A candidate therapeutic vaccine for prevention of post-treatment TB recurrence has proved efficacious in a phase 2 clinical trial involving the universities of Cape Town and Stellenbosch, TASK Applied Science, Fred Hutchinson Cancer Research Institute and the Infectious Disease Research Institute.
The results, published in The Lancet Respiratory Medicine, found that the ID93+GLA-SE candidate vaccine displayed an acceptable safety profile and encouraging evidence of vaccine-induced immune responses when given to cured TB patients at the end of treatment.
The paper, 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 reports the results from a trial conducted in the Western Cape of South Africa, which investigated the safety and induced immune responses of the ID93+GLA-SE candidate vaccine between June 2015 and May 2016. Study participants were HIV-uninfected adult TB patients with microbiological confirmation of cure at the end of standard antibiotic treatment.
Professor Mark Hatherill, Director at SATVI said “These results tell us that ID93 + GLA-SE should be tested at the end of treatment as a vaccine to prevent recurrent TB. The next logical step is to test whether the vaccine can be given earlier during TB treatment to improve treatment outcomes”.
Professor Rhea Coler, Senior Investigator at the Seattle Children’s Hospital said “For ID93 + GLA-SE, the groundwork is being laid for follow-on studies to evaluate the vaccine as a therapeutic adjunct to antibiotic treatment in people not only with rifampicin-susceptible TB, but also drug-resistant TB”.
Professor Andreas Diacon said that it was an honour for Task Applied Science to be part of this project conducted by leading clinical trial sites in South Africa, where TB is epidemic. A vaccine to consolidate cure achieved by daily antibiotics for months would be welcomed by TB patients. Recurrent TB is a major obstacle to shortening and simplifying treatment for TB”.
The ID93 + GLA-SE investigational vaccine was developed for prevention of tuberculosis disease in people infected with M. tuberculosis; and as an adjunctive therapeutic vaccine to improve treatment outcomes, including reduction of post- treatment recurrent TB. ID93 is a polyprotein comprised of four M. tuberculosis antigens (Rv1813c, Rv2608, Rv3619c, and Rv3620c) formulated with GLA-SE adjuvant, a synthetic toll-like receptor 4 agonist in a stable oil-in-water emulsion.
Recurrence of TB after treatment is a significant contributor to disease burden in endemic settings, with between 2-9 % of patients developing recurrent TB after completing treatment. Recurrent disease is also a major limiting factor in efforts to shorten and simplify the 6-month standard treatment course for drug-sensitive TB and the longer and more toxic treatment regimens for drug-resistant TB. A vaccine that lowers rates of disease recurrence might allow shorter and less toxic TB treatment regimens.
This study found that 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 observed in placebo recipients and persisted for the 6-month study duration. The data also showed that the vaccine had an acceptable safety profile. These findings help selection of a dose regimen of the ID93 + GLA-SE vaccine in patients with treated tuberculosis and provide a strong rationale for further testing of the vaccine. Future clinical trials of ID93 + GLA-SE should test the efficacy of post- treatment ID93 + GLA-SE vaccination for the prevention of recurrent drug-sensitive tuberculosis and explore the safety and potential of ID93 + GLA-SE to improve therapeutic outcomes when administered during treatment.
Professor Tom Scriba noted that TB patients typically already have substantial levels of T cell responses to the TB bacterium, M. tuberculosis. It was not known if vaccination after TB cure would be capable of modulating or boosting these pre- existing T cell responses. He said “The ID93 + GLA-SE vaccine boosted T cell responses to much higher levels than were present before vaccination, while it also induced high levels of antibody responses. These responses persisted at high levels until the end of the trial follow up, which is an encouraging result”. Follow-up trials designed to test the efficacy of the vaccine would be needed to determine if these immune responses are capable of protecting against recurrent TB disease.
The data also support the suitability of ID93 + GLA-SE for further evaluation as vaccine that aims to protect against TB in M. tuberculosis-infected populations, a role that will be crucial for interruption of tuberculosis transmission and the success of global tuberculosis control efforts.
This research was funded by the Wellcome Trust.
STUDY DETAILS
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
Day, T., Penn-Nicholson, A., Luabeya, A.K.K., Fiore-Gartland, A., Du Plessis, N., Loxton, A.G., Vergara, J., Rolf, T.A., Reid, T.D., Toefy, A., Shenje, J., Geldenhuys, H., Tameris, M., Mabwe, S., Bilek, N., Bekker, L.G., Diacon, A., Walzl, G., Ashman, J., Frevol, A., Sagawa, Z.K., Arlehamn, C.L., Sette, A., Reed, S.G., Coler, R.N., Scriba, T.J., Hatherill, M., Beckmann, A.M., Hsu, F., Albertson, S., Veldsman, A., Schreuder, C., Smit, E., Cloete, Y., Ontong, C., Filander, E., Jacobs, G., Keyser, A., Africa, H., Mulenga, H., Noble, J., Makhethe, L., Steyn, M., de Kock, M., Quaqala, N., Lu, Y., Gutschmidt, A., Thienneman, F., Kahn, S., Mouton, A., van Rooyen, E., Opperman, F., Swarts, A., Van Schalkwyk, A., Herselman, Y., Hofmeester, D., Amsterdam, J., Hassanally, L., van der Merwe, L., Companie, A., Rossouw, S., Jones, C., Botes, N., van der Riet, E., Goliath, S., Kruger, S., Sinandile, E.
The Lancet Respiratory Medicine, 9 December 2020
ABSTRACT
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.
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