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

ABSTRACT: AERAS-402 is a novel tuberculosis vaccine designed to boost immunity primed by bacillus Calmette-Guérin (BCG), the only licensed vaccine.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.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. Participants were monitored for 6 months, with all adverse effects documented. Vaccine-induced CD4(+) and CD8(+) T-cell immunity was characterized by an intracellular cytokine staining assay of whole blood and peripheral blood mononuclear cells.AERAS-402 was well tolerated, and no vaccine-related serious adverse events were recorded. The vaccine induced a robust CD4(+) T-cell response dominated by cells coexpressing IFN-gamma, tumor necrosis factor-alpha, and IL-2 ("polyfunctional" cells). AERAS-402 also induced a potent CD8(+) T-cell response, characterized by cells expressing IFN-gamma and/or tumor necrosis factor-alpha, which persisted for the duration of the study.Vaccination with AERAS-402 is safe and immunogenic in healthy adults. The immunity induced by the vaccine appears promising: polyfunctional T cells are thought to be important for protection against intracellular pathogens such as Mycobacterium tuberculosis, and evidence is accumulating that CD8(+) T cells are also important. AERAS-402 induced a robust and durable CD8(+) T-cell response, which appears extremely promising. Clinical trial registered with www.sanctr.gov.za (NHREC no. 1381).

SUBMITTER: Abel B

PROVIDER: S-EPMC2894413 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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

Abel Brian B Tameris Michele M Mansoor Nazma N Gelderbloem Sebastian S Hughes Jane J Abrahams Deborah D Makhethe Lebohang L Erasmus Mzwandile M de Kock Marwou M van der Merwe Linda L Hawkridge Anthony A Veldsman Ashley A Hatherill Mark M Schirru Giulia G Pau Maria Grazia MG Hendriks Jenny J Weverling Gerrit Jan GJ Goudsmit Jaap J Sizemore Donata D McClain J Bruce JB Goetz Margaret M Gearhart Jacqueline J Mahomed Hassan H Hussey Gregory D GD Sadoff Jerald C JC Hanekom Willem A WA

American journal of respiratory and critical care medicine 20100218 12

<h4>Rationale</h4>AERAS-402 is a novel tuberculosis vaccine designed to boost immunity primed by bacillus Calmette-Guérin (BCG), the only licensed vaccine.<h4>Objectives</h4>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.<h4>Methods</h4>Escalating doses of AERAS-402 vaccine were administered intramuscularly to each of three groups of healthy South African BCG-vacc ...[more]

PMID: 20167847

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Project description:Despite the widespread use of BCG, tuberculosis (TB) remains a global threat. Existing vaccine candidates in clinical trials are designed to replace or boost BCG which does not provide satisfying long-term protection. AERAS-402 is a replication-deficient Ad35 vaccine encoding a fusion protein of the M. tuberculosis (Mtb) antigens 85A, 85B, and TB10.4. The present phase I trial assessed the safety and immunogenicity of AERAS-402 in participants living in India - a highly TB-endemic area. Healthy male participants aged 18-45 years with a negative QuantiFERON-TB Gold in-tube test (QFT) were recruited. Enrolled participants (n=12) were randomized 2:1 to receive two intramuscular injections of either AERAS-402 (3 x 1010 viral particles [vp]); (n=8) or placebo (n=4) on study days 0 and 28. Safety and immunogenicity parameters were evaluated for up to 182 days post the second injection. Immunogenicity was assessed by a flow cytometry-based intracellular cytokine staining (ICS) assay and transcriptional profiling. The latter was examined using dual-color-Reverse-Transcriptase-Multiplex-Ligation-dependent-Probe-Amplification (dc-RT MLPA) assay. AERAS-402 was well tolerated, and no vaccine-related serious adverse events were recorded. The vaccine-induced CD8+ T-cell responses were dominated by cells co-expressing IFN-γ, TNF-α, and IL-2 ("polyfunctional" cells) and were more robust than CD4+ T-cell responses. Five genes (CXCL10, GNLY, IFI35, IL1B and PTPRCv2) were differentially expressed between the AERAS-402-group and the placebo group, suggesting vaccine-induced responses. Further, compared to pre-vaccination, three genes (CLEC7A, PTPRCv1 and TAGAP) were consistently up-regulated following two doses of vaccination in the AERAS-402-group. No safety concerns were observed for AERAS-402 in healthy Indian adult males. The vaccine-induced predominantly polyfunctional CD8+ T cells in response to Ag85B, humoral immunity, and altered gene expression profiles in peripheral blood mononuclear cells (PBMCs) indicative of activation of various immunologically relevant biological pathways.

Project description:The immunopathogenesis of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) remains unclear. We determined the association between pathogen-specific T-cell responses and development of paradoxical TB-IRIS on antiretroviral therapy (ART).This study was nested within a prospective cohort study of HIV-infected patients with active pulmonary tuberculosis and baseline CD4 counts ?125 cells/µL initiating ART. T-cell immune activation (CD38, HLA-DR, and PD-1 expression), phenotype, and polyfunctional pathogen-specific cellular immune responses prior to and 4 weeks after ART initiation were determined by flow cytometry. Patients with TB-IRIS were compared to non-IRIS controls using ?(2) and rank-sum tests and logistic regression.TB-IRIS patients and controls had similar CD4 counts, levels of T-cell-associated immune activation, frequencies of T-cell memory subsets, and frequencies of interferon gamma (IFN-?(+))/interleukin 2 (IL-2(+))/tumor necrosis factor alpha (TNF-?(+)) CD4(+) T-cells prior to ART initiation. After ART initiation, cellular immune activation and T-cell subsets also were similar in TB-IRIS patients and controls. In contrast, TB-IRIS patients had significantly greater early increases in the frequency of tuberculosis-specific polyfunctional IFN-?(+)/IL-2(+)/TNF-?(+) CD4(+) T-cells on ART (P = .02); each quartile increase in the percentage of these cells was independently associated with a 2.8-fold increased risk of TB-IRIS (95% confidence interval, 1.1 to 7.5-fold). In a secondary analysis, patients with TB-IRIS had rapid, concomitant increases in tuberculosis-specific adaptive immune responses and interleukin 6 (IL-6) levels, whereas controls with similarly rapid increases in cellular immune function had IL-6 levels that tended to decrease on ART.Rapid expansion of tuberculosis-specific polyfunctional CD4(+) T-cell responses, likely linked to increases in IL-6, is associated with development of paradoxical TB-IRIS.

Project description:This phase I/II partially blinded, randomized, dose-ranging study assessed the safety and immunogenicity of a novel human immunodeficiency virus type 1 (HIV-1) vaccine candidate consisting of a recombinant fusion protein (F4) containing 4 HIV-1 clade B antigens (Gag p24, Pol reverse transcriptase, Nef, and Gag p17) adjuvanted with AS01 in HIV-seronegative volunteers. Methods. Two doses of the recombinant F4 protein (10, 30, or 90 ?g/dose), adjuvanted with AS01 or reconstituted with water for injection, were administered 1 month apart to 180 healthy volunteers aged 18-40 years. F4-specific CD4(+) T cell responses were measured using intracellular cytokine staining after in vitro stimulation by overlapping peptide pools covering the 4 individual antigens. Results. Reactogenicity was higher during the 7-day period after each vaccine dose in the adjuvanted than in the nonadjuvanted groups. In the adjuvanted groups, the overall immune response rate was high after the second vaccine dose, with highest responder rates seen in the 10-?g F4/AS01 group (100% to 3 HIV-1 antigens and 80% to all 4 HIV-1 antigens). High and long-lasting CD4(+) T cell frequencies were observed (up to a median value of 1.2% F4-specific CD4(+) T cells at day 44), with strongest responses directed against reverse transcriptase. Antigen-specific CD4(+) T cells exhibited a polyfunctional phenotype, expressing at least CD40 ligand and interleukin 2, often in combination with tumor necrosis factor ? and/or interferon ?. Vaccine-induced CD4(+) T cell responses were broadly cross-reactive to all 4 antigens derived from HIV-1 clades A and C. Conclusions. These results support further clinical investigation of this HIV-1 vaccine candidate both in a prophylactic setting (alone, in conjunction with an envelope-based antigen or in combination with other vaccine approaches in a heterologous prime-boost regimen) and as a potentially disease-modifying therapeutic vaccine in HIV-1-infected subjects.NCT00434512.

Dataset Information

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

Publications

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

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