Early Antibody-Mediated Immunity to Tuberculosis in Mice Requires NLRP3.

While antibodies have emerged as potential mediators of protective immunity against (Mtb), their mechanisms of action remain incompletely understood. Here, we demonstrate that immune complexes of Mtb and monoclonal antibodies targeting the Mtb phosphate transporter subunit PstS1 robustly activate the NLRP3 inflammasome in human and murine macrophages, leading to enhanced interleukin-1β secretion. Surprisingly, antibody-mediated inflammasome activation occurred independently of cell-surface Fcγ receptors, as confirmed using Fc-domain glycosylation mutant mAbs and macrophages from Fcγ receptor-deficient mice.

Deconvoluting the interplay of innate and adaptive immunity in BCG-induced nonspecific and TB-specific host resistance.

BCG is the oldest vaccine in continuous use. While current intradermal vaccination regimens confer limited protection outside the context of pediatric extrapulmonary tuberculosis (TB), promising new data indicate that when administered mucosally or intravenously at a higher dose, BCG can induce sterilizing immunity against pulmonary TB in nonhuman primates. BCG is also known to promote nonspecific host resistance against a variety of unrelated infections and is a standard immunotherapy for bladder cancer, suggesting that this innate immune function may contribute to its protective role against TB.

Intravenous BCG-mediated protection against tuberculosis requires CD4+ T cells and CD8α+ lymphocytes.

Tuberculosis (TB) is a major health burden worldwide despite widespread intradermal (ID) BCG vaccination in newborns. We previously demonstrated that changing the BCG route and dose from 5 × 105 CFUs ID to 5 × 107 CFUs i.v.

High-dose intravenous BCG vaccination induces enhanced immune signaling in the airways.

Intradermal Bacillus Calmette-Guérin (BCG) is the most widely administered vaccine, but it does not sufficiently protect adults against pulmonary tuberculosis. Recent studies in nonhuman primates show that intravenous BCG administration offers superior protection against (). We used single-cell analysis of bronchoalveolar lavage cells from rhesus macaques vaccinated via different routes and doses of BCG to identify alterations in the immune ecosystem in the airway following vaccination.

Humoral correlate of vaccine-mediated protection from tuberculosis identified in humans and non-human primates.

Development of an effective tuberculosis (TB) vaccine has been challenged by incomplete understanding of specific factors that provide protection against (Mtb) and the lack of a known correlate of protection (CoP). Using a combination of samples from a vaccine showing efficacy (DarDar [NCT00052195]) and Bacille Calmette-Guerin (BCG)-immunized humans and nonhuman primates (NHP), we identify a humoral CoP that translates across species and vaccine regimens. Antibodies specific to the DarDar vaccine strain () sonicate (MOS) correlate with protection from the efficacy endpoint of definite TB.

Humoral correlates of protection against following intravenous BCG vaccination in rhesus macaques.

Altering Bacille Calmette-Guérin (BCG) immunization from low-dose intradermal (i.d.) to high-dose intravenous (i.

Markov Field network model of multi-modal data predicts effects of immune system perturbations on intravenous BCG vaccination in macaques.

Analysis of multi-modal datasets can identify multi-scale interactions underlying biological systems, but can be beset by spurious connections due to indirect impacts propagating through an unmapped biological network. For example, studies in macaques have shown that BCG vaccination by an intravenous route protects against tuberculosis, correlating with changes across various immune data modes. To eliminate spurious correlations and identify critical immune interactions in a public multi-modal dataset (systems serology, cytokines, cytometry) of vaccinated macaques, we applied Markov Fields (MF), a data-driven approach that explains vaccine efficacy and immune correlations via multivariate network paths, without requiring large numbers of samples (i.

Markov field network model of multi-modal data predicts effects of immune system perturbations on intravenous BCG vaccination in macaques.

Analysis of multi-modal datasets can identify multi-scale interactions underlying biological systems but can be beset by spurious connections due to indirect impacts propagating through an unmapped biological network. For example, studies in macaques have shown that Bacillus Calmette-Guerin (BCG) vaccination by an intravenous route protects against tuberculosis, correlating with changes across various immune data modes. To eliminate spurious correlations and identify critical immune interactions in a public multi-modal dataset (systems serology, cytokines, and cytometry) of vaccinated macaques, we applied Markov fields (MFs), a data-driven approach that explains vaccine efficacy and immune correlations via multivariate network paths, without requiring large numbers of samples (i.

Antibody-mediated depletion of select T cell subsets in blood and tissue of nonhuman primates.

Understanding the immunological control of pathogens requires a detailed evaluation of the mechanistic contributions of individual cell types within the immune system. While knockout mouse models that lack certain cell types have been used to help define the role of those cells, the biological and physiological characteristics of mice do not necessarily recapitulate that of a human. To overcome some of these differences, studies often look towards nonhuman primates (NHPs) due to their close phylogenetic relationship to humans.

Immune Activation Profiles Elicited by Distinct, Repeated TLR Agonist Infusions in Rhesus Macaques.

TLR agonists are a promising class of immune system stimulants investigated for immunomodulatory applications in cancer immunotherapy and viral diseases. In this study, we sought to characterize the safety and immune activation achieved by different TLR agonists in rhesus macaques (Macaca mulatta), a useful preclinical model of complex immune interactions. Macaques received one of three TLR agonists, followed by plasma cytokine, immune cell subset representation, and blood cell activation measurements.

Intravenous Bacille Calmette-Guérin vaccination protects simian immunodeficiency virus-infected macaques from tuberculosis.

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is the most common cause of death in people living with human immunodeficiency virus (HIV). Intra-dermal Bacille Calmette-Guérin (BCG) delivery is the only licensed vaccine against tuberculosis; however, it offers little protection from pulmonary tuberculosis in adults and is contraindicated in people living with HIV. Intravenous BCG confers protection against Mtb infection in rhesus macaques; we hypothesized that it might prevent tuberculosis in simian immunodeficiency virus (SIV)-infected macaques, a model for HIV infection.

Blood transcriptional correlates of BCG-induced protection against tuberculosis in rhesus macaques.

Blood-based correlates of vaccine-induced protection against tuberculosis (TB) are urgently needed. Here, we analyze the blood transcriptome of rhesus macaques immunized with varying doses of intravenous (i.v.

Airway T cells are a correlate of i.v. Bacille Calmette-Guerin-mediated protection against tuberculosis in rhesus macaques.

Bacille Calmette-Guerin (BCG), the only approved Mycobacterium tuberculosis (Mtb) vaccine, provides limited durable protection when administered intradermally. However, recent work revealed that intravenous (i.v.

Vaccination with intravenous BCG protects macaques with pre-existing SIV infection from tuberculosis.

Tuberculosis (TB) is the most common cause of death in people living with HIV. BCG delivered intradermally (ID) is the only licensed vaccine to prevent TB. However, it offers little protection from pulmonary TB in adults.

Robust IgM responses following intravenous vaccination with Bacille Calmette-Guérin associate with prevention of Mycobacterium tuberculosis infection in macaques.

Development of an effective tuberculosis (TB) vaccine has suffered from an incomplete understanding of the correlates of protection against Mycobacterium tuberculosis (Mtb). Intravenous (i.v.

T Cells Specific for a Mycobacterial Glycolipid Expand after Intravenous Bacillus Calmette-Guérin Vaccination.

Intradermal vaccination with bacillus Calmette-Guérin (BCG) protects infants from disseminated tuberculosis, and i.v. BCG protects nonhuman primates (NHP) against pulmonary and extrapulmonary tuberculosis.

Measurement of leukocyte trafficking kinetics in macaques by serial intravascular staining.

Leukocyte trafficking enables detection of pathogens, immune responses, and immune memory. Dysregulation of leukocyte trafficking is often found in disease, highlighting its important role in homeostasis and the immune response. Whereas some of the molecular mechanisms mediating leukocyte trafficking are understood, little is known about the regulation of trafficking, including trafficking kinetics and its impact on immune homeostasis.

Evaluation of heterologous prime-boost vaccination strategies using chimpanzee adenovirus and modified vaccinia virus for TB subunit vaccination in rhesus macaques.

Tuberculosis (TB) still is the principal cause of death from infectious disease and improved vaccination strategies are required to reduce the disease burden and break TB transmission. Here, we investigated different routes of administration of vectored subunit vaccines based on chimpanzee-derived adenovirus serotype-3 (ChAd3) for homologous prime-boosting and modified vaccinia virus Ankara (MVA) for heterologous boosting with both vaccine vectors expressing the same antigens from (Ag85B, ESAT6, Rv2626, Rv1733, RpfD). Prime-boost strategies were evaluated for immunogenicity and protective efficacy in highly susceptible rhesus macaques.

Prevention of tuberculosis in macaques after intravenous BCG immunization.

Mycobacterium tuberculosis (Mtb) is the leading cause of death from infection worldwide. The only available vaccine, BCG (Bacillus Calmette-Guérin), is given intradermally and has variable efficacy against pulmonary tuberculosis, the major cause of mortality and disease transmission. Here we show that intravenous administration of BCG profoundly alters the protective outcome of Mtb challenge in non-human primates (Macaca mulatta).

Monocytes Acquire the Ability to Prime Tissue-Resident T Cells via IL-10-Mediated TGF-β Release.

Using non-human primates (NHPs), mice, and human primary cells, we found a role for interleukin-10 (IL-10) in the upregulation of the tissue-resident memory T cell (T) marker CD103. In NHPs, intravenous, but not subcutaneous, immunization with peptide antigen and an adjuvant combining an agonistic anti-CD40 antibody plus poly(IC:LC) induced high levels of CD103 Ts in the lung, which correlated with early plasma IL-10 levels. Blocking IL-10 reduced CD103 expression on human T cells stimulated in vitro with the adjuvant combination as well as diminished CD103 on lung-resident T cells in vivo in mice.