Humans are the only natural host of Neisseria meningitidis, which normally colonizes the throat and nasopharynx. This colonization may lead to a carrier state; about 5 to 10% of adults at any given time are healthy carriers. This colonization may also lead to invasive disease. What determines carriage or disease? Many meningococci recovered from healthy carriers have very low pathogenic potential; only some strains are of high virulence, and expression of a capsular polysaccharide is required. Studies by Gotschlich et al⁴ clearly show that only individuals lacking bactericidal antibodies against the encountered meningococcal strain go on to develop disease.

Prior to the development of antibiotics and effective vaccines, marked reductions in lethality were achieved using therapeutic sera. The success of this therapy demonstrated very early the central role of humoral antibody in protection against meningococcal bacteremia and meningitis.¹ The critical role of bactericidal antibodies has been further demonstrated in a number of ways. (a) The highest incidence of meningococcal disease occurs in individuals 6-12 months of age. This age group has the lowest bactericidal antibody levels. (b) Studies in US Army recruits in the mid- 1960's showed a direct correlation between susceptibility to meningitis and absence of serum bactericidal antibodies.⁴ (c) Individuals deficient in complement components C5, C6, C7, or C8 have a significantly increased susceptibility to invasive meningococcal infection, even though they may have high levels of anti-meningococcal antibodies. (d) A correlation has been shown between the efficacy of meningococcal vaccines and induction and persistence of bactericidal antibodies. Thus, measurement of bactericidal antibody can serve as a surrogate for protective immunity. In the development of meningococcal vaccines, both PS-conjugate and outer membrane protein (OMP), it is of primary importance to demonstrate induction of bactericidal antibodies, though antibody responses will also be quantified by ELISA.

Immunological memory may also play an important role in protection against meningococcal disease. Induction of immunological priming for an anamnestic response has been well demonstrated using Haemophilus influenzae type b (Hib) and meningococcal conjugate vaccines.^5,6 The role of memory in providing long-term protection against meningococcal disease has not been shown but should not be very different from Hib, another cause of meningitis. Infants in the UK receive a Hib conjugate vaccine at 2, 3, and 4 months of age, but receive no booster immunization, and clear evidence of protection is evident to at least 6 years of age.⁷

Opsonophagocytosis has not been well studied, but is likely important in overall protection against meningococcal disease. Vaccination with the serogroup A and C PS induces opsonic antibody.^7a Turbid CSF specimens from meningococcal patients have many polymorphonuclear leukocytes with internalized meningococci. Meningococci in phagolysosomes are rapidly killed. However, meningococci are protected from phagocytosis by their capsules in the absence of anticapsular or anti-outer membrane antibodies. Opsonic antibodies may be more important in protection against group B, whose capsular polysaccharide is virtually nonimmunogenic.

Meningococci colonize and invade the tonsillar tissue of the throat.⁸ An intracellular niche for the meningococcus is consistent with the observation that only antibiotics (e.g., rifampicin) effective against intracellular pathogens will clear meningococcal carriage. An intracellular niche suggests that cellular immunity may also play a role in protection against meningococcal disease.

An additional virulence mechanism may be associated with the organism's ability to switch capsules. Meningococci of serogroups B, C, Y and W135 all express capsules containing sialic acid, and capsule switching between group B and group C strains have been confirmed.^9,10 Capsule switching can occur in vivo by horizontal transfer of the SiaD genes encoding polysialyltransferases. Presumably, the opportunity for capsule-switching arises from co-colonization of serogroup B and C strains in the human nasopharynx. A potential outcome of capsule switching is immune escape, but the military in many countries has routinely used the polysaccharide vaccine against group C, without observing increased group B disease.

Meningococcal PS vaccines do not effectively stimulate the immune system in young children and are largely nonimmunogenic in infants. The exception is group A meningococcal PS which, for reasons not understood, is immunogenic in infants as young as 3 mo of age and is effective if used in young children in a two-dose immunization schedule.¹¹ However, infants do respond well to PS-conjugate vaccines. These are polysaccharide-protein hybrids formed by the covalent attachment of a protein through its amino groups to a chemically modified ("activated") PS. Attachment of the protein provides a number of T-cell epitopes that interact with CD4 helper T cells, greatly facilitating an antibody response to the attached polysaccharide. The T-helper-cell-dependent response to a conjugate vaccine results in both serum IgG antibodies and memory B cells, even in infants. Additionally, the immunogenicity of the PS-conjugate, in contrast to the native PS, does not depend upon the size of the conjugated PS; conjugates prepared with either PS or oligosaccharides have similar immunogenicity (see Table 1).

Studies of conjugate vaccines in immunologically naïve individuals have shown that a conjugate can induce memory B cells without induction of circulating serum IgG. This was demonstrated in Finland using a subpotent Hib conjugate vaccine called PRP-D.¹² In the Finnish studies, some infants were nonresponders after three doses of PRP-D at 2, 4 and 6 mo of age. These nonresponder children received a 4^th dose at 15 mo of age and responded with antibody levels far higher than could have been expected from primary immunization at 15 mo of age. The role of priming alone in protective immunity to meningococci remains unclear.