Cover Image

PAPERBACK
$43.50



View/Hide Left Panel

Appendix D-8
The Prospects for Immunizing Against Neisseria meningitidis

This appendix addresses both the prospects for improving vaccines against groups A, C, Y, and W135 Neisseria meningitidis, which are relatively promising, and vaccines against group B, for which significant problems remain to be resolved. Meningococcal disease, the associated immunological phenomena, and vaccination strategies have been recently reviewed (Frasch, 1983, 1985; Griffiss, 1982; Peltola, 1983).

DISEASE DESCRIPTION

Neisseria meningitidis causes about one-third of all cases of bacterial meningitis worldwide. The disease is severe; the untreated case fatality rate approaches 100 percent. The case-fatality rate for properly treated meningitis ranges from 5 percent toward the end of an epidemic when disease is expected, to 15 percent earlier in an epidemic or for sporadic cases. About 10 percent of survivors have neurological sequelae, primarily hearing and vision loss, but motor disorders, seizure disorders, and mental retardation also may occur. This pathogen also causes fulminant meningococcemia, a syndrome of rapidly developing intravascular coagulation and profound shock, pneumonia, arthritis, and carditis. The case-fatality rate for fulminant meningococcemia is from 50 to 70 percent, despite treatment. During epidemics, fulminant

meningococcemia accounts for about 5 percent of cases. Meningococcal disease occurs in two epidemiologic forms: endemic and epidemic. Endemic disease is caused by strains of differing serogroups and serotypes (i.e., A, B, C, Y, and W135), occurs with greatest frequency in infants and very young children, and is uniformly distributed throughout the world. In developed countries, strains of

The committee gratefully acknowledges the efforts of J. McL.Griffiss, who prepared major portions of this appendix, and the advice and assistance of R.Austrian, C.Broome, C.Frasch, E.C.Gotschlich, and A.Reingold. The committee assumes full responsibility for all judgments and assumptions.



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 251
New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Appendix D-8 The Prospects for Immunizing Against Neisseria meningitidis This appendix addresses both the prospects for improving vaccines against groups A, C, Y, and W135 Neisseria meningitidis, which are relatively promising, and vaccines against group B, for which significant problems remain to be resolved. Meningococcal disease, the associated immunological phenomena, and vaccination strategies have been recently reviewed (Frasch, 1983, 1985; Griffiss, 1982; Peltola, 1983). DISEASE DESCRIPTION Neisseria meningitidis causes about one-third of all cases of bacterial meningitis worldwide. The disease is severe; the untreated case fatality rate approaches 100 percent. The case-fatality rate for properly treated meningitis ranges from 5 percent toward the end of an epidemic when disease is expected, to 15 percent earlier in an epidemic or for sporadic cases. About 10 percent of survivors have neurological sequelae, primarily hearing and vision loss, but motor disorders, seizure disorders, and mental retardation also may occur. This pathogen also causes fulminant meningococcemia, a syndrome of rapidly developing intravascular coagulation and profound shock, pneumonia, arthritis, and carditis. The case-fatality rate for fulminant meningococcemia is from 50 to 70 percent, despite treatment. During epidemics, fulminant meningococcemia accounts for about 5 percent of cases. Meningococcal disease occurs in two epidemiologic forms: endemic and epidemic. Endemic disease is caused by strains of differing serogroups and serotypes (i.e., A, B, C, Y, and W135), occurs with greatest frequency in infants and very young children, and is uniformly distributed throughout the world. In developed countries, strains of The committee gratefully acknowledges the efforts of J. McL.Griffiss, who prepared major portions of this appendix, and the advice and assistance of R.Austrian, C.Broome, C.Frasch, E.C.Gotschlich, and A.Reingold. The committee assumes full responsibility for all judgments and assumptions.

OCR for page 251
New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries serogroups B, C, Y, and W135 account for almost all cases. It is unknown whether a similar distribution of serogroups accounts for endemic disease in developing countries. Epidemic meningococcal disease occurs both as focal outbreaks and diffuse epidemics. Outbreaks are usually caused by strains of a single serogroup or serotype (the epidemic strain) or both. Epidemic disease often occurs in older children and young adults (as well as in infants and young children) and is geographically restricted. In the developed world prior to World War II, most outbreaks were caused by strains of serogroup A; this remains the case in most developing countries today. Epidemics of group A disease occur at roughly 10-year intervals in the African meningitis belt and may be associated with periods of warfare or economic decline. Group B and group C strains are also capable of causing epidemics, although the epidemics are usually less severe than those caused by group A strains. Group W135 has only a limited epidemic potential, and group Y is not known to have caused outbreaks. Previous Efforts at Vaccination Six purified capsular polysaccharides have been tested as vaccines in man. In individuals over 2 years of age, vaccines from strains of groups A, C, Y, and W135 reliably induce bactericidal antibodies that provide protection. The group C polysaccharide is not effectively immunogenic in children under 2 years of age. The group A polysaccharide induces low but protective levels of antibody in this age group. Protection as predicted by antibody levels afforded by the group C vaccine is long-lived in those who respond. The duration of protection against group A meningococcal disease appears to be related to world geography and age at time of immunization. Children under 4 years of age have a rapid fall off in antibody. In comparing the African and Finnish experience, the duration of protective efficacy appeared shorter in Africa. One contributing factor may be the presence of endemic malaria; Williamson and Greenwood (1978) observed a rapid decline in group A polysaccharide antibodies in individuals with malaria. Studies have not been conducted of the kinetics of antibodies to the polysaccharides of groups Y and W135. The group B capsule is a homopolymer of alpha 2–8 linked sialic acid and, as such, closely resembles the terminal sialic acid residues on a number of gangliosides, and on polysialyl glycopeptides found in fetal brains. The polysaccharide is also found on the common gut organism E. coli K1; and, as a result, most individuals have primarily IgM antibodies to the B polysaccharide. These antibodies apparently do not facilitate bactericidal killing of the group B organisms. In assessing the effectiveness of the current A, C, Y, and W135 tetravalent vaccine, it is imperative to distinguish between efficacy in the individual vaccinee and efficacy as a public health policy. in vaccinees older than 2 years of age, these four polysaccharides are highly immunogenic (about 85 to 95 percent) with no significant adverse reactions. Administration of the tetravalent vaccine may be less than optimally effective as a public health policy, however, for at least two reasons:

OCR for page 251
New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Epidemics frequently occur in highly mobile populations in which new “recruits” enter the epidemic focus as older residents leave. In such settings, vaccination programs must occur frequently or be continuous. The model for this setting is the military recruit camp, but similar situations have existed during outbreaks of group A disease in the U.S. Pacific Northwest and in Africa. Endemic disease is concentrated in infants and very young children who do not respond to antigens in the existing vaccine(s) or in whom the duration of immunity is short. In general, public health policy has resulted in the utilization of a staggered, case-triggered, pulse-vaccination model that has been shown to be only partially effective. When vaccination has been maintained for long periods of time, as in Finland and in the U.S. military, meningococcal disease has been reliably controlled. Such an approach is quite expensive and involves a level of medical infrastructure that is not present in most countries, even the most highly developed. Thus, even though safe and effective for certain age groups, the currently available vaccines have been used infrequently in the developed world. Their potential benefits in developing countries are difficult to predict from studies conducted in developed countries or from their even more limited use in developing countries. Certain improvements (described below) would undoubtedly render existing meningococcal vaccines more valuable in combating meningococcal diseases in developing countries. PATHOGEN DESCRIPTION The meningococcus is a common commensal of human nasopharyngeal mucous membranes. It spreads from person to person by aerosol droplets. Its colonization of the nasopharynx is often unnoticed in terms of causing disease, and it may persist there for up to 18 months. Factors that influence acquisition are poorly understood. Only encapsulated N. meningitidis strains can cause disseminated disease. The capsule is composed of linear polymers of various sugars that have been chemically characterized. Of the 12 defined capsular groups, only groups A, B, C, Y, and W135 are clinically important. Because the capsular polysaccharides are both chemically and immunologically distinct, a polyvalent approach to vaccine development using these polysaccharides has been necessary. Only the group B polysaccharide is not effectively immunogenic in humans. The outer membrane of the meningococcus also contains protein and lipooligosaccharide (LOS) antigens that, collectively, comprise the serotypes. The same serotype antigens may be found in different serogroups, although those of group A strains are largely distinct from those of the other serogroups. To date, at least five protein serotypes and five LOS serotypes have been associated with epidemic disease. Endemic disease, in contrast, is caused by strains of much greater serotype diversity. However, vaccines containing noncapsular surface antigens are the only practical option for a group B vaccine.

OCR for page 251
New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Progress has been made in developing vaccines containing the outer membrane protein antigens. Recent studies using such vaccines adsorbed to adjuvants indicate that the immunogenicity of some proteins can be markedly improved. Vaccines utilizing LOS antigens have not been clinically evaluated. HOST IMMUNE RESPONSE Organisms residing in the nasopharynx are able to invade the blood stream through as yet unknown mechanisms. Once in the bloodstream, they are rapidly lysed by complement-mediated mechanisms if antibodies are present. Their clearance from the blood stream is markedly improved by the presence of bactericidal antibodies that initiate immune lysis and by the presence of polymorphonuclear leukocytes (Reller et al., 1973). Such antibodies may be directed at the capsular polysaccharides (Käyhty et al., 1981) or at LOS and proteins. The former are responsible for serogroup designations, the latter two for serotype designations (Griffiss et al., 1984). In the absence of antibody, the capsular polysaccharides interfere with the deposition of complement components on the surface of the organism. Among the various capsular groups, the group B capsule is the most “anticomplementary.” This property allows bloodstream survival of the organism, which is necessary for invasion of the meninges. Organisms are able to survive in the sera of infants who lack maternally passed bactericidal antibodies and whose complement systems are poorly developed. They are also able to survive in individuals with isolated deficiencies of immunoglobulins, particularly IgM, and complement components, and in those in whom circulating IgA blocks bactericidal activity (Griffiss, personal communication, 1985). Griffiss (1982) has theorized that the first two mechanisms could account for endemic disease, the third for epidemic disease. Protection against invasive N. meningitidis disease results primarily from circulating antibodies that induce immune lysis (Goldschneider et al., 1969). Protective antibodies are induced to the capsular polysaccharides and to protein and LOS antigens. The antigenic determinants found on the meningococcal capsular polysaccharides are also present on a number of other gram positive and gram negative bacteria. Naturally acquired immunity as measured by the presence of bactericidal antibodies is directed primarily against the capsular polysaccharides and is largely derived from exposure to cross-reacting organisms. Following the decline of maternally acquired antibodies (primarily directed at serotype antigens) between 2 and 6 months of age, serum bactericidal activity gradually rises (to an extent that varies with location and individual) and is clearly detectable in most children by 18 to 36 months of age. It then rises slowly, reaching adult levels by 12 years of age. The mechanism by which bactericidal antibodies are induced is unclear. Colonization with N. lactamica has been documented in populations throughout the world. It occurs at an earlier age than does colonization with N. meningitidis and is often, but not invariably,

OCR for page 251
New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries associated with the induction of bactericidal activity. Nasopharyngeal colonization with meningococcal strains also results in the induction of bactericidal antibody, although induction of antibody to the capsular polysaccharides is variable. Enteric colonization with organisms of other genera that elaborate the same or similar surface antigens as those of the meningococcus occurs commonly and also probably induces bactericidal antibody. Induction of capsular antibodies early in life is the goal of the current polysaccharide vaccines. DISTRIBUTION OF DISEASE Geographic Distribution The Sahel region of Africa represents a geographic and epidemiologic special case. The climatically defined area between the 300 mm and 1,100 mm isohyets (lines joining points receiving equal amounts of precipitation over a specified period of time) has been termed the “meningitis belt.” It extends across the Sahel from Ethiopia to eastern Senegal and The Gambia. An extension extends southward through Uganda, Kenya, and Tanzania. All or parts of the following countries are included in the belt: Ethiopia, Sudan, Central African Republic, Chad, Niger, Nigeria, Cameroon, Benin, Ghana, Ivory Coast, Burkina Faso (formerly Upper Volta), Mali, Guinea, Senegal, The Gambia, and Mauritania. In this belt, massive epidemics of group A meningococcal disease occur about every 10 years. Because of the devastating nature of these predictable epidemics, global strategies for preventing meningococcal disease must be targeted to this area to be successful. Meningococcal disease is seasonal. Survival of the meningococcus in aerosolized droplets is highly dependent on humidity, but not temperature. Humidity conditions favorable to transmission of the meningococcus can occur in temperate climes in late winter and early spring, and with the transition from dry to wet seasons in South America and sub-Saharan Africa. During these times the incidence of endemic disease increases and epidemics occur. Epidemics have also occurred in recent years in southwest Asia, Nepal, India, China, Brazil, and Finland. Epidemic meningococcal disease does not occur in deserts or in invariably humid climates, such as in rain forests or deserts. Endemic meningococcal disease is presumed to be distributed worldwide, although data are not available from most areas. Disease Burden Estimates Little reliable data are available on the worldwide incidence of meningococcal meningitis from which to estimate the disease burden arising from endemic and epidemic disease caused by N. meningitidis. The following calculations have been extrapolated from those studies that have been published and rely, of necessity, on informed judgment.

OCR for page 251
New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-8.1 Population of Countries in the African Meningitis Belt Country Population (millions) Benin 3.9 Burkina Faso 6.7 Cameroon 9.4 Central African Republic 2.6 Chad 5 Ethiopia 32 Ghana 14.3 Guinea 5.6 Ivory Coast 9.2 Kenya 19.4 Mali 7.6 Mauritania 1.8 Niger 6.3 Nigeria 88.1 Senegal 6.5 Sudan 21.1 Tanzania 21.2 The Gambia 0.7 Uganda 14.3 Total 275.7   SOURCE: Population Reference Bureau (1984). Epidemic Meningococcal Meningitis Incidence rates in epidemic years were estimated from data for the 1979 epidemic in Burkina Faso (Broome et al., 1983). The rates derived by this approach are consistent with those reported from Zaria, Nigeria (Greenwood, 1984), with the exception of the youngest age groups, for which they are higher. To derive an estimate of the population at risk of epidemic disease, the total population of countries in the African meningitis belt was assumed to be at risk (Table D-8.1). No attempt was made to include estimates of epidemic disease occurring in other parts of the world. This omission is counterbalanced to an unknown extent by including in the calculation of populations at risk, portions of some countries (e.g., Ivory Coast, Cameroon, and Guinea) or major population centers (e.g., The Gambia, Nigeria, Kenya, and Benin) that lie outside the belt. Epidemics are assumed to occur about every 10 years, and an average fatality rate of 10 percent is assumed on the basis of reported fatality rates in recent epidemics (Broome et al., 1983; Greenwood, 1984; Greenwood et al., 1979). Table D-8.2 shows the annual number of epidemic N. meningitidis cases and deaths estimated to occur on adopting these assumptions.

OCR for page 251
New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-8.2 Estimated Annual Number of Epidemic N. meningitidis Cases and Deaths Age Group (years) Incidence per 100,000 Population Population Number of Cases Average Number of Cases Case Fatality Rate (percent) Average Number of Deaths Under 5 736 50,337,040 370,481 37,048 10 3,705 5–14 600 73,588,680 441,532 44,153 10 4,415 15–59 200 138,034,520 276,069 27,607 10 2,761 60 and over 50 14,189,760 7,095 709 10 71 TABLE D-8.3 Estimated Annual Number of Endemic N. meningitidis Cases and Deaths Age Group (years) Incidence per 100,000 Population Population Number of Cases Case Fatality Rate (percent) Number of Deaths Under 5 5.4 498,559,000 26,922 20 5,384 5–14 6.1 909,366,000 55,471 10 5,547 15–59 2.4 1,954,728,000 46,913 25 11,728 60 and over 0.8 232,347,000 1,859 80 1,487 Endemic Meningococcal Meningitis Incidence rates for endemic meningococcal meningitis can be derived from the data reported by Cadoz et al. (1981) for Dakar, Senegal (a city that lies outside the major meningitis belt). In the absence of alternative methods for estimating the disease burden, these rates are assumed to apply to the populations of all developing countries. Age-specific mortality rates were estimated from data presented by Cadoz et al. (1981). The number of endemic meningococcal cases and deaths derived from the application of these assumptions is shown in Table D-8.3. It is assumed that all acute cases of N. meningitidis fall into morbidity category C. The total average number of endemic and epidemic N. meningitidis cases and deaths is shown in Table D-8.4. Information is scant on the sequelae of meningococcal meningitis in developing countries. On the basis of observations of a recent epidemic in The Gambia by Griffiss (personal communication, 1985), it was assumed that 15 percent of survivors suffer mild (category D) neurological sequelae (e.g., hearing loss), and that 1 percent suffer moderate (category E) chronic neurological problems. Adopting these assumptions yields the total disease burden for N. meningitidis shown in Table D-8.5.

OCR for page 251
New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-8.4 Disease Burden: Neisseria meningitidis—Acute Epidemic and Endemic Cases       Under 5 Years 5–14 Years 15–59 Years 60 Years and Over Morbidity Category Description Condition Number of Cases Duration Number of Cases Duration Number of Cases Duration Number of Cases Duration A Moderate localized pain and/or mild systemic reaction, or impairment requiring minor change in normal activities, and associated with some restriction of work activity                   B Moderate pain and/or moderate impairment requiring moderate change in normal activities, e.g., housebound or in bed, and associated with temporary loss of ability to work                   C Severe pain, severe short-term impairment, or hospitalization Meningitis 63,970 14 99,624 14 74,520 14 2,568 14 D Mild chronic disability (not requiring hospitalization, institutionalization, or other major limitation of normal activity, and resulting in minor limitation of ability to work)     n.a.   n.a.   n.a.   n.a. E Moderate to severe chronic disability (requiring hospitalization, special care, or other major limitation of normal activity, and seriously restricing ability to work)     n.a.   n.a.   n.a.   n.a. F Total impairment     n.a.   n.a.   n.a.   n.a. G Reproductive impairment resulting in infertility     n.a.   n.a.   n.a.   n.a. H Death   9,089 n.a. 9,962 n.a. 14,489 n.a. 1,558 n.a.   Survivors   54,881   89,662   60,031   1,010  

OCR for page 251
New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-8.5 Disease Burden: Neisseria meningitidis—Total Disease Burden       Under 5 Years 5–14 Years 15–59 Years 60 Years and Over Morbidity Category Description Condition Number of Cases Duration Number of Cases Duration Number of Cases Duration Number of Cases Duration A Moderate localized pain and/or mild systemic reaction, or impairment requiring minor change in normal activities, and associated with some restriction of work activity                   B Moderate pain and/or moderate impairment requiring moderate change in normal activities, e.g., housebound or in bed, and associated with temporary loss of ability to work                   C Severe pain, severe short-term impairment, or hospitalization Meningitis 63,970 14 99,624 14 74,520 14 2,568 14 D Mild chronic disability (not requiring hospitalization, institutionalization, or other major limitation of normal activity, and resulting in minor limitation of ability to work) Neurological sequelae, e.g., mild hearing loss, motor disorders 8,232 n.a. 13,449 n.a. 9,005 n.a. 152 n.a. E Moderate to severe chronic disability (requiring hospitalization, special care, or other major limitation of normal activity, and seriously restricting ability to work) Neurological sequelae, e.g., vision loss 549 n.a. 897 n.a. 600 n.a. 10 n.a. F Total impairment     n.a.   n.a.   n.a.   n.a. G Reproductive impairment resulting in infertility     n.a.   n.a.   n.a.   n.a. H Death   9,089 n.a. 9,962 n.a. 14,489 n.a. 1,558 n.a.

OCR for page 251
New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Uncertainty in the Disease Burden Estimates The omission of epidemic disease occurring outside the sub-Saharan meningitis belt from the estimates is probably only partly counterbalanced by including certain nonepidemic risk areas or major population centers from some countries within the belt in estimated calculations. Major epidemics occur in regions of the world other than the recognized belt (e.g., South America), and minor ones occur in many parts of the world, including such developed countries as Finland (Feldman, 1982). These facts suggest that the estimate, at least for epidemic disease, is probably a minimal one. Calculations for endemic disease—based on the extrapolation of data from one region to the entire developing world—are highly uncertain because of the limited data base. Rates of incidence of endemic disease suggested by Gotschlich (1984) would yield lower estimates of the total burden of disease. PROBABLE VACCINE TARGET POPULATION Two separate vaccine strategies are required to combat disease caused by N. meningitidis—one for endemic disease and another for epidemic disease. Endemic disease is frequently caused by serogroup B. Most of this endemic disease would not be preventable by the candidate vaccine for serogroups A, C, Y, and W135 considered in this report. Some endemic disease caused by serogroups C, Y, and W135 might be prevented, however, by a conjugated polysaccharide vaccine administered universally to infants and young children through the World Health Organization Expanded Program on Immunization (WHO-EPI). Such a vaccine would have to be efficacious with doses given to children under 1 year of age. For the calculations that follow (and that are shown in Chapter 7), the vaccine target population for endemic disease is considered to be the birth cohort in developing countries. Epidemic disease most often occurs in young children, but it also may occur in older children and young adults. It is most frequently caused by serogroup A strains. Because persons over age 2 generally respond well to immunization with polysaccharides from serogroups A, C, Y, and W135, successful prevention of most epidemic disease should be feasible with the candidate vaccine. The universal immunization program described above eventually would (in the steady state for which calculations have been made) protect against most epidemic disease. However, an interim vaccine strategy would be necessary to prevent disease in persons too old to have been included in the initial WHO-EPI effort. Two alternative strategies could be used: one would involve targeted vaccination of susceptible individuals in areas where epidemics are anticipated, the other would consist of universal preschool immunization.

OCR for page 251
New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Vaccine Preventable Illness* Estimates of the proportion of the disease burden that is potentially vaccine preventable are based on the assumptions that an improved vaccine for groups A, C, Y, and W135 (but not B) that confers long-lasting immunity when administered to infants is developed and used universally in the developing world. Estimates provided by Griffiss (personal communication, 1985) suggest that, for the meningitis belt, about 95 percent of epidemic disease is caused by group A, 4 percent by group C, and 1 percent by group W135. Group Y does not appear to cause epidemics, and epidemic group B disease has rarely been reported from developing countries. (However, an epidemic of group B disease is currently occurring in Chile.) Of endemic disease in the Sahel (i.e., in the absence of epidemics), about 60 percent is caused by group C, 35 percent by group A, 3 percent by group W135, and the remainder by groups B and Y (Griffiss, personal communication, 1985). (Endemic cases may continue to occur during an epidemic.) These estimates are in agreement with the suggestion by Feldman (1982) that group B is responsible only for localized outbreaks or sporadic cases. These patterns cannot be extrapolated, perhaps, to the entire developing world. However, in parts of the world other than the meningitis belt, the general pattern that group B is a relatively minor cause of disease seems to be consistent. For example, the Brazilian epidemics of the 1970s were caused by group A or group C (Feldman, 1982). Although there are some indications that group B is now a problem in Niger (Griffiss, personal communication, 1985), there is little basis on which to predict shifts from the pattern described above. The small proportion of the total meningococcal disease burden in developing countries that is caused by group B (for which the vaccine will not provide protection) suggests that a very high proportion of the disease burden will be vaccine preventable. In the youngest vaccine recipients, only partial protection will be provided until the full course of immunization (probably at least two doses) has been completed. However, relatively little disease occurs in children under 6 months of age. Based on the above considerations, it is estimated that 95 percent of meningococcal meningitis is theoretically preventable with a hypothetical fully effective improved vaccine for groups A, C, Y, and W135. *   Vaccine preventable illness is defined as that portion of the disease burden that could be prevented by immunization of the entire target population (at the anticipated age of administration) with a hypothetical vaccine that is 100 percent effective (see Chapter 7).

OCR for page 251
New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries SUITABILITY FOR VACCINE CONTROL Meningococcal disease theoretically is well suited to control by active immunization for several reasons: the organism is pathogenic only in man, antibody appears to provide protection, protective antibody is reliably induced in infancy in most individuals, and an opportunity to induce humoral immunity exists between the decline of maternal antibodies (2 to 6 months) and the onset of disease (after 6 months). Current treatment regimens are quite effective if initiated promptly, but they are expensive and difficult to administer in developing countries. They are followed also by unacceptably high rates of neurologic sequelae. The social and economic burden of this disease, particularly in Africa, is enormous. There is a critical need to develop an appropriate preventive strategy. Alternative Control Measures and Treatments Chemoprophylaxis provides an alternative approach to the prevention of meningococcal disease. Prior to the development of polysaccharide vaccines, Chemoprophylaxis with sulfonamides was used routinely. Since 1960, many strains of meningococci have become resistant to sulfonamides, and sulfonamide prophylaxis can no longer be recommended. Chemoprophylaxis with rifampin is an alternative that has been used in developed countries. Because of its expense, however, it is unsuited for use in developing areas (Blakebrough and Gilles, 1980). Minocycline is also effective, but it causes a rather high rate of side effects (18 to 35 percent). In most of Africa, meningococcal meningitis is treated with a single dose (3 g) of chloramphenicol in oil (Wali et al., 1979). The case fatality rate following such treatment is about 10 percent. Other treatment regimens have been developed, but none is superior to chloramphenicol. PROSPECTS FOR VACCINE DEVELOPMENT Gotschlich (1984) has comprehensively reviewed the development of existing meningococcal vaccines and their characteristics. The principal drawback of the existing polysaccharide vaccines against N. meningitidis (groups A, C, Y, and W135) is their inability to induce protective, long-lasting immunity in young children and in some older individuals. The reasons for this failure are poorly understood. Additional research is required into the basic mechanisms of the immune response to polysaccharides. The poor immunogenicity of some capsular polysaccharides may be a result of immunologic tolerance, suggesting the presence of cross-reactive human epitopes. Genetic differences and environmental factors (such as co-existing infection) also may affect the response to polysaccharide antigens. Finally, researchers need to learn more about the optimum size and physiochemical form of polysaccharides selected for use in vaccines.

OCR for page 251
New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Additional research is required on the basic mechanisms of the immune response to polysaccharides, including the role of serum IgA in meningococcal immunity. Potential New Vaccines To gain worldwide acceptance, a new vaccine for N. meningitidis should (1) be safe; (2) be immunogenic in infancy, or at least by 6 months of age; (3) be inexpensive to make and administer; (4) be easy to administer; and (5) provide long-term protection. The capacity to provide herd immunity, possibly via reduction in carriage of meningococci, would be an added advantage. The most promising candidates to date are the protein conjugate vaccines. Polysaccharide-protein conjugates have been studied extensively in the preparation of H. influenzae type b vaccines. Early clinical studies demonstrated that these vaccines, prepared with high molecular weight polysaccharide attached either to diphtheria or to tetanus toxoid, provide greater immunogenicity than the polysaccharide alone in children under age 3 (Lepow and Gordon, 1984; Zahradnik and Gordon, 1984). Research on the potential use of such conjugates in N. meningitidis vaccines will focus on determination of the best polysaccharide-protein combinations, the optimal chain length of the polysaccharide, and the degree and method of coupling the protein. The committee believes the prospects for improved (conjugate) vaccines for groups A, C, Y, and W135 are promising, but that for reasons discussed below the short-term prospects for a broadly effective vaccine against group B are not good. Other potential candidates for N. meningitidis vaccines include the lipopolysaccharide-derived (LPS) vaccines (Zollinger and Mandrell, 1980; Zollinger et al., 1979), live vaccines, immune complex vaccines, vaccines from surface peptides and fimbriae, and anti-idiotype vaccines. The development of successful immunization programs would also be greatly aided by better descriptive epidemiological and immunologic information for meningococcal disease from various populations over time. Conclusions drawn from studies in developed countries are of limited use for developing areas of the world. Also, a standardized methodology for measuring antipolysaccharide antibodies of different isotypes does not yet exist. The development of new laboratory methods to profile the immune response to N. meningitidis and to identify bacterial strains will increase the usefulness of future clinical trials. Obstacles to Development of Vaccines Against Group B Strains The major obstacle to preparation of a vaccine against this important cause of meningococcal meningitis is that the group B capsular polysaccharide is not an effective immunogen in mice or in humans (Frasch, personal communication, 1984; Wyle et al., 1972). Attempts to increase its immunogenicity by noncovalent linkage to the

OCR for page 251
New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries outer membrane proteins have been only minimally successful (Zollinger and Mandrell, 1983; Zollinger et al., 1979, 1982). Although the resultant vaccine stimulates antibodies, they are all of the IgM class, they usually do not persist beyond a few weeks, and they are variably bactericidal with human complement. Efforts to improve the polysaccharide’s immunogenicity by using adjuvants or covalent linkage to proteins must be pursued with caution because certain structures in the human fetal and newborn brain contain short oligosaccharides of sialic acid with the same alpha 2–8 linkage (Finne et al., 1983; Soderstrom et al., 1984; Zollinger et al., 1979). This potential cross-reactivity may explain, in part, the poor immunogenicity of the group B polysaccharide. The serotype proteins of the outer membrane, when prepared properly, induce a more promising antibody response. The antibodies persist for at least 8 months, appear to be of reasonably high avidity, and are bactericidal with human complement (Zollinger and Mandrell, 1983; Zollinger et al., 1979, 1982). However, their protective efficacy remains unproven. The drawback is that these antibodies are primarily type specific and probably would not provide protection against heterologous group B strains. More research needs to be done to determine how many serotypes would be required in a vaccine to provide a reasonable level of protection, the rate at which new serotypes appear, and the breadth of antigenic specificity of each of the membrane proteins. However, only a few serotypes, principally types 2 and 15, are associated with most group B meningococcal disease. In addition to pursuing more information on outer membrane/group B polysaccharide vaccines, researchers are evaluating other surface antigens (e.g., lipopolysaccharides, pili, and iron-binding proteins) that may be common to all group B strains. REFERENCES Blakebrough, I.S., and H.M.Gilles. 1980. The effect of rifampicin on meningococcal carriage in family contacts in northern Nigeria, J. Infect. Dis. 2:137–143. Broome, C.V., M.A.Rugh, A.A.Yada, L.Giat, H.Giat, J.M.Zeltner, W.R.Sanborn, and D.W.Fraser. 1983. Epidemic group C meningococcal meningitis in Upper Volta, 1979. Bull. WHO 61(2):325–330. Cadoz, M., F.Denis, and I.Diop Mar. 1981. An epidemiological study of purulent meningitis cases admitted to hospitals in Dakar, 1970–1979 (in French). Bull. Organ. Mond. Santé 59(4):575–584. Feldman, H.A. 1982. Meningococcal infections. Pp. 327–344 in Bacterial Infections of Humans, A.S.Evans and H.A.Feldman, eds. New York: Plenum. Finne, J., M.Leinonen, and P.H.Mäkelä. 1983. Antigenic similarities between brain components and bacteria causing meningitis. Implications for vaccine development and pathogenesis. Lancet II(8346): 355–357.

OCR for page 251
New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Frasch, C.E. 1983. Immunization against Neisseria meningitidis. Pp. 115–144 in Medical Microbiology Volume 2: Immunization Against Bacterial Disease, C.S.F.Easmon and J.Jelijaszewicz, eds. New York: Academic. Frasch, C.E. 1984. Personal communication, Food and Drug Administration, Bethesda, Md. Frasch, C.E. 1985. Status of a group B Neisseria meningitidis vaccine. Eur. J.Clin. Microbiol. 4(6):533–536. Goldschneider, I., E.C.Gotschlich, and M.S.Artenstein. 1969. Human immunity to the meningococcus. I. The role of humoral antibodies. J. Exp. Med. 129:1307–1326. Gotschlich, E.C. 1984. Meningococcal meningitis. Pp. 237–255 in Bacterial Vaccines, R.Germanier, ed. New York: Academic Press. Greenwood, B.M. 1984. Selective primary health care: Strategies for control of disease in the developing world. XIII. Acute bacterial meningitis. Rev. Infect. Dis. 6(3):374–389. Greenwood, B.M., P.G.Cleland, M.H.K.Haggie, L.S.Lewis, J.T. MacFarlane, A.Taqi, and H.C.Whittle. 1979. An epidemic of meningococcal infection at Zaria, Northern Nigeria. 2. The changing clinical pattern. Trans. Roy. Soc. Trop. Med. Hyg. 73(5):563–566. Griffiss, J. McL. 1982. Epidemic meningococcal disease: Synthesis ofa hypothetical immmunologic model. Rev. Infect. Dis. 4:159–172. Griffiss, J.McL. 1985. Personal communication, University of California School of Medicine, San Francisco, Calif. Griffiss, J.McL., B.L.Brandt, D.D.Broud, D.K.Goroff, and C.J.Baker. 1984. Immune response of infants and children to disseminated Neisseria meningitidis infection. J. Infect. Dis. 150:71–79. Käyhty, H., H.Jousimies-Somer, H.Peltola, and P.H.Mäkelä. 1981. Antibody response to capsular polysaccharides of groups A and C Neisseria meningitidis and Haemophilus influenzae type b during bacteremic disease. J. Infect. Dis. 143:32–41. Lepow, M.L., and L.K.Gordon. 1984. Immunogenicity and safety of PRP-D, a synthetic conjugate of H. influenzae b polysaccharide (PRP) with diphtheria toxoid (D). Abstract 951 in Abstracts of the Twenty-Third Interscience Conference on Antimicrobial Agents and Chemotherapy, Las Vegas, Oct. 24–26, 1983. Peltola, H. 1983. Meningococcal disease: Still with us. Rev. Infect. Dis. 5:71–91. Population Reference Bureau. 1984. 1984 World Population Data Sheet. Washington, D.C.: Population Reference Bureau. Reller, L.B., R.R.MacGregor, and H.N.Beaty. 1973. Bactericidal antibody after colonization with Neisseria meningitidis. J. Infect. Dis. 127:56–62. Soderstrom, T., G.Hansson, and G.Larson. 1984. The Escherichia coli K1 capsule shares antigenic determinants with the human gangliosides GM3 and GD3. N. Engl. J. Med. 310(11):726–727. Wali, S.S., J.T.MacFarlane, W.R.C.Weir, P.G.Cleland, P.A.J.Ball, M.Hassan-King, H.C.Whittle, and B.M.Greenwood. 1979. Single injection treatment of meningococcal meningitis. 2. Long-acting chloramphenicol. Trans. Roy. Soc. Trop. Med. Hyg. 73:698–702.

OCR for page 251
New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Williamson, W.A., and B.M.Greenwood. 1978. Impairment of the immune response to vaccination after acute malaria. Lancet I:1328–1330. Wyle, F.A., M.S.Artenstein, B.L.Brandt, E.C.Tramont, D.L.Kasper, P.L.Altieri, S.L.Berman, and J.P.Lowenthal. 1972. Immunologic response of man to group B meningococcal polysaccharide vaccines. J. Infect. Dis. 126(4):514–522. Zahradnik, J.M., and L.K.Gordon. 1984. Augmented antibody responses in infants administered a new Haemophilus influenzae type b capsular polysaccharide (PRP) diphtheria toxoid conjugate vaccine (PRP-D). Abstract 1162. Pediatr. Res. 18:289A. Zollinger, W.D., and R.E.Mandrell. 1980. Type-specific antigens of group A Neisseria meningitidis: Lipopolysaccharide and heat-modifiable outer membrane proteins. Infect. Immun. 28:451–458. Zollinger, W.D., and R.E.Mandrell. 1983. Importance of complement source in bactericidal activity of human antibody and murine monoclonal antibody to meningococcal group B polysaccharide. Infect. Immun. 40(1):257–264. Zollinger, W.D., R.E.Mandrell, J.McL. Griffiss, P.Altieri, and S.Berman. 1979. Complex of meningococcal group B polysaccharide and type 2 outer membrane protein immunogenic in man. J. Clin. Invest. 63(5):836–848. Zollinger, W.D., R.E.Mandrell, and J.McL. Griffiss. 1982. Enhancement of immunologic activity by noncovalent complexing of meningococcal group B polysaccharide and outer membrane proteins. Pp. 254–262 in Seminars in Infectious Disease. Volume IV: Bacterial Infections, L.Weinstein and B.N.Fields, eds. New York: Thieme-Stratton.