Current and future trends in immunization against meningitis

Transcription

1 Journal of Antimicrobial Chemotherapy (1993) 31, Suppl. B Current and future trends in immunization against meningitis D. M. Jones Manchester Public Health Laboratory, Withington Hospital, Manchester M20 8LR, UK The progress in vaccines for Haemophihis influenzae type b infection is followed; it is the disadvantages of pure polysaccharide vaccines that have stimulated the development of the present generation of polysaccharide-protein conjugated vaccines. From extensive clinical trials it is apparent that these are very effective in preventing disease in children. Conjugated haemophilus vaccines were introduced into the routine immunization schedules in the UK in Autumn Meningococcal A and C polysaccharide vaccines, effective for epidemic disease, are only now being developed in a protein conjugated form with the prospect of protecting young children and producing durable immunity Group B outer membrane-based meningococcal vaccines produce only a low degree of protection and much further work is needed before even the optimum vaccine constituents of this organism can be identified. Vaccines to replace multivalcnt pneumococcal polysaccharide mixtures are only in the very earliest stages of development. Introduction Bacterial meningitis is a major health problem worldwide. In Great Britain at least one child in every thousand may contract meningitis before the age of ten. The major causes are Neisseria meningitidis, Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae. The majority (86%) of Hib infections occur in children undet five, and in a recent survey in England and Wales the estimated incidence was 26-4/100,000 in children of this age (Nazareth et al., 1992). Most of these infections present as meningitis but bacteraemia, epiglottitis, cellulitis and pneumonia also occur. The mortality from Hib meningitis is about 5% and a portion of survivors have some neurological sequelae such as hearing loss. Just over 50% of meningococcal infections also occur in children under five; this infection therefore has a more extended age range than Hib infection. In England and Wales meningococcal infections are rather more common than Hib infections and have an overall mortality of about 10%, with the bacteraemic form having a poorer prognosis. About 20% of cases of bacterial meningitis are caused by S. pneumoniae and these also occur in a wider age range than just children. All forms of bacterial meningitis still have a significant mortality and morbidity and this underscores the desirability of the prevention of these infections. Chemoprophylaxis at best offers little chance of control and the increasing frequency of resistance to ampicillin and chloramphenicol among Hib isolates, and penicillin resistance in pneumococci (Ridgway et al., 1992), complicates the choice of antibiotic for /93/31B J08.00/ The Britiih Society for Antimicrobial Chemotherapy

2 94 D. M. Jones therapy. Active immunization of children offers the only real long-term solution to reducing the incidence of these infections. Haemophilus inftuenzae type b vaccines It has been known for many years that antibody to the capsule of Hib (polyribosylribitol phosphate, PRP) was effective in preventing disease caused by this bacterium. This protective effect was the stimulus to produce a purified polysaccharide vaccine, and although this vaccine produced antibody in adults and children, it was poorly immunogenic in children younger than two years. Furthermore, no booster response was elicited, a feature of T-cell independent antigens. A large study in Finland (Peltola et al., 1977a) confirmed the lack of protection in children under 18 months of age and at the same time demonstrated 90% efficacy in older children. Another disadvantage of this vaccine is that certain ethnic groups can respond significantly less well than others. Native American children (Eskimo, Inuit, Navajo, Apache) have a high incidence of Hib infection and this has been shown to correlate with a poor immunological response to Hib polysaccharide (Siber et al., 1990). It is therefore possible that there are other ethnic groups that respond poorly to similar bacterial polysaccharides. These experiences led to attempts to improve the immunogenicity of the vaccine by covalently unking the polysaccharide to a protein carrier to produce a 'conjugate' vaccine. A variety of proteins have been investigated and different conjugate vaccines produced (Table). PRP-T is a large polysaccharide polymer linked to tetanus toxoid via a sixcarbon spacer molecule by multiple linkages resulting in a three-dimensional complex. PRP-D vaccine consists of a medium sized polysaccharide polymer linked to diphtheria toxoid by a six-carbon spacer, so the molecular structure differs from PRP-T. Outer-membrane vesicles of N. meningitidis are linked to a medium size PRP polymer via a spacer molecule in the PRP-OMP conjugate vaccine. In another variation, HbOC, the protein carrier is derived from a non-toxigenic mutant of diphtheria toxin covalently linked to several short oligosaccharides of PRP. Although protective levels of PRP antibody have not been adequately defined, they are likely to be between 0125 and 1-0 mg/l. On this basis the conjugate vaccines are highly immunogenic. In a field trial of PRP-D vaccine in Finland given to children at ages 3, 4, 6, and months, the protective efficacy was 94%, and mean antibody levels after the fourth dose were 45-2 mg/l. It is likely therefore that prolonged immunity was produced although the exact duration remains to be determined. The effectiveness of this vaccine programme was confirmed by a six-fold reduction in the incidence of Hib disease in Finland during (Eskola et al., 1990). In a trial of PRP-OMP vaccine (two doses, at ages of two months and four months) in Navajo infants, a protective efficacy of 95% was observed indicating that at least in some instances an ethnically determined poor response to Vaccine Polysaccharide size Table H. tnftuenzae type b conjugate vaccines Protein carrier Linkage PRP-T PRP-D PRP-OMP HbOC large medium medium small tetanus toxoid diphtheria toxoid meningococcal outer-membrane protein diphtheria toxin mutant spacer spacer spacer direct link

3 Meningitis immunization 95 polysaccharides may be overcome with a conjugate vaccine (Santosham et al., 1991). There are significant differences in the kinetics of the immunological response in infants caused by the different vaccines (Lieberman, Greenberg & Ward, 1990). As the majority of cases of the disease occur in the first two years of life, it is the focus on performance of these vaccines in this age group that is particularly relevant, together with their suitability for inclusion in infant vaccination programmes. The outer membrane protein conjugate [PRP-OMP] produces protective levels of antibody after the first dose, PRP-T after two doses and HbOC requires three. Antibody levels drop more rapidly after administration of PRP-OMP and slowest after HbOC (Pinson & Weart, 1992). The choice of vaccine is therefore not straightforward and to some extent depends on the environment where they are to be used. In the UK conjugated Hib vaccines have been incorporated into the routine immunization schedule for infants. In this situation the likelihood of completion of a course of three injections is high and the choice of vaccine may be dififerent from that in a less developed healthcare situation where more than one attendance at a clinic is unusual. Whether the conjugate vaccines can be co-administered with diphtheria-tetanus toxoid-pertussis vaccine, needs to be considered; this has been investigated for PRP-T (Ferreccio et al., 1991). The results indicate a slight diminution in the response to the conjugate if the vaccines are given in the same injection, but this may well be outweighed by the practical advantages and recipient acceptability. Similar studies are needed, for other conjugate vaccines. There is little information on what would happen if the same vaccine was not used thoughout the vaccination course and the practical problem of having alternative and quite different conjugate vaccines available in a particular locality has not yet been addressed. Another interesting and probably very important phenomenon has been observed, that the pharyngeal carriage rate of Hib appears to be reduced in children immunized with PRP-D (Takala et al., 1991). Concurrent carriage of non-capsulated H. influenzae and pneumococci were not affected, suggesting that this was a very specific effect and one that was not seen in children immunized with pure polysaccharide vaccine. These observations were made in Finland and could presage a much more powerful preventive effect on Hib disease than was expected. Such effects will need to be monitored in other communities where conjugate vaccines are to be introduced. While we still need to know more about delivery of these vaccines, they are effective and have a low incidence of adverse events (Tudor-Williams et al., 1989). The present stage of development with regard to disease caused by haemophilus is exciting, as almost complete control of this infection would seem to be ultimately within our grasp. The experiences with conjugate haemophilus vaccine will have some bearing on the further development of meningococcal polysaccharide vaccines. Group A and C meningococcal vaccines Polysaccharide vaccines derived from group A and group C meningococci were developed over 20 years ago and shown to be effective. They were used for controlling group C disease in the military personnel in the USA and later for epidemic group A disease in Africa. That group A polysaccharide vaccine protects young children was shown in Finland in the course of a large epidemic (Peltola et al., 19776). However, immunity is not long lasting and three tofiveyears after vaccination protection is much reduced (Reingold et al., 1985). This has obvious disadvantages for use in the African

4 96 D. M. Jones 'meningitis belt' where the disease is constantly present with epidemic waves every few years. Group A vaccine has been a potent force in controlling local epidemics in Africa and other areas, for example the 1987 outbreak in Saudi Arabia associated with the Haj. The lack of durable immunity means that the overall impact of polysaccharide vaccine on the continuing problem of group A disease has been less than was hoped. Group C polysaccharide elicits a weaker response than the group A polysaccharide and is poorly immunogenic in children under two years of age. This vaccine has been used effectively in outbreak control, particularly in schools and military camps (Masterton et al., 1988) where durable protection is not required. That it may not always be effective in outbreak control was shown by the occurrence of post-vaccination cases in an outbreak of group C meningococcal infection among Australian aboriginal children. An investigation of post-vaccination sera indicated that 25% of these children failed to respond to the group C polysaccharide (unpublished observations). Although only a small amount of disease is due to group Y and W135, the meningococcal polysaccharide vaccines have been formulated in quadrivalent form (groups A, C, Y, W135) to maximize coverage. The appreciation of the importance of the shortcomings of these polysaccharide vaccines has been slow and conjugate vaccines are only now being developed. If these are effective in the young and produce a more durable immunity they will be much more useful in Africa and other epidemic or hyper-endemic areas. As with disease caused by haemophilus, protection in infants is desirable and a group C conjugate vaccine would credibly form a component of an infant vaccination schedule in the future. Group B meningococcal vaccines In the majority of developed countries most meningococcal disease is due to group B meningococci. The polysaccharide capsule of this organism is poorly immunogenic and although anti-b polysaccharide antibody is detectable both in normal and in convalescent sera this is of low titre, is IgM and appears to have little bactericidal activity (Skevakis et al., 1984). There may be some immune tolerance to the group B polysaccharide based on similarities between this and polysialicacid glycopeptides in brain tissue. As a result of these observations the search for an effective group B vaccine has concentrated largely on sub-capsular antigens, the outer membrane proteins and lipooligosaccharides. The antigens that elicit the protective response to group B infection have not yet been identified, although much is known about the immunogenicity and structure of various surface-exposed antigens. There have been a number of candidate vaccines that have proven immunogenicity, but demonstrating that they produce protection has been more difficult. As a response to hyperendemic group B disease in Cuba in the late 1970s and early 1980s a vaccine derived from outer membrane proteins of the epidemic strain was developed also incorporating group C polysaccharide and aluminium hydroxide. In a controlled trial in school children this vaccine was shown to have an efficacy of 83%. The vaccine was given widely in Cuba but at a time when the epidemic was waning, making it difficult to assess its efficacy in the general community. However, laboratory data was consistent with the level of protection attained in school children and also indicated that protection against other group B serotypes was likely (Sierra el al., 1991). The constituents of this relatively crude vaccine containing many bacterial antigens make it difficult to standardize, and this also might result in significant batch to batch variation and therefore possibly variation in protection. In a

5 Meningitis immunization 97 recent outbreak of mcningococcal disease in Sao Paulo, 2-4 million children were given the Cuban vaccine and a concurrent small case control study conducted. The antibody response in under two yean olds was particularly poor and estimates of efficacy were much lower than those obtained in Cuba (Costa et al., 1991). A more refined outer membrane based vaccine was tested for efficacy in Chile in This vaccine contained reduced levels of some outer membrane proteins, very little lipo-oligosaccharide and was complexed to group C polysaccharide. Although immunogenic, the antibody levels were not long-lasting and the efficacy was 51%. Most recently the results of a trial in Norway have become available (Bjune et al., 1991). In this trial 171,800 students took part in a double-blind placebo-controlled trial of an outer membrane vesicle based vaccine derived from the serotype responsible for most of the disease in Norway for more than 15 years. This vaccine was composed of the whole outer membrane complex adsorbed to aluminium hydroxide and was shown to be immunogenic and to stimulate bactericidal antibodies. However, the efficacy was only 57%, so although conferring some protection the performance was not regarded as adequate for a general vaccination programme. There is therefore evidence that some protection is being afforded by outer membrane based vaccines, and this provides a forceful stimulus to the continued development of an effective vaccine along these lines. Some outer membrane proteins may be undesirable in a vaccine, for example the Class IV proteins, which probably block the bactericidal antibody response (Munkley et al., 1991). It is clear that these vaccines need a great deal of further refinement and should incorporate those elements that are shown in particular to stimulate protective antibodies. Research into an effective group B vaccine is being pursued in many directions, and further investigation of outer membrane proteins, the lipo-oligosaccharides and group B polysaccharide (Devi, Robbins & Schneerson, 1991) are all in progress. Pneumococcal vaccines The present generation of pneumococcal vaccines consists of a mixture of capsular polysaccharides derived from up to 23 serotypes. Although immunogenic and protective in adults, they elicit a poor response in children under five (Douglas et al., 1983) and are therefore unsuitable for the prevention of meningitis in childhood. Protein-polysaccharide conjugates are under development, but it is difficult to produce conjugates that incorporate more than a few of the type specific polysaccharides. A promising alternative approach is to consider a virulence factor such as pneumolysin, as a vaccine candidate. A non-toxigenic variant of this toxin conjugated to a pnemococcal capsular polysaccharide is in the earliest stages of development. Conclusion Haemophilus conjugate vaccines are now at the point of general adoption into infant immunization schedules and offer great promise of profoundly reducing the incidence of haemophilus disease. If meningococcal polysaccharide conjugate vaccines have similar biological activities they will be more effective in controlling both epidemic meningococcal disease and outbreaks of infection. Only when the current work on group B meningococcal vaccines is successful, may we then be within reach of a

6 98 D. M. Jones composite 'meningitis vaccine' that will reduce or even eliminate an important cause of morbidity and mortality in the young. References Bjune, G., Heiby, E. A., Gronnesby, J. K., Arnesen, O., Fredriksen, J. H., Halstensen, A. et al. (1991). Effect of outer-membrane vesicle vaccine against group B meningococcal disease in Norway. Lancet 338, Costa, W., Saachi, C. T., Ramos, S., Milagnes, L. & Prigenzi, L. S. (1991). Meningococcal disease in Sao Paulo, Brazil. NIPH Annals 14, Devi, S. J. N., Robbins, J. B. & Schneerson, R. (1991). Antibodies to poly[(2-8)-<i-n-acetyl neuraminic acid] and poly[(2-9)-a-n-acetylneuraminjc acid] are elicited by immunization of mice with Escherichia coli K92 conjugates: potential vaccines for groups B and C meningococci and E. coli Kl. Proceedings of the National Academy of Science of the USA 88, Douglas, R. M., Paton, J. C, Duncan, S. J. & Hansman, D. J. (1983). Antibody response to pneumococcal vaccination in children younger than five years of age. Journal of Infectious Diseases 148, Eskola, J., Kiyhty, H., Takala, A. K., Peltola, H., Ronnberg, P., Kela, E. et al. (1990). A randomized prospective field trial of a conjugate vaccine in the protection of infants and young children against invasive Haemophilia influenzae type b disease. New England Journal of Medicine 323, Ferreccio, C, Clemens, J., Avendano, A., Horwitz, I., Floras, C, Avila, L. et al. (1991). The clinical and immunologic response of Chilean, infants to Haemophilia influenzae type b polysaccharide-tetanus protein conjugate vaccine coadministered in the same syringe with diphtheria-tetanus toxoids-pertussis vaccine at two, four and six months of age. Pediatric Infectious Disease Journal 10, Lieberman, J. M., Greenberg, D. P. & Ward, J. I. (1990). Prevention of bacterial meningitis. Infectious Disease Clinics of North America 4, Masterton, R. G., Youngs, E. R., Wardle, K. R., Croft, K. R. & Jones, D. M. (1988). Epidemiology-control of an outbreak of group C meningococcal meningitis with a polysaccharide vaccine. Journal of Infection 17, Munkley, A., Tinsley, C. R., Virji, M. & Heckels, J. E. (1991). Blocking of bactericidal killing of Neisseria meningitidis by antibodies directed against dass-4 outer membrane protein. Microbial Pathogenesis 11, Nazareth, B., Slack, M. P. E., Howard, A. J., Waight, P. A. & Begg, N. T. (1992). A survey of invasive Haemophilus influenzae infections. CDR Review 2, No. 2, R13-R16. Peltola, H., Kayhty, H., Sivonen, A. & Makela, H. (1977a). Haemophilus influenzae type b capsular polysaccharide vaccine in children: a double-blind field study of 100,000 vaccinees 3 months to 5 years of age in Finland. Pediatrics 60, Peltola, H., Makela, H., Kfiyhty, H., Jousimies, H., Herva, E., Hallstrom et al. (19776). Clinical efficacy of meningococcus group A capsular polysaccharide vaccine in children three months to five years of age. New England Journal of Medicine 297, Pinson, J. B. & Wcart, C. W. (1992). New considerations for Haemophilus influenzae type b vaccination. Clinical Pharmacy 11, Reingold, A. L., Broome, C. V., Hightower, A. W., Ajello, G. W., Bolan, G. A., Adamsbaum, C. et al. (1985). Age-specific differences in duratioin of clinical protection after vaccination with meningococcal polysaccharide A vaccine. Lancet it Ridgway, E. J., Allan, K. D., Neal, T. J., Lombard, M. & Rigby, A. (1992). Penicillin-resistant pneumococcal meningitis. Lancet 339, 931. Santosham, M., Wolff, M., Reid, R., Hohenboken, M., Bateman, M., Goepp, J. et al. (1991). The efficacy in Navajo infants of a conjugate vaccine consisting of Haemophilus influanzae type b polysaccharide and Neisseria meningitidis outer-membrane protein complex. New England Journal of Medicine 324, Siber, G. R., Santosham, M., Reid, G. R., Thompson, C, Abneido-HiU, J., Morell, A. et al. (1990). Impaired antibody response to Haemophilus influenzae type b polysaccharide and low IgG2 and IgG4 concentrations in Apache children. New England Journal of Medicine 323,

7 Meningitis immunization 99 Sierra, V. G., Campa, H., Garcia, I., Sotolongo, P. & Izquierdo, P. (1991). Efficacy evaluation of the Cuban vaccine VA-MENGOC-BC against disease caused by serogroup B Neisseria meningitidis. In Neisseria 1990 (Achtman, M., et al., Eds), pp de Gruyter & Co., Berlin. Skevalris, L., Frasch, C. E., Zahradnik, J. M. & Dolin, R. (1984). Class-specific human bactericidal antibodies to capsular and noncapsular surface antigens of Neisseria meningitidis. Journal of Infectious Diseases 149, Takala, A. K., Eskola, J., Leinonen, M., KSyhty, H., Nissinen, A., Peklcanen, E. et al. (1991). Reduction of oropharyngeal carriage of HaemophUus influenzae type b (Hib) in children immunized with an Hib conjugate vaccine. Journal of Infectious Diseases 164, Tudor-Williams, G., Frankland, J., Isaacs, D., Mayon-White, R. T., McFarlane, J. A. et al. (1989). HaemophUus influenzae type b conjugate vaccine trial in Oxford: implications for the United Kingdom. Archives of Diseases in Childhood 64,

8