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BACKGROUND: Mycobacterium tuberculosis is the main causative agent of tuberculosis. BCG, the only licensed vaccine, provides inadequate protection against pulmonary tuberculosis. Controlled human infection models are useful tools for vaccine development. We aimed to determine a safe dose of aerosol-inhaled live-attenuated Mycobacterium bovis BCG as a surrogate for M tuberculosis infection, then compare the safety and tolerability of infection models established using aerosol-inhaled and intradermally administered BCG. METHODS: This phase 1 controlled human infection trial was conducted at two clinical research facilities in the UK. Healthy, immunocompetent adults aged 18-50 years, who were both M tuberculosis-naive and BCG-naive and had no history of asthma or other respiratory diseases, were eligible for the trial. Participants were initially enrolled into group 1 (receiving the BCG Danish strain); the trial was subsequently paused because of a worldwide shortage of BCG Danish and, after protocol amendment, was restarted using the BCG Bulgaria strain (group 2). After a dose-escalation study, during which participants were sequentially allocated to receive either 1 × 103, 1 × 104, 1 × 105, 1 × 106, or 1 × 107 colony-forming units (CFU) of aerosol BCG, the maximum tolerated dose was selected for the randomised controlled trial. Participants in this trial were randomly assigned (9:12), by variable block randomisation and using sequentially numbered sealed envelopes, to receive aerosol BCG (1 × 107 CFU) and intradermal saline or intradermal BCG (1 × 106 CFU) and aerosol saline. Participants were masked to treatment allocation until day 14. The primary outcome was to compare the safety of a controlled human infection model based on aerosol-inhaled BCG versus one based on intradermally administered BCG, and the secondary outcome was to evaluate BCG recovery in the airways of participants who received aerosol BCG or skin biopsies of participants who received intradermal BCG. BCG was detected by culture and by PCR. The trial is registered at ClinicalTrials.gov, NCT02709278, and is complete. FINDINGS: Participants were assessed for eligibility between April 7, 2016, and Sept 29, 2018. For group 1, 15 participants were screened, of whom 13 were enrolled and ten completed the study; for group 2, 60 were screened and 33 enrolled, all of whom completed the study. Doses up to 1 × 107 CFU aerosol-inhaled BCG were sufficiently well tolerated. No significant difference was observed in the frequency of adverse events between aerosol and intradermal groups (median percentage of solicited adverse events per participant, post-aerosol vs post-intradermal BCG: systemic 7% [IQR 2-11] vs 4% [1-13], p=0·62; respiratory 7% [1-19] vs 4% [1-9], p=0·56). More severe systemic adverse events occurred in the 2 weeks after aerosol BCG (15 [12%] of 122 reported systemic adverse events) than after intradermal BCG (one [1%] of 94; difference 11% [95% CI 5-17]; p=0·0013), but no difference was observed in the severity of respiratory adverse events (two [1%] of 144 vs zero [0%] of 97; 1% [-1 to 3]; p=0·52). All adverse events after aerosol BCG resolved spontaneously. One serious adverse event was reported-a participant in group 2 was admitted to hospital to receive analgesia for a pre-existing ovarian cyst, which was deemed unrelated to BCG infection. On day 14, BCG was cultured from bronchoalveolar lavage samples after aerosol infection and from skin biopsy samples after intradermal infection. INTERPRETATION: This first-in-human aerosol BCG controlled human infection model was sufficiently well tolerated. Further work will evaluate the utility of this model in assessing vaccine efficacy and identifying potential correlates of protection. FUNDING: Bill & Melinda Gates Foundation, Wellcome Trust, National Institute for Health Research Oxford Biomedical Research Centre, Thames Valley Clinical Research Network, and TBVAC2020.
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Vacuna BCG , Humanos , Adulto , Vacuna BCG/administración & dosificación , Vacuna BCG/inmunología , Vacuna BCG/efectos adversos , Masculino , Femenino , Reino Unido , Persona de Mediana Edad , Inyecciones Intradérmicas , Adulto Joven , Administración por Inhalación , Mycobacterium bovis/inmunología , Adolescente , Aerosoles , Vacunas Atenuadas/administración & dosificación , Tuberculosis/prevención & controlRESUMEN
OBJECTIVE: To report the early and mid-term outcome of complex endovascular repair (EVAR) for paravisceral infective native aortic aneurysms (INAA). METHODS: Interrogation of a prospectively maintained database identified consecutive patients who underwent non-elective complex EVAR for paravisceral INAAs in a single institution between December 2013 and June 2020. All patients were considered to have definite INAAs based on diagnostic criteria. Patients who had prior aortic repair were excluded. RESULTS: A total of 26 patients (19 men; mean age 67 years [SD = 11.4]; median diameter 60 mm [IQR: 55-73]) with acute symptomatic (n = 24) or contained ruptured (n = 2) aneurysms underwent surgeon-modified fenestrated EVAR (SM-FEVAR; n = 24) or chimney-periscope EVAR (CHIMPS; n = 2). Median observed follow-up was 36.2 months (18.3-53.5). Nine patients had positive venous blood cultures and a further seven had recent or concomitant infection. All patients received pre- and post-operative antibiotic therapy and rifampicin-soaked endografts. A total of 95 vessels were targeted for preservation and 86 were stent-grafted. One vessel occluded intra-operatively and a further 3 occluded within 30 days. The 30-day/in-hospital mortality was 11.5% (n = 3), and the estimated 1- and 3-year survival (±SD) was 85% ± 7%. Infection-related complications (IRCs) occurred in two patients: both developed new INAA within 30 days of index repair and were treated by EVAR with no mortality. Estimated 3-year freedom from late re-intervention was 100%. One patient required infrarenal EVAR for a non-infective aneurysm at 43 months. CONCLUSION: Complex EVAR for paravisceral INAAs is associated with acceptable early and mid-term outcomes and is an acceptable alternative to open surgery. We propose that these patients are managed with long-term antimicrobials, impregnation of graft material with rifampicin, and rigorous post-operative surveillance. CLINICAL IMPACT: A multi-disciplinary approach is required to deliver the best possible outcome for patients with this challenging aortic pathology.
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Bacille Calmette-Guérin (BCG), the only currently licenced tuberculosis vaccine, may exert beneficial non-specific effects (NSE) in reducing infant mortality. We conducted a randomised controlled clinical study in healthy UK adults to evaluate potential NSE using functional in-vitro growth inhibition assays (GIAs) as a surrogate of protection from four bacteria implicated in infant mortality. Volunteers were randomised to receive BCG intradermally (n = 27) or to be unvaccinated (n = 8) and were followed up for 84 days; laboratory staff were blinded until completion of the final visit. Using GIAs based on peripheral blood mononuclear cells, we observed a significant reduction in the growth of the Gram-negative bacteria Escherichia coli and Klebsiella pneumonia following BCG vaccination, but no effect for the Gram-positive bacteria Staphylococcus aureus and Streptococcus agalactiae. There was a modest association between S. aureus nasal carriage and growth of S. aureus in the GIA. Our findings support a causal link between BCG vaccination and improved ability to control growth of heterologous bacteria. Unbiased assays such as GIAs are potentially useful tools for the assessment of non-specific as well as specific effects of TB vaccines. This study was funded by the Bill and Melinda Gates Foundation and registered with ClinicalTrials.gov (NCT02380508, 05/03/2015; completed).
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Vacuna BCG , Vacunas contra la Tuberculosis , Adulto , Humanos , Lactante , Leucocitos Mononucleares , Staphylococcus aureus , VacunaciónRESUMEN
The immunogenicity of the candidate tuberculosis (TB) vaccine MVA85A may be enhanced by aerosol delivery. Intradermal administration was shown to be safe in adults with latent TB infection (LTBI), but data are lacking for aerosol-delivered candidate TB vaccines in this population. We carried out a Phase I trial to evaluate the safety and immunogenicity of MVA85A delivered by aerosol in UK adults with LTBI (NCT02532036). Two volunteers were recruited, and the vaccine was well-tolerated with no safety concerns. Aerosolised vaccination with MVA85A induced mycobacterium- and vector-specific IFN-γ in blood and mycobacterium-specific Th1 cytokines in bronchoalveolar lavage. We identified several important barriers that could hamper recruitment into clinical trials in this patient population. The trial did not show any safety concerns in the aerosol delivery of a candidate viral-vectored TB vaccine to two UK adults with Mycobacterium tuberculosis (M.tb) infection. It also systemically and mucosally demonstrated inducible immune responses following aerosol vaccination. A further trial in a country with higher incidence of LTBI would confirm these findings.
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BACKGROUND: Joint replacement is an effective intervention and prosthetic joint infection (PJI) is one of the most serious complications of such surgery. Diagnosis of PJI is often complex and requires multiple modalities of investigation. We describe a rare cause of PJI which highlights these challenges and the role of whole-genome sequencing to achieve a rapid microbiological diagnosis to facilitate prompt and appropriate management. CASE PRESENTATION: A 79-year-old man developed chronic hip pain associated with a soft-tissue mass, fluid collection and sinus adjacent to his eight-year-old hip prosthesis. His symptoms started after intravesical Bacillus Calmette-Guerin (BCG) therapy for bladder cancer. Synovasure™ and 16S polymerase chain reaction (PCR) tests were negative, but culture of the periarticular mass and genome sequencing diagnosed BCG infection. He underwent a two-stage joint revision and a prolonged duration of antibiotic therapy which was curative. CONCLUSIONS: BCG PJI after therapeutic exposure can have serious consequences, and awareness of this potential complication, identified from patient history, is essential. In addition, requesting appropriate testing is required, together with recognition that traditional diagnostics may be negative in non-pyogenic PJI. Advanced molecular techniques have a role to enhance the timely management of these infections.
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Artritis Infecciosa/etiología , Vacuna BCG/efectos adversos , Infecciones Relacionadas con Prótesis/etiología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Administración Intravesical , Anciano , Artritis Infecciosa/diagnóstico , Artritis Infecciosa/terapia , Vacuna BCG/administración & dosificación , Vacuna BCG/genética , Vacuna BCG/aislamiento & purificación , Genoma Bacteriano/genética , Prótesis de Cadera/efectos adversos , Prótesis de Cadera/microbiología , Humanos , Masculino , Infecciones Relacionadas con Prótesis/diagnóstico , Infecciones Relacionadas con Prótesis/terapia , Resultado del TratamientoRESUMEN
BACKGROUND: This phase I trial evaluated the safety and immunogenicity of a candidate tuberculosis vaccination regimen, ChAdOx1 85A prime-MVA85A boost, previously demonstrated to be protective in animal studies, in healthy UK adults. METHODS: We enrolled 42 healthy, BCG-vaccinated adults into 4 groups: low dose Starter Group (nâ¯=â¯6; ChAdOx1 85A alone), high dose groups; Group A (nâ¯=â¯12; ChAdOx1 85A), Group B (nâ¯=â¯12; ChAdOx1 85A prime - MVA85A boost) or Group C (nâ¯=â¯12; ChAdOx1 85A - ChAdOx1 85A prime - MVA85A boost). Safety was determined by collection of solicited and unsolicited vaccine-related adverse events (AEs). Immunogenicity was measured by antigen-specific ex-vivo IFN-γ ELISpot, IgG serum ELISA, and antigen-specific intracellular IFN-γ, TNF-α, IL-2 and IL-17. RESULTS: AEs were mostly mild/moderate, with no Serious Adverse Events. ChAdOx1 85A induced Ag85A-specific ELISpot and intracellular cytokine CD4+ and CD8+ T cell responses, which were not boosted by a second dose, but were boosted with MVA85A. Polyfunctional CD4+ T cells (IFN-γ, TNF-α and IL-2) and IFN-γ+, TNF-α+ CD8+ T cells were induced by ChAdOx1 85A and boosted by MVA85A. ChAdOx1 85A induced serum Ag85A IgG responses which were boosted by MVA85A. CONCLUSION: A ChAdOx1 85A prime - MVA85A boost is well tolerated and immunogenic in healthy UK adults.
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Vacuna BCG/administración & dosificación , Vacunas contra la Tuberculosis/administración & dosificación , Tuberculosis/prevención & control , Vacunación/métodos , Adulto , Vacuna BCG/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Citocinas/inmunología , Estudios de Seguimiento , Humanos , Inmunización Secundaria , Inmunogenicidad Vacunal , Tuberculosis/inmunología , Vacunas contra la Tuberculosis/efectos adversos , Vacunas contra la Tuberculosis/inmunología , Reino Unido , Vacunación/efectos adversos , Vacunas de ADNAsunto(s)
Neoplasias Encefálicas/patología , Encéfalo/diagnóstico por imagen , Infecciones por VIH/complicaciones , Histoplasma/aislamiento & purificación , Histoplasmosis/diagnóstico , Anfotericina B/uso terapéutico , Antifúngicos/uso terapéutico , Biopsia , Recuento de Linfocito CD4 , Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológico , Histoplasma/genética , Histoplasmosis/tratamiento farmacológico , Humanos , Itraconazol/uso terapéutico , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Resultado del TratamientoRESUMEN
BACKGROUND: There is an urgent need for an effective tuberculosis (TB) vaccine. Heterologous prime-boost regimens induce potent cellular immunity. MVA85A is a candidate TB vaccine. This phase I clinical trial was designed to evaluate whether alternating aerosol and intradermal vaccination routes would boost cellular immunity to the Mycobacterium tuberculosis antigen 85A (Ag85A). METHODS AND FINDINGS: Between December 2013 and January 2016, 36 bacille Calmette-Guérin-vaccinated, healthy UK adults were randomised equally between 3 groups to receive 2 MVA85A vaccinations 1 month apart using either heterologous (Group 1, aerosol-intradermal; Group 2, intradermal-aerosol) or homologous (Group 3, intradermal-intradermal) immunisation. Bronchoscopy and bronchoalveolar lavage (BAL) were performed 7 days post-vaccination. Adverse events (AEs) and peripheral blood were collected for 6 months post-vaccination. The laboratory and bronchoscopy teams were blinded to treatment allocation. One participant was withdrawn and was replaced. Participants were aged 21-42 years, and 28/37 were female. In a per protocol analysis, aerosol delivery of MVA85A as a priming immunisation was well tolerated and highly immunogenic. Most AEs were mild local injection site reactions following intradermal vaccination. Transient systemic AEs occurred following vaccination by both routes and were most frequently mild. All respiratory AEs following primary aerosol MVA85A (Group 1) were mild. Boosting an intradermal MVA85A prime with an aerosolised MVA85A boost 1 month later (Group 2) resulted in transient moderate/severe respiratory and systemic AEs. There were no serious adverse events and no bronchoscopy-related complications. Only the intradermal-aerosol vaccination regimen (Group 2) resulted in modest, significant boosting of the cell-mediated immune response to Ag85A (p = 0.027; 95% CI: 28 to 630 spot forming cells per 1 × 106 peripheral blood mononuclear cells). All 3 regimens induced systemic cellular immune responses to the modified vaccinia virus Ankara (MVA) vector. Serum antibodies to Ag85A and MVA were only induced after intradermal vaccination. Aerosolised MVA85A induced significantly higher levels of Ag85A lung mucosal CD4+ and CD8+ T cell cytokines compared to intradermal vaccination. Boosting with aerosol-inhaled MVA85A enhanced the intradermal primed responses in Group 2. The magnitude of BAL MVA-specific CD4+ T cell responses was lower than the Ag85A-specific responses. A limitation of the study is that while the intradermal-aerosol regimen induced the most potent cellular Ag85A immune responses, we did not boost the last 3 participants in this group because of the AE profile. Timing of bronchoscopies aimed to capture peak mucosal response; however, peak responses may have occurred outside of this time frame. CONCLUSIONS: To our knowledge, this is the first human randomised clinical trial to explore heterologous prime-boost regimes using aerosol and systemic routes of administration of a virally vectored vaccine. In this trial, the aerosol prime-intradermal boost regime was well tolerated, but intradermal prime-aerosol boost resulted in transient but significant respiratory AEs. Aerosol vaccination induced potent cellular Ag85A-specific mucosal and systemic immune responses. Whilst the implications of inducing potent mucosal and systemic immunity for protection are unclear, these findings are of relevance for the development of aerosolised vaccines for TB and other respiratory and mucosal pathogens. TRIAL REGISTRATION: ClinicalTrials.gov NCT01954563.
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Aciltransferasas/inmunología , Antígenos Bacterianos/inmunología , Vacunas contra la Tuberculosis/administración & dosificación , Tuberculosis/prevención & control , Administración por Inhalación , Adulto , Aerosoles , Esquema de Medicación , Femenino , Vectores Genéticos/administración & dosificación , Vectores Genéticos/efectos adversos , Humanos , Inmunización Secundaria , Inmunogenicidad Vacunal , Inyecciones Intradérmicas , Masculino , Mycobacterium tuberculosis/inmunología , Método Simple Ciego , Tuberculosis/inmunología , Vacunas contra la Tuberculosis/efectos adversos , Vacunas contra la Tuberculosis/inmunología , Vacunación/efectos adversos , Vacunas de ADN , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/efectos adversos , Vacunas Sintéticas/inmunología , Adulto JovenAsunto(s)
Tuberculosis Meníngea , Adulto , VIH , Humanos , Estudios Prospectivos , Manejo de EspecímenesRESUMEN
Whipple's disease is considered an infection of middle-aged white men of European ancestry. Cases are rare and disproportionately associated with occupational exposure to soil or animals. We report the case of a man aged 22 years with no risk factors, erroneously diagnosed with, and treated for, toxoplasmosis on the basis of consistent lymph node histology. The correct diagnosis was delayed by the dramatic symptomatic improvement resulting from this therapy. Whipple's disease should be considered in cases of granulomatous lymphadenopathy of unknown cause, even if the age of the patient does not fit the classic presentation of the disease.