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.tb- and/or HIV-infected persons in a setting where TB and HIV are endemic. METHODS: An open-label, phase IIa trial was conducted in 48 adults with M.tb and/or HIV infection. Safety and immunogenicity were analyzed up to 52 weeks after intradermal vaccination with 5 × 10(7) plaque-forming units of MVA85A. Specific T-cell responses were characterized by IFN-γ enzyme-linked immunospot and whole blood intracellular cytokine staining assays. MEASUREMENTS AND MAIN RESULTS: MVA85A was well tolerated and no vaccine-related serious adverse events were recorded. MVA85A induced robust and durable response of mostly polyfunctional CD4(+) T cells, coexpressing IFN-γ, tumor necrosis factor-α, and IL-2. Magnitudes of pre- and postvaccination T-cell responses were lower in HIV-infected, compared with HIV-uninfected, vaccinees. No significant effect of antiretroviral therapy on immunogenicity of MVA85A was observed. CONCLUSIONS: MVA85A was safe and immunogenic in persons with HIV and/or M.tb infection. These results support further evaluation of safety and efficacy of this vaccine for prevention of TB in these target populations.

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. METHODS: Infants aged 5-12 months were vaccinated intradermally with either 2.5 × 10(7), 5 × 10(7), or 10 × 10(7) plaque-forming units of MVA85A, or placebo. Adverse events were documented, and T-cell responses were assessed by interferon γ (IFN-γ) enzyme-linked immunospot assay and intracellular cytokine staining. RESULTS: The 3 MVA85A doses were well tolerated, and no vaccine-related serious adverse events were recorded. MVA85A induced potent, durable T-cell responses, which exceeded prevaccination responses up to 168 d after vaccination. No dose-related differences in response magnitude were observed. Multiple CD4 T cell subsets were induced; polyfunctional CD4 T cells co-expressing T-helper cell 1 cytokines with or without granulocyte-macrophage colony-stimulating factor predominated. IFN-γ-expressing CD8 T cells, which peaked later than CD4 T cells, were also detectable. CONCLUSIONS: MVA85A was safe and induced robust, polyfunctional, durable CD4 and CD8 T-cell responses in infants. These data support efficacy evaluation of MVA85A to prevent tuberculosis in infancy. Clinical Trials Registration. NCT00679159.

Safety and immunogenicity of the adjunct therapeutic vaccine ID93 + GLA-SE in adults who have completed treatment for tuberculosis: a randomised, double-blind, placebo-controlled, phase 2a trial.

BACKGROUND: A therapeutic vaccine that prevents recurrent tuberculosis would be a major advance in the development of shorter treatment regimens. We aimed to assess the safety and immunogenicity of the ID93 + GLA-SE vaccine at various doses and injection schedules in patients with previously treated tuberculosis. METHODS: This randomised, double-blind, placebo-controlled, phase 2a trial was conducted at three clinical sites near Cape Town, South Africa. Patients were recruited at local clinics after receiving 4 months of tuberculosis treatment, and screened for eligibility after providing written informed consent. Participants were aged 18-60 years, BCG-vaccinated, HIV-uninfected, and diagnosed with drug-sensitive pulmonary tuberculosis. Eligible patients had completed standard treatment for pulmonary tuberculosis in the past 28 days. Participants were enrolled after completing standard treatment and randomly assigned sequentially to receive vaccine or placebo in three cohorts: 2 µg intramuscular ID93 + 2 µg GLA-SE on days 0 and 56 (cohort 1); 10 µg ID93 + 2 µg GLA-SE on days 0 and 56 (cohort 2); 2 µg ID93 + 5 µg GLA-SE on days 0 and 56 and placebo on day 28 (cohort 3); 2 µg ID93 + 5 µg GLA-SE on days 0, 28, and 56 (cohort 3); or placebo on days 0 and 56 (cohorts 1 and 2), with the placebo group for cohort 3 receiving an additional injection on day 28. Randomisation was in a ratio of 3:1 for ID93 + GLA-SE and saline placebo in cohorts 1 and 2, and in a ratio of 3:3:1 for (2 ×) ID93 + GLA-SE, (3 ×) ID93 + GLA-SE, and placebo in cohort 3. The primary outcomes were safety and immunogenicity (vaccine-specific antibody response and T-cell response). For the safety outcome, participants were observed for 30 min after each injection, injection site reactions and systemic adverse events were monitored until day 84, and serious adverse events and adverse events of special interest were monitored for 6 months after the last injection. Vaccine-specific antibody responses were measured by serum ELISA, and T-cell responses after stimulation with vaccine antigens were measured in cryopreserved peripheral blood mononuclear cells specimens using intracellular cytokine staining followed by flow cytometry. This study is registered with ClinicalTrials.gov, number NCT02465216. FINDINGS: Between June 17, 2015, and May 30, 2016, we assessed 177 patients for inclusion. 61 eligible patients were randomly assigned to receive: saline placebo (n=5) or (2 ×) 2 µg ID93 + 2 µg GLA-SE (n=15) on days 0 and 56 (cohort 1); saline placebo (n=2) or (2 ×) 10 µg ID93 + 2 µg GLA-SE (n=5) on days 0 and 56 (cohort 2); saline placebo (n=5) on days 0, 28 and 56, or 2 µg ID93 + 5 µg GLA-SE (n=15) on days 0 and 56 and placebo injection on day 28, or (3 ×) 2 µg ID93 + 5 µg GLA-SE (n=14) on days 0, 28, and 56 (cohort 3). ID93 + GLA-SE induced robust and durable antibody responses and specific, polyfunctional CD4 T-cell responses to vaccine antigens. Two injections of the 2 µg ID93 + 5 µg GLA-SE dose induced antigen-specific IgG and CD4 T-cell responses that were significantly higher than those with placebo and persisted for the 6-month study duration. Mild to moderate injection site pain was reported after vaccination across all dose combinations, and induration and erythema in patients given 2 µg ID93 + 5 µg GLA-SE in two or three doses. One participant had grade 3 erythema and induration at the injection site. No vaccine-related serious adverse events were observed. INTERPRETATION: Vaccination with ID93 + GLA-SE was safe and immunogenic for all tested regimens. These data support further evaluation of ID93 + GLA-SE in therapeutic vaccination strategies to improve tuberculosis treatment outcomes. FUNDING: Wellcome Trust (102028/Z/13/Z).

Safety and immunogenicity of the novel tuberculosis vaccine ID93 + GLA-SE in BCG-vaccinated healthy adults in South Africa: a randomised, double-blind, placebo-controlled phase 1 trial.

BACKGROUND: A vaccine that prevents pulmonary tuberculosis in adults is needed to halt transmission in endemic regions. This trial aimed to assess the safety and immunogenicity of three administrations at varying doses of antigen and adjuvant of an investigational vaccine (ID93 + GLA-SE) compared with placebo in previously BCG-vaccinated healthy adults in a tuberculosis endemic country. METHODS: In this randomised, double-blind, placebo-controlled phase 1 trial, we enrolled HIV-negative, previously BCG-vaccinated adults (aged 18-50 years), with no evidence of previous or current tuberculosis disease, from among community volunteers in the Worcester region of Western Cape, South Africa. Participants were randomly assigned to receive varying doses of ID93 + GLA-SE or saline placebo at day 0, day 28, and day 112. Enrolment into each cohort was sequential. Cohort 1 participants were Mycobacterium tuberculosis uninfected (as defined by negative QuantiFERON [QFT] status), and received 10 µg ID93 plus 2 µg GLA-SE, or placebo; in cohorts 2-4, QFT-negative or positive participants received escalating doses of vaccine or placebo. Cohort 2 received 2 µg ID93 plus 2 µg GLA-SE; cohort 3 received 10 µg ID93 plus 2 µg GLA-SE; and cohort 4 received 10 µg ID93 plus 5 µg GLA-SE. Dose cohort allocation was sequential; randomisation within a cohort was according to a randomly-generated sequence (3 to 1 in cohort 1, 5 to 1 in cohorts 2-4). The primary endpoint was safety of ID93 + GLA-SE as defined by solicited and unsolicited adverse events up to 28 days after each study injection and serious adverse events for the duration of the study. Specific immune responses were measured by intracellular cytokine staining, flow cytometry, and ELISA. All analyses were done according to intention to treat, with additional per-protocol analyses for immunogenicity outcomes. This trial is registered with ClinicalTrials.gov, number NCT01927159. FINDINGS: Between Aug 30, 2013, and Sept 4, 2014, 227 individuals consented to participate; 213 were screened (three participants were not included as study number was already met and 11 withdrew consent before screening occurred, mostly due to relocation or demands of employment). 66 healthy, HIV-negative adults were randomly allocated to receive the vaccine (n=54) or placebo (n=12). All study participants received day 0 and day 28 study injections; five participants did not receive an injection on day 112. ID93 + GLA-SE was well tolerated; no severe or serious vaccine-related adverse events were recorded. Vaccine dose did not affect frequency or severity of adverse events, but mild injection site adverse events and flu-like symptoms were common in M tuberculosis-infected participants compared with uninfected participants. Vaccination induced durable antigen-specific IgG and Th1 cellular responses, which peaked after two administrations. Vaccine dose did not affect magnitude, kinetics, or profile of antibody and cellular responses. Earlier boosting and greater T-cell differentiation and effector-like profiles were seen in M tuberculosis-infected than in uninfected vaccinees. INTERPRETATION: Escalating doses of ID93 + GLA-SE induced similar antigen-specific CD4-positive T cell and humoral responses, with an acceptable safety profile in BCG-immunised, M tuberculosis-infected individuals. The T-cell differentiation profiles in M tuberculosis-infected vaccinees suggest priming through natural infection. While cohort sample sizes in this phase 1 trial were small and results should be interpreted in context, these data support efficacy testing of two administrations of the lowest (2 µg) ID93 vaccine dose in tuberculosis endemic populations. FUNDING: Aeras and the Paul G Allen Family Foundation.

Effect of isoniazid therapy for latent TB infection on QuantiFERON-TB gold in-tube responses in adults with positive tuberculin skin test results in a high TB incidence area: a controlled study.

BACKGROUND: T-cell interferon-γ release assays (IGRAs) are used in the diagnosis of Mycobacterium tuberculosis infection and could be useful biomarkers of response to treatment of latent TB infection for clinical trials, infection control units, and TB programs. METHODS: This investigation was a prospective, controlled substudy of IGRA responses in 82 healthy South African adults with HIV seronegative and positive tuberculin skin test results randomly assigned to treatment with 6 months of daily isoniazid preventive therapy (IPT) or observation before Bacillus Calmette-Guérin revaccination in a clinical trial. QuantiFERON-TB Gold In-Tube (QFT-GIT) assay was used to measure interferon-γ (IFN-γ) response to mycobacterial antigens at baseline and after IPT or observation. RESULTS: IFN-γ levels declined between baseline and the end of IPT (signed rank test P≤.0001) and between baseline and a similar period of observation without IPT (signed rank test P=.03). The rate of decrease in IFN-γ responses over time did not differ between the groups (Mann-Whitney-Wilcoxon test P=.31). QFT-GIT test results in two subjects (5%) in the IPT group and two subjects (5%) in the observation group reverted from positive to negative during follow-up. No significant difference was found between the groups with respect to baseline positivity or the proportion of patients whose tests reverted to negative. CONCLUSIONS: IPT had no effect on changes in QFT-GIT readouts during short-term follow-up of adults with positive tuberculin skin tests in a high TB incidence setting. QFT-GIT is unlikely to be a useful biomarker of response to treatment of latent TB infection. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01119521; URL: www.clinicaltrials.gov.

Safety and reactogenicity of BCG revaccination with isoniazid pretreatment in TST positive adults.

RATIONALE: Global tuberculosis (TB) control may require mass vaccination with a new TB vaccine, such as a recombinant bacille Calmette Guerin (BCG) or attenuated Mycobacterium tuberculosis (MTB). The safety profile of live mycobacterial vaccines in latently infected adults with prior infant BCG vaccination is unknown. OBJECTIVES: Evaluate safety and reactogenicity of BCG revaccination, with or without isoniazid (INH) pretreatment, in adults with latent MTB infection (LTBI). METHODS: Eighty-two healthy, HIV uninfected, South African adults, with a BCG scar and tuberculin skin test (TST) diameter ≥ 15 mm, were randomized to receive 6 months of INH, starting either before, or 6 months after, intradermal revaccination with BCG Vaccine SSI (Statens Serum Institut, Copenhagen). Safety and reactogenicity data are reported through 3 months post BCG revaccination. RESULTS: Baseline characteristics were similar between treatment arms. Mean baseline TST diameter was 20 ± 4 mm. Seventy-two subjects received BCG revaccination. Injection site erythema (68%) and induration (86%) peaked 1 week after revaccination. Ulceration (76%) peaked at 2 weeks, and resolved by 3 months in all but 3 subjects. Diameter of ulceration was >10mm in only 8%, but a residual scar was common (85%). No regional lymphadenitis or serious morbidity related to BCG was seen. Reactogenicity was not affected by INH pretreatment. CONCLUSION: BCG revaccination of MTB infected adults is safe, well tolerated, and reactogenicity is similar to that of primary BCG vaccination. Clinical trials of live recombinant BCG or attenuated MTB vaccines may be considered in latently infected adults, with or without INH pretreatment (ClinicalTrials.gov identifier: NCT01119521).