Written informed consent was obtained from all volunteers

Written informed consent was obtained from all volunteers. of circulating 6BPS IgGsecreting memory B cells at baseline. There were no associations between protection from carriage and baseline levels of 6BPS IgG in serum or nasal wash, PspA-specific, or PspC-specific memory B cells or plasma cells. In volunteers who did not develop carriage, the number of circulating 6BPS memory B cells decreased and the number of 6BPS plasma cells increased postinoculation. Conclusions: Our data indicate that naturally acquired PS-specific memory B cells, but not levels of circulating IgG at time of pneumococcal exposure, are associated with protection against carriage acquisition. Keywords: pneumococcal carriage, pneumococcal polysaccharide, memory B cells, plasma B cells, antibodies == At a Glance Commentary == == Scientific Knowledge on the Subject == Animal models have demonstrated that immunoglobulins play a role in host defense against carriage acquisition. Using our experimental model of human pneumococcal carriage, we have demonstrated that preexisting levels of antibody to pneumococcal proteins and capsular polysaccharide were not associated with protection against pneumococcal colonization. == What This Study Adds to the Field == Here we present data that demonstrate that naturally acquired polysaccharide-specific memory B cells to capsular polysaccharide of the inoculated strain are associated with protection against carriage acquisition. Pneumococcal carriage is a prerequisite of infection and the primary reservoir for transmission (1, 2). Carriage is also an important immunizing event in healthy adults and we have previously Saquinavir demonstrated that experimental carriage protects against reacquisition of carriage after reinoculation with the same strain (homologous) for up to 11 months after clearance of the first carriage episode (3). Animal models have demonstrated that immunoglobulins play a role in host defense against carriage acquisition (4) and IL-17secreting CD4+T cells play a role in the clearance of carriage (5). Although these immunologic responses are well described in murine models, the immunologic responses that mediate protection in humans have not been identified. We have previously observed that pneumococcal colonization increases the level and Saquinavir functional capacity of pneumococcal-specific IgG and IgA in serum and nasal wash, and that colonization also increases the number of pneumococcal-specific IL-17secreting CD4+T cells in the lung (3, 6, 7). Epidemiologic data support the role of polysaccharide (PS)-mediated immunity in protection against carriage. Vaccination with pneumococcal conjugate vaccine (PCV) has reduced carriage of vaccine-type strains (8), and has resulted in serotype replacement in vaccinated communities (9, 10). We have recently demonstrated the direct impact of PCV vaccination on pneumococcal carriage acquisition (11). In a double-blind randomized control trial, the rate of carriage acquisition, Saquinavir after challenge with 6B pneumococcus, was reduced by 78% in PCV-vaccinated volunteers compared with control vaccinated volunteers. We have previously demonstrated that baseline levels of both PS-specific IgG and capacity for opsonphagocytic killing did not predict carriage outcome after intranasal pneumococcal inoculation (3, 6, 12). PS-specific memory B cells (BMEM) are not present in the mucosal Saquinavir immune tissue of the human nasopharynx (13). This suggests that the localized stimulation and differentiation of BMEMinto plasma cells (BPLAS) is unlikely to occurin situat the mucosa, and that PS-specific immunoglobulin from systemic circulation may instead mediate protection against carriage acquisition at the mucosal surface. Here we identified healthy volunteers that were naturally colonized with pneumococcus and 916 months after clearance of their carriage episode challenged them with a heterologous pneumococcal serotype, resulting in a 50% rate of carriage. We have previously demonstrated 0% carriage reacquisition up to 11 months after a carriage episode when rechallenged with Rabbit polyclonal to ALX3 the same strain (3). We further assessed B-cellmediated immunity among volunteers with no current pneumococcal carriage and an unknown history of previous pneumococcal carriage exposure. We observed that volunteers protected from carriage (carriage-negative) had similar levels of circulating IgG but higher number of PS-specific BMEMthan volunteers susceptible to carriage (carriage-positive). Responses to protein-based antigens were not associated with protection against carriage. Taken together these data suggest that naturally acquired PS-specific immunity plays a prominent role in mediating protection against acquisition of pneumococcal carriage in unvaccinated volunteers. == Methods == == Ethical Approval, Study Protocol, and Sampling == Eight healthy nonsmoking adult volunteers aged between 18 and 60 years, who had a confirmed previous natural carriage episode, and who had no close contact with risk individuals were recruited to cohort A..