Biology subjects

Markham, R. B.

Publications and source records attributed to Markham, R. B..

3 recordsLinked to original sources

bioRxiv2024

MIP3α-RelMtb intranasal DNA vaccination induces reactive T-cell infiltration into the lungs in mice and macaques

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is the leading cause of mortality due to a single infectious organism. While generally curable, TB requires a lengthy and complex antibiotic regimen, due in large part to bacteria that can shift to a persistent state in the presence of antibiotic pressure. RelMtb is the primary enzyme regulating the stringent response, which contributes to the metabolic shift of Mtb to a persistent state. Targeting RelMtb with a vaccine to eliminate persistent bacteria through the induction of RelMtb-specific T-cell immunity in combination with antibiotics to kill dividing bacteria has shown promise in model systems. In a mouse model of Mtb infection, a vaccine created by genetically fusing relMtb to the chemokine macrophage inflammatory protein 3 (MIP3), a ligand for the CC chemokine receptor type 6 (CCR6) present on immature dendritic cells, has been shown to enhance T-cell responses and accelerate eradication of infection in mouse models compared to a vaccine lacking the chemokine component. In this study, immunogenicity studies in the mouse and rhesus macaque models provide evidence that intranasal administrations of the DNA form of the MipRel vaccine led to enhanced lung infiltration of T cells after a series of immunizations. Furthermore, despite similar T-cell immunity seen in PBMCs between MipRel and Rel vaccinations, lung and bronchoalveolar lavage cell samples are more enriched for cytokine-secreting T cells in MipRel groups compared to Rel groups. We conclude that intranasal immunization with a MIP-3 fusion vaccine represents a novel strategy for use of a simple DNA vaccine formulation to elicit T-cell immune responses within the respiratory tract. That this formulation is immunogenic in a non-human primate model historically viewed as poorly responsive to DNA vaccines indicates the potential for clinical application in the treatment of Mtb infection, with possible application to other respiratory pathogens. Future studies will further characterize the protective effect of this vaccination platform.

immunology↗

bioRxiv2024

Therapeutic DNA Vaccine Targeting Mycobacterium tuberculosis Persisters Shortens Curative Tuberculosis Treatment

Mycobacterium tuberculosis (Mtb) is one of the leading infectious causes of death worldwide. There is no available licensed therapeutic vaccine that shortens active tuberculosis (TB) disease drug treatment and prevents relapse, despite the World Health Organizations calls. Here, we show that an intranasal DNA vaccine containing a fusion of the stringent response relMtb gene with the gene encoding the immature dendritic cell-targeting chemokine, MIP-3/CCL20, shortens the duration of curative TB treatment in immunocompetent mice. Compared to the first-line regimen for drug-susceptible TB alone, our novel adjunctive vaccine induced greater RelMtb-specific T-cell responses associated with optimal TB control in spleen, blood, lungs, mediastinal lymph nodes, and bronchoalveolar lavage (BAL) fluid. These responses were sustained, if not augmented, over time. It also triggered more effective dendritic cell recruitment, activation, and colocalization with T cells, implying enhanced crosstalk between innate and adaptive immunity. Moreover, it potentiated a 6-month TB drug-resistant regimen, rendering it effective across treatment regimens, and also showed promising results in CD4+ knockout mice, perhaps due to enhanced Rel-specific CD8+ T-cell responses. Notably, our novel fusion vaccine was also immunogenic in nonhuman primates, the gold standard animal model for TB vaccine studies, eliciting antigen-specific T-cell responses in blood and BAL fluid analogous to those observed in protected mice. Our findings have critical implications for therapeutic TB vaccine clinical development in immunocompetent and immunocompromised populations and may serve as a model for defining immunological correlates of therapeutic vaccine-induced protection. One sentence summaryA TB vaccine shortens curative drug treatment in mice by eliciting strong TB-protective immune responses and induces similar responses in macaques.

immunology↗

bioRxiv2019

A Vaccine Composed of Antigen Fused to a Ligand for a Receptor on Immature Dendritic Cells Elicits Protective Antibody Responses to Malaria Sporozoites in Infant Macaques

Infants and young children are the groups at greatest risk for severe disease resulting from Plasmodium falciparum infection. We previously demonstrated in mice that a protein vaccine composed of the chemokine macrophage inflammatory protein 3 genetically fused to the minimally truncated circumsporozoite protein of P. falciparum (MCSP) elicits high concentrations of specific antibody and significant reduction of liver sporozoite load in a mouse model system. In the current study, a squalene based adjuvant (AddaVax, InvivoGen, San Diego, Ca) equivalent to the clinically approved MF59 (Seqiris, Maidenhead, UK) elicited greater antibody responses in mice than the previously employed adjuvant polyinosinic:polycytidylic acid, ((poly(I:C), InvivoGen, San Diego, Ca) and the clinically approved Aluminum hydroxide gel (Alum, Invivogen, San Diego, Ca) adjuvant. Use of the AddaVax adjuvant also expanded the range of IgG subtypes elicited by mouse vaccination. Sera passively transferred into mice from MCSP/AddaVax immunized one and six month old macaques significantly reduced liver sporozoite load upon sporozoite challenge. Protective antibody concentrations attained by passive transfer in the mice were equivalent to those observed in infant macaques 18 weeks after the final immunization. The efficacy of this vaccine in a relevant non-human primate model indicates its potential usefulness for the analogous high risk human population.

immunology↗