Pneumococcal colonization impairs mucosal immune responses to live attenuated influenza vaccine.

Influenza virus infections affect millions of people annually, and current available vaccines provide varying rates of protection. However, the way in which the nasal microbiota, particularly established pneumococcal colonization, shape the response to influenza vaccination is not yet fully understood. In this study, we inoculated healthy adults with live Streptococcus pneumoniae and vaccinated them 3 days later with either tetravalent-inactivated influenza vaccine (TIV) or live attenuated influenza vaccine (LAIV). Vaccine-induced immune responses were assessed in nose, blood, and lung. Nasal pneumococcal colonization had no impact upon TIV-induced antibody responses to influenza, which manifested in all compartments. However, experimentally induced pneumococcal colonization dampened LAIV-mediated mucosal antibody responses, primarily IgA in the nose and IgG in the lung. Pulmonary influenza-specific cellular responses were more apparent in the LAIV group compared with either the TIV or an unvaccinated group. These results indicate that TIV and LAIV elicit differential immunity to adults and that LAIV immunogenicity is diminished by the nasal presence of S. pneumoniae. Therefore, nasopharyngeal pneumococcal colonization may affect LAIV efficacy

Additional file 1: of Human alveolar macrophages predominately express combined classical M1 and M2 surface markers in steady state

Table S1. Demographics of the EHPC study participants- UK. Table S2. Demographics of study participants – Malawi. Table S3. Summary of the panel composition at the UK site (no shading) and Malawi site (grey shading). Fig. S1. Gating strategy used to identify human alveolar macrophages in the UK Cohort. Fig. S2. Gating strategy used to identify human alveolar macrophages in the Malawi Cohort. (DOCX 681 kb

Extended enantiopure ortho-phenylene ethylene (o-OPE)-based helical systems as scaffolds for supramolecular architectures: a study of chiroptical response and its connection to the CISS effect

A novel synthetic strategy based on a bifunctional stapled chiral nucleus from which segments of different lengths can be added to both ends of o-phenylene ethynylenes (o-OPEs) has been developed to obtain a new type of foldamer and a novel chiral Pd2L2 metallacycle. For the first time, an enantiopure fully conjugated helical foldamer having 14 phenyl rings and 13 alkynes is reported. The folded structure has four complete loops and is able to host three Ag(i) cations in their cavity with high binding constants. The complete photophysical and chiroptical (ECD, CPL and VCD) characterization of these foldamers has shown that these molecules show intense chiroptical responses with dissymmetry ratios in the range of 10(-2). Theoretical modeling of these systems reveals the origin of these remarkable responses and points out a potential connection with the chiral induced spin selectivity (CISS) effect. The magnetic dipole moment is proposed as a key physical variable connecting the chiroptical properties and CISS-based spin filtering properties observed in chiral compounds

Experimental Human Challenge Defines Distinct Pneumococcal Kinetic Profiles and Mucosal Responses between Colonized and Non-Colonized Adults

Occurrence of lower respiratory tract infections requires prior colonization of the upper respiratory tract with a pathogen. Most bacterial infection and colonization studies have been performed in murine and in vitr

Nasal curettage yields reproducible and consistent results over time.

<p>(A) The percentage of granulocytes (closed circles) and T cells (open circles) in 218 nasal cell samples collected over a five month period (n = 117 volunteers, sampled up to five times). Individual samples and loess curves are depicted for both populations. (B, C) The correlation for individuals in four repeated measurements over a 33-day period for (B) granulocytes and (C) T cells.</p

Comparison of samples collected by nasal wash and nasal curette.

<p>(A) Epithelial (open circles) and immune (closed circles) and cell yields were compared between nasal wash pellets and nasal curette samples. Individuals samples and median and interquartile range are shown. (B) Median proportions of granulocytes, T cells, monocytes, lineage^- HLA-DR⁺ and uncharacterized cells among immune cells in nasal curette (n = 139 individuals) and nasal wash (n = 8) samples. *p < 0.05, ***p < 0.001, ****p < 0.0001 Mann-Whitney test.</p

Comparison of samples from nasal mucosa and blood.

<p>(A) Median proportions of granulocytes, T cells, monocytes, lineage^- HLA-DR⁺ and uncharacterized cells among immune cells in blood (n = 10) and nasal curette (n = 139). **** p < 0.0001 Mann-Whitney test. (B) The percentage of HLA-DR⁺ T cells in blood and nasal curette samples and mean fluorescent intensity (MFI) of HLA-DR and CD66b on granulocytes was measured for blood, nasal curette and nasal wash (n = 8) samples. Median and interquartile range are shown. *p < 0.05, ***p < 0.001 Kruskal-Wallis, followed by Dunn’s Multiple Comparison Test. (C) Multi-dimensional scaling analysis shows the clustering of samples from blood (grey circles), nasal curette (open squares, 11 randomly selected) and nasal wash (black triangles). The epithelial cell yield, activation state of granulocytes and composition of the immune cells were taken into account. Kruskal stress = 5.8% and Analysis of Similarity ANOSIM p-value = 0.001.</p

Tolerability of novel nasal sampling methods.

<p>The percentage of volunteers rating (A) nasal curettage and (B) nasosorption on discomfort, pain and lacrimation.</p

A Randomized Controlled Clinical Trial of Nasal Immunization with Live Virulence Attenuated Streptococcus pneumoniae Strains Using Human Infection Challenge

Rationale: Pneumococcal pneumonia remains a global health problem. Pneumococcal colonization increases local and systemic protective immunity, suggesting that nasal administration of live attenuated Streptococcus pneumoniae (Spn) strains could help prevent infections. Objectives: We used a controlled human infection model to investigate whether nasopharyngeal colonization with attenuated S. pneumoniae strains protected against recolonization with wild-type (WT) Spn (SpnWT). Methods: Healthy adults aged 18-50 years were randomized (1:1:1:1) for nasal administration twice (at a 2-wk interval) with saline solution, WT Spn6B (BHN418), or one of two genetically modified Spn6B strains, SpnA1 (Δfhs/piaA) or SpnA3 (ΔproABC/piaA) (Stage I). After 6 months, participants were challenged with SpnWT to assess protection against the homologous serotype (Stage II). Measurements and Main Results: 125 participants completed both study stages per intention to treat. No serious adverse events were reported. In Stage I, colonization rates were similar among groups: SpnWT, 58.1% (18 of 31); SpnA1, 60% (18 of 30); and SpnA3, 59.4% (19 of 32). Anti-Spn nasal IgG levels after colonization were similar in all groups, whereas serum IgG responses were higher in the SpnWT and SpnA1 groups than in the SpnA3 group. In colonized individuals, increases in IgG responses were identified against 197 Spn protein antigens and serotype 6 capsular polysaccharide using a pangenome array. Participants given SpnWT or SpnA1 in Stage I were partially protected against homologous challenge with SpnWT (29% and 30% recolonization rates, respectively) at stage II, whereas those exposed to SpnA3 achieved a recolonization rate similar to that in the control group (50% vs. 47%, respectively). Conclusions: Nasal colonization with genetically modified live attenuated Spn was safe and induced protection against recolonization, suggesting that nasal administration of live attenuated Spn could be an effective strategy for preventing pneumococcal infections. Clinical trial registered with the ISRCTN registry (ISRCTN22467293)

A Randomised Controlled Trial of Nasal Immunisation with Live Virulence Attenuated Streptococcus pneumoniae Strains Using Human Infection Challenge

RATIONALE: Pneumococcal pneumonia remains a global health problem. Pneumococcal colonisation increases local and systemic protective immunity, suggesting nasal administration of live attenuated S. pneumoniae strains could help prevent infections. OBJECTIVES: We used a controlled human infection model to investigate whether nasopharyngeal colonisation with attenuated S. pneumoniae strains protected against re-colonisation with wild-type (WT) S. pneumoniae (Spn). METHODS: Healthy adults aged 18-50 years were randomised (1:1:1:1) for nasal administration twice (two weeks interval) with saline, WT Spn6B (BHN418) or one of two genetically modified Spn6B strains - SpnA1 (∆fhs/piaA) or SpnA3 (∆proABC/piaA) (Stage I). After 6 months, participants were challenged with SpnWT to assess protection against the homologous serotype (Stage II). MEASUREMENTS AND MAIN RESULTS: 125 participants completed both study stages as per intention to treat. No Serious Adverse Events were reported. In Stage I, colonisation rates were similar amongst groups: SpnWT 58.1% (18/31), SpnA1 60% (18/30) and SpnA3 59.4% (19/32). Anti-Spn nasal IgG levels post-colonisation were similar in all groups whilst serum IgG responses were higher in the SpnWT and SpnA1 groups than the SpnA3 group. In colonised individuals, increases in IgG responses were identified against 197 Spn protein antigens and serotype 6 capsular polysaccharide using a pangenome array. Participants given SpnWT or SpnA1 in stage 1 were partially protected against homologous challenge with SpnWT (29% and 30% recolonisation rates, respectively) at stage II, whereas those exposed to SpnA3 achieved recolonisation rate similar to control group group (50% vs 47%, respectively). CONCLUSION: Nasal colonisation with genetically modified live attenuated Spn was safe and induced protection against recolonisation, suggesting nasal adminstration of live attenuated Spn could be an effective stategy for preventing pneumococcal infections