Safety, tolerability, and immunogenicity of the novel antituberculous vaccine RUTI: randomized, placebo-controlled phase II clinical trial in patients with latent tuberculosis infection

Abstract

Objectives: To evaluate the safety, tolerability and immunogenicity of three different doses (5, 25 and 50 µg) of the novel antituberculous vaccine RUTI compared to placebo in subjects with latent tuberculosis infection.

Methods and findings: Double-blind, randomized, placebo-controlled Phase II Clinical Trial (95 patients randomized). Three different RUTI doses and placebo were tested, randomized both in HIV-positive (n = 47) and HIV-negative subjects (n = 48), after completion of one month isoniazid (INH) pre-vaccination. Each subject received two vaccine administrations, 28 Days apart. Five patients withdrew and 90 patients completed the study. Assessment of safety showed no deaths during study. Two subjects had serious adverse events one had a retinal detachment while taking INH and was not randomized and the other had a severe local injection site abscess on each arm and was hospitalized; causality was assessed as very likely and by the end of the study the outcome had resolved. All the patients except 5 (21%) patients of the placebo group (3 HIV+ and 2 HIV-) reported at least one adverse event (AE) during the study. The most frequently occurring AEs among RUTI recipients were (% in HIV+/-): injection site reactions [erythema (91/92), induration (94/92), local nodules (46/25), local pain (66/75), sterile abscess (6/6), swelling (74/83), ulcer (20/11), headache (17/22) and nasopharyngitis (20/5)]. These events were mostly mild and well tolerated. Overall, a polyantigenic response was observed, which differed by HIV- status. The best polyantigenic response was obtained when administrating 25 µg RUTI, especially in HIV-positive subjects which was not increased after the second inoculation.

Conclusion: This Phase II clinical trial demonstrates reasonable tolerability of RUTI. The immunogenicity profile of RUTI vaccine in LTBI subjects, even being variable among groups, allows us considering one single injection of one of the highest doses in future trials, preceded by an extended safety clinical phase.

Trial registration: ClinicalTrials.gov NCT01136161.

Conflict of interest statement

Competing Interests: The following statement was included in the cover letter: Jordi Picas and Mercè Amat are employees of Archivel Farma S.L., Pere-Joan Cardona is consultant of Archivel Farma S.L., Andre S. Nell and Eva D’lom are employees of PAREXEL (South Africa) and PAREXEL International (Spain), respectively. Patrick Bouic is employee of Synexa Life Sciences (SouthAfrica), Ramon Bosser is employee of Janus Developments (Spain), and Montserrat Sabaté is an employee of TFS Develop (Spain). This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials. Pere Joan Cardona is editor of PLOS ONE. The authors confirm that this does not alter their adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Consort chart representing the participant flow of the CT.

From the 111 subjects included, ninety-five patients were randomised and included in both the safety and immunogenic analyses. Five patients withdrew the study, being a total of 90 patients who completed the trial.

Figure 2. Study design of the clinical trial.

Figure 3. TB ELISPOT.

A–F represents the change from baseline in TB ELISPOT vs placebo by treatment in HIV-positive (A, B, C) and HIV-negative (D, E, F) groups. G–L represents the percentage of responders in TB ELISPOT by treatment in HIV-positive (G, H, I) and HIV-negative (J, K, L) subjects. Responders at each time point were defined as those subjects for whom the change from baseline induced by vaccination for the specific stimulus and time point was higher than the median of the change from baseline obtained in the placebo group (i.e. horizontal bar) at the same time point and stimulus. *Statistically significant change from baseline (p-value

Figure 4. WHO test.

A, B represents the change from baseline in the WHO test vs placebo by treatment and HIV-status. C, D represents the percentage of responders in the WHO test by treatment and HIV-status. Responders at each time point were defined as those subjects for whom the change from baseline induced by vaccination for the specific stimulus and time point was higher than the median of the change from baseline obtained in the placebo group (i.e. horizontal bar) at the same time point and stimulus. *Statistically significant change from baseline (p-value