- Abstract: Toll-like receptor (TLR) agonists are currently being examined as adjuvants for vaccines, with several lead candidates now in licensed products or in late-stage clinical development. Guinea pigs are widely used for preclinical testing of drugs and vaccines; however, evaluation of TLR agonists in this model is hindered by the limited availability of immunological tools and reagents. In this study, we validated the use of a branched-chain DNA (bDNA) assay known as the QuantiGene Plex 2.0... Show More
- Abstract: An effective protein-based vaccine for tuberculosis will require a safe and effective adjuvant. There are few adjuvants in approved human vaccines, including alum and the oil-in-water-based emulsions MF59 (Novartis Vaccines and Diagnostics), AS03 and AS04 (GlaxoSmithKline Biologics), AF03 (Sanofi), and liposomes (Crucell). When used with pure, defined proteins, both alum and emulsion adjuvants are effective at inducing primarily humoral responses. One of the newest adjuvants in approved... Show More
- Abstract: Considerable effort has been directed to develop Mycobacterium tuberculosis vaccines to boost bacille Calmette-Guérin or for those who cannot be immunized with bacille Calmette-Guérin. We hypothesized that CD4(+) and CD8(+) T cell responses with a heterologous prime/boost vaccine approach could induce long-lived vaccine efficacy against M. tuberculosis in C57BL/6 mice. We produced an adenovirus vector expressing ID93 (Ad5-ID93) for induction of CD8 T cells to use with our candidate... Show More
Publications citing this author (86)
[Show abstract] [Hide abstract] ABSTRACT: Background. Mycobacterium tuberculosis infects one third of the world's population and causes >8 million cases of tuberculosis annually. New vaccines are necessary to control the spread of tuberculosis. T cells, interferon γ (IFN-γ), and tumor necrosis factor (TNF) are necessary to control M. tuberculosis infection in both humans and unvaccinated experimental animal models. However, the immune responses necessary for vaccine efficacy against M. tuberculosis have not been defined. The multifunctional activity of T-helper type 1 (TH1) cells that simultaneously produce IFN-γ and TNF has been proposed as a candidate mechanism of vaccine efficacy. Methods. We used a mouse model of T-cell transfer and aerosolized M. tuberculosis infection to assess the contributions of TNF, IFN-γ, and inducible nitric oxide synthase (iNOS) to vaccine efficacy. Results. CD4+ T cells were necessary and sufficient to transfer protection against aerosolized M. tuberculosis, but neither CD4+ T cell–produced TNF nor host cell responsiveness to IFN-γ were necessary. Transfer of Tnf−/− CD4+ T cells from vaccinated donors to Ifngr−/− recipients was also sufficient to confer protection. Activation of iNOS to produce reactive nitrogen species was not necessary for vaccine efficacy. Conclusions. Induction of TH1 cells that coexpress IFN-γ and TNF is not a requirement for vaccine efficacy against M. tuberculosis, despite these cytokines being essential for control of M. tuberculosis in nonvaccinated animals.
- CD4 + T cells also play an important role in helping the priming and expansion of CD8 + T cells. However, this is unlikely to be the key means by which vaccineinduced CD4 + T cells control M. tuberculosis, as ID93+GLA-SE vaccination was sufficient to protect H2-D −/− ; 2H2-K −/− mice that fail to develop mature CD8 + T cells . Identifying the mechanisms of vaccine efficacy would greatly facilitate the rational development of new tuberculosis vaccines.
[Show abstract] [Hide abstract] ABSTRACT: We have previously identified 17 biomarker genes which were upregulated by whole virion influenza vaccines, and reported that gene expression profiles of these biomarker genes had a good correlation with conventional animal safety tests checking body weight and leukocyte counts. In this study, we have shown that conventional animal tests showed varied and no dose-dependent results in serially diluted bulk materials of influenza HA vaccines. In contrast, dose dependency was clearly shown in the expression profiles of biomarker genes, demonstrating higher sensitivity of gene expression analysis than the current animal safety tests of influenza vaccines. The introduction of branched DNA based-concurrent expression analysis could simplify the complexity of multiple gene expression approach, and could shorten the test period from 7 days to 3 days. Furthermore, upregulation of 10 genes, Zbp1, Mx2, Irf7, Lgals9, Ifi47, Tapbp, Timp1, Trafd1, Psmb9, and Tap2, was seen upon virosomal- adjuvanted vaccine treatment, indicating that these biomarkers could be useful for the safety control of virosomal-adjuvanted vaccines. In summary, profiling biomarker gene expression could be a useful, rapid, and highly sensitive method of animal safety testing compared with conventional methods, and could be used to evaluate the safety of various types of influenza vaccines, including adjuvanted vaccine.
- Further, the 17 biomarkers could be analyzed by a bDNA-lysate method that is more straightforward and quicker than traditional RNA expression profiling, because no RNA purification or amplification steps are needed, and target genes can be analyzed simultaneously. A bDNAbased assay has been recently used for gene expression analysis25262728, and we expect that concurrent expression analysis of biomarkers such as a bDNA-based assay will shorten the quality control test period of influenza vaccines in the future. As shown inFig 4 and Tables 2–4, data from bDNA-RNA, bDNA-lysate, and RT-PCR were well correlated with each other.
[Show abstract] [Hide abstract] ABSTRACT: More than one third of the global population are Mycobacterium tuberculosis carriers. Nevertheless, no adequate vaccine against tuberculosis has been developed. The article reviews the limitations of BCG, the only tuberculosis vaccine in current use, the main difficulties in the development of tuberculosis vaccines, and novel strategies in the development of next-generation vaccines. All types of new vaccines in the pipeline are considered. Special attention is paid to DNA- and protein subunit vaccines. The most efficient delivery methods for tuberculosis vaccines are discussed. Long-run prospects in designing novel tuberculosis vaccines are outlined.
- It is supplemented with the GLA-SE adjuvant, which contains a TLR4 agonist. The vaccine reliably elicits a Th1-mediated response in mice and guinea pigs and stimulates theformation of multifunctional CD4+ T cells producing IFNγ, TNFα, and IL2, thereby protecting the animals from TB (Bertolet et al., 2010;Baldwin et al., 2012). The clinical trial of this vaccine on healthy adults has just been launched.