SA clinical trial finds TB vaccine well tolerated

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TuberculosisvaccineResearchers at the South African Tuberculosis Vaccine Initiative (SATVI) at the University of Cape Town (UCT), the Infectious Disease Research Institute (IDRI) and Aeras have released the first results from a clinical trial reporting safety and induced immune responses of ID93 + GLA-SE, a novel tuberculosis vaccine candidate developed by scientists at IDRI.

The trial in South African adults demonstrated that the vaccine was well tolerated, had an acceptable safety profile and induced a specific immune response, supporting further development and clinical testing of this novel vaccine candidate.

The researchers tested escalating doses of the vaccine in 54 healthy adults living outside of Cape Town, South Africa. At the time of vaccination, some of the study participants had been living with a natural infection of Mycobacterium tuberculosis (M.tb), the bacterium that causes TB disease.

Professor Mark Hatherill, the lead researcher from UCT, said: “Globally, approximately 10% of people infected with the TB bug develop TB disease over their lifetime, but a vaccine such as ID93 + GLA-SE could help to prevent the disease, which is spread by coughing. In South Africa, 50-80% of adults are infected with M.tb, and the incidence of TB disease is one of the highest in the world, so there is an urgent need to stop TB before it is spread.”

Four proteins from M.tb are included in the ID93 + GLA-SE vaccine, none of which have ever been tested in a vaccine formulation in humans before. The scientists combined the vaccine proteins with a special adjuvant compound, an oil emulsion called GLA-SE, that greatly enhances immune responses to vaccination. This is the first report of this particular adjuvant – developed by IDRI – in a clinical trial for a TB vaccine. The vaccine was given to participants by injection into the arm muscle, and was well tolerated, demonstrating an acceptable safety profile in adults living in a setting where TB is endemic.

The ID93 + GLA-SE vaccine induced potent immune responses, in the form of both antibodies and T cells.

Dr Adam Penn-Nicholson, immunologist at SATVI (UCT) and lead author of the published paper, said: “We found that the vaccine induces immune responses with distinct characteristics to each of the TB antigens included in the ID93 + GLA-SE vaccine. We believe that a response with diverse characteristics may be more likely to provide immunity than a narrow response against the TB bacterium.”

The ID93 + GLA-SE vaccine is now advancing to the important next phase of human studies. A trial is underway in which the vaccine has been given to patients who have finished TB treatment to test whether it is safe and induces immune responses that might prevent another episode of TB disease. The scientists are currently analysing results from this trial and the findings are likely to be available later in 2018.

Tuberculosis causes 1.7m deaths a year and is the biggest global cause of mortality from any infectious disease. The World Health Organisation reports that despite accounting for about 2% of deaths globally, TB receives only 0.25% of the estimated $265bn spent worldwide on medical research each year.

Dr Rhea Coler, IDRI’s senior vice president of preclinical and translational research said “TB research is significantly underfunded. Governments must make a greater commitment to fund the R&D that will end TB once and for all”.

Summary
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.

Authors
Adam Penn-Nicholson, Michele Tameris, Erica Smit, Tracey A Day, Munyaradzi Musvosvi, Lakshmi Jayashankar, Julie Vergara, Simbarashe Mabwe, Nicole Bilek, Hendrik Geldenhuys, Angelique Kany-Kany Luabeya, Ruth Ellis, Ann M Ginsberg, Willem A Hanekom, Steven G Reed, Rhea N Coler, Thomas J Scriba, Mark Hatherill

The Lancet Respiratory Medicine article summary

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