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

• Published in: PloS one Vol. 12; no. 5; p. e0175215
• Main Authors: von Reyn, C. Fordham, Lahey, Timothy, Arbeit, Robert D., Landry, Bernard, Kailani, Leway, Adams, Lisa V., Haynes, Brenda C., Mackenzie, Todd, Wieland-Alter, Wendy, Connor, Ruth I., Tvaroha, Sue, Hokey, David A., Ginsberg, Ann M., Waddell, Richard
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12.05.2017; Public Library of Science (PLoS)
• Subjects: Abnormalities; Acquired immune deficiency syndrome; Adolescent; Adolescents; Adult; Adults; Agar; Aged; AIDS; Animal models; Antibodies, Bacterial - immunology; Antigens; Antiretroviral agents; Antiretroviral therapy; Assaying; Attenuation; Bacilli; Bacillus Calmette-Guerin vaccine; BCG; BCG Vaccine - adverse effects; BCG Vaccine - immunology; Biology and Life Sciences; CD4 antigen; Cell culture; Children; Clarity; Clinical trials; Colony-forming cells; Disease prevention; Dosage and administration; Double-Blind Method; Drug dosages; Enzyme-linked immunosorbent assay; Erythema - immunology; Evaluation; Female; Genetic diversity; Heat; Hepatitis; Hepatitis B surface antigen; Hepatitis C; HIV; Homology; Human immunodeficiency virus; Humans; Immune response; Immunization; Immunogenicity; Immunology; Incidence; Infections; Injection; Interferon; Interferon-gamma Release Tests; Leprosy; Male; Manufacturing; Masking; Medical research; Medicine; Medicine and Health Sciences; Middle Aged; Mycobacterium bovis - immunology; Mycobacterium tuberculosis; Pregnancy; Prevention; Public health; Quality; Research and Analysis Methods; Risk factors; Safety; Toxicity; Tuberculosis; Tuberculosis - immunology; Tuberculosis - prevention & control; Tuberculosis vaccines; Tuberculosis Vaccines - immunology; Tuberculosis Vaccines - standards; Urine; Vaccines; Young Adult; γ-Interferon; United States > US; Maryland; New Hampshire
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0175215

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. 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. 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. 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. ClinicalTrials.gov NCT02063555.