ml. of DPT. If no reaction ensues, the recommended schedule for normal children is followed thereafter. Thrombocytopenia following pertussis vaccination has been reported and is a contraindication to further pertussis vaccination. 2 Human gamma globulin, prepared from individuals hyperimmunized with pertussis vaccine, is available for use in the therapy of acute disease. The results of clinical studies of the efficacy of passive immunization with such sera have been contradictory, but most controlled studies indicate that it has no value. 2

Typhoid Fever Although typhoid fever was a major health problem in the United States, its incidence has steadily declined and fewer than 400 cases are now reported annually. However, the disease continues to be a significant public health hazard in many areas of the world, particularly in countries in which housing, clean water, and the delivery of health care to diseased individuals are inadequate. Furthermore, therapy often fails, and carriers are potential public health hazards. Thus, the possibility of preventing the disease through immunization has been actively studied.

400

DAVID

H.

SMITH AND GEORGES PETER

Vaccines, composed of extracts of killed whole bacteria, have been available since 1898, but their use was not enthusiastically or generally supported in the past. Some of the doubts regarding the vaccines were directed at the question of immunity to typhoid fever: several studies have indicated that active disease produces only relative resistance to reinfection, and that the presence of circulating antibodies to H, 0 and Vi antigens does not produce immunity. The lack of controlled studies of vaccine efficacy raised other doubts about the vaccines. Recent studies conducted under the auspices of the World Health Organization have answered certain of these questions. The efficacy of whole bacterial vaccine, prepared by acetone inactivation (to preserve the Vi antigen), was compared to that of a similar vaccine, prepared by heat-phenol inactivation, and to tetanus toxoid in over 100,000 children. Despite problems in follow-up of the vaccine recipients, the results were clear cut: for 2 to 3 years following immunization, the acetone-inactivated vaccine reduced symptomatic, culture-proven disease by 79 to 94 per cent, while the phenol-inactivated vaccine was 51 to 73 per cent effective. 51 In Guyana, where follow-up was continued 7 years, the former vaccine reduced disease by 94 per cent during the first 3 years following immunization and 81 per cent during the succeeding 4 years; during the same periods, the protection produced by the phenol-inactivated vaccine was 76 and 67 per cent respectively." One primary dose was as effective as or more effective than 2 doses. No correlation existed between vaccine efficacy and the titers of circulating antibody activities produced; thus, the basis for the resistance produced remains undefined. Many of these studies were conducted in endemic areas and, therefore, the vaccine's effectiveness may have been due, at least in part, to an enhancement of resistance acquired from subclinical infection(s). Since reduction of disease attack rates is the only true measure of vaccine efficacy, similar studies cannot be conducted in nonexposed populations. Therefore, the question of the relevance of these observations to populations such as those in the United States may be questioned. Immunization reduced significantly the attack rate among adult volunteers who were challenged with an oral dose of typhoid bacilli that caused disease in 25 per cent of nonimmunized individuals (ID25 ), but it did not affect attack rates among individuals challenged with ID50 doses. 23 Thus, if comparison of the field and volunteer studies is valid, immunization would appear to reduce disease among individuals exposed to a dose of bacteria that produces disease in only a minority of susceptible individuals. 23 The indications for typhoid vaccine in the United States are: intimate exposure to a known household carrier; outbreak of typhoid fever in the community or an institution; travel to endemic areas. Attendance at summer camp and flood conditions are not accepted as specific indications. A dose of 0.5 mI. administered subcutaneously is recommended for primary and booster immunization of individuals over 10 years old, and 0.25 mI. for those under that age. Febrile and local reactions are common and prophylactic antipyretics in young children may be indicated. A dose of 0.1 m!. given intradermally may produce equal immunogenicity

VACCINES FOR BACTERIAL DISEASES

401

and fewer side reactions than the larger subcutaneous dose and therefore may be used as a booster injection. Killed typhoid bacilli administered orally in keratinized tablets are widely used as vaccines in certain European countries. Their efficacy has not been subjected to controlled field trials, and their use at recommended doses did not reduce disease among exposed volunteers.23 However, some resistance was produced by very large quantities of oral vaccine. Preliminary studies with oral vaccines composed of attenuated, live typhoid bacilli appear promising and are currently continuing. The effectiveness of paratyphoid A vaccine has not been established, and the paratyphoid B vaccines used in "TAB" vaccines are not effective. "TAB only increases the risk of vaccine reaction and should not be used."55

Cholera Cholera is one of the major problems of world health. It is endemic in the Indian sub-continent and in Southeast Asia. Over the past decade it has spread to the Middle East and, recently, to Africa and Europe. Hygienic measures, particularly clean water, can eliminate the disease, and therapy is effective and cheap. However, a vaccine that provided effective and long-term immunity would be a helpful adjunct to the prevention of the disease. Cholera vaccines were introduced before the turn of this century, but much of the available knowledge regarding the pathogenesis of the disease, host immunity, and vaccine efficacy has been acquired in the past decade. An exotoxin of the vibrio produces the dramatic loss of intestinal fluid that is responsible for the clinical symptomatology of the disease. Elevated titers of circulating vibriocidal antibody and antitoxin generally develop in convalescent patients. Recent studies of children in East Pakistan, examined before and after they had the disease, indicated that the incidence of symptomatic disease was reduced almost 4 times by detectable circulating vibriocidal antibody, but it was not significantly affected by the presence of circulating antitoxin. Milder disease was associated, however, with antitoxin activity.59 Thus, vibriocidal antibody, but not antitoxin, reduces the risk of infection, whereas antitoxin alters the course of disease. Since the same individual may suffer more than one bout of disease caused by the same type of vibrio, immunity appears to be incomplete. Low doses of live, virulent vibrio were used unsuccessfully as the first cholera vaccine. Subsequently, attenuated live strain vaccines and the killed, whole bacterial vaccine used at present were developed. In a series of nine controlled field trials in the Philippines, East Pakistan, and India, the best results obtained with the current vaccine were 75 per cent protection for 6 months and 60 per cent for 18 months. In most studies, the average protection over a 3 month period was 30 to 40 per cent. 14 A vaccine composed of lipopolysaccharide antigen extracted from the wall of the cholera bacillus appears to be more promising: short-term protection of up to 90 per cent has been observed. Available data indicate that: this vaccine, like the classical vaccine, produces circulating anti-

402

DAVID

H.

SMITH AND GEORGES PETER

bacterial (vibriocidal) antibodies but no antitoxin; efficacy is greater among adults than in children (although disease is more common among children), and is correlated to titers of circulating vibriocidal antibody produced; some vaccine preparations are superior to others; the resistance produced is relatively short-lived (6 to 18 months) and probably specific for the type of bacillus from which it is prepared.51 If the cholera toxin can be converted to a nonpathogenic but immunogenic toxoid, it might provide more effective and longer-lasting resistance to the disease than available vaccines, or it might be useful as an adjunct to an antibacterial vaccine. The return on the investment in cholera vaccine research and immunization programs has, however, been discouraging. The cost benefits of methods of controlling cholera have been extensively evaluated and indicate that "comparable expenditures devoted to the treatment and isolation of patients and contacts, and to the control of wate disposal and water supplies ... would produce more satisfactory results at far less cost. "22 Routine cholera immunization is not recommended, even in endemic areas. Thus, the only indication in the United States for cholera vaccination is anticipation of travel to countries where cholera exists. In view of the recent spread of the disease, physicians should consult their local health officials for current information on areas requiring immunization. Immunization of infants under 6 months of age is not recommended and is not required by most countries. Ideally, travellers should be vaccinated within 2 months of their departure. Only one vaccination is required to fulfill international travel requirements, but two vaccinations spaced 1 week to 1 month apart are strongly recommended to ensure optimal immunity. Cholera vaccine is not required for individuals returning to the United States from endemic areas. Suggested dosage schedules are given in Table 3. Many individuals develop local tenderness, mild swelling, erythema, and occasionally fever. Delayed reactions 6 to 12 days after vaccination have only been reported in individuals over 10 years of age previously exposed or vaccinated. The only contraindication to vaccination is a previous and significant reaction. BeG Vaccine

BCG is an attenuated live derivative of a virulent strain of Mycobacterium tuberculosis var. bovis isolated in 1908 by Calmette and Guerin. Subs trains of this original isolate have been available for active immunization for tuberculosis since 1921. Although this immunization is widely used in many areas of the world, its use remains controversial in the United States. Table 3. Recommended Schedule for Cholera Immunization 55 AGE (YEARS) NUMBER OF DOSES

2 and boosters

Under 5

5 to 10

Over 10

0.1 ml. 0.3 mI.

0.3 ml. 0.5 mI.

0.5ml. 1.0 mI.

VACCINES FOR BACTERIAL DISEASES

403

Objections to BCG which have been raised are: efficacy has not been established; the vaccine may deteriorate and lose potency; it may not be safe; vaccination renders useless the tuberculin test for detection of active cases of tuberculosis; BCG is not needed, because of the efficacy of INH prophylaxis. Earlier preparations were unstable, particularly to heat, but the development of heat-resistant, freeze-dried preparations has obviated this problem. The concern over the safety of BCG resulted primarily from the Lubeck disaster in 1930 in which 72 of 251 infants immunized with BCG died from tuberculosis. Although this incident was clearly due to contamination of vaccine with virulent M. tuberculosis, the suggestion that the vaccine strain may revert to virulence has survived. Current regulations for the preparation and testing of vaccine and considerable recent experience with the vaccine belie that contention. Since 1951, the World Health Organization and United Nations Children's Fund have sponsored over 250 million vaccinations with BCG in developing countries,43 and immunization is routinely practiced in many Western European countries. The most severe complication, regional lymphadenopathy, is observed in no more than 5 per cent of the children. No evidence exists for the activation of latent tuberculosis by BCG.43 The results of BCG field trials are affected by several variables, including the age and tuberculin reactivity of individuals immunized; the expected attack rate in the population; the rate of natural infection by atypical mycobacteria, which enhance resistance to subsequent infection by M. tuberculosis; the potency of the vaccine; the methods used in administering the vaccine. The consistency of the results of reported field trials are therefore somewhat surprising. With the exception of 3 trials conducted by the United States Public Health Service, BCG has been found in each of several field trials to reduce subsequent active tuberculosis by 30 to 80 per cent for periods of up to 20 years. 43 Typical of those studies have been two that have examined the efficacy of BCG in preventing disease among newborn infants delivered into a household with a tuberculous adult. The earlier observation is that of Rosenthal46 who found that BCG reduced the attack rate among exposed infants by 80 per cent. More recently, 105 infants born of known tuberculous mothers in Richmond, Virginia were followed for a mean period of 11 years. Of 30 who received BCG, none contracted tuberculosis; of 75 nonvaccinated infants, tuberculosis developed in 38 infants, 2 of whom died from active disease (meningitis)P Many authorities therefore conclude that a potent BCG vaccine, given to subjects not previously infected with tubercule bacilli or other mycobacteria, can significantly reduce all forms of tuberculosis for years. The effect of BCG on the subsequent usefulness of the tuberculin test remains hotly debated. The United States Public Health Service states that "the procedure (BCG vaccination) makes it impossible to use the tuberculin test as evidence of recent infection in the individual."54 The counter arguments are that BCG generally produces low grade « 10 mm.), transient « 1 year) reactivity to 5 TU of PPD and that the level of sensitivity of a vaccinated subject is markedly increased following su-

i

, ,

404

DAVID

H.

SMITH AND GEORGES PETER

perinfection with tubercule bacilli; thus, repeated tuberculin tests of the individual patient should permit identification of recent infection by virulent tubercle bacilli. Lifschitz has recently presented convincing evidence of the value of the tuberculin test (5TU) in case identification among a population of Indian infants immunized with Rosenthal strain BCG.;)! The United States Public Health Service has taken the position that "modern methods for detection, isolation, treatment and chemoprophylaxis are highly successful in controlling tuberculosis," and it reserves BCG for "situations in which these methods cannot be applied."54 However, these situations are not specified, and the latest "Collected Recommendations of the Public Health -Service Advisory Committee on Immunization Practices" contains no mention of BCG.55 Even the most enthusiastic advocates of BCG in this country favor its use only for certain high risk populations: tuberculin-negative medical, laboratory, and military personnel; and infants, children and adolescents living in an environment where risk of exposure, and the potential of inadequate chemoprophylaxis, is great. The efficacy of isoniazid (INH) for newborn infants to families with a tuberculous member is not questioned, but Avery and Wolfsdorf have emphasized the current ignorance about the potential neurotoxicity associated with this practice." Furthermore, the problem of delivering successful chemoprophylaxis is illustrated by the findings of Sweet. ':' He reviewed the records of 25 infants living in the inner city of Cleveland who were born into families in which at least one member had tuberculosis. In spite of referral of all infants to a special follow-up clinic, 16 (64 per cent) were lost to follow-up, 15 by 1 year of age. Of 10 infants for whom INH was prescribed, only 2 received the drug for the prescribed 1 year. The Committee on Drugs of . the American Academy of Pediatrics has concluded that "infants born into families with gross social pathology are those whose parents usually will not obtain or accept supervised treatment," and recommends that "these babies should be ... immunized with BCG before they return to their home environment." The tuberculin conversion rate among children of lower socioeconomic status in the District of Columbia rose from 2.7 per cent among children aged 5 to 9 years, to 5.5 per cent for those aged 10 to 14 years, and 16.8 per cent for those aged 20 to 25 years. 29 These data suggest that infection was acquired outside the home from unidentified individuals. The use of BCG would appear to be justifiable among this type of population in view of the failure to identify active contacts and the problems inherent in adequate INH administration. The American Indian reservations, with their high incidence of tuberculosis, would appear to be another setting in which BCG is indicated. General agreement exists that BCG should be given to the tuberculin-negative child going abroad to live in an endemic area, where the potential for case identification is a practical problem. Recipients of BCG should have negative tuberculin reactions « 10 mm. induration to 5 TU PPD) and negative chest x-ray films. Infants of ':'Quoted in reference 1.

VACCINES FOR BACTERIAL DISEASES

405

mothers with active disease should be isolated from the mother for at least 6 weeks. Kendig recommends that if the mother has miliary or advanced sputum-positive pulmonary disease, the child should be isolated, treated with INH and observed for 3 months, at which time BCG should be given if there is no evidence of disease. These infants should then be isolated another 6 weeks, unless the mother's disease is no longer activeP Contraindications for the use of BCG include a deficiency of cellular immunity, acquired genetically or from the use of immunosuppressive drugs, fresh smallpox vaccination, and burns. Immunity cannot be assumed until the tuberculin test becomes positive. Isoniazid-resistant BCG is not available in the United States; thus, BCG cannot be given during administration of INH.

POTENTIAL BACTERIAL VACCINES Group A Streptococci The pathogenesis of group A streptococcal infection depends primarily on the bacterial M protein, and host resistance is mediated by anti-M protein antibodies. Natural infection produces long lasting, type-specific antibody activity which can be recalled readily. Thus, immunization with M proteins might be expected to produce prolonged and specific immunity. Although there are 52 distinct M serotypes of group A streptococci, and many, if not all, are associated with rheumatic fever, only 5 types, including type 12, account for the vast majority of the strains recovered from patients with acute pharyngitis. 52 However, many of the strains associated with acute glomerulonephritis have the type 12 M protein. Rheumatic fever is a disease of crowded living conditions, and the highest incidence occurs in central, urban areas. Because of deficiencies in the health care available to those living in these areas, it is perhaps not surprising that the majority of children with initial attacks of rheumatic fever either do not seek medical attention for a symptomatic streptococcal infection, or deny its existence. 17 Therefore, despite the potential for eliminating rheumatic fever with penicillin therapy of group A streptococcal infections, the incidence of first attacks of the disease has not fallen significantly: the attack rate in Baltimore, Maryland was 28.5 per 100,000 children aged 5 to 19 years in 1935-1936 and 21 per 100,000 from 1960 to 1964.17 For these reasons the potential for immunization with selected purified M proteins has been explored. Several problems have slowed the progress of these studies: the lack of a convenient, accurate method for measuring protective antibody; purification of the various M proteins; and the toxicity of the present vaccines. 52 The concern that injection of M protein might elicit antibodies that are cross-reactive with heart tissue has not been realized with purer preparations. "Booster" responses are elicited by relatively small amounts of antigen, but primary responses require concentrations of antigen that produce unacceptable local reactions mediated by cellular immune mechanisms in a relatively high proportion of children and adults. Studies of primary immunization of infants and of further purifica-

406

DAVID

H. SMITH AND GEORGES PETER

tion of M proteins continue, but the prospects for success in the immediate future appear doubtful. Pneumococci Vaccines composed of suspensions of heat-inactivated pneumococci were introduced over 5 decades ago. Following the demonstration of the critical role of the capsule in the pathogenesis of pneumococcal disease and documentation that purified capsular polysaccharide produced antibody in man and animals that protected animals from lethal experimental infection, attention turned to these polysaccharides as active immunizing agents. Efficacy of the polysaccharide vaccines in preventing pneumococcal pneumonia in adults was well documented. In a study of more than 7600 young men in an Air Force School in which 6 types of pneumococci had caused epidemics of pneumonia during the 2 previous years, immunization with polysaccharides of 4 of the types significantly reduced the nasopharyngeal carriage rate of "vaccine," but not other strains among vaccine recipients. Immunization also reduced 10-fold the incidence of clinically diagnosed pneumonia caused by "vaccine" strains, but it did not affect the incidence of "non-vaccine" pneumococcal pneumonia. 34 Pneumococcal vaccines also protected elderly adults: in studies of over 10,000 individuals older than 50 years, immunization reduced 10-fold the incidence of disease caused by vaccine strains. 26 Unfortunately, the introduction of penicillin and its remarkable effect on pneumococcal disease brought these studies to a close. Recent experience with pneumococcal pneumonia indicates that it is still one of the two infectious diseases among the 10 leading causes of death in the United States; the death rate during the first 5 days of the disease is similar in patients who receive no, or appropriate, antibiotic therapy; the majority of the cases are now and have been caused by only 6 of the more than 80 types of pneumococci.1 These observations have prompted Austrian to advocate the reevaluation of selective immunization of individuals in high risk groups.7 It can be argued that immunization with only a few of the pneumococcal polysaccharides might shift the "natural" balance in favor of non-vaccine types. However, the types of pneumococci most prevalent in nasopharyngeal cultures of healthy individuals rarely cause disease. On the other hand, the types currently causing most of the pneumonia in adults were also the most common cause of disease 3 or more decades ago in the United States, and they produce most of the disease in other areas as well. These data strongly suggest that certain types of pneumococci are genetically more "pathogenic" than others. Finally, the previous experiences with pneumococcal vaccines provided no evidence that the ecology of pneumococcal disease was altered by immunization. Available evidence indicates that 7 types cause about two thirds of the pneumococcal bacteremia and otitis media in children; only 3 of these types are included among those most commonly causing adult disease. The use of a polyvalent pneumococcal vaccine, if effective in children, would provide a new adjunct in the care of children with those conditions (e.g., hemoglobinopathies, splenectomy, nephrosis) that en-

V ACCINES

FOR BACTERIAL DISEASES

407

hance susceptibility to systemic pneumococcal disease. However, the role of such a vaccine as a routine immunizing agent for children remains to be determined. Meningococcus The potential for epidemic spread and the rapidity of the course of bacteremic disease prompted early studies of active immunization for meningococcal disease. However, the introduction of therapeutically effective antibiotics, the success of sulfonamides in chemoprophylaxis, and the virtual disappearance from the United States of group A strains, the most common cause of epidemic disease, dampened enthusiasm for this approach. The recent increase in the prevalence of sulfonamide-resistant strains and the lack of satisfactory alternatives to sulfonamides as chemoprophylactic agents has renewed interest in the immunoprophylaxis of meningococcal diseases. A prospective study of 594 army recruits provided evidence that bactericidal antibody provides resistance to systemic meningococcal diseases. Bactericidal titers of> 4 were present at the time of their arrival at training camp in 5.6 per cent of those who subsequently developed systemic meningococcal disease, but in 82.2 per cent of those who did not develop disease. Indeed, of those who became nasopharyngeal carriers of a meningococcus but had no bactericidal activity to that organism, 38.5 per cent developed systemic disease during their 8 week training camp experience. 'S Meningococci are typed by their capsular polysaccharides. Of the seven types, types C and B currently cause nearly all meningococcal disease in the United States. 56 The capsular polysaccharides of type A and C meningococci have been purified in a form that is non-toxic and that raises bactericidal antibody in young adults. 'S ' 19 Purification of a type B antigen that raises antibody in recipients has not yet been accomplished. Immunization of military recruits with type C vaccine reduced the acquistion of homologous strains by 2 to 3 times, but it did not affect the acquisition of heterologous strains or the carriage of strains present at the time of immunization. A single injection (50 micrograms) of the type C vaccine reduced the incidence of systemic disease caused by type C . organisms among 13,000 recipients by 87 per cent; the attack rate by type B organisms was slightly, but not significantly, higher among vaccine recipients than controls in these first trials. 5 Further studies have confirmed the efficacy of immunization against disease caused by homologous strains, and do not indicate that those immunized have an increased risk of disease caused by "non-vaccine" meningococci. 4 The duration of the immunity produced by the vaccine has not been evaluated. Prevention of meningococcal disease in military training camps should solve a major health problem for those in that environment. However, systemic meningococcal disease is primarily a problem of infants and young children: the reported attack rate of 10 per 100,000 among children 1 to 5 years of age in the United States is approximately 10 times that among older individuals.56 Therefore, the results of studies of the im-

408

DAVID

H.

SMITH AND GEORGES PETER

munogenicity for infants and children of these polysaccharides, the availability of a group B vaccine, and the demonstration of the efficacy of these vaccines in children are awaited.

Hemophilus influenzae b H. influenzae causes disease of the lower and upper respiratory tract, including about 25 per cent of the cases of otitis media in children, and it is the most common cause of bacterial meningitis in North America. For reasons which are not clear, the absolute and relative prevalence of systemic diseases, such as meningitis and septic arthritis, caused by H. influenzae has been increasing for several decades. Table 4 summarizes the experiences with meningitis in two medical centers from which data are available over several years. These data do not reveal that the increases in H. infiuenzae meningitis have not been accompanied by similar increases in other proven types of bacterial meningitis, and that this trend can not be explained by changes in the patterns of admission to the involved institutions. Retrospective studies in certain communities indicate that approximately 1 in every 2000 children 6 to 48 months of age in the United States develop H. infiuenzae meningitis. 24 • 44 This attack rate is equal to, or greater than, that of the pre-immunization experience with several other infectious diseases for which active immunization is now practiced. Furthermore, the mortality and morbidity rates of H. infiuenzae meningitis have remained relatively constant at approximately 5 and 30 per cent respectively over the past 15 to 20 years, although these bacteria are sensitive to many antibiotics. These observations suggest to some the need for a new approach to H. infiuenzae diseases. Since nearly all systemic H. infiuenzae diseases are caused by type b strains, and since evidence indicates that anticapsular antibody produces immunity, consideration of active im-

Absolute and Relative Importance of Hemophilus Injiuenzae Meningitis

Table 4.

PER CENT OF TOTAL CASES HOSPITAL

DATES

NO. OF CASES

OF BACTERIAL

PER YEAR

MENINGITIS

Children's Hospital Medical Center, Boston

1920-1931 1933-1936 1942-1947 1951-1960 1961-1969

6.5 13 19 26 30

19% 27% 34% 45% 48%

Children's Hospital of Pittsburgh

1941-1950 1951-1960 1961-1970

9 18 38

21% 38% 60%

VACCINES FOR BACTERIAL DISEASES

409

munization with purified capsular antigen has recently been suggested. The capsular antigen of type b strains, polyribophosphate (PRP), can be purified in a form that is stable, nontoxic and immunogenic for adultsY' 45, 48 Human anti-PRP antibody protects animals from lethal experimental infection. 3 Studies of the immunogenicity of PRP in infants and children and its efficacy in preventing human disease have been initiated. Shigella Shigellosis is another epidemic disease that has far more importance in other parts of the world than in the United States. For example, a strain of Shigella dysenteriae resistant to multiple antibiotics caused an estimated 112,000 cases with 8300 deaths in the first 10 months of a continuing epidemic in Central America. I5 The success with typhoid vaccine prompted study of killed whole bacterial vaccines injected parenterally for shigellosis. Unfortunately, such vaccines do not protect animals from experimental infection and, therefore, various types of attenuated bacteria that retain their surface antigens are being evaluated as oral vaccines. One type, selected in vitro for dependence on streptomycin, lacks virulence because of its inability to multiply in the absence of the drug. Another type of avirulent shigella was found spontaneously, while a third type is a laboratory derivative of a genetic cross between'virulent shigella and avirulent E. coli. Genetic reversion of the bacteria and post-immunization intestinal symptoms have been problems, but vaccination partially protects against disease38 caused by serologically related strains, and the studies are being continued. Pseudomonas Aeruginosa The prevalence and high mortality rates of systemic infections caused by Pseudomonas aeruginosa in patients with burns and certain malignancies and the pulmonary infections in patients with cystic fibrosis have prompted evaluation of both active and passive immunization against these bacteria. 35 The antibody synthetic capacity of patients with burns and malignancies is not impaired, but the role of antibody and other immune factors in host resistance to Pseudomonas is not well defined. Several laboratory problems,have been encountered, including the basis for typing different strains of P. aeruginosa and the identification of the antigen(s) important for the production of host immunity. Vaccines prepared from extracts of killed bacteria, and composed primarily of lipopolysaccharide, have been tested in animals and man. Partial protection has been reported, but high (25 micrograms per kg. of bodyweight) multiple (weekly) doses have been required, and the incidence of toxicity has often been considerable. The resistance produced has not been clearly correlated with measured antibody activities, and the possibility that it may be mediated by nonspecific stimulation of the reticuloendothelial system requires further study. Thus, the results of continuing studies are needed to determine the future of immunotherapy for Pseudomonas infections.

410

DAVID H. SMITH AND GEORGES PETER

CONCLUSION Recent advances have emphasized the potential for new vaccines to prevent bacterial disease and the empirical basis for the development of current vaccines and immunization practices. These developments have, in turn, prompted increased study of these vaccines. In this article, we have attempted to summarize certain aspects of the need, toxicity, na~ ture, efficacy, and use of several of the vaccines already available or currently under evaluation.

REFERENCES 1. American Academy of Pediatrics, Committee on Drugs: Infants of tuberculous mothers: Further thoughts. Pediatrics, 42:393, 1968. 2. American Academy of Pediatrics, Committee on Infectious Diseases: Active Immunization Procedures, 1970. 3. Anderson, P., Peter, G., Johnston, R B., Wetterlow, L. H., and Smith, D. H.: Immunization of humans with polyribophosphate, the capsular antigen of Haemophilus infiuenzae, type b. J. Clin. Invest., 51 :39, 1972. 4. Arternstein, M. S.: Personal communication. 5. Artenstein, M. S., Gold, R, Zimmerly, J. G., Wyle, F. A., Schneider, H., and Harkins, C.: Prevention of meningococcal disease by group C polysaccharide vaccine. New Eng. J. Med., 282:417, 1970. 6. Ashcroft, M. T., Singh, B., Nicholson, C. C., Ritchie, J. M., Sobryan, K, and Williams, F.: A seven year field trial of two typhoid vaccines in Guyana. Lancet, 2:1056,1967. 7. Austrian, R, and Gold, J.: Pneumococcal bacteremia with especial reference to bacteremic pneumococcal pneumonia. Ann. Intern. Med., 60:759,1964. 8. Avery, M. K, and Wolfsdorf, J.: Diagnosis and treatment: Approaches to newborn infants of tuberculous mothers. Pediatrics, 42:519, 1968. 9. Bennett, J. V.: Personal communication. 10. Bigler, J. A., and Werner, M.: Active immunization against tetanus and diphtheria in infants and children. J.A.M.A., 116:2355,1941. 11. Brooks, G. F.: Recent trends in diphtheria in the United States. J. Infect. Dis., 120:500, 1969. 12. Brooks, G. F., and Buchanan, T. M.: Pertussis in the United States. J. Infect. Dis., 122:123, 1970. 13. Byers, R K., and Moll, F. C.: Encephalopathies following prophylactic pertussis vaccine. Pediatrics, 1 :437, 1948. 14. Edsall, G.: Cholera. In Proceedings of the International Conference on the Application of Vaccines Against Viral, Rickettsial, and Bacterial Diseases of Man. Pan American Health Organization, Washington, D.C., 1971, p. 342. 15. Gangarosa, K J., Perera, D. R, Mata, L. J., et al.: Epidemic Shiga bacillus dysentery in Central America: II. Epidemiologic studies in 1969. J. Infect. Dist., 122: 181, 1970. 16. Goldschneider, I., Gotschlich, K C., and Artenstein, M. S.: Human immunity to the meningococcus. I. The role of humoral antibodies. J Exper. Med., 129:1307, 1969. 17. Gordis, L., and Markowitz, M.: Prevention of rheumatic fever revisited. PEDIAT. CLIN. N. AMER., 18:1243, 1971. 18. Gotschlich, K C., Liu, T. V., and Artenstein, M. S.: Human immunity to the meningococcus. III. Preparation and immunochemical properties of the group A, group B and group C meningococcal polysaccharides. J. Exper. Med., 129:1349,1969. 19. Gotschlich, E. C., Goldschneider, I., and Artenstein, M. S.: Human immunity to the meningococcus. IV., Immunogenicity of group A and group C meningococcal polysaccharides in human volunteers. J. Exper. Med., 129:1367,1969. 20. Hardegree, M. C., Barile, M. F., Pittman, M., Schofield, F. D., MacLennan, R, and Kelly, A.: Immunization against neonatal tetanus in New Guinea. 2. Duration of primary antitoxin responses to adjuvant tetanus toxoids and comparison of booster responses to adjuvant and plain toxoids. Bull. W. H. 0.,43:439,1970. 21. Heidelberger, M.: Persistence of antibodies in man after immunization. In Pappenheimer, A. M., Jr., ed.: The Nature and Significance of the Antibody Response. New York, Columbia University Press, 1953, pp. 90-101. 22. Henderson, D. A., Labusquiere, R, Millar, J. D., N'Dow, P. J., Nicholson, J. J., Rey, M., Ristori, C., and Sulianti-Saroso, J.: Design for immunization programs in the developing

V ACCINES

FOR BACTERIAL DISEASES

411

countries. In Proceedings of the International Conference on the Application of Vaccines Against Viral, Rickettsial, and Bacterial Diseases of Man. Pan American Health Organization, Washington, D.C., 1971, p. 626. 23. Hornick, R B., Greisman, S. E., Woodward, T. E., DuPont, H. L., Dawkins, A. T., and Snyder, M. J.: Typhoid fever: Pathogenesis and immunologic contro!' New Eng. J. Med., 283:739,1970. 24. Howie, V. M.: Personal communication. 25. Ipsen, J.: Circulating antitoxin at the onset of diphtheria in 425 patients. J. Immuno!., 54:325, 1946. 26. Kaufman, P.: Pneumonia in old age. Arch. Intern. Med. (Chicago), 79:518,1947. 27. Kendig, E. L., Jr.: The place of BCG vaccine in the management of infants born of tuberculous mothers. New Eng. J. Med., 281 :520,1969. 28. Kendrick, P., and Elderling, G.: A study in active immunization against pertussis. Amer. J. Hyg., 29:133,1939. 29. Khoury, S. A., Theodore, E., and Platts, V. J.: Isoniazid prophylaxis in a slum area. Amer. Rev. Resp. Dis., 99:345, 19(19. 30. LaForce, F. M., Young,L. S., and Bennett, J .. V.: Tetanus in the United States (1965-1966). New Eng. J. Med., 280:569,1969. 31. Lifschitz, M.: The value of the tuberculin skin test as a screening test for tuberculosis among BCG-vaccinated children. Pediatrics, 36:624, 1965. 32 .. Long, A. P., and Sartwell, P. E.: Tetanus in United States Army in World War II. Bull U.S. Army M. Dept., 7:371,1947. 33. MacLennan, R., Schofield, F. D., Pittman, M. Hardegree, M. C., and Barile, M. F.: Immunization against neonatal tetanus in New Guinea. I. Antitoxin response of pregnant women to adjuvant and plain toxoids. Bull. W.H.O., 32:683, 1965. 34. MacLeod, C. M., Hodges, R G., Heidelberger, M., and Bernhard, W. G.: Prevention of pneumococcal pneumonia by immunization with specific capsular polysaccharides. J. Exper. Med., 82:445, 1945. 35. Markley, K.: Vaccine prophylaxis for Pseudomonas infections. Ann. Intern. Med., 74:140, 1971. 36. Medical Research Council, the Whooping-cough Immunization Committee: The prevention of whooping-cough by vaccination. Brit. Med. J., 1 :1463,1951. 37. Medical Research Council, the Whooping-cough Immunization Committee: Vaccination against whooping-cough. Brit. Med. J., 1 :994, 1959. 38. Mel, D. M., Arsic, B. L., Nikolic, B. D., and Radovanic, M. L.: Studies on vaccination against bacillary dysentery. Four oral immunizations with live monotypic and combined vaccines. Bull. W.H.O., 39:375, 1968. 39. Newell, K. W., Lehmann, A. D., Leblanc, D. R., and Osorio, N. G.: The use of toxoid for the prevention of tetanus neonatorum. Final report of a double-blind controlled field trial. Bul!. W.H.O., 35:863, 1966. 40. Osborn, J. J., Dancis, J., and Julia, J. F.: Studies of the immunology of the newborn infant. I. Age and antibody production. Pediatrics, 9: 736, 1952. 41. Peehles, T. C., Levine, L., Eldred, M. C., and Edsall, G.: Tetanus-toxoid emergency boosters .. New Eng. J. Med., 280:575, 1969. 42. Provenzano, R. W., Wetterlow, L. H., and Sullivan, C. L.: Immunization and antibody response in the newborn infant. I. Pertussis inoculations within 24 hours of birth. New Eng. J. Med., 273:959, 1965. 43. Rees, R J. W.: BCG vaccination in mycobacterial infections. Brit. Med. Bul!., 25: 183, 1969. 44. Robbins, J. B.: Personal communication. 45. Rodrigues, L. P., Schneerson, R, and Robbins, J. B.: Immunity to Haemophilus influenzae type b. I. The isolation and some physicochemical, serologic, and biologic properties of the capsular polysaccharide of H. influenzae type b. J. Immuno!., 107:1071, 1971. 46. Rosenthal, S. R, Loewinsohn, E., Graham, M. L., Liveright, D., Thorne, M. G., and John· son, V.: BCG vaccination in tuberculous households. Amer. Rev. Resp. Dis., 84:690, 1961. 47. di Sant'Agnese, P. A.: Combined immunization against diphtheria, tetanus and pertussis in newborn infants. I. Production of antibodies in early infancy. Pediatrics, 3:20, 1949. 48. Schneerson, R, Rodrigues, L. P., Parke, J. C., Jr., and Robbins, J. B.: Immunity to disease caused by H. influenzae type b. II. Specificity and some biologic characteristics of "natural," infection·acquired, and immunization·induced antibodies to the capsular polysaccharide of H. influenzae type b. J. Immuno!., 107:1081,1971. 49. Smith, D. H.: The need and potential for a vaccine against H. influenzae, type b. Submitted for publication. 50. Smith, J. W. G.: Diphtheria and tetanus toxoid. Brit. Med. Bul!., 25:177,1969. 51. Standfast, A. F. B.: Pertussis, typhoid-paratyphoid and cholera vaccines. Brit. Med. Bull., 25:189,1969. 52. Stollerman, G. H.: Prospects for a vaccine against group A streptococci: The problem of the immunology of M proteins. Arthritis Rheumatism, 10:245,1967.

412

DAVID

H.

SMITH AND GEORGES PETER

53. Strom, J.: Further experience -of reactions, especially of a -cerebral nature, in conjunction with triple vaccination: A study based on vaccinations in Sweden, 1959·1965. Brit. Med. J.,4:320, 1967. 54. United States Public Health Service, National Communicable Disease Center: Hecommendations on the use of BCG vaccination in the United States. Morbidity and Mortality, 15:350,1966. 55. United States Public Health Service, National Communicable Disease Center: Collected Recommendations of the Public Health Advisory Committee on Immunization Practices. Morbidity and Mortality, 18(Suppl.), 43,1969. 56. United States Pu.blic Health SeTvice, National Communicable Disease Center: Meningococcal diseases - United -States, epidemiological year 1970. Morbidity and Momality; 19:42, 1970. 57. United States Public Health Service, National Communicable Disease Center: Recommendations of the Public Health Advisory Committee on Immunization Practices-diphtheria and tetanus toxoids and pertussi.'S vaccine. Morbidity and Mortality, 20:43, 1971. 58. Wilkins, J., Williams, F. F., Wehrle, P. F., and Portnoy, B.: AgglUtinin response to pertussis vaccine. I. Effect of dosage and interval. J. Pediat., 79:1-97, 1971. 59. Woodward, W. E., Mosley, W. H., and McCormack, W. M.: The spectrum of cholera in ruxal East Pakistan. I. Correlation of bacteriologic and serologic results. J. Infect. Dis., 121 :S10, 1970. 60. Zalma, V. M., Older, J. J., and Brooks, G. F.: The Austin, Texas, diphtheria outbreak. J.A.M.A., 211 :2125, 1970. Division of Infectious Disea'Ses Children'S Hospital Medical Center 300 Longwood Avenue Boston, Massachusetts 02115