Hyperproliferation of B Cells Specific for a Weakly Immunogenic PorA in a Meningococcal Vaccine Model

Abstract

Highly homologous meningococcal porin A (PorA) proteins induce protective humoral immunity against Neisseria meningitidis group B infection but with large and consistent differences in the levels of serum bactericidal activity achieved. We investigated whether a poor PorA-specific serological outcome is associated with a limited size of the specific B-cell subpopulation involved. The numbers of PorA-specific splenic plasma cells, bone marrow (BM) plasma cells, and splenic memory B cells were compared between mice that received priming and boosting with the weakly immunogenic PorA (P1.7-2,4) protein and those that received priming and boosting with the highly immunogenic PorA (P1.5-1,2-2) protein. Immunoglobulin G (IgG) titers (except at day 42), bactericidal activity, and the avidity of IgG produced against P1.7-2,4 were significantly lower at all time points after priming and boosting than against P1.5-1,2-2. These differences, however, were not associated with a lack of P1.7-2,4-specific plasma cells. Instead, priming with both of the PorAs resulted in the initial expansion of comparable numbers of splenic and BM plasma cells. Moreover, P1.7-2,4-specific BM plasma cells, but not P1.5-1,2-2-specific plasma cells, expanded significantly further after boosting. Likewise, after a relative delay during the priming phase, the splenic P1.7-2,4-specific memory B cells largely outnumbered those specific for P1.5-1,2-2, upon boosting. These trends were observed with different vaccine formulations of the porins. Our results show for the first time that B-cell subpopulations involved in a successfully maturated antibody response against a clinically relevant vaccine antigen are maintained at smaller population sizes than those associated with poor affinity maturation. This bears consequences for the interpretation of immunological memory data in clinical vaccine trials.

Age Related Differences in Dynamics of Specific Memory B Cell Populations after Clinical Pertussis Infection

“…Blomberg and coworkers showed that elderly have a reduced ability to generate high affinity antibodies and IgG1 and IgG3 responses against influenza A hemagglutinin [68] , [69] . Failure to produce high affinity antibodies could also account for a prolonged expansion of the B mem cell compartment, due to the absence of negative feedback of immune complexes on B cell proliferation [70] . A study interrogating such qualitative aspects of B cell responses in our age cohorts is currently on-going.…”

Immunogenicity of a Glycoconjugate from Hydrazine‐Detoxified Lipopolysaccharide of Vibrio cholerae O139

“…Memory B cells have potential to rapidly differentiate into novel antibody‐secreting plasma cells, with even more adapted antibodies upon re‐exposure to antigen or infection . Understanding the mechanism by which vaccines generate and sustain these B cell subpopulations is essential to explaining and predicting the long‐term efficacy of vaccines which mediate protection through functional antibodies . MBCs develop following natural infection and immunization, and could be the entity by which the long‐term immunity to cholera is mediated .…”

Fast, Antigen-Saving Multiplex Immunoassay To Determine Levels and Avidity of Mouse Serum Antibodies to Pertussis, Diphtheria, and Tetanus Antigens

“…Avidity of DTP-specific IgG antibodies in mouse reference serum was evaluated in six parallel ELISAs using different concentrations of the chaotropic reagent NaSCN in PBS (40), ranging from 0 M (untreated condition) to 3 M, as described elsewhere (28). NaSCN concentrations resulting in a reduction of 50% of the OD 450 of the untreated controls were determined to be 1.5 M for P.69 Prn and Dtx, 2 M for FHA and Fim2/3, and 2.5 M for Ptx and TT (data not shown) and were considered the optimal conditions for avidity analysis of specific IgG antibodies in mouse immune sera.…”