Naturally acquired protective immunity against Neisseria meningitidis is thought to partially explain the disparity between the high levels of carriage in the human nasopharynx and the rare incidence of disease. To investigate this immunity to Neisseria meningitidis at the mucosal level, in vitro cellular responses to outer membrane vesicle preparations derived from this pathogen were examined using mononuclear cells from the palatine tonsils of adults and children. Characterization of these responses was achieved by depletion of CD45RA+, CD45RO+, and CD19+ populations and outer membrane vesicles derived from isogenic mutants expressing different serosubtypes of the major outer membrane protein, porin A (PorA), no PorA and membrane preparations from a mutant with no LPS (LpxA−). The magnitude of cellular proliferative responses against the outer membrane vesicles were strongly associated with age and were largely T cell mediated, involving both CD45RO+ and CD45RA+ T cell phenotypes. Responses were not dependent on LPS but consisted of both PorA cross-specific and non-PorA-dependent responses. Cellular immunity against Neisseria meningitidis was found to be frequently associated with systemic IgG Abs but was not associated with serum bactericidal Abs. For the first time our results demonstrate an age-associated acquisition of mucosal T effector/memory cell responses to Neisseria meningitidis. This mucosal cellular immunity can be present in the absence of serum bactericidal Abs, a classical marker of protective immunity.

We sought to determine whether palatine tonsils (PTs) harbor naturally acquired influenza-specific T cell immunity and whether routine parenteral immunization with influenza vaccine influences mucosal and systemic T cell reactivity. We demonstrate that tonsillar and peripheral blood mononuclear cells (PBMCs) proliferate strongly to influenza antigens, suggesting that naturally acquired immunity exists within both the mucosal and systemic compartments. Influenza vaccination induced significantly stronger T cell responses in both PTs and blood, in addition to increasing titers of anti-influenza antibodies in serum and saliva. More-rapid proliferative responses of PTs after vaccination were associated with a shift from a response involving both CD45RA+ and CD45RO+ T cells to an entirely CD45RO+-dependent response. Interestingly, the ratio of interferon- gamma to interleukin-5 was dramatically higher in cultures of PT T cells responding to influenza than in PBMCs. Our data indicate that parenteral influenza vaccination influences both mucosal and systemic naturally acquired T cell immunity.

Asymptomatic carriage of Neisseria meningitidis is common (5-35% of individuals) while the incidence of invasive meningococcal disease is fairly low (<1-5 per 100,000 per annum in Europe). Naturally acquired protective immunity may account for this difference. In this study, we investigated the relationship between anti-meningococcal salivary IgA and age and carriage. We showed that salivary IgA to a range of meningococcal antigens increased successively with age with some specificity for commonly circulating serosubtypes. In a group of 258 students 37 (14%) of whom were carriers of N. meningitidis serogroup B, higher levels of specific IgA were associated with carriage. Stratified analysis revealed a positive relationship between smoking and specific anti- N. meningitidis IgA independent of current carriage, weighted odds ratio (OR) 4.1 (95% CI 1.1-18) and OR 3.8 (95% CI 0.96-16) for reference strains B:1:P1.14 and B:4:P1.5,4 respectively. These data implicate IgA as a factor in host defence from meningococcal invasion, although the precise mechanisms remain uncertain.

Parenteral MenB vaccination selectively reprograms preexisting naturally acquired mucosal immunity. As new-generation protein-based MenB vaccine candidates undergo evaluation, the impact of these vaccines on mucosal immunity in both adults and children will need to be addressed.

The mouse humoral immune response toward native or detergent-extracted outer membrane vesicles (NOMVs and DOMVs, respectively) from Neisseria meningitidis was determined after intranasal immunization. Both preparations elicited high frequencies of NOMV-specific antibody-forming cells (AFCs) locally in the nasal associated lymphoid tissue (NALT) after three or four weekly doses. The diffuse NALT (D-NALT) contained ca. 10-fold more NOMV-specific AFCs than those observed in the mediastinal lymph node, spleen, and bone marrow. AFCs observed in the D-NALT were primarily immunoglobulin A positive (IgA ؉ ) and were maintained for at least 1 month. In contrast, the organized NALT (O-NALT) contained low numbers of AFCs, and the response was relatively short-lived. In other lymphoid tissues, AFCs producing various IgG subclasses and IgM were present with IgG2b-producing AFCs being dominant or codominant with IgA or IgG2a. In serum and in all of the tissues examined, with the exception of the NALT, NOMVs clearly induced a stronger antibody response and a broader range of antibody isotypes than DOMVs. The development of NOMV-specific AFCs in spleen and bone marrow after intranasal immunization was slow compared to intravenous immunization but, once established, the intranasally elicited responses increased steadily for at least 75 days. NOMV-specific antibodies induced via several routes of immunization had high bactericidal activities in serum. Our results indicated that intranasally administered OMVs induced strong local and systemic antibody responses in mice that were relatively long-lived.