Advax adjuvant formulations promote protective immunity against aerosol Mycobacterium tuberculosis in the absence of deleterious inflammation and reactogenicity

3区 · 医学

Article

作者: Petrovsky, Nikolai ; Triccas, James A ; Britton, Warwick J ; Pinto, Rachel ; Counoupas, Claudio ; Quan, Diana H ; Nagalingam, Gayathri

The development of safe and effective adjuvants is a critical goal of vaccine development programs. In this report, we defined the immunostimulatory profile and protective effect against aerosol Mycobacterium tuberculosis infection of vaccine formulations incorporating the semi-crystalline adjuvant δ-inulin (Advax). Advax formulated with CpG oligonucleotide and the QS-21 saponin (Advax^CpQS) was the most effective combination, demonstrated by the capacity of CysVac2/Advax^CpQS to significantly reduce the bacterial burden in the lungs of M. tuberculosis-infected mice. CysVac2/Advax^CpQS protection was associated with rapid influx of neutrophils, macrophages and monocytes to the site of vaccination and the induction of antigen-specific IFN-γ⁺/IL-2⁺/TNF⁺ polyfunctional CD4⁺ T cells in the lung. When compared to the highly potent adjuvant combination of monophosphoryl lipid A and dimethyldioctadecylammonium bromide (MPL/DDA), Advax^CpQS imparted a similar level of protective efficacy yet without the profound stimulation of inflammatory cytokines and vaccination site ulceration observed with MPL/DDA. Addition of DDA to CysVac2/Advax^CpQS further improved the protective effect of the vaccine, which correlated with increased polyfunctional CD4⁺ T cells in the lung but with no increase in vaccine reactogenicity. The data demonstrate that Advax formulations can decouple protective tuberculosis immunity from reactogenicity, making them ideal candidates for human application.

2018-05-01·Vaccine3区 · 医学

Protective efficacy of recombinant BCG over-expressing protective, stage-specific antigens of Mycobacterium tuberculosis

3区 · 医学

Article

作者: James A. Triccas ; Warwick J. Britton ; Claudio Counoupas ; Rachel Pinto ; Gayathri Nagalingam

Tuberculosis (TB) remains a major cause of mortality and morbidity worldwide, yet current control strategies, including the existing BCG vaccine, have had little impact on disease control. CysVac2, a fusion protein comprising stage-specific Mycobacterium tuberculosis antigens, provided superior protective efficacy against chronic M. tuberculosis infection in mice, compared to BCG. To determine if the delivery of CysVac2 in the context of BCG could improve BCG-induced immunity and protection, we generated a recombinant strain of BCG overexpressing CysVac2 (rBCG:CysVac2). Expression of CysVac2 in BCG was facilitated by the M. tuberculosis hspX promoter, which is highly induced inside phagocytic cells and induces strong cellular immune responses to antigens expressed under its regulation. Intradermal vaccination with rBCG:CysVac2 resulted in increased monocyte/macrophage recruitment and enhanced antigen-specific CD4⁺ T cell priming compared to parental BCG, indicating CysVac2 overexpression had a marked effect on rBCG induced-immunity. Further, rBCG:CysVac2 was a more potent inducer of antigen-specific multifunctional CD4⁺ T cells (CD4⁺IFN-γ⁺TNF⁺IL-2⁺) than BCG after vaccination of mice. This improved immunogenicity however did not influence protective efficacy, with both BCG and rBCG:CysVac2 affording comparable level of protection aerosol infection with M. tuberculosis. Boosting either BCG or rBCG:CysVac2 with the CysVac2 fusion protein resulted in a similar improvement in protective efficacy. These results demonstrate that the expression of protective antigens in BCG can augment antigen-specific immunity after vaccination but does not alter protection against infection, further highlighting the challenge of developing effective vaccines to control TB.

npj Vaccines1区 · 医学

Mycobacterium tuberculosis components expressed during chronic infection of the lung contribute to long-term control of pulmonary tuberculosis in mice

1区 · 医学

ArticleOA

作者: Counoupas, Claudio ; Britton, Warwick J ; Triccas, James A ; Hill-Cawthorne, Grant A ; Feng, Carl G ; Nagalingam, Gayathri ; Pinto, Rachel

AbstractTuberculosis (TB) remains a major cause of mortality and morbidity worldwide, yet current control strategies, including the existing BCG vaccine, have had little impact on disease control. The tubercle bacillus modifies protein expression to adapt to chronic infection of the host, and this can potentially be exploited to develop novel therapeutics. We identified the gene encoding the first step of the Mycobacterium tuberculosis sulphur assimilation pathway, cysD, as highly induced during chronic infection in the mouse lung, suggesting therapies based on CysD could be used to target infection. Vaccination with the composite vaccine CysVac2, a fusion of CysD and the immunogenic Ag85B of M. tuberculosis, resulted in the generation of multifunctional CD4+ T cells (interferon (IFN)-γ+TNF+IL-2+IL-17+) in the lung both pre- and post-aerosol challenge with M. tuberculosis. CysVac2 conferred significant protection against pulmonary M. tuberculosis challenge and was particularly effective at controlling late-stage infection, a property not shared by BCG. CysVac2 delivered as a booster following BCG vaccination afforded greater protection against M. tuberculosis challenge than BCG alone. The antigenic components of CysVac2 were conserved amongst M. tuberculosis strains, and protective efficacy afforded by CysVac2 was observed across varying murine MHC haplotypes. Strikingly, administration of CysVac2 to mice previously infected with M. tuberculosis reduced bacterial load and immunopathology in the lung compared with BCG-vaccinated mice. These results indicate that CysVac2 warrants further investigation to assess its potential to control pulmonary TB in humans.

100 项与 Tuberculosis vaccine(Vaxine) 相关的药物交易

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