DNA Vaccines Encoding Antigen Targeted to MHC Class II Induce Influenza-Specific CD8+ T Cell Responses, Enabling Faster Resolution of Influenza Disease

Current influenza vaccines are effective but imperfect, failing to cover against emerging strains of virus and requiring seasonal administration to protect against new strains. A key step to improving influenza vaccines is to improve our understanding of vaccine induced protection. Whilst it is clear that antibodies play a protective role, vaccine induced CD8+ T cells can improve protection. To further explore the role of CD8+ T cells we used a DNA vaccine that encodes antigen dimerised to an immune cell targeting module. Immunising CB6F1 mice with the DNA vaccine in a heterologous prime boost regime with the seasonal protein vaccine improved the resolution of influenza disease compared to protein alone. This improved disease resolution was dependent on CD8+ T cells. However, DNA vaccine regimes that induced CD8+ T cells alone were not protective and did not boost the protection provided by protein. The MHC targeting module used was an anti-I-Ed single chain antibody specific to the BALB/c strain of mice. To test the role of MHC targeting we compared the response between BALB/c, C57BL/6 mice and an F1 cross of the two strains (CB6F1). BALB/c mice were protected, C57BL/6 were not and the F1 had an intermediate phenotype; showing that the targeting of antigen is important in the response. Based on these findings, and in agreement with other studies using different vaccines, we conclude that in addition to antibody, inducing a protective CD8 response is important in future influenza vaccines

Corrigendum: Airway T cells protect against RSV infection in the absence of antibody

Correction to: Mucosal Immunology (2018) 11, 249–256; doi:10.1038/mi.2017.46; published online 24 May 201

Competing priorities and second chances - A qualitative exploration of prisoners’ journeys through the Hepatitis C continuum of care.

High levels of undiagnosed and untreated HCV infection exist in prison populations globally. Prisons are a key location to identify, treat and prevent HCV infection among people who inject drugs (PWID). Understanding prisoners’ lived experiences of the HCV continuum of care informs how HCV care can be effectively delivered to this marginalised and high-risk population. This study aimed to explore Irish prisoners’ experience of prison and community-based HCV care. We conducted one-to-one interviews with 25 male prisoners with chronic HCV infection. Data collection and analysis was informed by grounded theory. The mean age of participants and first incarceration was 39.5 and 18.3 years respectively. The mean number of incarcerations was eight. The following themes were identified: medical and social factors influencing engagement (fear of treatment and lack of knowledge, HCV relevance and competing priorities), adverse impact of HCV on health and wellness, positive experience of prison life and health care and the transformative clinical and non-clinical changes associated with HCV treatment and cure. Findings suggest that prison release was associated with multiple stressors including homelessness and drug dependence which quickly eroded the health benefits gained during incarceration. The study generated a substantive theory of the need to increase the importance of HCV care among the routine competing priorities associated with the lives of PWID. HCV infected prisoners often lead complex lives and understanding their journeys through the HCV continuum can inform the development of meaningful HCV care pathways. Many challenges exist to optimising HCV treatment uptake in this group and incarceration is an opportunity to successfully engage HCV infected prisoners who underutilise and are underserved by community-based medical services. Support and linkage to care on release is essential to optimising HCV management

Integrated Hepatitis C Care for People Who Inject Drugs (Heplink): Protocol for a Feasibility Study in Primary Care (Preprint)

Background: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and death. Drug use remains the significant cause of new infections in the European Union, with estimates of HCV antibody prevalence among people who inject drugs ranging from 5% to 90% in 29 European countries. In Ireland and the European Union, primary care is a key area to focus efforts to enhance HCV diagnosis and treatment among people who inject drugs. Objective: The Heplink study aims to improve HCV care outcomes among opiate substitution therapy (OST) patients in general practice by developing an integrated model of HCV care and evaluating its feasibility, acceptability, and likely efficacy. Methods: The integrated model of care comprises education of community practitioners, outreach of an HCV-trained nurse into general practitioner (GP) practices, and enhanced access of patients to community-based evaluation of their HCV disease (including a novel approach to diagnosis, that is, Echosens FibroScan Mini 430). A total of 24 OST-prescribing GP practices were recruited from the professional networks and databases of members of the research consortium. Patients were eligible if they are aged ≥18 years, on OST, and attend the practice for any reason during the recruitment period. Baseline data on HCV care processes and outcomes were extracted from the clinical records of participating patients. Results: This study is ongoing and has the potential to make an important impact on patient care and provide high-quality evidence to help GPs make important decisions on HCV testing and onward referral. Conclusions: A substantial proportion of HCV-positive patients on OST in general practice are not engaged with specialist hospital services but qualify for direct-acting antiviral drugs treatment. The Heplink model has the potential to reduce HCV-related morbidity and mortality. Registered Report Identifier: RR1-10.2196/904

Hepatitis c treatment and prevention in people who inject drugs (PWID) and prisoners: A narrative review of the extant literature

Background. Hepatitis C is a curable and preventable disease. People who inject drugs (PWID) and prisoners are at-risk groups for acquisition of Hepatitis C Virus (HCV), yet treatment rates remain low. Agonist Opioid Treatment (AOT) and needle syringe programs (NSP) reduce HCV transmission, yet coverage, particularly in prisons, is inadequate. ‘Treatment as prevention’ is a key public health strategy to help achieve the World Health Organisation (WHO) goal of HCV elimination by 2030. Aim: To review the recent literature on HCV treatment and prevention in PWID and prisoners. Methods: Electronic data base (Medline, PubMed, Cochrane library and Embase) and key website search using search terms related to the topic. Results: HCV related disease burden in PWID and prisoners is greater than the general population, yet treatment rates remain low. Direct acting anti-virals, mobile elastography, integration of treatment into community and prison settings and less restrictive treatment guidelines have removed many treatment barriers. Treatment adherence and outcomes, among PWID (even current injectors) and prisoners are equivalent to the general population. HCV treatment in both groups is cost-effective but is dependent on up scaling treatment levels, continuing treatment on prison release and preventing re-infection. The public health strategies of treatment as prevention and micro-elimination along with adequate coverage of AOT and NSP has the potential to achieve the WHO goal of HCV elimination by 2030. Conclusion: Upscaling HCV treatment levels and increasing AOT and NSP coverage among PWID and prisoners remains a challenge but is an essential public health strategy to reduce the increasing HCV burden

Hepatitis C Virus (HCV) screening in people who inject drugs (PWID) and prisoners - a narrative review of extant literature

Background: Injecting drug use (IDU) is the major driver of Hepatitis C Virus (HCV) infection in European and other developed countries. People who inject drugs (PWID) and prisoners, both marginalised and underserved populations are recognised as key groups to target for HCV screening and treatment. Aim: To review the most up to date published literature on HCV screening in PWID and prisoners Methods: Electronic data base (Medline, PubMed, Cochrane library and Embase) and relevant website search using key search terms related to the topic. Results: Data on HCV screening in these two groups is incomplete. Over half of PWID and a quarter of prisoners globally have been exposed to HCV. Multiple personal and institutional barriers, including; lack of knowledge, fear, stigma , complex testing procedures and competing priorities , have been identified to the upscaling of screening in these two groups. Focussed screening at targeted locations, increasing screening methods including the use of dried blood spot testing (DBS), peer-worker involvement and opt-out screening in prisons has the potential to enable uptake. Reflex-RNA testing streamlines identification of active infection and improves linkage to care. Supporting community linkage on prison release is critical to optimise HCV management. Active case finding in PWID and prisoners, provided within an ethical and human rights framework, increases diagnosis, assessment, and treatment, reduces transmission and is cost-effective. Conclusion: Optimising HCV screening in PWID and prisoners underpins any public and prison health strategy aimed at HCV elimination but requires political will and targeted resources to be successfully implemented

Fragment reattachment, reproductive status, and health indicators of the invasive colonial tunicate Didemnum vexillum with implications for dispersal

This manuscript is not subject to U.S. copyright. The definitive version was published in Biological Invasions 14 (2012): 2133-2140, doi:10.1007/s10530-012-0219-8.The invasive colonial tunicate Didemnum vexillum is now widespread in coastal and offshore waters of New England, USA. D. vexillum can inflict ecological and economic damage through biofouling and habitat modification. Natural and anthropogenic processes that fragment colonies of D. vexillum may be accelerating the spread of this invader. Reattachment success and fragment viability were confirmed in the laboratory after four weeks of suspension in experimental aquaria. The shape of suspended D. vexillum fragments progressed from flattened to globular spheres and then flattened again after reattachment to the substrate. Reproductive activity, confirmed by the presence of eggs and larvae, was observed for fragments suspended up to three weeks suggesting that D. vexillum is capable of reproducing while in a fragmented, suspended state. An index of colony health was used to monitor change in D. vexillum health while in suspension. Overall, colony health declined with time in suspension although colonies that appeared dead (black and gray in overall color) still contained a substantial number of healthy live zooids. These results suggest that activities that cause fragmentation can significantly facilitate the spread of D. vexillum. Coastal managers should consider reducing or eliminating, when practical, activities that return fragmented colonies of D. vexillum to the water. In-water cleaning of biofouling and dredging are likely expediting the spread of this invasive species unless biofouling can be contained and removed from the water.This research was funded by the NOAA Aquatic Invasive Species Program

miR-132/212 knockout mice reveal roles for these miRNAs in regulating cortical synaptic transmission and plasticity

miR-132 and miR-212 are two closely related miRNAs encoded in the same intron of a small non-coding gene, which have been suggested to play roles in both immune and neuronal function. We describe here the generation and initial characterisation of a miR-132/212 double knockout mouse. These mice were viable and fertile with no overt adverse phenotype. Analysis of innate immune responses, including TLR-induced cytokine production and IFNβ induction in response to viral infection of primary fibroblasts did not reveal any phenotype in the knockouts. In contrast, the loss of miR-132 and miR-212, while not overtly affecting neuronal morphology, did affect synaptic function. In both hippocampal and neocortical slices miR-132/212 knockout reduced basal synaptic transmission, without affecting paired-pulse facilitation. Hippocampal long-term potentiation (LTP) induced by tetanic stimulation was not affected by miR-132/212 deletion, whilst theta burst LTP was enhanced. In contrast, neocortical theta burst-induced LTP was inhibited by loss of miR-132/212. Together these results indicate that miR-132 and/or miR-212 play a significant role in synaptic function, possibly by regulating the number of postsynaptic AMPA receptors under basal conditions and during activity-dependent synaptic plasticity

HEPCARE EUROPE- A Case study of a Service Innovation Project Aiming at Improving the Elimination of HCV in Vulnerable Populations in Four European Cities

OBJECTIVES: Hepatitis C Virus (HCV) is an important cause of chronic liver disease. Among at-risk populations, access to diagnosis and treatment is challenging. We describe an integrated model of care, Hepcare Europe, developed to address this challenge. METHODS: Using a case-study approach, we describe the cascade of care outcomes at all sites. Costing analyses estimated the cost per person screened and linked to care. RESULTS: A total of 2608 participants were recruited across 218 clinical sites. HCV antibody test results were obtained for 2568(98.5%), 1074(41.8%) were antibody-positive, 687(60.5%) tested positive for HCV-RNA, 650(60.5%) were linked to care and 319(43.5%) started treatment. 196(61.4%) of treatment initiates achieved a Sustained Viral Response (SVR) at dataset closure, 108(33.9%) were still on treatment, 8(2.7%) defaulted from treatment, and 7(2.6%) had a virologic failure or died. The cost per person screened varied from Є194 to Є635, while cost per person linked to care varied from Є364 to Є2035. CONCLUSIONS: Hepcare enhanced access to HCV treatment and cure, costs were affordable in all settings, offering a framework for scale-up and reproducibility