RESUMEN
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.
Asunto(s)
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
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).
Asunto(s)
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.
RESUMEN
Tuberculosis (TB) is a major global health problem and the only currently-licensed vaccine, BCG, is inadequate. Many TB vaccine candidates are designed to be given as a boost to BCG; an understanding of the BCG-induced immune response is therefore critical, and the opportunity to relate this to circumstances where BCG does confer protection may direct the design of more efficacious vaccines. While the T cell response to BCG vaccination has been well-characterized, there is a paucity of literature on the humoral response. We demonstrate BCG vaccine-mediated induction of specific antibodies in different human populations and macaque species which represent important preclinical models for TB vaccine development. We observe a strong correlation between antibody titers in serum versus plasma with modestly higher titers in serum. We also report for the first time the rapid and transient induction of antibody-secreting plasmablasts following BCG vaccination, together with a robust and durable memory B cell response in humans. Finally, we demonstrate a functional role for BCG vaccine-induced specific antibodies in opsonizing mycobacteria and enhancing macrophage phagocytosis in vitro, which may contribute to the BCG vaccine-mediated control of mycobacterial growth observed. Taken together, our findings indicate that the humoral immune response in the context of BCG vaccination merits further attention to determine whether TB vaccine candidates could benefit from the induction of humoral as well as cellular immunity.
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Anticuerpos Antibacterianos/inmunología , Vacuna BCG/inmunología , Inmunoglobulina G/inmunología , Células B de Memoria/inmunología , Células Plasmáticas/inmunología , Adulto , Animales , Anticuerpos Antibacterianos/sangre , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Linfocitos B/metabolismo , Vacuna BCG/administración & dosificación , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , Inmunidad Celular/efectos de los fármacos , Inmunidad Celular/inmunología , Inmunidad Humoral/efectos de los fármacos , Inmunidad Humoral/inmunología , Inmunoglobulina A/sangre , Inmunoglobulina A/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/metabolismo , Inmunoglobulina M/sangre , Inmunoglobulina M/inmunología , Macaca fascicularis/inmunología , Macaca mulatta/inmunología , Masculino , Células B de Memoria/metabolismo , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/fisiología , Células Plasmáticas/metabolismo , Tuberculosis/inmunología , Tuberculosis/microbiología , Tuberculosis/prevención & control , Vacunación/métodosRESUMEN
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 ADNRESUMEN
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 JovenRESUMEN
Fungal diseases are an increasingly recognized cause of mortality worldwide and often pose diagnostic challenges. This article focuses on common fungal diseases as they may present in the acute medical unit, looking at the initial investigation and management of four common diseases: Pneumocystis jirovecii pneumonia, cryptococcal meningitis, candidaemia and allergic bronchopulmonary aspergillosis. There is an increase in morbidity and mortality if these conditions are not correctly diagnosed and thus appropriate therapy is delayed. A better understanding of the initial investigation and management of these conditions will improve the outcome of patients with fungal diseases presenting to the 'medical front door'.
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Aspergilosis Broncopulmonar Alérgica/diagnóstico , Candidemia/diagnóstico , Infección Hospitalaria/diagnóstico , Meningitis Criptocócica/diagnóstico , Neumonía por Pneumocystis/diagnóstico , Corticoesteroides/uso terapéutico , Antibacterianos/uso terapéutico , Antifúngicos/uso terapéutico , Aspergilosis Broncopulmonar Alérgica/tratamiento farmacológico , Candidemia/tratamiento farmacológico , Infección Hospitalaria/tratamiento farmacológico , Humanos , Huésped Inmunocomprometido , Meningitis Criptocócica/tratamiento farmacológico , Meningitis Criptocócica/inmunología , Neumonía por Pneumocystis/tratamiento farmacológico , Neumonía por Pneumocystis/inmunologíaRESUMEN
A major challenge to tuberculosis (TB) vaccine development is the lack of a validated immune correlate of protection. Mycobacterial growth inhibition assays (MGIAs) represent an unbiased measure of the ability to control mycobacterial growth in vitro. A successful MGIA could be applied to preclinical and clinical post-vaccination samples to aid in the selection of novel vaccine candidates at an early stage and provide a relevant measure of immunogenicity and protection. However, assay harmonisation is critical to ensure that comparable information can be extracted from different vaccine studies. As part of the FP7 European Research Infrastructures for Poverty Related Diseases (EURIPRED) consortium, we aimed to optimise the direct MGIA, assess repeatability and reproducibility, and harmonise the assay across different laboratories. We observed an improvement in repeatability with increased cell number and increased mycobacterial input. Furthermore, we determined that co-culturing in static 48-well plates compared with rotating 2â¯ml tubes resulted in a 23% increase in cell viability and a 500-fold increase in interferon-gamma (IFN-γ) production on average, as well as improved reproducibility between replicates, assay runs and sites. Applying the optimised conditions, we report repeatability to be <5% coefficient of variation (CV), intermediate precision to be <20% CV, and inter-site reproducibility to be <30% CV; levels within acceptable limits for a functional cell-based assay. Using relevant clinical samples, we demonstrated comparable results across two shared sample sets at three sites. Based on these findings, we have established a standardised operating procedure (SOP) for the use of the direct PBMC MGIA in TB vaccine development.
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Técnicas Bacteriológicas/normas , Criopreservación/normas , Desarrollo de Medicamentos/normas , Ensayos de Liberación de Interferón gamma/estadística & datos numéricos , Leucocitos Mononucleares/microbiología , Mycobacterium bovis/efectos de los fármacos , Vacunas contra la Tuberculosis/farmacología , Técnicas de Cultivo de Célula/normas , Células Cultivadas , Interacciones Huésped-Patógeno , Humanos , Interferón gamma/metabolismo , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Mycobacterium bovis/crecimiento & desarrollo , Mycobacterium bovis/inmunología , Reproducibilidad de los ResultadosRESUMEN
INTRODUCTION: There is an urgent need for a new and effective tuberculosis vaccine because BCG does not sufficiently prevent pulmonary disease. IMX313 is a novel carrier protein designed to improve cellular and humoral immunity. MVA85A-IMX313 is a novel vaccine candidate designed to boost immunity primed by bacillus Calmette-Guérin (BCG) that has been immunogenic in pre-clinical studies. This is the first evaluation of IMX313 delivered as MVA85A-IMX313 in humans. METHODS: In this phase 1, open-label first-in-human trial, 30 healthy previously BCG-vaccinated adults were enrolled into three treatment groups and vaccinated with low dose MVA85A-IMX313 (group A), standard dose MVA85A-IMX313 (group B), or MVA85A (group C). Volunteers were followed up for 6 months for safety and immunogenicity assessment. RESULTS: The majority of adverse events were mild and there were no vaccine-related serious AEs. Both MVA85A-IMX313 and MVA85A induced a significant increase in IFN-γ ELISpot responses. There were no significant differences between the Ag85A ELISpot and intracellular cytokine responses between the two study groups B (MVA85A-IMX313) and C (MVA85A) at any time point post-vaccination. CONCLUSION: MVA85A-IMX313 was well tolerated and immunogenic. There was no significant difference in the number of vaccine-related, local or systemic adverse reactions between MVA85A and MVA85A-IMX313 groups. The mycobacteria-specific cellular immune responses induced by MVA85A-IMX313 were not significantly different to those detected in the MVA85A group. In light of this encouraging safety data, further work to improve the potency of molecular adjuvants like IMX313 is merited. This trial was registered on clinicatrials.gov ref. NCT01879163.
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Vacunas contra la Tuberculosis/inmunología , Tuberculosis/prevención & control , Adulto , Anticuerpos Antibacterianos/sangre , Vacuna BCG/administración & dosificación , Citocinas/inmunología , Ensayo de Inmunoadsorción Enzimática , Ensayo de Immunospot Ligado a Enzimas , Femenino , Humanos , Inmunidad Celular , Inmunoglobulina G/sangre , Masculino , Persona de Mediana Edad , Vacunas contra la Tuberculosis/administración & dosificación , Vacunas contra la Tuberculosis/efectos adversos , Vacunas de ADN , Adulto JovenRESUMEN
BACKGROUND: The West African outbreak of Ebola virus disease that peaked in 2014 has caused more than 11,000 deaths. The development of an effective Ebola vaccine is a priority for control of a future outbreak. METHODS: In this phase 1 study, we administered a single dose of the chimpanzee adenovirus 3 (ChAd3) vaccine encoding the surface glycoprotein of Zaire ebolavirus (ZEBOV) to 60 healthy adult volunteers in Oxford, United Kingdom. The vaccine was administered in three dose levels--1×10(10) viral particles, 2.5×10(10) viral particles, and 5×10(10) viral particles--with 20 participants in each group. We then assessed the effect of adding a booster dose of a modified vaccinia Ankara (MVA) strain, encoding the same Ebola virus glycoprotein, in 30 of the 60 participants and evaluated a reduced prime-boost interval in another 16 participants. We also compared antibody responses to inactivated whole Ebola virus virions and neutralizing antibody activity with those observed in phase 1 studies of a recombinant vesicular stomatitis virus-based vaccine expressing a ZEBOV glycoprotein (rVSV-ZEBOV) to determine relative potency and assess durability. RESULTS: No safety concerns were identified at any of the dose levels studied. Four weeks after immunization with the ChAd3 vaccine, ZEBOV-specific antibody responses were similar to those induced by rVSV-ZEBOV vaccination, with a geometric mean titer of 752 and 921, respectively. ZEBOV neutralization activity was also similar with the two vaccines (geometric mean titer, 14.9 and 22.2, respectively). Boosting with the MVA vector increased virus-specific antibodies by a factor of 12 (geometric mean titer, 9007) and increased glycoprotein-specific CD8+ T cells by a factor of 5. Significant increases in neutralizing antibodies were seen after boosting in all 30 participants (geometric mean titer, 139; P<0.001). Virus-specific antibody responses in participants primed with ChAd3 remained positive 6 months after vaccination (geometric mean titer, 758) but were significantly higher in those who had received the MVA booster (geometric mean titer, 1750; P<0.001). CONCLUSIONS: The ChAd3 vaccine boosted with MVA elicited B-cell and T-cell immune responses to ZEBOV that were superior to those induced by the ChAd3 vaccine alone. (Funded by the Wellcome Trust and others; ClinicalTrials.gov number, NCT02240875.).
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Vacunas contra el Virus del Ébola/inmunología , Ebolavirus/inmunología , Fiebre Hemorrágica Ebola/prevención & control , Adenovirus de los Simios/inmunología , Adulto , Animales , Anticuerpos Antivirales/sangre , Linfocitos B/fisiología , Citocinas/sangre , Vacunas contra el Virus del Ébola/administración & dosificación , Femenino , Fiebre Hemorrágica Ebola/inmunología , Humanos , Inmunidad Celular , Inmunización Secundaria , Masculino , Persona de Mediana Edad , Pan troglodytes , Linfocitos T/fisiología , Vaccinia , Adulto JovenRESUMEN
BACKGROUND: There is an urgent need for an improved tuberculosis vaccine. The lack of a validated correlate of protection slows progress in achieving this goal. A human mycobacterial challenge model, using bacille Calmette-Guérin (BCG) as a surrogate for a Mycobacterium tuberculosis challenge, would facilitate vaccine selection for field efficacy testing. Optimization of this model is required. METHODS: Healthy BCG-naive adults were assigned to receive intradermal standard-dose BCG SSI (group A), standard-dose BCG TICE (group B), high-dose BCG SSI (group C), and high-dose BCG TICE (group D). Two weeks after BCG challenge, skin biopsy of the challenge site was performed. BCG mycobacterial load was quantified by solid culture and quantitative polymerase chain reaction. RESULTS: BCG was well tolerated, and reactogenicity was similar between groups, regardless of strain and dose. There was significantly greater recovery of BCG from the high-dose challenge groups, compared with standard-dose challenge. BCG strain did not significantly affect BCG recovery. CONCLUSIONS: BCG challenge dose affects sensitivity of this model. We have selected high-dose BCG SSI to take forward in future challenge studies. Assessment of candidate tuberculosis vaccine effectiveness with this optimized model could contribute to vaccine selection for efficacy trials. CLINICAL TRIALS REGISTRATION: NCT02088892.
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Vacuna BCG/inmunología , Mycobacterium bovis/fisiología , Vacunas contra la Tuberculosis/inmunología , Adolescente , Adulto , Carga Bacteriana , Ensayo de Immunospot Ligado a Enzimas , Femenino , Voluntarios Sanos , Humanos , Inyecciones Intradérmicas , Interferón gamma , Masculino , Piel/inmunología , Piel/microbiología , Tuberculosis/inmunología , Tuberculosis/prevención & control , Adulto JovenRESUMEN
BACKGROUND: MVA85A and AERAS-402 are two clinically advanced viral vectored TB vaccine candidates expressing Mycobacterium tuberculosis antigens designed to boost BCG-induced immunity. Clinical trials with candidate malaria vaccines have demonstrated that adenoviral vector based priming immunisation, followed by MVA vector boost, induced high levels of immunity. We present the safety and immunogenicity results of the first clinical trial to evaluate this immunisation strategy in TB. METHODS: In this phase 1, open-label trial, 40 healthy previously BCG-vaccinated participants were enrolled into three treatment groups and vaccinated with 1 or 2 doses of AERAS-402 followed by MVA85A; or 3 doses of AERAS-402. RESULTS: Most related adverse events (AEs) were mild and there were no vaccine related serious AEs. Boosting AERAS-402 with MVA85A significantly increased Ag85A-specific T-cell responses from day of vaccination. Two priming doses of AERAS-402 followed by MVA85A boost, resulted in a significantly higher AUC post-peak Ag85A response compared to three doses of AERAS-402 and historical data with MVA85A vaccination alone. The frequency of CD8+ T-cells producing IFN-γ, TNF-α and IL-2 was highest in the group receiving two priming doses of AERAS-402 followed by MVA85A. CONCLUSIONS: Vaccination with AERAS-402 followed by MVA85A was safe and increased the durability of antigen specific T-cell responses and the frequency and polyfunctionality of CD8+ T-cells, which may be important in protection against TB. Further clinical trials with adenoviral prime-MVA85A boost regimens are merited to optimise vaccination intervals, dose and route of immunisation and to evaluate this strategy in the target population in TB high burden countries. TRIAL REGISTRATION: ClinicalTrials.gov NCT01683773.
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Adenoviridae , Antígenos Bacterianos , Inmunización Secundaria , Mycobacterium bovis/inmunología , Mycobacterium tuberculosis/inmunología , Vacunas contra la Tuberculosis , Adolescente , Adulto , Antígenos Bacterianos/administración & dosificación , Antígenos Bacterianos/inmunología , Linfocitos T CD8-positivos/inmunología , Citocinas/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vacunas contra la Tuberculosis/administración & dosificación , Vacunas contra la Tuberculosis/inmunologíaRESUMEN
Chronic obstructive pulmonary disease (COPD) guidelines suggest using inhaled corticosteroids (ICS) in patients with severe airflow limitation or those at high risk of exacerbations. This recommendation is based on evidence demonstrating that ICS, especially when prescribed in fixed-dose combinations (FDC) with long-acting ß2 agonists (LABA), improve quality of life (QoL), decrease exacerbations and hospitalisations, and have been associated with a trend towards a reduction in all-cause mortality. Audit shows that routine prescribing practice frequently uses inhaler therapies outside current guidelines recommendations; severe to very severe disease constitutes about 20% of all COPD patients, but up to 75% of COPD patients are prescribed an ICS, with significant numbers given ICS/LABA as first-line maintenance therapy. The role of ICS in the treatment paradigm for COPD is changing, driven by the growing evidence of increased risk of pneumonia, and the introduction of a new class of FDC; LABA and long-acting muscarinic antagonists (LAMA), which simplify dual bronchodilation and present a plausible alternative therapy. As the evidence base for dual therapy bronchodilation expands, it is likely that maximal bronchodilation will move up the treatment algorithm and ICS reserved for those with more severe disease who are not controlled on dual therapy. This change has already manifested in local COPD algorithms, such as those at Tayside, and represents a significant change in recommended prescribing practice. This review reassesses the role of ICS in the shifting treatment paradigm, in the context of alternative treatment options that provide maximal bronchodilation.
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Corticoesteroides/uso terapéutico , Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Antagonistas Muscarínicos/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Administración por Inhalación , Corticoesteroides/efectos adversos , Broncodilatadores/uso terapéutico , Preparaciones de Acción Retardada , Combinación de Medicamentos , Prescripciones de Medicamentos/estadística & datos numéricos , Humanos , Neumonía/inducido químicamente , Guías de Práctica Clínica como Asunto , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Índice de Severidad de la EnfermedadRESUMEN
The development of an effective TB vaccine remains paramount to achieving the goal of global eradication of TB by 2050. The only licensed vaccine, BCG, has variable efficacy and is poorly effective in high burden countries. The development of promising candidate vaccines to either 'boost' a BCG primed immune system or replace BCG altogether is a key area for innovative research. Here, we discuss some of the issues encountered in the development of potential candidate vaccines and the future challenges.