Nasopharyngeal carriage with Streptococcus pneumoniae augments the immunizing effect of pneumolysin toxoid B

Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom. Electronic address: .
The Journal of allergy and clinical immunology (Impact Factor: 11.48). 12/2012; 131(5). DOI: 10.1016/j.jaci.2012.11.004
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Available from: Daniel R. Neill,
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    ABSTRACT: Streptococcus pneumoniae is a pathogen of great importance worldwide. We have previously described the efficacy of a nasal vaccine composed of the pneumococcal surface protein A and the whole-cell pertussis vaccine as an adjuvant against a pneumococcal invasive challenge in mice. Spread of bacteria to the bloodstream was probably prevented by the high levels of systemic antibodies induced by the vaccine, but bacteria were only cleared from the lungs 3 weeks later, indicating that local immune responses may contribute to survival. Here we show that a strict control of inflammatory responses in lungs of vaccinated mice occurs even in the presence of high numbers of pneumococci. This response was characterized by a sharp peak of neutrophils and lymphocytes with a simultaneous decrease in macrophages in the respiratory mucosa at 12 h postchallenge. Secretion of interleukin-6 (IL-6) and gamma interferon (IFN-γ) was reduced at 24 h postchallenge, and the induction of tumor necrosis factor alpha (TNF-α) secretion, observed in the first hours postchallenge, was completely abolished at 24 h. Before challenge and at 12 h postchallenge, vaccinated mice displayed higher numbers of CD4(+) T, CD8(+) T, and B lymphocytes in the lungs. However, protection still occurs in the absence of each of these cells during the challenge, indicating that other effectors may be related to the prevention of lung injuries in this model. High levels of mucosal anti-PspA antibodies were maintained in vaccinated mice during the challenge, suggesting an important role in protection.
    Clinical and vaccine Immunology: CVI 07/2012; 19(9):1382-92. DOI:10.1128/CVI.00171-12 · 2.47 Impact Factor
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    ABSTRACT: RATIONALE: The immunological and protective role of pneumococcal carriage in healthy adults is not known but high rates of disease and death in 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 re-challenged intranasally with live 6B Streptococcus pneumoniae up to 11 months after clearance of first carriage episode. Serum and nasal wash antibody response were measured before and after each challenge. MEASUREMENTS AND MAIN RESULTS: 29 subjects were experimentally colonized. No subjects were colonized by experimental re-challenge 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 post-carriage 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 pre-carriage sera (30%) or saline (10%). CONCLUSIONS: Experimental human carriage resulted in mucosal and systemic immunological responses that conferred protection against re-colonization and invasive pneumococcal disease. These data suggest that mucosal pneumococcal vaccination strategies maybe important for vulnerable patient groups, particularly the elderly, who do not sustain carriage.
    American Journal of Respiratory and Critical Care Medicine 01/2013; 187(8). DOI:10.1164/rccm.201212-2277OC · 13.00 Impact Factor
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    ABSTRACT: 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 non-invasive 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 utilized to characterize immune responses in the airways during carriage. Measurements and Main Results We describe the previously unknown immunological basis of non-invasive carriage and highlight mechanisms whose perturbation may lead to invasive disease. We identify the induction of active TGFB1 by S. pneumoniae in human host cells and highlight the key role for TGFB1 and T regulatory cells in establishment and maintenance of nasopharyngeal carriage in mice and humans. We identify the ability of pneumococci to drive TGFB1 production from nasopharyngeal cells in vivo and show that an immune tolerance profile, characterized by elevated TGFB1 and high nasopharyngeal T regulatory cell numbers is crucial for prolonged carriage of pneumococci. Blockade of TGFB1 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.
    American Journal of Respiratory and Critical Care Medicine 04/2014; 189(10). DOI:10.1164/rccm.201401-0128OC · 13.00 Impact Factor
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