Pediatric Infectious Disease Journal:
Danzig, Lisa MD
From Chiron Vaccines, Clinical Research and Medical Affairs, Emeryville, CA
Address for reprints: Lisa Danzig, MD, Chiron Corporation, Clinical Research and Medical Affairs, 4560 Horton Street, Emeryville, CA 94608-2916. Fax 510-923-3450; E-mail email@example.com.
Background: The 5 major pathogenic serogroups of the Gram-negative encapsulated bacterium Neisseria meningitidis are A, B, C, Y, and W135. In the 1960s, vaccines consisting of purified capsular polysaccharide antigens were developed against serogroups A, C, Y, and W135. These vaccines were highly effective among adults but were not efficacious among infants and young children. Capsular polysaccharide-protein conjugate vaccines were subsequently developed.
Methods: The development of second-generation capsular polysaccharide glycoconjugate vaccines that are effective among infants and children is reviewed. The approaches for development of a broadly protective serogroup B vaccine, including attempts toward optimization of outer membrane vesicle vaccines and identification of conserved antigens, are discussed.
Conclusions: Monovalent serogroup C conjugate vaccines have been successful in reducing the burden of serogroup C meningococcal disease among infants, older children, and adults in the United Kingdom and Canada. Tetravalent serogroup A/C/W/Y conjugate vaccines are in late stage development. The use of serogroup B capsular polysaccharide as the basis for a vaccine for prevention of serogroup B meningococcal disease has proved problematic. The recent sequencing of the serogroup B genome led to the identification of additional, genome-derived, neisserial antigens, through a process called “reverse vaccinology.”
Meningococcal disease can result in meningitis, septicemia, or both and is usually associated with fever and a characteristic nonblanching rash. Prevention with vaccines is an important part of the management of meningococcal disease because, even with antibiotic intervention, the disease is associated with high morbidity and mortality rates.1–3 Neisseria meningitidis, Haemophilus influenzae type b (Hib), and Streptococcus pneumoniae are the 3 main pathogens that cause bacterial meningitis. In the past 15 years, the introduction of effective polysaccharide-protein conjugate vaccines has significantly decreased the incidence of invasive disease caused by Hib and is expected to decrease the incidence of invasive disease caused by S. pneumoniae among vaccinated individuals.4–10 These developments leave N. meningitidis as a particularly important vaccine target in the 21st century.
N. meningitidis is enveloped in a polysaccharide capsule and is divided into 12 meningococcal serogroups on the basis of the chemical composition of the capsular polysaccharide.11 N. meningitidis is classified into serotypes and serosubtypes, which are based on the antigenic differences of the outer membrane proteins (OMPs) PorB (class 2 or 3 OMP) and PorA (class 1 OMP).12–15 The lipopolysaccharide in the outer membrane is used to classify strains into immunotypes. N. meningitidis nomenclature follows a classification scheme similar to the O:K:H typing scheme used for Escherichia coli and Salmonella, namely, serogroup:serotype:serosubtype:immunotype (eg, B:2a:P1.2:L3).12,14,16 The nomenclature of N. meningitidis is historically based on differences in monoclonal antibody recognition of the capsular polysaccharide, PorB, PorA, and lipopolysaccharide (Table 1).
Five N. meningitidis serogroups, ie, A, B, C, Y, and W135, are the principle pathogenic serogroups.17 There are significant geographic differences in the distribution of specific serogroups of meningococcal disease. For example, surveillance by the Centers for Disease Control and Prevention indicated that serogroups C (28%), Y (34%), and B (33%) were the most prevalent in the United States from 1995 to 1998 (Centers for Disease Control and Prevention, personal communication), whereas serogroup A (86%) was the most prevalent in Niamey, Niger, from 1981 to 1996.18 Serogroup B meningococcus (MenB) is prevalent in Europe, and New Zealand has been experiencing a MenB epidemic since 1991.19 Surveillance of serogroup distribution shows that prevalence can change with time. Serogroup Y accounted for only 2% of cases in the United States from 1988 to 1991, but this value increased to approximately 30% from 1995 to 1998.20–22 Serogroup distribution is important for understanding the potential effectiveness of capsular polysaccharide and capsular polysaccharide conjugate vaccines, and serosubtype distribution is important to the applicability of outer membrane vesicle (OMV) vaccines.
Plain Capsular Polysaccharide Vaccines.
With purified capsular polysaccharide as an antigen, vaccines against serogroup A meningococcus (MenA) and serogroup C meningococcus (MenC) were developed in the 1960s.23–25 A tetravalent polysaccharide vaccine against serogroups A, C, Y, and W-135 has been developed and is available worldwide.17,26,27 However, clinical studies have demonstrated that the antibody response to capsular polysaccharide vaccines is not long-lived, particularly among young children.28–34 In addition, although the clinical significance is not known, it has been shown that multiple doses of a capsular polysaccharide vaccine may result in hyporesponsiveness among infants, toddlers, and young adults.35–39
Data suggest that the hyporesponsiveness of the capsular polysaccharide vaccines may be attributable to the T cell-independent nature of the immune response to these vaccines.40,41 It has been hypothesized that T cell-independent stimulation of memory B cells in response to repeat doses of plain polysaccharide vaccine may result in terminal differentiation of B cells.37 Terminal differentiation of B cells would result in a depleted pool of B cells available for activation by subsequent vaccine doses, with reduced antibody titer.
Because of the relative ineffectiveness of the capsular polysaccharide vaccines among children <2 years of age and the limited duration of protection, routine vaccination with these polysaccharide vaccines is not recommended by the Advisory Committee on Immunization Practices (ACIP).42,43 However, capsular polysaccharide meningococcal vaccines are recommended for use in control of meningococcal outbreaks and for routine vaccination for individuals at high risk of infection, including individuals with complement deficiencies, asplenic individuals, and laboratory personnel exposed to N. meningitidis. In 2000, the ACIP recommended that entering college students be informed of the risk of meningococcal disease and the availability of the polysaccharide vaccine, after 4 epidemiologic studies reported that college freshmen, particularly those living in dormitories, were at modestly increased risk for meningococcal disease, compared with other individuals of the same age.44–46 With the prospect of new meningococcal conjugate vaccines becoming available in the near future, the ACIP is now reviewing this recommendation.
Capsular Polysaccharide-Protein Conjugate Vaccines.
Conjugating a polysaccharide to a protein can render the polysaccharide a T cell-dependent antigen.47 The first successful examples of polysaccharide-protein conjugate vaccines were conjugate vaccines against Hib.5,48–55 Hib conjugate vaccines were developed by conjugating oligosaccharides derived from the Hib capsular polysaccharide (polyribosylribitol phosphate) with carrier proteins, including diphtheria cross-reactive material (CRM)197 protein (a nontoxic mutant of diphtheria toxin), MenB OMP complex, and tetanus toxoid protein.6,54,55 The routine use of Hib conjugate vaccines has dramatically reduced the incidence of Hib disease in many countries.6,7
With the use of this conjugate vaccine technology, meningococcal vaccines were developed.56–58 Conjugation of the N. meningitidis capsular polysaccharide to a carrier protein allows the vaccine to induce a stronger immune response among infants, compared with plain polysaccharide vaccines, to prime immunologic memory, and to elicit booster responses to subsequent doses.36,37,58–71 These vaccines were first licensed in the United Kingdom on the basis of their ability to induce serum bactericidal activity, as a correlate of efficacy.72–74 MenC conjugate vaccines have also been shown to reduce nasopharyngeal carriage of N. meningitidis.75,76
A reduction in the incidence of bacterial meningitis caused by MenC infection was observed in the United Kingdom after a MenC conjugate vaccine campaign (using 3 different vaccines) that was initiated in November 1999 in response to an increase in MenC disease in that country.77 Since the initiation of the campaign, MenC vaccine has been offered to all infants on a 3-dose schedule (at 2, 3, and 4 months of age), administered at the same time as other primary immunizations, with no booster.26 A catch-up campaign targeted all children >4 months and <18 years of age. Individuals <1 year of age received 2 doses of vaccine, and those ≥1 year of age received 1 dose.26 Within 1 year after campaign initiation, an 85% reduction in the number of confirmed cases of invasive MenC disease was observed.77 A MenC CRM197 protein-conjugated vaccine was also found to be effective in a mass-immunization campaign in Quebec, Canada, that was implemented in response to a MenC epidemic that occurred there in 2001.78
It was demonstrated that serum bactericidal activity was induced after MenC-CRM197 protein conjugate vaccine administration to infants, toddlers, 3-5-year-old children, adolescents, and adults (Fig. 1). 59,79 These bactericidal assays were performed with exogenous human complement.80 Capsular polysaccharide-protein conjugate meningococcal vaccines are more immunogenic than plain capsular polysaccharide vaccines among infants, toddlers, children, and adolescents, who represent important populations at risk for meningococcal disease. Therefore, the introduction of meningococcal conjugate vaccines for routine immunization has the potential to reduce dramatically the meningococcal disease burden in affected countries. A MenC conjugate vaccine is available in Europe, and meningococcal conjugate vaccines for MenC and serogroup A/C/Y/W meningococci should be available soon in the United States. MenB, however, provides unique challenges for vaccine development.
MENB VACCINE DEVELOPMENT
MenB disease is endemic in North America and Europe and is especially prevalent, compared with other serogroups, in the Netherlands, Germany, and Denmark.2,81 Epidemics have occurred in Iceland, Norway, Belgium, the United States, Cuba, Brazil, and Chile.82–90 A MenB epidemic has been occurring in New Zealand since 1991, with some of the highest rates of MenB disease ever recorded in an industrialized country.19 Because the incidence of MenB disease is highest among children <1 year of age, the development of a MenB vaccine that is effective among young children has been of particular concern. For several reasons, however, conventional methods of vaccine development in the past 25 years have failed to produce a vaccine with a broad range of protection against circulating MenB strains.
CAPSULAR POLYSACCHARIDE-BASED VACCINE DEVELOPMENT
MenB plain capsular polysaccharide vaccines are poorly immunogenic among human subjects (both children and adults).91 In addition, the MenB capsular polysaccharide structure (α2-8-N-acetylneuraminic acid) is homologous to that of a nerve cell adhesion molecule that is present in developing neural tissue and in small amounts in adult tissues.92 A MenB capsular polysaccharide conjugate vaccine has been developed in an attempt to overcome this obstacle; however, it appears to lack immunogenicity.93 Several other conventional noncapsular approaches to MenB vaccine development have also been attempted.
NON-CAPSULAR POLYSACCHARIDE-BASED VACCINE DEVELOPMENT
Spheres of bacterial outer membrane or OMVs that contain OMPs, lipopolysaccharides, and periplasmic proteins are constantly released by N. meningitidis and other Gram-negative bacteria. OMVs prepared from meningococcal bacterial cells through detergent extraction can be used as vaccine antigens. MenB OMV vaccines have been used successfully for outbreak control; however, their success is limited to clonal outbreaks of MenB disease, because the immunogenicity of the OMV vaccines is directed primarily at PorA, which is highly variable among MenB strains.
Two MenB OMV vaccines were developed and successfully used in the late 1980s and early 1990s, in response to meningococcal outbreaks in Norway and Cuba. The first vaccine was developed by the Finlay Institute in Cuba (B:4:P1.19,15), and the second, with a different PorA, was developed by the National Institute of Public Health in Norway (B:15:P1.7,16).82,83 Efficacy studies of these vaccines were conducted during epidemics that occurred in Norway, Cuba, Brazil, and Chile.82,84–87 The vaccines were found to be immunogenic among adults and older children (70–80% efficacy within 1 year), but immunogenicity was markedly reduced among young children and infants (Table 2). In Norway, 87% efficacy was observed among adults 10 months after immunization with 2 doses, administered 6 weeks apart, although efficacy was reduced to 57% by 29 months after immunization.83,94,95
The specificity of MenB OMV vaccines was demonstrated in a study that assessed bactericidal antibody responses with the Norwegian OMV vaccine against the H4476 strain (the strain from which the vaccine was developed) and 2 distinct serosubtypes of MenB. Infants, adults, and children were given 3 injections of the Norwegian OMV vaccine, at intervals of 2 months. Ninety-eight percent of immunized infants, 98% of children, and 96% of adults exhibited a ≥4-fold antibody response against the H4476 strain.96 However, only 2% of infants, 24% of children, and 46% of adults exhibited a ≥4-fold bactericidal response against a Cuban strain (CU385), and only 12% of infants, 35% of children, and 60% of adults exhibited a bactericidal response against a strain from Chile (CH539). These results demonstrate the effects of PorA specificity among MenB serosubtypes on the immunogenicity of MenB OMV vaccines. The amino acid variability of PorA is restricted to 2 of 8 exposed loops in the predicted structure.97,98 These 2 loops account for most of the antibody response to OMV vaccines, which is why protection elicited by OMV vaccines is generally limited to the strain from which the vaccine was developed.96
MenB OMV vaccines can be useful during epidemics, when disease is caused by a single circulating serosubtype and an appropriately matched MenB OMV vaccine has been developed. Because MenB epidemics can last for more than a decade, the development of a matched vaccine may be feasible in such settings. An OMV vaccine derived from the Norwegian strain is currently undergoing evaluation under a provisional licensure in New Zealand, where a MenB epidemic has been ongoing since 1991.99 However, the OMV-based approach is not useful for routine vaccination in many areas where MenB disease is endemic and is likely to be caused by a heterogeneous population of strains expressing different PorA variants. In the United States, for example, a MenB OMV vaccine would need to be developed from 16 serosubtypes of N. meningitidis B to cover 80% of endemic MenB disease.100
In an attempt to develop a more broadly protective OMV vaccine, a hexavalent PorA OMV vaccine was developed at the National Institute for Public Health and the Environment.101 Two vaccine strains were constructed, through recombinant DNA technology, to express 3 PorA proteins each, representing the majority of circulating serosubtypes in the Netherlands and other countries in Europe.81,101 The vaccine is composed of 2 OMV preparations, 1 from each of these strains. Phase I and II studies have demonstrated that this vaccine is safe and immunogenic.102,103 This vaccine may prove to be useful for preventing MenB disease in areas where these serosubtypes are endemic.
Other noncapsular approaches to MenB vaccine development include the use of OMPs, such as transferrin-binding protein B, neisserial surface protein A, and H.8, and the use of antigens from a commensal species of Neisseria, ie, Neisseria lactamica. Transferrin-binding protein is a meningococcal surface-exposed lipoprotein that plays a role in scavenging iron from the environment.26 Transferrin-binding protein B is a subunit of this protein. Bactericidal antibodies were produced in animals immunized with recombinant transferrin-binding protein B,104 but a recombinant transferrin-binding protein B vaccine failed to elicit high titers of bactericidal antibodies in animal models.105 Efforts to improve the vaccine are ongoing.106
Neisserial surface protein A is a highly conserved meningococcal membrane protein of unknown function. Immunization of animals with recombinant neisserial surface protein A elicited bactericidal antibodies,107,108 but these antibodies were bactericidal against only 50% of genetically diverse MenB strains.109 H.8 is a surface-exposed OMP that was evaluated as a putative antigen.110 Antibodies against this protein failed to show bactericidal activity.111 N lactamica is a commensal species of Neisseria that is associated with natural immunity against meningococcal disease.112 This finding led to the hypothesis that N lactamica antigens may be useful in the development of vaccines against MenB. Development of a MenB vaccine with the use of N lactamica is ongoing.113
Various methods have been used for the development of an effective vaccine against endemic MenB disease. Although some vaccines have proved to be effective in epidemic situations and others provide some inconsistent protection against MenB strains, it is clear that a novel approach to vaccine development is necessary. The sequencing of the genome of one strain of MenB (strain MC58) has yielded a unique, genome-based approach to vaccine development.
GENOME-DERIVED VACCINE DEVELOPMENT
Conventional methods of vaccine development use proteins purified from components of organisms to identify candidate antigens. The genome-based approach to vaccine development uses the genomic sequence of an organism to identify sequences of proteins that are candidate antigens; this approach has been called reverse vaccinology.114 This approach has the potential to identify a broadly protective vaccine with improved immunogenicity, because it can access targets that might have been missed with the conventional methods for purification of bacterial components. The MenB genome-sequencing project identified 2158 open reading frames in the genome of MenB strain MC58.115 Potentially conserved amino acid sequences were identified through comparison with sequences from the genome of a MenA strain.115 Six hundred proteins that were thought to be conserved were cloned, and 350 were expressed in E coli, purified, and used to immunize mice. Twenty-nine were found to induce antibodies with bactericidal activity against MenB, a property that correlates with protective immunity. Several genome-derived antigens have been further evaluated as potential vaccine candidates, including surface-expressed proteins such as adhesion proteins and lipoproteins. Some of these genome-derived antigens are now undergoing evaluation in clinical trials.
Meningococcal disease is a major cause of morbidity and death worldwide, particularly among young children. Because it is associated with a high fatality rate even with early antibiotic intervention, the identification of a vaccine that could be used for routine prevention is a major research target. Vaccines against MenA and MenC were developed with the use of purified capsular polysaccharides from the bacterial capsule. These polysaccharide vaccines were found to elicit serum bactericidal activity among adults but not among children <2 years of age. MenC conjugate vaccines have been shown to be more immunogenic than plain polysaccharide vaccines and have been effective in reducing MenC disease in the United Kingdom and Canada. However, a vaccine against MenB that is immunogenic across a broad range of serosubtypes has not yet been developed.
To date, conventional approaches have failed to identify broadly immunogenic MenB vaccines. The capsule polysaccharide of MenB is poorly immunogenic. An OMV-based approach to vaccine development has been successful in the control of clonal outbreaks of MenB but is unlikely to produce a broadly protective vaccine because the immunodominant antigen, PorA, is hypervariable among MenB strains. Several major membrane proteins identified with conventional bacterial purification methods have been investigated, but none appear to be useful for vaccine development. Therefore, novel approaches to vaccine development for MenB are being investigated.
A genome-based vaccine approach has been initiated, with information available through the MenB genome-sequencing project. Conserved candidate proteins that elicit bactericidal activity in a mouse model have been identified. Additional study of these candidate proteins in clinical trials is ongoing, in an attempt to develop a broadly protective vaccine. Coupled with the advances in understanding of the molecular basis of the immune response and the development of new adjuvants, these new technologies offer promising new vaccine candidates for even the most challenging pathogens.
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