The current vaccines strategies for the treatment of the three forms of bacterial meningitis are purified polysaccharide vaccines (PPV), and protein-polysaccharide conjugate vaccines (PCV).

Polysaccharide Vaccines are made of extracted and purified forms of the bacterial outer polysaccharide coat. The rationale behind these purified polysaccharide vaccines is that they would trigger the formation of circulating antibodies. These antibodies would then coat the bacterial capsules with antibodies and/or complement, promoting phagocytosis and removal by cells of the innate immune system (through macrophages and neutrophils).

Purified polysaccharides activate B cells in a thymus-independent type 2 (TI-2) manner. They cross-link antibodies on the B cell surface, which leads to the formation of plasma B cells and antibodies without the help of helper T cells. As a result of this T independent activation, IgM is the predominant isotype produced due to little class switching, no affinity maturation, and little development of memory cells. Therefore, vaccines composed solely of purified polysaccharides are only effective in older children and adults for an average of three to five years. They are not effective for infants and children under two years of age, who have immature immune systems. Since they rely on antibodies that are maternally passed down to them before birth, they are unable to respond to bacteria like those causing meningitis. Therefore, conjugate vaccines against some forms of meningitis have been developed.

Protein-Polysaccharide Conjugate Vaccines link purified bacterial polysaccharides to purified protein carriers, which involve helper T cells in the polysaccharide antigen response. Several protein carriers have been used effectively for conjugate vaccine strategies, including tetanus toxoid, diphtheria toxoid, H. influenzae protein D, N. meningitides outer-membrane protein complex (OMPC), and a non-toxic variant of diphtheria toxin (CRM197)¹.

The protein carrier of the conjugate vaccine leads to antigen presentation on B cells, or other antigen presenting cells. The interaction of the CD40 on B cells and CD40L on T helper cells allow class switching from IgM to IgG, which makes plasma cells more specific, longer-lasting effectors. Memory B cells are also induced to participate in a secondary response upon exposure to the bacterial pathogen².

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[HAEMOPHILUS INFLUENZAE]

Haemophilus influenzae type b (Hib)

A safe and effective purified polysaccharide vaccine (PPV) for meningitis caused by Haemophilus influenzae type b (Hib) bacteria has been available since the early 1990’s. The purified polysaccharide vaccine using the polyribosylribitol phosphate (PRP) polysaccharide on the capsule of this bacteria has proven to be 90% effective in children over 18 months; however, it has been poorly immunogenic for those that are younger than 18 months³. The development of a conjugate vaccine solved this problem.

Many conjugate vaccines are available, in which PRP is conjugated to different protein carriers: diphtheria toxoid (PRP-D), a diphtheria-like protein (PRP-HbOC), tetanus toxoid (PRP-T), or a meningococcal outer membrane protein (PRP-OMP). These vaccines differ in their protein carriers, method of chemical conjugation, and size of PRP. Therefore, they possess varying immunological properties. As mentioned before, the conjugation of PRP to a protein carrier leads to a T-cell dependent immune response to the PRP (Hib polysaccharide)⁴.

The Hib vaccine has been introduced into the child immunization program in 1992. It is given to infants as repeated doses with other vaccines of the national childhood immunization programs. Some countries recommend booster doses at 12-18 months; however, this may be unnecessary since most of this disease occurs before this age. In adults and children over 18 months, one dose is enough to induce protective immunity against a subsequent infection. All conjugate Hib vaccines are given intramuscularly, and have minimal side effects. Now that H. influenzae is under control, current meningitis research is focused on the other two classes of bacterial meningitis: Pneumococcal meningitis and Meningococcal meningitis.

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[STREPTOCOCCUS PNEUMONIAE]

Streptococcus pneumoniae (pneumococcal meningitis)

Both purified polysaccharide vaccines and protein-polysaccharide conjugate vaccines are used to treat pneumococcal meningitis. Conjugate vaccines are used for infants and children under 2 years old, and polysaccharide vaccines are used for children and adults over 2 years of age.

Polysaccharide Vaccine- PPV23

The polysaccharide vaccine, PPV23, contains 23 antigenically distinct polysaccharides found on the surface capsules of Streptococcus pneumoniae. These 23 serotypes were chosen based on their distribution within most cases of pneumococcal infections¹. Like other polysaccharide vaccines, it induces the production of phagocytic antibodies in a T cell independent manner. Also like other polysaccharide vaccines, PPV23 is not effective in children under 2 years of age. According to several studies, initial PPV vaccination in infants leads to variable immunogenicity to different polysaccharides. There were good antibody responses to serotypes 3, 4, 8, 9N, and 18c, intermediate responses to 1, 2, 7F, 19F, and 25, and poor responses to 12, 14, 23F, 6A, and 6B. IgG classes predominated in these first, short-lived responses. A second dose elicited no response^5,6. These transient and variable responses to the different polysaccharides are poor in young children, but have been shown to improve with age.

Some studies have shown that PPV23 could actually increase one’s susceptibility to pneumococcal meningitis. Several studies have shown that successively smaller antibody responses have been shown after repeated administration of doses of certain polysaccharide antigens. The mechanism of hyporesponsiveness is yet unknown, but some have hypothesized that repeated antigenic stimulation depletes B memory cell pools while failing to sufficiently restore them¹. Therefore, PPV administration can lead to transient protection, then may cause subsequent immunological paralysis. Further study about this concern is in progress.

Conjugate Vaccine- PCV7

The main conjugate vaccine, Prevnar, contains 7 different polysaccharides from the seven strains that cause over 85% of severe pneumococcal infections in infants and children in the USA and Canada. It is currently recommended for use in infancy as a four-dose schedule: 2, 4, 6, and 12-15 months.

Pneumococcal-CRM conjugates have been most extensively studied. Each of the 7 polysaccharides is coupled to CRM197, a nontoxic diphtheria protein analogue. Additional 9-valent and 11-valent conjugate vaccines are also available. Conjugate vaccines increase young children’s responses to polysaccharide antigens through protein carriers. Use of these vaccines generates antibody titers of 5 to 10 fold increase, even to the poorly immunogenic serotypes when administered purified polysaccharides without the protein carrier. Infants are usually given this conjugate vaccine during infancy. A booster dose of either PPV or PCV at age two leads to a marked, rapid increase in antibodies, which have higher avidity and opsono-phagocytic activity. These conjugate vaccines induce B-cell affinity maturation as well. The number of doses that should be given to infants has not yet been determined. Though it has been suggested that 3 doses are required to achieve optimum protection and the induction of immunological memory, some studies have suggested that adequate protection and memory could be achieved with two doses⁷. Further studies are investigating this issue of adequate dosage for conferring immunity.

Experiments have shown that children who received PCV CRM197 in infancy, and a second dose of PPV23 at 18 months, have successfully shown a reduction of vaccine serotypes. However, those who received three doses of PCV showed a significant increase in non-vaccine-type pneumococci than unvaccinated children⁸. In most studies of this nature, there were 50% reductions of vaccine serotype carriage, but a rise in non-conjugate vaccine serotypes. This serotype replacement effect could be a result of “unmasking” antigens that were formerly competitively inhibited by the more predominant serotypes. Once the vaccines caused a decreased in these serotypes, these non-vaccine types were able to take effect⁹. Therefore, the administration of conjugate vaccines could pose a serious danger by leading to greater disease rather than protection against it.

Surface Protein Vaccine Development

The development of PCV7 has had a great impact on pneumococcal meningitis; however, its effectiveness is limited by restrictions in the polysaccharide antigen distribution in the vaccine, multiple-dose requirements, and high cost. Over the last 10 years, much research has been done concerning the use of protein antigens of streptococcus pneumoniae. As shown in the previous figure, S. pneumoniae has many proteins, such as PspA and CbpA, that are covalently and non-covalently attached to the cell surface. These surface proteins have various functions, such as adherence to tissues of the host, protein processing, binding to immune system components, and DNA uptake from the environment¹⁰. Antibodies elicited against these surface proteins could lead to third-generation vaccines that are more broadly useful for greater serotypes, and more cost effective than conjugate vaccines.

A recent study screened a pneumococcal cell wall protein extract from the sera of children of different age groups. Antigenic proteins from the cell wall were discovered. Out of 150 proteins that were extracted for investigation, 30 proved to elicit an immune response from children and adults. These proteins have functions in glycolysis, protein synthesis, and other physiological pathways. The antigenic proteins were divided into 3 groups: low antigenicity, antigenicity that increased with age of children, and highly antigenic in children and adults. Increase in antibodies to bacterial proteins and decrease in morbidity was observed. Further studies are required in order to develop new vaccines using protein antigens¹¹.

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[NEISSERIA MENINGITIS]

Neisseria meningitis (meningococcal meningitis)

Meningococcal meningitis is caused by bacteria of five different serogroups: A, B, C, w135, and Y. Vaccines currently exist for A, C, Y, and w135. The development of a comprehensive capsule-based vaccine has been constrained by the poor immunogenicity of serogroup B¹².

Serogroups A, C, Y, W-135

Polyvalent polysaccharide vaccines are used to immunize against this type of meningitis. The quadrivalent polysaccharide vaccine, Menomune, targets the capsular antigens on groups A, C, w135, and Y, and has been available since the 1970’s. As with the other purified polysaccharide vaccines, this vaccine is only suitable for adults and children greater than two years of age. A booster dose must be administered every three years to maintain immunity to these specified groups of bacteria. The quadrivalent vaccine is useful for people traveling to high risk areas, such as Africa, the Middle East, and Northern India, for meningococcal group epidemics occur regularly in these areas¹³. A meningococcal polysaccharide (A/C/Y/W-135) diphtheria toxin conjugate vaccine, Menactra, has just been approved in January 2005¹⁴.

Serogroup A

A serogroup A meningococcal conjugate vaccine (MenA) is being developed by the Meningitis Vaccine Project with the World Health Organization (WHO), and financially supported by the Bill and Melinda Gates Foundation. The Project is paving the way for the development of a conjugate vaccine for Group A in sub-Saharan Africa. Phase I and II clinical studies of a potential group A conjugate vaccine has begun in 2005. Licensure of the vaccine is expected in 2009¹⁵.

Serogroup B

Group B, the most common serotype causing meningococcal meningitis, does not have an effective vaccine yet. Until MenB is developed, meningococcal disease will continue to be a great global burden. It is a poor immunogen because of its mechanism of incorporating sialic acid, which is expressed by many different host tissues, into its polysaccharide capsules. As a result of the resulting cross-reactivity, polysaccharide capsules of this bacterial group cannot be used in vaccine production like the other groups because of the risk of autoimmune effects. Researchers have been targeting cell-surface outer membrane protein antigens (OMP) to develop effective vaccines. Immunity to group B infection has been elicited by the surface proteins, Rib and alpha, expressed on most Group B streptococcus strains that lead to invasive infections. A bivalent vaccine, using these two proteins, and aluminum hydroxide as an adjuvant, was tested in adult mice in a 1998 study¹⁶.

Serogroup C

A monovalent serogroup C glycoconjugate vaccine (MenC) was introduced in 1999¹⁷.
This vaccine is now part of the routine immunization schedule as a three-dose course in infancy, or a single dose at 12-14 months¹⁸. It is given to all children less than 18 years old, and has proven to be highly safe and effective. There are several problems associated with this development of MenC. Capsule switching, or the change of a clone from associating with one capsular polysaccharide to a different one, has been shown to occur. Such instances leads to concerns that the administration of MenC vaccine could cause the serogroup C to switch to another serogroup, including B. Since there is no viable vaccine for serogroup B yet, this could have serious effects on global meningitis infection. A recent outbreak in Northern Spain, found 20 of 39 reported cases due to sergroup B. Before this outbreak, an immunization campaign using A/C PPV and the MenC conjugate vaccine was implemented throughout the region¹⁹. Though it is not definite whether these widespread immunizations caused this capsule switching, it is nonetheless a real concern for the future of vaccination. Serotype replacement is again another vaccine concern. A reduction in a particular vaccine-targeted serotype could lead to an increase in another non-vaccine serotype.

Hopes for a Comprehensive Vaccine

Outer membrane proteins (OMP) have provided hope to create a comprehensive vaccine that includes all disease-causing serotypes of N. meningitidis. Three OMPS (FetA, PorA, and PerB) have been present in collections of meningococcal isolates that represent major invasive complexes, and have been proposed as potential vaccine candidates¹². PorA is the most significant protein, for it is expressed by almost all meningococci and is the major inducer of and target for serum antibodies. There are, however, many PorA proteins, and mounting an immune response against one does not provide protection against strains of meningococci type B with different antigens²⁰.

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[RECOMMENDED VACCINE SCHEDULE]

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