Immunogenicity and Protective Potential of Mucosal Vaccine Formulations Based on Conserved Epitopes of Influenza A Viruses Fused to an Innovative Ring Nanoplatform in Mice and Chickens.

Current inactivated vaccines against influenza A viruses (IAV) mainly induce immune responses against highly variable epitopes across strains and are mostly delivered parenterally, limiting the development of an effective mucosal immunity. In this study, we evaluated the potential of intranasal formulations incorporating conserved IAV epitopes, namely the long alpha helix (LAH) of the stalk domain of hemagglutinin and three tandem repeats of the ectodomain of the matrix protein 2 (3M2e), as universal mucosal anti-IAV vaccines in mice and chickens. The IAV epitopes were grafted to nanorings, a novel platform technology for mucosal vaccination formed by the nucleoprotein (N) of the respiratory syncytial virus, in fusion or not with the C-terminal end of the P97 protein (P97c), a recently identified Toll-like receptor 5 agonist. Fusion of LAH to nanorings boosted the generation of LAH-specific systemic and local antibody responses as well as cellular immunity in mice, whereas the carrier effect of nanorings was less pronounced towards 3M2e. Mice vaccinated with chimeric nanorings bearing IAV epitopes in fusion with P97c presented modest LAH- or M2e-specific IgG titers in serum and were unable to generate a mucosal humoral response. In contrast, N-3M2e or N-LAH nanorings admixed with Montanide™ gel (MG) triggered strong specific humoral responses, composed of serum type 1/type 2 IgG and mucosal IgG and IgA, as well as cellular responses dominated by type 1/type 17 cytokine profiles. All mice vaccinated with the [N-3M2e + N-LAH + MG] formulation survived an H1N1 challenge and the combination of both N-3M2e and N-LAH nanorings with MG enhanced the clinical and/or virological protective potential of the preparation in comparison to individual nanorings. Chickens vaccinated parenterally or mucosally with N-LAH and N-3M2e nanorings admixed with Montanide™ adjuvants developed a specific systemic humoral response, which nonetheless failed to confer protection against heterosubtypic challenge with a highly pathogenic H5N8 strain. Thus, while the combination of N-LAH and N-3M2e nanorings with Montanide™ adjuvants shows promise as a universal mucosal anti-IAV vaccine in the mouse model, further experiments have to be conducted to extend its efficacy to poultry.

Marked increase in incidence for bloodstream infections due to Escherichia coli, a side effect of previous antibiotic therapy in the elderly.

We conducted a survey including 3334 bloodstream infections (BSIs) due to E. coli diagnosed in 2005-2014 at a stable cohort of hospitals. Marked increases in incidence were observed for community-acquired (CA) BSIs in patients aged >75 years, CA-BSIs of digestive origin in patients aged 60-74 years, healthcare-associated BSIs, and BSIs associated with ESBL (extended-spectrum B-lactamase)-producing E. coli (ESBLEc). Using MLST, we studied the genetic diversity of 412 BSI isolates recovered during the 2014 survey: 7 major sequence type complexes (STCs) were revealed in phylogenetic group B2, 3 in group A/B1 and 2 in group D. Among the 31 ESBLEc isolates, 1/3 belonged to STC 131. We searched for possible associations between clonal groups, clinical determinants and characteristics of BSIs: isolates from groups B2 (except STC 131) and D were susceptible to antibiotics and associated with BSIs of urinary origin in patients <60 years. STC 131 and group A/B1 isolates were multi-drug resistant and associated with CA-BSIs of digestive origin in patients aged 60-74 with a recent history of antibiotic treatment. STC 131 isolates were associated with HCA-BSIs in patients with recent/present hospitalization in a long-stay unit. We provide a unique population-based picture of the epidemiology of E. coli BSI. The aging nature of the population led to an increase in the number of cases caused by the B2 and D isolates generally implicated in BSIs. In addition, the association of a trend toward increasing rates of gut colonization with multi drug-resistant isolates revealed by the rise in the incidence of BSIs of digestive origin caused by STC 131 and A/B1 (STCs 10, 23, and 155) isolates, and a significant increase in the frequency of BSIs in elderly patients with recent antibiotic treatment suggested that antibiotic use may have contributed to the growing incidence of BSI.