Corrigendum: Defining discriminatory antibody fingerprints in active and latent tuberculosis.

[This corrects the article DOI: 10.3389/fimmu.2022.

Defining Discriminatory Antibody Fingerprints in Active and Latent Tuberculosis.

Tuberculosis (TB) is among the leading causes of death worldwide from a single infectious agent, second only to COVID-19 in 2020. TB is caused by infection with (Mtb), that results either in a latent or active form of disease, the latter associated with Mtb spread. In the absence of an effective vaccine, epidemiologic modeling suggests that aggressive treatment of individuals with active TB (ATB) may curb spread.

Inflammatory Determinants of Differential Tuberculosis Risk in Pre-Adolescent Children and Young Adults.

The risk of progression from ( infection to active tuberculosis (TB) disease varies markedly with age. TB disease is significantly less likely in pre-adolescent children above 4 years of age than in very young children or post-pubescent adolescents and young adults. We hypothesized that pro-inflammatory responses to in pre-adolescent children are either less pronounced or more regulated, than in young adults.

HIV Is Associated with Modified Humoral Immune Responses in the Setting of HIV/TB Coinfection.

Tuberculosis (TB) represents the largest cause of death in human immunodeficiency virus (HIV)-infected individuals in part due to HIV-related CD4 T cell loss, rendering patients immunocompromised and susceptible to a loss of control. However, in light of increasing data pointing to a role for humoral immunity in controlling infection, here, we aimed to define whether HIV infection also alters the humoral immune response in subjects with active and latent TB. We show that in the setting of active TB, HIV-positive individuals have significantly lower IgG responses to LAM and Ag85 than HIV-negative individuals.

HIV Infection Is Associated With Downregulation of BTLA Expression on -Specific CD4 T Cells in Active Tuberculosis Disease.

Nearly a quarter of the global population is infected with (Mtb), with 10 million people developing active tuberculosis (TB) annually. Co-infection with human immunodeficiency virus (HIV) has long been recognized as a significant risk factor for progression to TB disease, yet the mechanisms whereby HIV impairs T cell-mediated control of Mtb infection remain poorly defined. We hypothesized that HIV infection may promote upregulation of inhibitory receptors on Mtb-specific CD4 T cells, a mechanism that has been associated with antigen-specific T cell dysfunction in chronic infections.

PD-1 Expression on -Specific CD4 T Cells Is Associated With Bacterial Load in Human Tuberculosis.

Persistent antigen stimulation in chronic infections has been associated with antigen-specific T cell dysfunction and upregulation of inhibitory receptors, including programmed cell death protein 1 (PD-1). Pulmonary tuberculosis (TB) disease is characterized by high levels of (Mtb), yet the relationship between bacterial load, PD-1 expression, and Mtb-specific T cell function in human TB has not been well-defined. Using peripheral blood samples from adults with LTBI and with pulmonary TB disease, we tested the hypothesis that PD-1 expression is associated with bacterial load and functional capacity of Mtb-specific T cell responses.

Application of a whole blood mycobacterial growth inhibition assay to study immunity against Mycobacterium tuberculosis in a high tuberculosis burden population.

The determinants of immunological protection against Mycobacterium tuberculosis (M.tb) infection in humans are not known. Mycobacterial growth inhibition assays have potential utility as in vitro surrogates of in vivo immunological control of M.

HIV-1 Infection Is Associated with Depletion and Functional Impairment of -Specific CD4 T Cells in Individuals with Latent Tuberculosis Infection.

Coinfection with HIV is the single greatest risk factor for reactivation of latent infection (LTBI) and progression to active tuberculosis disease. HIV-associated dysregulation of adaptive immunity by depletion of CD4 Th cells most likely contributes to loss of immune control of LTBI in HIV-infected individuals, although the precise mechanisms whereby HIV infection impedes successful T cell-mediated control of have not been well defined. To further delineate mechanisms whereby HIV impairs protective immunity to , we evaluated the frequency, phenotype, and functional capacity of -specific CD4 T cells in HIV-infected and HIV-uninfected adults with LTBI.

The novel tuberculosis vaccine, AERAS-402, is safe in healthy infants previously vaccinated with BCG, and induces dose-dependent CD4 and CD8T cell responses.

Background: Efforts to reduce risk of tuberculosis disease in children include development of effective vaccines. Our aim was to test safety and immunogenicity of the new adenovirus 35-vectored tuberculosis vaccine candidate AERAS-402 in infants, administered as a boost following a prime with the Bacille Calmette-Guerin vaccine.

Methods: In a phase 1 randomised, double-blind, placebo-controlled, dose-escalation trial, BCG-vaccinated infants aged 6-9 months were sequentially assigned to four study groups, then randomized to receive an increasing dose-strength of AERAS-402, or placebo.

Patients with tuberculosis disease have Mycobacterium tuberculosis-specific CD8 T cells with a pro-apoptotic phenotype and impaired proliferative capacity, which is not restored following treatment.

CD8 T cells play a critical role in control of chronic viral infections; however, the role of these cells in containing persistent bacterial infections, such as those caused by Mycobacterium tuberculosis (Mtb), is less clear. We assessed the phenotype and functional capacity of CD8 T cells specific for the immunodominant Mtb antigens CFP-10 and ESAT-6, in patients with pulmonary tuberculosis (TB) disease, before and after treatment, and in healthy persons with latent Mtb infection (LTBI). In patients with TB disease, CFP-10/ESAT-6-specific IFN-γ+ CD8 T cells had an activated, pro-apoptotic phenotype, with lower Bcl-2 and CD127 expression, and higher Ki67, CD57, and CD95 expression, than in LTBI.

Maturation of innate responses to mycobacteria over the first nine months of life.

Newborns and young infants are particularly susceptible to infections, including Mycobacterium tuberculosis. Further, immunogenicity of vaccines against tuberculosis and other infectious diseases appears suboptimal early in life compared with later in life. We hypothesized that developmental changes in innate immunity would underlie these observations.

Lessons learnt from the first efficacy trial of a new infant tuberculosis vaccine since BCG.

Background: New tuberculosis (TB) vaccines are being developed to combat the global epidemic. A phase IIb trial of a candidate vaccine, MVA85A, was conducted in a high burden setting in South Africa to evaluate proof-of-concept efficacy for prevention of TB in infants.

Objective: To describe the study design and implementation lessons from an infant TB vaccine efficacy trial.

Induction and regulation of T-cell immunity by the novel tuberculosis vaccine M72/AS01 in South African adults.

Rationale: Tuberculosis (TB) is a major cause of morbidity and mortality worldwide, thus there is an urgent need for novel TB vaccines.

Objectives: We investigated a novel TB vaccine candidate, M72/AS01, in a phase IIa trial of bacille Calmette-Guérin-vaccinated, HIV-uninfected, and Mycobacterium tuberculosis (Mtb)-infected and -uninfected adults in South Africa.

Methods: Two doses of M72/AS01 were administered to healthy adults, with and without latent Mtb infection.

Longitudinal changes in CD4(+) T-cell memory responses induced by BCG vaccination of newborns.

Background: Improved vaccination strategies against tuberculosis are needed, such as approaches to boost immunity induced by the current vaccine, BCG. Design of these strategies has been hampered by a lack of knowledge of the kinetics of the human host response induced by neonatal BCG vaccination. Furthermore, the functional and phenotypic attributes of BCG-induced long-lived memory T-cell responses remain unclear.

A phase IIa trial of the new tuberculosis vaccine, MVA85A, in HIV- and/or Mycobacterium tuberculosis-infected adults.

Rationale: Novel tuberculosis (TB) vaccines should be safe and effective in populations infected with Mycobacterium tuberculosis (M.tb) and/or HIV for effective TB control.

Objective: To determine the safety and immunogenicity of MVA85A, a novel TB vaccine, among M.

Randomized trial of type 1 and type 3 oral monovalent poliovirus vaccines in newborns in Africa.

Background: The Global Polio Eradication Initiative aims to eradicate wild poliovirus by the end of 2012. Therefore, more-immunogenic polio vaccines, including monovalent oral poliovirus vaccines (mOPVs), are needed for supplemental immunization activities. This trial assessed the immunogenicity of monovalent types 1 and 3, compared with that of trivalent oral poliovirus vaccine (tOPV), in South Africa.

Optimization of a whole blood intracellular cytokine assay for measuring innate cell responses to mycobacteria.

Innate cells are essential for host defense against invading pathogens, and the induction and direction of adaptive immune responses to infection. We developed and optimized a flow cytometric assay that allows measurement of intracellular cytokine expression by monocytes, dendritic cells (DC) and granulocytes, as well as cellular uptake of green-fluorescent protein (GFP)-expressing mycobacteria, in very small volumes of peripheral blood. We show that innate cell stimulation resulted in increased granularity of monocytes and mDC and decreased granulocyte granularity that precluded flow cytometric discernment of granulocytes from monocytes and myeloid DC by forward and side scatter gating.

Association of human TLR1 and TLR6 deficiency with altered immune responses to BCG vaccination in South African infants.

The development of effective immunoprophylaxis against tuberculosis (TB) remains a global priority, but is hampered by a partially protective Bacillus Calmette-Guérin (BCG) vaccine and an incomplete understanding of the mechanisms of immunity to Mycobacterium tuberculosis. Although host genetic factors may be a primary reason for BCG's variable and inadequate efficacy, this possibility has not been intensively examined. We hypothesized that Toll-like receptor (TLR) variation is associated with altered in vivo immune responses to BCG.

Functional capacity of Mycobacterium tuberculosis-specific T cell responses in humans is associated with mycobacterial load.

High Ag load in chronic viral infections has been associated with impairment of Ag-specific T cell responses; however, the relationship between Ag load in chronic Mycobacterium tuberculosis infection and functional capacity of M. tuberculosis-specific T cells in humans is not clear. We compared M.

Dose-finding study of the novel tuberculosis vaccine, MVA85A, in healthy BCG-vaccinated infants.

Background: BCG, the only licensed tuberculosis vaccine, affords poor protection against lung tuberculosis in infants and children. A new tuberculosis vaccine, which may enhance the BCG-induced immune response, is urgently needed. We assessed the safety of and characterized the T cell response induced by 3 doses of the candidate vaccine, MVA85A, in BCG-vaccinated infants from a setting where tuberculosis is endemic.

HIV-specific gag responses in early infancy correlate with clinical outcome and inversely with viral load.

Many HIV-infected infants progress to AIDS during the first year of life when antiretroviral therapy (ART) is not given. The immune determinants of progression to AIDS are not known. We hypothesized that distinct HIV-specific T cell responses correlate with viral load and survival over the first year of life.

Higher human CD4 T cell response to novel Mycobacterium tuberculosis latency associated antigens Rv2660 and Rv2659 in latent infection compared with tuberculosis disease.

One third of the world's population is infected with Mycobacterium tuberculosis (M.tb). A vaccine that would prevent progression to TB disease will have a dramatic impact on the global TB burden.

Novel application of Ki67 to quantify antigen-specific in vitro lymphoproliferation.

Antigen-specific proliferation is a critical function of memory T cells that is often utilised to measure vaccine immunogenicity and T cell function. We proposed that measurement of intracellular expression of the nuclear protein, Ki67, could reliably assess specific T cell proliferation in vitro. Ki67 was expressed in CD4+ and CD8+ T cells that had undergone in vitro proliferation after 6-day culture of human whole blood or PBMC with antigens.

The novel tuberculosis vaccine, AERAS-402, induces robust and polyfunctional CD4+ and CD8+ T cells in adults.

Rationale: AERAS-402 is a novel tuberculosis vaccine designed to boost immunity primed by bacillus Calmette-Guérin (BCG), the only licensed vaccine.

Objectives: We investigated the safety and immunogenicity of AERAS-402 in healthy Mycobacterium tuberculosis-uninfected BCG-vaccinated adults from a tuberculosis-endemic region of South Africa.

Methods: Escalating doses of AERAS-402 vaccine were administered intramuscularly to each of three groups of healthy South African BCG-vaccinated adults, and a fourth group received two injections of the maximal dose.