Safety and immunogenicity of an inactivated whole cell tuberculosis vaccine booster in adults primed with BCG: A randomized, controlled trial of DAR-901

Abstract

Background: Development of a tuberculosis vaccine to boost BCG is a major international health priority. SRL172, an inactivated whole cell booster derived from a non-tuberculous mycobacterium, is the only new vaccine against tuberculosis to have demonstrated efficacy in a Phase 3 trial. In the present study we sought to determine if a three-dose series of DAR-901 manufactured from the SRL172 master cell bank by a new, scalable method was safe and immunogenic.

Methods: We performed a single site, randomized, double-blind, controlled, Phase 1 dose escalation trial of DAR-901 at Dartmouth-Hitchcock Medical Center in the United States. Healthy adult subjects age 18-65 with prior BCG immunization and a negative interferon-gamma release assay (IGRA) were enrolled in cohorts of 16 subjects and randomized to three injections of DAR-901 (n = 10 per cohort), or saline placebo (n = 3 per cohort), or two injections of saline followed by an injection of BCG (n = 3 per cohort; 1-8 x 106 CFU). Three successive cohorts were enrolled representing DAR-901 at 0.1, 0.3, and 1 mg per dose. Randomization was performed centrally and treatments were masked from staff and volunteers. Subsequent open label cohorts of HIV-negative/IGRA-positive subjects (n = 5) and HIV-positive subjects (n = 6) received three doses of 1 mg DAR-901. All subjects received three immunizations at 0, 2 and 4 months administered as 0.1 mL injections over the deltoid muscle alternating between right and left arms. The primary outcomes were safety and immunogenicity. Subjects were followed for 6 months after dose 3 for safety and had phlebotomy performed for safety studies and immune assays before and after each injection. Immune assays using peripheral blood mononuclear cells included cell-mediated IFN-γ responses to DAR-901 lysate and to Mycobacterium tuberculosis (MTB) lysate; serum antibody to M. tuberculosis lipoarabinomannan was assayed by ELISA.

Results: DAR-901 had an acceptable safety profile and was well-tolerated at all dose levels in all treated subjects. No serious adverse events were reported. Median (range) 7-day erythema and induration at the injection site for 1 mg DAR-901 were 10 (4-20) mm and 10 (4-16) mm, respectively, and for BCG, 30 (10-107) mm and 38 (15-55) mm, respectively. Three mild AEs, all headaches, were considered possibly related to DAR-901. No laboratory or vital signs abnormalities were related to immunization. Compared to pre-vaccination responses, three 1 mg doses of DAR-901 induced statistically significant increases in IFN-γ response to DAR-901 lysate and MTB lysate, and in antibody responses to M. tuberculosis lipoarabinomannan. Ten subjects who received 1 mg DAR-901 remained IFN-γ release assay (IGRA) negative after three doses of vaccine.

Conclusions: A three-injection series of DAR-901 was well-tolerated, had an acceptable safety profile, and induced cellular and humoral immune responses to mycobacterial antigens. DAR-901 is advancing to efficacy trials.

Trial registration: ClinicalTrials.gov NCT02063555.

Conflict of interest statement

Competing Interests: The affiliation of the 3 Aeras co-authors does not alter our adherence to PLOS ONE policies on data sharing and materials.

Figures

Fig 1. Consort diagram for cohorts A1, A2, A3 A4, B1 and B2.

Fig 2. Study design.

Fig 3. Immunogenicity of DAR-901 among 10 subjects who received three injections of 1 mg DAR-901 (Cohort A3).

Samples for Visit 1, pre-dose 2, and pre-dose 3 were collected 2 months apart. (A) Immunization with DAR-901 at the 1 mg dose elicited greater interferon gamma responses (IFN-γ) to DAR-901 lysate at pre-dose 3 and post-dose 3 day 28 compared to pre-vaccination levels. (B) IFN-γ responses to Mycobacterium tuberculosis (MTB) whole cell lysate were significantly greater, compared to pre-vaccination levels pre-dose 3, post-dose 3 day 7, and 180 (EOS). (C) Antibody responses to MTB lipoarabinomannan (LAM) were significantly greater than pre-vaccination responses at pre-dose 3, and post-dose 3 day 7, day 28, 56, and 180 (EOS). Graphs depict individual subject values along with error bars indicating median and interquartile range; * indicates P<0.05; ** indicates P<0.01.