Spread of an Enterococcus faecalis sequence type 6 (CC2) clone in patients undergoing selective decontamination of the digestive tract

Enterococcus faecalis (E. faecalis) is a common cause of nosocomial infection in immunocompromised patients. The presence and dissemination of high‐risk clonal complexes, such as CC2, is an ongoing problem in hospitals. The aim of this work was to characterize 24 E. faecalis isolates from ICU patients undergoing selective decontamination of the digestive tract (SDD) by phenotypical (antimicrobial susceptibility) and genotypical (presence of virulence genes, RAPD‐PCR and MLST) methods. Our results showed high prevalence of the ST6 E. faecalis clone (91.6%), especially adapted to the hospital environment, with a multidrug resistance pattern and a multitude of putative virulence genes. In addition, ST179 (4.2%) and ST191 (4.2%) were detected. By RAPD–PCR analysis, the 22 isolates identified as ST6 showed six different DNA patterns, while the two remaining isolates, ST179 and ST191, showed two additional profiles. CC2 is a known clonal complex with high adaptability to hospital environment and worldwide distribution. The high prevalence of the ST6 clone in the studied population could be related to the presence of gentamicin in the SDD mixture since most strains were gentamicin resistant. Consequently, strict surveillance should be applied for rapid detection and control of this clone to prevent future spread outside the ICU.     

Durability of humoral immune responses to rubella following MMR vaccination

BackgroundWhile administration of the measles-mumps-rubella (MMR-II®) vaccine has been effective at preventing rubella infection in the United States, the durability of humoral immunity to the rubella component of MMR vaccine has not been widely studied among older adolescents and adults.MethodsIn this longitudinal study, we sought to assess the durability of rubella virus (RV)-specific humoral immunity in a healthy population (n = 98) of adolescents and young adults at two timepoints: ~7 and ~17 years after two doses of MMR-II® vaccination. Levels of circulating antibodies specific to RV were measured by ELISA and an immune-colorimetric neutralization assay. RV-specific memory B cell responses were also measured by ELISpot.ResultsRubella-specific IgG antibody titers, neutralizing antibody titers, and memory B cell responses declined with increasing time since vaccination; however, these decreases were relatively moderate. Memory B cell responses exhibited a greater decline in men compared to women.ConclusionsCollectively, rubella-specific humoral immunity declines following vaccination, although subjects’ antibody titers remain well above the currently recognized threshold for protective immunity. Clinical correlates of protection based on neutralizing antibody titer and memory B cell ELISpot response should be defined.     

Longitudinal analysis of the in vitro activity of ceftazidime-avibactam vs. Pseudomonas aeruginosa, 2012–2016

The in vitro activities of ceftazidime-avibactam and comparator agents were analyzed against 14,330 isolates of Pseudomonas aeruginosa from 188 centers distributed globally (except North America) from 2012 (2014 for colistin) to 2016 as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance program. Susceptibility testing used in-house prepared broth microdilution panels following CLSI guidelines. Multiplex PCR assays identified the presence of β-lactamases. Ceftazidime-avibactam (MIC₉₀ 8 mg/L; 91.5% susceptibility) and colistin (N = 11,032; MIC₉₀ 2 mg/L, 96.2%) were the 2 most active agents. Susceptibility of multidrug-resistant isolates (N = 3770, 26.3%) was ≤54.4% to all agents except colistin (N = 2956; 95.2% susceptible) and ceftazidime-avibactam (68.2%). Metallo-β-lactamase–positive isolates (N = 621, 4.3%) were not susceptible to any agents except colistin (N = 504; 98.2% susceptible). Novel therapeutic options are needed for infections caused by P. aeruginosa–resistant phenotypes.     

Evaluation of protection induced by a dengue virus serotype 2 envelope domain III protein scaffold/DNA vaccine in non-human primates

We describe the preclinical development of a dengue virus vaccine targeting the dengue virus serotype 2 (DENV2) envelope domain III (EDIII). This study provides proof-of-principle that a dengue EDIII protein scaffold/DNA vaccine can protect against dengue challenge. The dengue vaccine (EDIII-E2) is composed of both a protein particle and a DNA expression plasmid delivered simultaneously via intramuscular injection (protein) and gene gun (DNA) into rhesus macaques. The protein component can contain a maximum of 60 copies of EDIII presented on a multimeric scaffold of Geobacillus stearothermophilus E2 proteins. The DNA component is composed of the EDIII portion of the envelope gene cloned into an expression plasmid. The EDIII-E2 vaccine elicited robust antibody responses to DENV2, with neutralizing antibody responses detectable following the first boost and reaching titers of greater than 1:100,000 following the second and final boost. Vaccinated and naïve groups of macaques were challenged with DENV2. All vaccinated macaques were protected from detectable viremia by infectious assay, while naïve animals had detectable viremia for 2–7 days post-challenge. All naïve macaques had detectable viral RNA from day 2–10 post-challenge. In the EDIII-E2 group, three macaques were negative for viral RNA and three were found to have detectable viral RNA post challenge. Viremia onset was delayed and the duration was shortened relative to naïve controls. The presence of viral RNA post-challenge corresponded to a 10–30-fold boost in neutralization titers 28 days post challenge, whereas no boost was observed in the fully protected animals. Based on these results, we determine that pre-challenge 50% neutralization titers of >1:6000 correlated with sterilizing protection against DENV2 challenge in EDIII-E2 vaccinated macaques. Identification of the critical correlate of protection for the EDIII-E2 platform in the robust non-human primate model lays the groundwork for further development of a tetravalent EDIII-E2 dengue vaccine.     

Synthetic conjugate peptide Fba-Met6 (MP12) induces complement-mediated resistance against disseminated Candida albicans

The fungal genus Candida includes common commensals of the human mucosal membranes, and the most prevalently isolated species, C. albicans, poses a threat of candidemia and disseminated infection associated with an unacceptably high mortality rate and an immense $4 billion burden (US) yearly. Nevertheless, the demand for a vaccine remains wholly unfulfilled and increasingly pressing. We developed a double-peptide construct that is feasible for use in humans with the intention of preventing morbid infection by targeting epitopes derived from fructose bisphosphate aldolase (Fba) and methionine synthase (Met6) which are expressed on the C. albicans cell surface. To test the applicability of the design, we vaccinated mice via the intramuscular (IM) route with the conjugate denoted Fba-Met6 MP12 and showed that the vaccine enhanced survival against a lethal challenge. Because overall endpoint IgG1 and IgG2a antibody titers were robust and these mouse subclasses are associated with protective functionality, we investigated the potential of Fba and Met6 specific antibodies to facilitate the well-defined anti-Candida response by complement, which opsonizes fungi for degradation by primary effectors. Notably, reductions in the fungal burdens and enhanced survival were both abrogated in MP12-vaccinated mice that were pre-challenge dosed with cobra venom factor (CVF), a complement depleting factor. Altogether, we demonstrated that complement is relevant to MP12-based protection against disseminated C. albicans, delineating that a novel, multivalent targeted vaccine against proteins on the surface of C. albicans can enhance the natural response to infection.     

Allergic fetal priming leads to developmental,behavioral and neurobiological changes in mice

The state of the mother''s immune system during pregnancy has an important role in fetal development and disruptions in the balance of this system are associated with a range of neurologic, neuropsychiatric and neurodevelopmental disorders. Epidemiological and clinical reports reveal various clues that suggest a possible association between developmental neuropsychiatric disorders and family history of immune system dysfunction. Over the past three decades, analogous increases have been reported in both the incidence of neurodevelopmental disorders and immune-related disorders, particularly allergy and asthma, raising the question of whether allergic asthma and characteristics of various neurodevelopmental disorders share common causal links. We used a mouse model of maternal allergic asthma to test this novel hypothesis that early fetal priming with an allergenic exposure during gestation produces behavioral deficits in offspring. Mothers were primed with an exposure to ovalbumin (OVA) before pregnancy, then exposed to either aerosolized OVA or vehicle during gestation. Both male and female mice born to mothers exposed to aerosolized OVA during gestation exhibited altered developmental trajectories in weight and length, decreased sociability and increased marble-burying behavior. Moreover, offspring of OVA-exposed mothers were observed to have increased serotonin transporter protein levels in the cortex. These data demonstrate that behavioral and neurobiological effects can be elicited following early fetal priming with maternal allergic asthma and provide support that maternal allergic asthma may, in some cases, be a contributing factor to neurodevelopmental disorders.     

Characterization of the RAGE-binding protein,Strongyloides venestatin,produced by the silkworm-baculovirus expression system

The receptor for advanced glycation end products (RAGE) recognizes Ca⁺⁺-binding proteins, such as members of the S100 protein family released by dead or devitalized tissues, and plays an important role in inflammatory responses. We recently identified the Ca⁺⁺-binding protein, venestatin, secreted from the rodent parasitic nematode, Strongyloides venezuelensis. We herein characterized recombinant venestatin, which is abundantly produced by the silkworm-baculovirus expression system (silkworm-BES), particularly in its interaction with RAGE. Venestatin from silkworm-BES possessed a binding capacity with Ca⁺⁺ ions and vaccine immunogenicity against S. venezuelensis larvae in mice, which is similar to venestatin produced by the E. coli expression system (EES). Venestatin from silkworm-BES had a higher affinity for human recombinant RAGE than that from EES, and their affinities were Ca⁺⁺-dependent. RAGE in the mouse lung co-immunoprecipitated with venestatin from silkworm-BES administered intranasally, indicating that it bound endogenous mouse RAGE. The present results suggest that venestatin from silkworm-BES affects RAGE-mediated pathological processes.