There are 90 serotypes of S. pneumoniae [32]. The strains are differentiated by the capsular polysaccharide coat, which stimulates the production of serotype-specific, protective antibody. The capsule protects the pneumococci from phagocytosis by polymorphonuclear leukocytes [33]. Virulence is based upon the chemical composition of the capsule and its size. The purified capsular protein itself does not stimulate an inflammatory response when delivered directly into the lung, which suggests it is not necessary for inflammation, but contributes to the infectivity of the S. pneumoniae [33].

Initially, S. pneumoniae was found to be susceptible to penicillin [34]. In 1977 a strain highly resistant to penicillin emerged in South Africa. Penicillin resistance and multidrug resistance have spread worldwide [35]. There are actually 4 strains which are responsible for most disease and drug-resistant S. pneumoniae (DRSP). These are strains 6B, 14, 19 and 23F [32]. For example, serotype 23F, which most likely originated in Spain, is now found in Mexico, South Africa, South Korea, Portugal, Croatia, France and the United States [35]. Many penicillin resistant strains are also resistant to other drugs such as chloramphenicol, erythromycin, tetracycline and trimethoprim-sulfamethoxazole [36]. There are numerous reports regarding the failure of antibiotics to treat meningitis because the pneumococci are resistant [35]. Between 3-35% of pneumococcal illness is due to DRSP, and the bacteria causes at least 15,000 cases of meningitis annually [32].

Pneumococcal meningitis is caused by direct spreading from the nasopharynx to the meninges or by hematogenous spread [30]. In hematogenous spread the bacteria usually initially infect the lungs, causing pneumonia. Infection spreads to the blood resulting in bacteremia. From the blood the bacteria is able to traverse the blood-brain barrier and infect the meninges [30, 37]. Diagnosis may be achieved by the isolation of S. pneumoniae from body fluids such as blood, spinal fluid or urine. Sputum may be analyzed by a Gram stain; S. pneumoniae is a Gram-positive coccus [30, 37].

The mucosal epithelium of the nasopharynx is the primary site of pneumococcal colonization [33]. Binding to the nasopharynx is dependent upon introconversion between two phenotypes: opaque and transparent. Only the transparent phenotype is able to persist in the nasopharynx in vivo [33]. Colonization involves pneumococcal surface adhesins which bind those epithelial cell receptors which display glycoconjugates with the disaccharide GlcNAcl-4Gal [37].

As stated earlier, S. pneumoniae may go directly to the meninges, or it may be aspirated into the lungs, spread to the blood and traverse the blood-brain barrier [30, 37]. The cell wall of pneumococcus bacteria is made of more than a dozen glycopeptides which are continuously inserted and released from the circumferential macromolecule [33]. Pneumococci adhere to platelet activating factor (PAF) receptors on cytokine activated cells by the phosphorylcholine in the teichoic acid component of their cell walls. Phosphorylcholine modulates the bioactivity of PAF, which results in the recruitment of leukocytes and platelets to the area [33, 37]. Leukocytes are also attracted by a selectin-CD18 integrin pathway which becomes actived during infection. The bacteria bind epithelia, endothelia and leukocytes and trigger production of interleukin-1 (IL-1), a key cytokine in the inflammatory response [33]. Among many functions, IL-1 increases vascular permeability and stimulates platelet production [39]. The cell wall is acted upon by components of the acute phase response and has the ability to fix complement. Cell wall components also enhance the permeability of the cerebral endothelia and pulmonary alveolar epithelia, stimulate cytokine production, activate the procoagulant cascade, damage neurons and affect cerebral blood flow and vascular-perfusion pressure [33].

Thus, due to the strong response created to the pneumococcal cell wall, the alternative complement pathway is activated prior to the production of specific anti-capsular antibody [37]. The result is complement fixation to pneumococci and clearance by the reticuloendothelial (RE) system (specifically the spleen). Once antibody to the capsule is formed, rapid opsonization and removal by the RE system results [37].

S. pneumoniae does not damage by bacterial toxins, but rather because the cell wall elicits such a strong inflammatory response. In the meninges, lethal intracranial pressure builds as meningitis progresses [37]. The recruitment of leukocytes decreases the number of bacteria at the infection site, but S. pneumoniae becomes deadly due to the precipitation of the inflammatory response created when the pneumococci die, leaving their cell walls to disintegrate and releasing components such as pneumolysin [33]. The cell wall components which result from degradation by the body’s own defenses are much more effective chemoattractants than the intact cell walls. If the concentration of cell wall components exceeds 100,000 particles per milliliter, a rapid inflammatory response is initiated [33]. If a patient is able to survive this event, the decline in bacterial products will decrease the inflammatory response. The trouble is that many people, especially the elderly and very young, are unable to successfully withstand the response. The situation may be exacerbated by lysis of bacteria caused by antibiotics [33].

The possibility of creating polysaccharide-protein conjugate vaccines was proposed when work with animals found polysaccharides could be made more immunogenic if coupled to proteins. Capsular polysaccharides of pneumococcus have been joined to tetanus toxoid, diphtheria toxoid, CRM197 (a nontoxic form of diphtheria toxoid), pneumolysin and outer membrane proteins of meningococcus [34]. The tetanus and diphtheria toxoid conjugates have been the most successful. The problem in the case of S. pneumoniae remains that many different capsular types must be included. Thus, individual conjugates must be made and placed in a vaccine together [34]. A certain amount of conjugate is required to stimulate a specific immune response. Thus, the number of different strains which can be included is limited [34]. Also, as mentioned above, it has been found that children do not respond well to polysaccharides until they are over 2 years of age. Thus, it would seem that there is some disadvantage in making a vaccine which attempts to elicit such a response. This encouraged the search for substances other than capsular polysaccharides which could serve as antigens and provide protection against pneumococcal infection [34].

A number of protein antigens are exposed on or released from the surface of the pneumococcus. Antibodies to some of these proteins, pneumolysin, autolysin and neuraminidase, have demonstrated protective activity [34]. Monoclonal antibodies have been used in the detection of other potential surface antigens, one of which is pneumococcal surface protein A (PspA). The role of PspA in virulence is not clear, but it seems to retard the clearance of pneumococci from the blood, as antibody to PspA facilitates the clearance of pneumococci [34]. Further laboratory work has indicated that PspA immunization results in antibody rather than cell-mediated immunity. Immunization with PspA stimulated IgG production, and passive administration of anti-PspA IgG and IgM monoclonal antibodies prevents against fatal infection [34].

The human reservoir of pneumococci is maintained through nasopharyngeal carriage. A vaccine which would prevent carriage of the bacteria would protect in addition to immunized individuals, those who are not immunized and those who are unable to stimulate an adequate immune response [34]. It was found that immunization using the full-length of PspA prevented nasopharyngeal carriage. Conjugates of tetanus toxoid and capsular type 6B polysaccharide with cholera toxin B subunit as the adjuvant also prevented carriage [34].

Antigenic variation is a major issue in S. pneumoniae vaccine development as so many strains of the bacteria exist. PspA is actually one of the more variable gene products of S. pneumoniae [34]. However, PspA was found to be highly cross reactive as it provided cross-protection against challenge strains, though responses to some strains were more effective than to others. Also, the same PspA epitopes are present in different combinations on PspAs from different strains. PspA still remains to undergo human vaccine trials [34].

As evidenced by the preceding discussion, in the face of difficulties with vaccine treatment, a variety of vaccine possibilities are currently being researched to improve upon the 23 capsular polysaccharide vaccine against S. pneumoniae. It is hoped that by impeding the ability of S. pneumoniae to infect humans, the diseases associated with this bacteria, specifically pneumococcal meningitis in this case, may be prevented.