Open Label, Dose Escalation and Age De-escalation for ChAdOx1 85A in Ugandan Adults and Adolescents, Followed by a Phase IIa Randomised, Open-label Trial Among Adolescents Comparing ChAdOx1 85A Prime Followed by MVA 85A Boost Versus BCG Re-vaccination.

The study will commence with a dose-escalation and age de-escalation study in healthy adults and adolescents from the previous Entebbe Mother and Baby Study (EMaBS) in Entebbe, Uganda, focusing on ChAdOx1 85A, to provide safety data for ChAdOx1 85A in this population. These measures are not required for MVA85A since this vaccine has been more widely used, including among adolescents in Uganda, and the dose has been standardised. ChAdOx1 85A dose escalation and age de-escalation will be followed by a Phase IIa randomised trial comparing the immunogenicity of ChAdOx1 85A and MVA85A with the immunogenicity of BCG revaccination. ChAdOx1 85A and MVA85A will be administered via the intramuscular route. The target dose for the Phase IIa trial is 2.5x10^10 viral particles (vp) because the lower dose is expected to have lower immunogenicity, based on the Oxford study, TB034. Data from the Oxford study suggest that this dose will be well tolerated. However, if this dose is not tolerated then the lower dose will be used. The dose of MVA85A will be 1 x 10^8 plaque-forming units (pfu) in the groups in which it is given. There will be 6 study groups with 3 to 30 volunteers in each group.
Dose escalation for ChAdOx1 85A in adults Group 1:
The first three adults will receive ChAdOx1 85A at 5 x10^9 vp.
Group 2:
The next three adults will be enrolled after safety data has been reviewed by the trial management team to one week after ChAdOx1 85A vaccination in group 1. These adults will receive ChAdOx1 85A at 2.5 x10^10 vp.
Age de-escalation and dose escalation for ChAdOx1 85A in adolescents Group 3:
The first three adolescents will be enrolled after safety data has been reviewed to one week after ChAdOx1 85A vaccination in group 2. These three adolescents will receive ChAdOx1 85A at 5 x10^9 vp Group 4. The next three adolescents will be enrolled after safety data has been reviewed to one week after ChAdOx1 85A vaccination in group 2. These three adolescents will receive ChAdOx1 85A at 2.5 x10^10 vp.
Randomised comparison of ChAdOx1 85A-MVA85A versus BCG revaccination:
Once safety data has been reviewed for groups 1 to 4 to one week post ChAdOx1 85A vaccination, recruitment to the randomised trial will commence. Sixty adolescents will be randomised, 30 (group 5) to receive ChAdOx1 85A at 2.5 x10^10 vp followed by MVA85A boost and 30 (group 6) to receive BCG revaccination.
BCG will be obtained from the Serum Institute of India, an approved provider for Uganda, and used at the standard dose of 0.1mL. BCG will be given intradermally.

开始日期2019-07-01

申办/合作机构

University of Oxford

NCT04121494 / Completed早期临床1期IIT

A Phase I Clinical Trial to Compare the Safety and Immunogenicity of Candidate TB Vaccine ChAdOx1 85A Administered by the Aerosol Inhaled Route and the Intramuscular Route in Healthy Adult Subjects

This is a dose escalating and a paired-placebo design study to describe the safety and immunogenicity profile of candidate TB vaccine ChAdOx1 85A given by aerosol inhaled vaccination versus intramuscular (IM) vaccination in adult healthy volunteers.
It is postulated that the aerosol inhaled route is practical and feasible and has an acceptable safety profile, comparable to the systemic safety profile of the IM route of administration of ChAdOx1 85A in adult healthy volunteers, and that the aerosol inhaled route of administration will induce greater mucosal immunity and comparable systemic immunity when compared to the IM (systemic) route of administration in these volunteers.
Volunteers are followed on a regular basis for safety and immunogenicity, with blood analysis for biological safety tests and immune tests.

开始日期2019-01-22

申办/合作机构

Centre Hospitalier Universitaire Vaudois

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2022-01-01·Letters in Applied Microbiology4区 · 生物学

Diagnosis of osteoarticular tuberculosis by immuno‐PCR assay based on mycobacterial antigen 85 complex detection

4区 · 生物学

Article

作者: Singh, R. ; Singh, V. ; Soni, A. ; Mehta, P.K. ; Gill, P.S. ; Chaudhary, D. ; Dhull, V. ; Yadav, A. ; Gupta, M.C. ; Sharma, S. ; Khan, A. ; Sheoran, A.

Diagnosis of osteoarticular tuberculosis (OATB) exhibits serious challenges owing to paucibacillary nature of specimens and localization of disease at sites that are difficult to access. We recently developed indirect immuno-PCR (I-PCR) and real-time I-PCR (RT-I-PCR) assays for the detection of mycobacterial antigen 85 complex (Ag85) in OATB patients. Detection limits for the purified Ag85 protein were found to be 1 and 41 fg ml^-1 by I-PCR and RT-I-PCR, respectively, which were at least 10⁵ -fold lower than respective ELISA. While spiking synovial fluids of non-TB control subjects with the purified Ag85 protein, LODs of 100 and 120 fg ml^-1 were obtained by I-PCR and RT-I-PCR, respectively, thus demonstrating the sample matrix effect. Sensitivities of 87·5 and 70·5% were observed in bodily fluids of confirmed (n = 8) and clinically suspected (n = 51) OATB cases, respectively, by I-PCR, with a specificity of 93·9% (n = 33). Markedly, the sensitivities obtained by I-PCR/RT-I-PCR were significantly higher (P < 0·05-0·01) than ELISA and GeneXpert assay (n = 30). However, no substantial difference in sensitivity was observed between the I-PCR and RT-I-PCR assays. After further improving the accuracy of I-PCR, this test may lead to development of an attractive diagnostic kit.

2021-08-01·Cell Reports Medicine

A recombinant bovine adenoviral mucosal vaccine expressing mycobacterial antigen-85B generates robust protection against tuberculosis in mice

Article

作者: Nookala, Sita ; Singh, Vipul K ; Dorta-Estremera, Stephanie ; Sastry, K Jagannadha ; Canaday, David H ; Wang, Jin ; Jagannath, Chinnaswamy ; Khan, Arshad ; Chen, Min ; Mishra, Abhishek ; Mittal, Suresh K ; Sayedahmed, Ekramy E

Although the BCG vaccine offers partial protection, tuberculosis remains a leading cause of infectious disease death, killing ∼1.5 million people annually. We developed mucosal vaccines expressing the autophagy-inducing peptide C5 and mycobacterial Ag85B-p25 epitope using replication-defective human adenovirus (HAdv^85C5) and bovine adenovirus (BAdv^85C5) vectors. BAdv^85C5-infected dendritic cells (DCs) expressed a robust transcriptome of genes regulating antigen processing compared to HAdv^85C5-infected DCs. BAdv^85C5-infected DCs showed enhanced galectin-3/8 and autophagy-dependent in vitro Ag85B-p25 epitope presentation to CD4 T cells. BCG-vaccinated mice were intranasally boosted using HAdv^85C5 or BAdv^85C5 followed by infection using aerosolized Mycobacterium tuberculosis (Mtb). BAdv^85C5 protected mice against tuberculosis both as a booster after BCG vaccine (>1.4-log₁₀ reduction in Mtb lung burden) and as a single intranasal dose (>0.5-log₁₀ reduction). Protection was associated with robust CD4 and CD8 effector (T_EM), central memory (T_CM), and CD103⁺/CD69⁺ lung-resident memory (T_RM) T cell expansion, revealing BAdv^85C5 as a promising mucosal vaccine for tuberculosis.

2021-01-01·European Journal of Medicinal Chemistry1区 · 医学

Lipolytic enzymes inhibitors: A new way for antibacterial drugs discovery

1区 · 医学

Review

作者: Camoin, Luc ; Canaan, Stéphane ; Spilling, Christopher D ; Cavalier, Jean-François ; Durand, Thierry

Tuberculosis (TB) caused by Mycobacterium tuberculosis (M. tb) still remains the deadliest infectious disease worldwide with 1.5 million deaths in 2018, of which about 15% are attributed to resistant strains. Another significant example is Mycobacterium abscessus (M. abscessus), a nontuberculous mycobacteria (NTM) responsible for cutaneous and pulmonary infections, representing up to 95% of NTM infections in cystic fibrosis (CF) patients. M. abscessus is a new clinically relevant pathogen and is considered one of the most drug-resistant mycobacteria for which standardized chemotherapeutic regimens are still lacking. Together the emergence of M. tb and M. abscessus multi-drug resistant strains with ineffective and expensive therapeutics, have paved the way to the development of new classes of anti-mycobacterial agents offering additional therapeutic options. In this context, specific inhibitors of mycobacterial lipolytic enzymes represent novel and promising antibacterial molecules to address this challenging issue. The results highlighted here include a complete overview of the antibacterial activities, either in broth medium or inside infected macrophages, of two families of promising and potent anti-mycobacterial multi-target agents, i.e. oxadiazolone-core compounds (OX) and Cyclophostin & Cyclipostins analogs (CyC); the identification and biochemical validation of their effective targets (e.g., the antigen 85 complex and TesA playing key roles in mycolic acid metabolism) together with their respective crystal structures. To our knowledge, these are the first families of compounds able to target and impair replicating as well as intracellular bacteria. We are still impelled in deciphering their mode of action and finding new potential therapeutic targets against mycobacterial-related diseases.