Defensive immunity to encapsulated bacteria entails an antibody response to a polysaccharide (PS) antigen, interactions with B and T lymphocytes, and host defense mechanisms. PS vaccines, like those developed against Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae type B, prevent infection by provoking an immune response against particular capsular polysaccharides. These vaccines, however, presented little protective immunity in young children and infants. The invention of glycoconjugate vaccines was a need of time to over come many limitations related with PS vaccines by entailing a quantitatively and qualitatively diverse immune response.
Encapsulated bacteria are significant pathogens that cause disease particularly among infants, the elderly, and persons with compromised immunity. In spite of antibiotic treatment, the morbidity and mortality from bacteremia, meningitis, and pneumonia caused by these organisms are still elevated in these populations. The mechanism by which nearly all encapsulated bacterial pathogens inflicts disease in children engross virulence factors e.g. surface capsular polysaccharides (PSs). The PS antigens contained in vaccines in the earlier period conversely, were weakly immunogenic and did not provoke defensive immunity in younger children.1
There was an immense need to enhance protective immunity in higher risk individuals particularly younger children which resulted in the development of conjugate vaccines. The pairing of PS antigens to a carrier protein overcame the immunologic restrictions faced with PS vaccines. The conjugation of Haemophilus influenzae type B (HiB) PS to diphtheria toxoid, tetanus toxoid, meningococcal outer membrane protein, or mutant diphtheria protein CRM197 and consequent vaccination with HiB PS as a glycoconjugate vaccine effectively resulted in a more than 97% decrease of HiB disease in certain Europian countries and United States of America.2
Capsular PSs are highly polar, hydrophilic cell surface polymers comprising of oligosaccharide repeat units. These molecules are the key antigens concerned in the defensive protection to encapsulated bacteria. Capsular PSs hinder with bacterial contact with phagocytes by jamming opsonization. Opsonization is the coating of the organisms by particular antibodies and complement, that enables host phagocytes to swallow and kill invading bacteria. Antibodies attached to capsular PSs might work as bacterial-cell-to-phagocytic-cell ligands or as complement activators.3
The reaction to a capsular PS is T-cell-independent, sensing that B lymphocytes flourish and generate antibody without the assistance of T cells. Conjugation combines a PS to a carrier protein, which alters the capsular PS from a T-cell-independent antigen to a T-cell-dependent antigen. The immune response brought by this protein antigen utilize helper T cells and thus is T-cell- dependent. Helper T cells facilitates a more fast and improved immune response to take place on re-exposure to an antigen. In this way, a conjugate vaccine imparts immunologic memory and grants long-standing protective immunity.
Along with an increased antibody production, an immune response imparted by a conjugate vaccine is different from that imparted by a PS vaccine in the kind of antibody produced and the result on nasopharyngeal carriage. The IgG antibodies elicited by a conjugate vaccine are of high affinity and are mainly IgG1; both these characteristics associate with better serum bactericidal activity. Reduced nasopharyngeal colonization, as experienced with long-standing use of HiB conjugate vaccines, has produced in herd immunity by reduced organism transfer to susceptible children. Characteristics of T-cell-dependent and T-cell-independent antigens and subsets of CD4+ T cells involved in antibody production are shown in following figure.
Immune response begins when antigens (e.g., T-dependent [TD]-antigen [Ag], polysaccharide [PS]-protein conjugate) inoculated into the body are taken up by antigen-presenting cells (APC) and presented to CD4+ helper T (TH) cells. TH1 cells and TH2 cells direct cellular and humoral immune responses, correspondingly, through the discharge of distinct cytokines. TH2 cells generate interleukin (IL)-4, IL-5, IL-10, and IL-13 and grant help to B cells for making immunoglobulins, e.g. IgG1 and IgG2a. T-cell-independent (TI) antigens are polymers comprising repeating units. They can be further divided into 2 groups, type 1 antigen (TI-1) and type 2 antigen (TI-2). TI-1 antigens, such as bacterial lipopolysaccharide (LPS) can trigger B cells in a polyclonal way, that is, all B cells are triggered without involving antigen specificity. In contrast, TI-2 antigens, such as bacterial PSs, induce B-cell activation and antibody generation and require some T-cell help.
Antibodies imparted to their offspring by mother starts waning after approximately 6 months. Since an immune response to most bacterial PSs is weak in children younger than 2 years, this is the time when children are most vulnerable to pathogens causing pneumococcal, meningococcal, and HiB infections. Its likelihood is mostly between ages 6 months and 24 months.
N meningitidis is a frequent cause of bacterial meningitis worldwide. It has 12 known serogroups out of which A, B, C, Y, and W-135 are accountable for most invasive meningococcal disease. Serogroup A mainly causes epidemic meningococcal disease in sub-Saharan Africa, while serogroups B and C are principal causes of endemic and epidemic meningococcal disease in Europe and the Americas.4
In USA, approximately about 2400 to 3000 cases of invasive meningococcal disease occur annually; the mortality linked with N meningitidis infection carries on to be about 10% to 20% in this country in spite of the high vulnerability of this pathogen to antibiotic treatment. In the early 1990s, serogroups B and C caused 91% of invasive meningococcal disease nationwide. On the other hand, from 1992 to 1995, few areas of the USA demonstrated an augmented proportion of invasive meningococcal disease due to serogroup Y. 12 local outbreaks of serogroup C infection took place between 1990 and 1993.The percentage of meningococcal infection due to serogroup W-135 has not changed considerably, and this serogroup at present responsible for about 1% of cases of invasive meningococcal disease.4
Two PS vaccines, a bivalent A, C (Menomune-A/C) and a tetrava- lent A, C, Y, W-135 (Menomune-A/C/Y/W-135) vaccine, are approved in the United States. The tetravalent A/C/Y/W-135 is the vaccine now available; it is efficient in controlling serogroup C meningococcal disease outbreaks. This vaccine is also recommended for persons 2 years or older traveling to areas with endemic or epidemic meningococcal disease and for routine inoculation in persons with terminal complement or factor P deficit, those with non functional spleen or are asplenic, and military workforce. The introduction of bactericidal antibodies is an accepted criterion for the efficacy of meningococcal PS vaccines.
In children 2 years or younger, the characteristics of the antibody response to a meningococcal PS vaccine component depend on the sero-group. Meningococcal serogroup A PS induces an antibody response in infants as young as 3 months, but these antibody levels are significantly lower than the responses achieved in children 4 to 5 years old and in adults. These infants demonstrated a booster response despite an initial suboptimal immune response and despite the fact that priming does not usually occur with T-cell-independent antigens.
The meningococcal serogroup C PS does not elicit an immune response until a child is 18 to 24 months old, and a booster effect is not observed with repeated immunization.Reduced immunogenicity among infants and young children and less duration of protection after vaccination with meningococcal PS vaccines has been observed. It is evidenced that early immunization with a meningococcal serogroup A and C PS vaccine might generate tolerance in children and adults to subsequent doses of the vaccine.Such noticeable difficulties limit the meningococcal PS vaccines contribution toward reducing the worldwide load of invasive meningococcal disease.
Utilizing the same carrier proteins incorporated in HiB conjugate vaccines, 3 meningococcal serogroup C conjugate vaccines were successfully developed, evaluated, and nowadays approved in the UK (Table). These vaccines have not been approved yet for in USA.
Characterization of licensed bacterial PS-protein conjugate vaccines
influenzae type b
Merck & Co, Inc
Aventis Pasteur, Inc
Aventis Pasteur, Inc
(types 4, 6B, 9V, 14,
18C, 19F, 23F)
Baxter Healthcare Ltd§
PS, polysaccharide; PRP-CRM, polyribosylribitol phosphate-diphtheria CRM197 protein; OS, oligosaccharide; PRP-OMP, polyribosylribitol phosphate-outer membrane protein; OMPC, outer membrane protein complex; PRP-T, polyribosylribitol phosphate-tetanus toxoid; TT, tetanus toxoid; PRP-D, polyribosylribitol phosphate-diphtheria toxoid; DT, diphtheria toxoid; PS-CRM, polysaccharide-diphtheria CRM197 protein; OS-CRM, oligosaccharide-diphtheria CRM197 protein; PS-T, polysaccharide-tetanus toxoid.
ActHIB, distributed by Aventis Pasteur; OmniHIB, distributed by GlaxoSmithKline.
Type 18C, OS.
Type 6B, 4 mg/dose.
Approved for use in the United Kingdom; not licensed in the United States.
Bivalent meningococcal vaccines are also being manufacured. A vaccine manufactured by Chiron Corporation (Italy), which includes serogroups A and C oligosaccharide conjugated to CRM197, the same carrier protein as one of the HiB conjugate vaccines (HiBTiTER), was assessed in 90 toddlers in southern California. After 2 doses, serum bactericidal titers to serogroup A and C were roughly 20 and 300 times higher, correspondingly, in children who received the conjugate vaccines than in those who received Menomune-A/C/Y/ W-135. In The Gambia, the effect of the Chiron conjugate vaccine as a booster dose was evaluated in toddlers who previously had received a primary series of either meningococcal conjugate or PS vaccine. Apart from the vaccine given in the primary series, antibody titers to serogroup C were higher in toddlers given the meningococcal conjugate vaccine than in those who were inoculated with the PS vaccine.
Analogous meningococcal serogroup A and C conjugate vaccines are being developed by Wyeth-Lederle and Aventis Pasteur, Inc. Experience with HiB conjugate suggests that meningococcal conjugate vaccines may decrease nasopharyngeal carriage of vaccine serogroups, which, in turn, could reduce transmission to susceptible children through herd immunity. The reduction of meningococcal disease by vaccine serogroups, on the other hand, may result in an increase in serogroups, such as serogroup B, for which there is at present no vaccine.
The development of a vaccine for managing and prevention of serogroup B meningococcal disease has delayed production of vaccines for serogroups A, C, Y, and W-135 because serogroup B PS is not immunogenic in humans. Because a structural similarity exists between this oligosaccharide antigen containing from 2 to more than 8 sialic acid units and those carbohydrates present on human glycoconjugates, e.g. gangliosides, a probable justification for a lack of immunogenicity may be linked to the possibility to induce an autoimmune response. Serogroup B PS conjugated to tetanus or CRM197 protein elicited a minimal antibody reaction. A few substitute to improve immunogenicity have instead paying attention on development of non-PS vaccines, that join a chemically customized serogroup B PS with outer membrane protein antigens or protein complexes.
In the USA, S pneumoniae causes an approximately 3000 cases of meningitis, 50,000 cases of bacteremia, 500,000 cases of pneumonia, and 7 million cases of acute otitis media annually. In children younger than 2 years, pneumococcus is the most common cause of bacterial meningitis. Of 90 capsular PSs reported, approximately 30 serotypes are responsible for most pneumococcal diseases. A 23-valent pneumococcal PS vaccine was approved in 1983, contains types 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F. However this PS vaccine is effective in healthy adults, it is poorly immunogenic in children younger than 2 years, immunocompromised persons, and aged persons. Children younger than 2 years are at the highest risk for invasive and mucosal pneumococcal infections.
This led to the need to develop pneumococcal conjugate vaccines to enhance antibody responses and bring on immunologic memory in those populations for whom response to pneumococcal PS vaccine was poor. Observations evaluated in clinical trials with multivalent pneumococcal conjugate vaccines include a reduction in the incidence of invasive pneumococcal disease, roentogenogramically confirmed pneumonia, otitis media, and nasopharyngeal colonization. Infants are most susceptible to colonization, reduction in nasopharyngeal colonization would be important for protection against mucosal diseases (such as otitis media and sinusitis) and decrease of the transmission of pneumococci to susceptible persons.5
Nowadays, infants are the largest target population for pneumococcal conjugate vaccines. Experience with HiB conjugate vaccines suggests that protective immunity in infants elicited with pneumococcal conjugate vaccines may also be augmented by maternal immunization with the same conjugate vaccine. Interpretation in a preclinical study showed a higher antibody response in the progeny of pregnant mice immunized with pneumococcal type 19F PS than in the progeny of nonimmunized mothers.5
Immunization of mothers with a 23-valent pneumococcal PS vaccine in a study conducted in Bangladesh induced an antibody response in infants that was 2- to 3-fold higher for types 6B and 19F than that in infants whose mothers received a meningococcal PS vaccine. Increased concentration of pneumococcal vaccine serotype- specific IgA antibody levels in breast milk and serum antibody reduced serious infections in the first months of life.6
1. Centers for Disease Control and Prevention. Prevention and control of meningococcal disease. MMWR. 2000;49(RR-7):1-10.
2. Peltola H, Kilpi T, Anttila M. Rapid disappearance of Haemophilus influenzae type b meningitis after routine childhood immunisation with conjugate vaccines. Lancet. 1992;340:592-594.
3. Rijkers G, Kuis W, Graeff-Meeder E, et al. Impaired immune response to polysaccharides. N Engl J Med. 1987;317:837-838.
4. Lieberman JM, Chiv SS, Wong VK, et al. Safety and immunogenicity of a serogroup A/C Neisseria meningitidis oligosaccharide-protein conjugate in young children: a randomized controlled trial. JAMA. 1996;275:1499-1503.
5. Advisory Committee on Immunization Practice. Prevention of pneumococcal disease. Recommendations of the Advisory Committee on Immunization Practice (ACIP). MMWR. 1997; 46(RR-8):1-24.
6. Gold R, Lepow ML, Goldschneider I, et al. Kinetics of antibody production to group A and group C meningococcal polysaccharide vac- cines administered during the first six years of life: prospects for routine immunization of infants and children. J Infect Dis. 1979;140:690-697.