a b s t r a c tA variety of Good Manufacturing Practice (GMP) compliant processes have been reported for production of non-replicating adenovirus vectors, but important challenges remain. Most clinical development of adenovirus vectors now uses simian adenoviruses or rare human serotypes, whereas reported manufacturing processes mainly use serotypes such as AdHu5 which are of questionable relevance for clinical vaccine development. Many clinically relevant vaccine transgenes interfere with adenovirus replication, whereas most reported process development uses selected antigens or even model transgenes such as fluorescent proteins which cause little such interference. Processes are typically developed for a single adenovirus serotype -transgene combination, requiring extensive further optimization for each new vaccine.There is a need for rapid production platforms for small GMP batches of non-replicating adenovirus vectors for early-phase vaccine trials, particularly in preparation for response to emerging pathogen outbreaks. Such platforms must be robust to variation in the transgene, and ideally also capable of producing adenoviruses of more than one serotype. It is also highly desirable for such processes to be readily implemented in new facilities using commercially available single-use materials, avoiding the need for development of bespoke tools or cleaning validation, and for them to be readily scalable for later-stage studies.Here we report the development of such a process, using single-use stirred-tank bioreactors, a transgene-repressing HEK293 cell -promoter combination, and fully single-use filtration and ion exchange components. We demonstrate applicability of the process to candidate vaccines against rabies, malaria and Rift Valley fever, each based on a different adenovirus serotype. We compare performance of a range of commercially available ion exchange media, including what we believe to be the first published use of a novel media for adenovirus purification (NatriFlo Ò HD-Q, Merck). We demonstrate the need for minimal process individualization for each vaccine, and that the product fulfils regulatory quality expectations. Cell-specific yields are at the upper end of those previously reported in the literature, and volumetric yields are in the range 1 Â 10 13 -5 Â 10 13 purified virus particles per litre of culture, such that a 2-4 L process is comfortably adequate to produce vaccine for early-phase trials. The process is readily transferable to any GMP facility with the capability for mammalian cell culture and aseptic filling of sterile products.
The advances in cancer therapy have included the development of drugs that inhibit immune checkpoint ligands. Two types of immune checkpoint inhibitors, both antibodies that target CTLA-4 and PD-1, have been approved for its use in NSCLC and melanoma as first-line or second-line therapy. Sadly, not desirable consequences of immunotherapy are immune-related adverse events. immune-related hypophysitis is the most common endocrine adverse event after thyroid disfunction. The particularity of endocrine immune-related adverse events is their non-reversibility, with incidence and prevalence destined to increase in the coming years, particularly if this form of therapy is used in the future for earlier stages of cancer. Therefore, hypophysitis represents a challenge for the physician, sometimes occurring without specific symptomatology and which should be considered for clinical management. In this review, we describe the current data regarding the pathophysiology and management for immune-related hypophysitis.
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.
Tuberculosis (TB) is the first cause of mortality by a single infectious agent in the world, causing more than one million deaths worldwide as reported by the World Health Organization (WHO). For the optimal control of TB infection, a protective immune response that limits bacterial spread without causing damage to the host is essential. Although most healthy individuals are capable of generating protective responses, patients who suffer pulmonary TB commonly present a defective immune function. Areas covered: We intend to highlight the potential of novel immunotherapeutic strategies that enhance and promote effective immune responses. The following methodology was undertaken for establishing a literature search: the authors used PubMed to search for 'Pulmonary Tuberculosis' and keywords that denoted the novel immunotherapeutic strategies discussed in length in the text including antibodies, antimicrobial peptides, cell therapy, cytokines and gene therapy. Expert commentary: The current therapeutic regimens for this disease are complex and involve the prolonged use of multiple antibiotics with diverse side effects that lead to therapeutic failure and bacterial resistance. The standard appliance of immunotherapy and its deployment to vulnerable populations will require coordinated work and may serve as a powerful tool to combat the ensuing threat of TB.
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