Evaluating aerosol administration of a candidate TB vaccine, MVA85A, as a way to induce potent local cellular immune responses and avoid anti-vector immunity

There is an urgent need for a better vaccine against TB than BCG, which confers variable protection against pulmonary TB. Heterologous prime-boost regimens with viral vector vaccines are a leading strategy for TB vaccine development. MVA85A is a viral vector candidate TB vaccine designed to boost BCG. This phase I clinical trial was designed to evaluate whether alternating aerosol and intradermal routes of vaccination can improve Ag85A immunogenicity; maybe by circumventing local anti- MVA immunity. Thirty-six BCG-vaccinated healthy UK adults received two MVA85A vaccinations one month apart as heterologous (aerosol-intradermal or intradermalaerosol) or homologous prime-boost (intradermal-intradermal). Bronchoscopies with bronchoalveolar lavages (BAL) were performed 7 days after each vaccination. Delivering MVA85A by aerosol as a priming immunisation was well tolerated and highly immunogenic. Boosting an intradermal MVA85A prime with an aerosolised MVA85A vaccination led to transient respiratory and systemic adverse events which resulted in vaccinations in this group ceasing. Aerosolised MVA85A induced potent Ag85A-specific T cell responses in mucosal and systemic compartments; and suggested a potential for dose sparing with this route. The intradermal-aerosol regimen boosted Ag85A-specific cellular immune responses in systemic and lung mucosal compartments. Serum antibodies to Ag85A and MVA were only detected after intradermal vaccination. Anti-Ag85A antibodies in serum were boosted by a second intradermal vaccination. The findings of this trial are important for the development of aerosolised TB vaccines but also for new viral vector vaccines for other respiratory pathogens.</p

Optimization of a human bacille Calmette-Guerin challenge model: a tool to evaluate antimycobacterial immunity

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.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.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.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.NCT02088892

Optimisation of a human BCG challenge model

Tuberculosis remains a significant global disease burden with an estimated 9 million new cases and 1.5 million deaths in 2013. BCG continues to be the only licensed TB vaccine, however it is poorly efficacious against adult pulmonary TB disease and there is a desperate need for a better vaccine to provide greater and more consistent protection. Development of such a vaccine has been hampered by the lack of reliable and validated correlates of protection. A human mycobacterial challenge model, using BCG as a surrogate for Mycobacterium tuberculosis challenge would facilitate improved vaccine selection for progression into future field efficacy testing. In this study we evaluate the effect of two BCG strains at two doses to optimise this model

Shifted concentration dependency of EpRE- and XRE-mediated gene expression points at monofunctional EpRE-mediated induction by flavonoids at physiologically relevant concentrations

Flavonoids are important bioactive compounds, omnipresent in the human diet, and are reported to be bifunctional inducers. These phytochemicals are able to induce xenobiotic-responsive element (XRE)- and electrophile-responsive element (EpRE)-mediated gene expression, resulting in the induction of biotransformation enzymes. To test whether flavonoid-induced EpRE-mediated gene expression could be the result of upstream XRE-mediated gene expression, several flavonoids were tested for their ability to induce XRE- and EpRE-mediated gene expression using two stably transfected reporter gene cell lines constructed in the same mouse Hepa-1c1c7 hepatoma background. Although classified as bifunctional inducers, all flavonoids were found to induce EpRE- and XRE-mediated gene expression in a different concentration range, which presents an issue not considered by the current definition of a bifunctional inducer. At physiological relevant concentrations, the induction of gene expression via the EpRE transcriptional enhancer element is dominant, leading in particular to elevated levels of EpRE-regulated detoxifying enzymes. Furthermore, these results strongly suggest that EpRE-mediated gene expression induced by flavonoids is not a downstream reaction of XRE-mediated gene expression

Safety and immunogenicity of a candidate tuberculosis vaccine MVA85A delivered by aerosol in BCG-vaccinated healthy adults: a phase 1, double-blind, randomised controlled trial.

BACKGROUND: Intradermal MVA85A, a candidate vaccine against tuberculosis, induces high amounts of Ag85A-specific CD4 T cells in adults who have already received the BCG vaccine, but aerosol delivery of this vaccine might offer immunological and logistical advantages. We did a phase 1 double-blind trial to compare the safety and immunogenicity of aerosol-administered and intradermally administered MVA85A METHODS: In this phase 1, double-blind, proof-of-concept trial, 24 eligible BCG-vaccinated healthy UK adults were randomly allocated (1:1) by sequentially numbered, sealed, opaque envelopes into two groups: aerosol MVA85A and intradermal saline placebo or intradermal MVA85A and aerosol saline placebo. Participants, the bronchoscopist, and immunologists were masked to treatment assignment. The primary outcome was safety, assessed by the frequency and severity of vaccine-related local and systemic adverse events. The secondary outcome was immunogenicity assessed with laboratory markers of cell-mediated immunity in blood and bronchoalveolar lavage samples. Safety and immunogenicity were assessed for 24 weeks after vaccination. Immunogenicity to both insert Ag85A and vector modified vaccinia virus Ankara (MVA) was assessed by ex-vivo interferon-γ ELISpot and serum ELISAs. Since all participants were randomised and vaccinated according to protocol, our analyses were per protocol. This trial is registered with ClinicalTrials.gov, number NCT01497769. FINDINGS: Both administration routes were well tolerated and immunogenic. Respiratory adverse events were rare and mild. Intradermal MVA85A was associated with expected mild local injection-site reactions. Systemic adverse events did not differ significantly between the two groups. Three participants in each group had no vaccine-related systemic adverse events; fatigue (11/24 [46%]) and headache (10/24 [42%]) were the most frequently reported symptoms. Ag85A-specific systemic responses were similar across groups. Ag85A-specific CD4 T cells were detected in bronchoalveolar lavage cells from both groups and responses were higher in the aerosol group than in the intradermal group. MVA-specific cellular responses were detected in both groups, whereas serum antibodies to MVA were only detectable after intradermal administration of the vaccine. INTERPRETATION: Further clinical trials assessing the aerosol route of vaccine delivery are merited for tuberculosis and other respiratory pathogens. FUNDING: The Wellcome Trust and Oxford Radcliffe Hospitals Biomedical Research Centre

An efficient algorithm for optimization in nonlinear model predictive control of large-scale systems

Available from TIB Hannover: RR 1606(2002,11) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDeutsche Forschungsgemeinschaft (DFG), Bonn (Germany)DEGerman

T-cell activation is an immune correlate of risk in BCG vaccinated infants

Vaccines to protect against tuberculosis (TB) are urgently needed. We performed a case–control analysis to identify immune correlates of TB disease risk in Bacille Calmette–Guerin (BCG) immunized infants from the MVA85A efficacy trial. Among 53 TB case infants and 205 matched controls, the frequency of activated HLA-DR+ CD4+ T cells associates with increased TB disease risk (OR=1.828, 95% CI=1.25–2.68, P=0.002, FDR=0.04, conditional logistic regression). In an independent study of Mycobacterium tuberculosis-infected adolescents, activated HLA-DR+ CD4+ T cells also associate with increased TB disease risk (OR=1.387, 95% CI=1.068–1.801, P=0.014, conditional logistic regression). In infants, BCG-specific T cells secreting IFN-γ associate with reduced risk of TB (OR=0.502, 95% CI=0.29–0.86, P=0.013, FDR=0.14). The causes and impact of T-cell activation on disease risk should be considered when designing and testing TB vaccine candidates for these populations