Experimental Human Pneumococcal Carriage

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169

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Rationale: The immunological and protective role of pneumococcal carriage in healthy adults is not known, but high rates of disease and death in the elderly are associated with low carriage prevalence. Objectives: We employed an experimental human pneumococcal carriage model to investigate the immunizing effect of a single carriage episode. Methods: Seventy healthy adults were challenged, and of those with carriage, 10 were rechallenged intranasally with live 6B Streptococcus pneumoniae up to 11 months after clearance of the first carriage episode. Serum and nasal wash antibody responses were measured before and after each challenge. Measurements and Main Results: A total of 29 subjects were experimentally colonized. No subjects were colonized by experimental rechallenge, demonstrating the protective effect of initial carriage against subsequent infection. Carriage increased both mucosal and serum IgG levels to pneumococcal proteins and polysaccharide, resulting in a fourfold increase in opsonophagocytic activity. Importantly, passive transfer of postcarriage sera from colonized subjects conferred 70% protection against lethal challenge by a heterologous strain in a murine model of invasive pneumococcal pneumonia. These levels were significantly higher than the protection conferred by either precarriage sera (30%) or saline (10%). Conclusions: Experimental human carriage resulted in mucosal and systemic immunological responses that conferred protection against recolonization and invasive pneumococcal disease. These data suggest that mucosal pneumococcal vaccination strategies may be important for vulnerable patient groups, particularly the elderly, who do not sustain carriage.

Section: Bacterial Stock Preparation and Inoculated Dosementioning

confidence: 99%

Section: Ehpc Studiesmentioning

confidence: 99%

Controlled Human Infection and Rechallenge with Streptococcus pneumoniae Reveals the Protective Efficacy of Carriage in Healthy Adults

Ferreira

Neill

Bangert

et al. 2013

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“…In cohort B, each volunteer was inoculated with 61,944 6 4,603 cfu/naris of S. pneumoniae serotype 6B (Table 1). Bacterial preparation and inoculation, as well as nasal wash sampling and carriage detection were performed as previously described (15). In cohort A, nasal wash samples were obtained 5 days before intranasal inoculation and then on Days 2, 7, and 14 after inoculation.…”

Section: Methodsmentioning

confidence: 99%

Polysaccharide-Specific Memory B Cells Predict Protection against Experimental Human Pneumococcal Carriage

Pennington

Pojar

Mitsi

et al. 2016

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Rationale: We have previously demonstrated that experimental pneumococcal carriage enhances immunity and protects healthy adults against carriage reacquisition after rechallenge with a homologous strain.Objectives: To investigate the role of naturally acquired pneumococcal protein and polysaccharide (PS)-specific immunity in protection against carriage acquisition using a heterologous challenge model. Methods:We identified healthy volunteers that were naturally colonized with pneumococcus and, after clearance of their natural carriage episode, challenged them with a heterologous 6B strain. In another cohort of volunteers we assessed 6BPS-specific, PspA-specific, and PspC-specific IgG and IgA plasma and memory B-cell populations before and 7, 14, and 35 days after experimental pneumococcal inoculation.Measurements and Main Results: Heterologous challenge with 6B resulted in 50% carriage among volunteers with previous natural pneumococcal carriage. Protection from carriage was associated with a high number of circulating 6BPS IgG-secreting 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.

“…Infectious doses were prepared as described previously (11). Samples from experimental human pneumococcal challenge were taken from patients challenged with serotype 6B pneumococci (12).…”

Section: Bacteriamentioning

confidence: 99%

Density and Duration of Pneumococcal Carriage Is Maintained by Transforming Growth Factor β1 and T Regulatory Cells

Neill

Coward

Gritzfeld

et al. 2014

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Rationale: Nasopharyngeal carriage of Streptococcus pneumoniae is a prerequisite for invasive disease, but the majority of carriage episodes are asymptomatic and self-resolving. Interactions determining the development of carriage versus invasive disease are poorly understood but will influence the effectiveness of vaccines or therapeutics that disrupt nasal colonization.Objectives: We sought to elucidate immunological mechanisms underlying noninvasive pneumococcal nasopharyngeal carriage.Methods: Pneumococcal interactions with human nasopharyngeal and bronchial fibroblasts and epithelial cells were investigated in vitro. A murine model of nasopharyngeal carriage and an experimental human pneumococcal challenge model were used to characterize immune responses in the airways during carriage. Measurements and Main Results:We describe the previously unknown immunological basis of noninvasive carriage and highlight mechanisms whose perturbation may lead to invasive disease. We identify the induction of active transforming growth factor (TGF)-b1 by S. pneumoniae in human host cells and highlight the key role for TGF-b1 and T regulatory cells in the establishment and maintenance of nasopharyngeal carriage in mice and humans. We identify the ability of pneumococci to drive TGF-b1 production from nasopharyngeal cells in vivo and show that an immune tolerance profile, characterized by elevated TGF-b1 and high nasopharyngeal T regulatory cell numbers, is crucial for prolonged carriage of pneumococci. Blockade of TGF-b1 signaling prevents prolonged carriage and leads to clearance of pneumococci from the nasopharynx.Conclusions: These data explain the mechanisms by which S. pneumoniae colonize the human nasopharynx without inducing damaging host inflammation and provide insight into the role of bacterial and host constituents that allow and maintain carriage.