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INTRODUCTION: Patient and staff experiences are strongly influenced by attitudes and behaviours, and provide important insights into care quality. Patient and staff feedback could be used more effectively to enhance behaviours and improve care through systematic integration with techniques for reflective learning. We aim to develop a reflective learning framework and toolkit for healthcare staff to improve patient, family and staff experience. METHODS & ANALYSIS: Local project teams including staff and patients from the acute medical units (AMUs) and intensive care units (ICUs) of three National Health Service trusts will implement two experience surveys derived from existing instruments: a continuous patient and relative survey and an annual staff survey. Survey data will be supplemented by ethnographic interviews and observations in the workplace to evaluate barriers to and facilitators of reflective learning. Using facilitated iterative co-design, local project teams will supplement survey data with their experiences of healthcare to identify events, actions, activities and interventions which promote personal insight and empathy through reflective learning. Outputs will be collated by the central project team to develop a reflective learning framework and toolkit which will be fed back to the local groups for review, refinement and piloting. The development process will be mapped to a conceptual theory of reflective learning which combines psychological and pedagogical theories of learning, alongside theories of behaviour change based on capability, opportunity and motivation influencing behaviour. The output will be a locally-adaptable workplace-based toolkit providing guidance on using reflective learning to incorporate patient and staff experience in routine clinical activities. ETHICS & DISSEMINATION: The PEARL project has received ethics approval from the London Brent Research Ethics Committee (REC Ref 16/LO/224). We propose a national cluster randomised step-wedge trial of the toolkit developed for large-scale evaluation of impact on patient outcomes.
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Cuidados Críticos/métodos , Educação Profissionalizante/métodos , Aprendizagem , Competência Profissional/normas , Qualidade da Assistência à Saúde/normas , Desenvolvimento de Pessoal/métodos , Atitude do Pessoal de Saúde , Educação Profissionalizante/organização & administração , Empatia , Humanos , Pesquisa Qualitativa , Desenvolvimento de Pessoal/organização & administração , Medicina Estatal , Reino UnidoRESUMO
INTRODUCTION: Vaccines may be key components of a curative strategy for HIV-1. We investigated whether a novel immunogen, HIVconsv, designed to re-direct T cell responses to conserved viral epitopes, could impact the HIV-1 reservoir in chronic antiretroviral therapy (ART)-treated subjects when delivered by modified vaccinia virus Ankara (MVA). METHODS: Nineteen virologically suppressed individuals were randomized to receive vaccinations with MVA.HIVconsv (5.5 × 107 plaque-forming units, pfu, n = 8; 2.2 × 108 pfu, n = 7) or placebo (n = 4) at 0, 4 and 12 weeks. Magnitude, breadth and antiviral function of vaccine-induced T cells, cell-associated HIV-1 DNA in circulating CD4+ T cells and residual viremia in plasma were measured before and after vaccination. RESULTS: 90% of subjects completed the vaccine regimen; there were no serious vaccine-related adverse events. The magnitude of HIVconsv-specific IFN-γ-secreting T cells was not significantly boosted in vaccinees when compared with placebos in ex vivo Elispot assays, due to greater than expected variation in HIV-specific T cell responses in the latter during the observation period. Ex vivo CD8+ T cell viral inhibitory capacity was modest but significantly increased post-vaccination with MVA.HIVconsv at the higher dose (p = 0.004) and was positively correlated with the frequency of HIVconsv-specific CD8+ CD107+ IFN-α± T cells (r = 0.57, p = 0.01). Total HIV-1 DNA and residual viral load did not change significantly from baseline in any group. CONCLUSIONS: Homologous prime-boost vaccination with MVA.HIVconsv was safe in HIV-positive ART-treated subjects but showed modest immunogenicity and did not significantly change the size of the viral reservoir. MVA.HIVconsv may be more effective when used in a heterologous prime-boost vaccination regimen and when combined with a latency-reversing agent. CLINICAL TRIALS REGISTRATION: NCT01024842.
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Vacinas contra a AIDS/imunologia , Infecções por HIV/terapia , Imunogenicidade da Vacina , Vacinas contra a AIDS/genética , Fármacos Anti-HIV/uso terapêutico , Sequência Conservada/imunologia , Método Duplo-Cego , Feminino , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , HIV-1/genética , Humanos , Masculino , Linfócitos T/imunologia , Vacinas Sintéticas/imunologia , Vaccinia virus , Carga ViralAssuntos
Fármacos Anti-HIV/efeitos adversos , Bursite/induzido quimicamente , Cobicistat/efeitos adversos , Infecções por HIV/tratamento farmacológico , Articulação do Quadril/patologia , Quinolonas/efeitos adversos , Articulação do Ombro/patologia , Fármacos Anti-HIV/administração & dosagem , Bursite/patologia , Cobicistat/administração & dosagem , Infecções por HIV/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Quinolonas/administração & dosagem , CintilografiaRESUMO
TRIAL DESIGN: HIV-1 vaccine development has advanced slowly due to viral antigenic diversity, poor immunogenicity and recently, safety concerns associated with human adenovirus serotype-5 vectors. To tackle HIV-1 variation, we designed a unique T-cell immunogen HIVconsv from functionally conserved regions of the HIV-1 proteome, which were presented to the immune system using a heterologous prime-boost combination of plasmid DNA, a non-replicating simian (chimpanzee) adenovirus ChAdV-63 and a non-replicating poxvirus, modified vaccinia virus Ankara. A block-randomized, single-blind, placebo-controlled phase I trial HIV-CORE 002 administered for the first time candidate HIV-1- vaccines or placebo to 32 healthy HIV-1/2-uninfected adults in Oxford, UK and elicited high frequencies of HIV-1-specific T cells capable of inhibiting HIV-1 replication in vitro. Here, detail safety and tolerability of these vaccines are reported. METHODS: Local and systemic reactogenicity data were collected using structured interviews and study-specific diary cards. Data on all other adverse events were collected using open questions. Serum neutralizing antibody titres to ChAdV-63 were determined before and after vaccination. RESULTS: Two volunteers withdrew for vaccine-unrelated reasons. No vaccine-related serious adverse events or reactions occurred during 190 person-months of follow-up. Local and systemic events after vaccination occurred in 27/32 individuals and most were mild (severity grade 1) and predominantly transient (<48 hours). Myalgia and flu-like symptoms were more strongly associated with MVA than ChAdV63 or DNA vectors and more common in vaccine recipients than in placebo. There were no intercurrent HIV-1 infections during follow-up. 2/24 volunteers had low ChAdV-63-neutralizing titres at baseline and 7 increased their titres to over 200 with a median (range) of 633 (231-1533) post-vaccination, which is of no safety concern. CONCLUSIONS: These data demonstrate safety and good tolerability of the pSG2.HIVconsv DNA, ChAdV63.HIVconsv and MVA.HIVconsv vaccines and together with their high immunogenicity support their further development towards efficacy studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT01151319.
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Vacinas contra a AIDS/imunologia , Adenovirus dos Símios/imunologia , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Vaccinia virus/imunologia , Adenovirus dos Símios/genética , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Sequência Conservada , Feminino , Vetores Genéticos , Células HEK293 , Anticorpos Anti-HIV/sangue , HIV-1/genética , Proteínas do Vírus da Imunodeficiência Humana/genética , Proteínas do Vírus da Imunodeficiência Humana/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Plasmídeos/genética , Método Simples-Cego , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Vaccinia virus/genética , Replicação Viral , Adulto JovemRESUMO
Virus diversity and escape from immune responses are the biggest challenges to the development of an effective vaccine against HIV-1. We hypothesized that T-cell vaccines targeting the most conserved regions of the HIV-1 proteome, which are common to most variants and bear fitness costs when mutated, will generate effectors that efficiently recognize and kill virus-infected cells early enough after transmission to potentially impact on HIV-1 replication and will do so more efficiently than whole protein-based T-cell vaccines. Here, we describe the first-ever administration of conserved immunogen vaccines vectored using prime-boost regimens of DNA, simian adenovirus and modified vaccinia virus Ankara to uninfected UK volunteers. The vaccine induced high levels of effector T cells that recognized virus-infected autologous CD4(+) cells and inhibited HIV-1 replication by up to 5.79 log10. The virus inhibition was mediated by both Gag- and Pol- specific effector CD8(+) T cells targeting epitopes that are typically subdominant in natural infection. These results provide proof of concept for using a vaccine to target T cells at conserved epitopes, showing that these T cells can control HIV-1 replication in vitro.
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Vacinas contra a AIDS/imunologia , Epitopos de Linfócito T/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Linfócitos T/imunologia , Vacinas contra a AIDS/genética , Adolescente , Adulto , Sequência de Aminoácidos , Células Cultivadas , Sequência Conservada/imunologia , Mapeamento de Epitopos , Epitopos de Linfócito T/química , Feminino , Infecções por HIV/prevenção & controle , HIV-1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Especificidade do Receptor de Antígeno de Linfócitos T/imunologia , Subpopulações de Linfócitos T/imunologia , Vacinas de DNA/genética , Vacinas de DNA/imunologia , Replicação Viral/imunologia , Adulto Jovem , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia , Produtos do Gene pol do Vírus da Imunodeficiência Humana/imunologiaRESUMO
We present a 19-year-old woman with severe encephalitis and raised intracranial pressure requiring decompressive craniectomy. Her clinical features were consistent with encephalitis in the context of acute primary Epstein-Barr virus (EBV) infection (infectious mononucleosis). Serology, bone marrow aspirate and PCR of blood and cerebrospinal fluid confirmed the diagnosis. She was treated with corticosteroids and aciclovir. She was critically unwell for 3 weeks, requiring artificial ventilation but eventually made a good recovery. EBV encephalitis is uncommon, making the diagnosis and decisions about clinical management challenging.