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CD4+ T cell cytokine responses to the DAR-901 booster vaccine in BCG-primed adults: A randomized, placebo-controlled trial.

ABSTRACT: BACKGROUND:DAR-901 is an inactivated whole cell tuberculosis booster vaccine, prepared using a new scalable, broth-grown method from the master cell bank of SRL172, a vaccine previously shown to prevent tuberculosis. This study examined whether DAR-901 (a) induces CD4+ T cell cytokine profiles previously proposed as correlates of protection and (b) has a specific vaccine-induced immunological signature compared to BCG or placebo. METHODS:We analysed CD4+ T cell cytokine immune responses from 10 DAR-901 recipients, 9 BCG recipients and 9 placebo recipients from the Phase I DAR-901 MDES trial. In that study, HIV-negative, IGRA-negative participants with prior BCG immunization were randomized (double-blind) to receive three intradermal injections of DAR-901 or saline placebo or two injections of saline placebo followed by an intradermal injection of BCG. Antigen-specific functional and phenotypic CD4+ T cell responses along with effector phenotype of responder cells were measured by intracellular cytokine staining. RESULTS:DAR-901 recipients exhibited increased DAR-901 antigen-specific polyfunctional or bifunctional T cell responses compared to baseline. Vaccine specific CD4+ IFN?, IL2, TNF? and any cytokine responses peaked at 7 days post-dose 3. Th1 responses predominated, with most responder cells exhibiting a polyfunctional effector memory phenotype. BCG induced greater CD4+ T cell responses than placebo while the more modest DAR-901 responses did not differ from placebo. Neither DAR-901 nor BCG induced substantial or sustained Th17 /Th22 cytokine responses. CONCLUSION:DAR-901, a TB booster vaccine grown from the master cell bank of SRL 172 which was shown to prevent TB, induced low magnitude polyfunctional effector memory CD4+ T cell responses. DAR-901 responses were lower than those induced by BCG, a vaccine that has been shown ineffective as a booster to prevent tuberculosis disease. These results suggest that induction of higher levels of CD4+ cytokine stimulation may not be a critical or pre-requisite characteristic for candidate TB vaccine boosters. TRIAL REGISTRATION:ClinicalTrials.gov NCT02063555.

SUBMITTER: Masonou T

PROVIDER: S-EPMC6532882 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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CD4+ T cell cytokine responses to the DAR-901 booster vaccine in BCG-primed adults: A randomized, placebo-controlled trial.

Masonou Tereza T Hokey David A DA Lahey Timothy T Halliday Alice A Berrocal-Almanza Luis C LC Wieland-Alter Wendy F WF Arbeit Robert D RD Lalvani Ajit A von Reyn C Fordham CF

PloS one 20190523 5

<h4>Background</h4>DAR-901 is an inactivated whole cell tuberculosis booster vaccine, prepared using a new scalable, broth-grown method from the master cell bank of SRL172, a vaccine previously shown to prevent tuberculosis. This study examined whether DAR-901 (a) induces CD4+ T cell cytokine profiles previously proposed as correlates of protection and (b) has a specific vaccine-induced immunological signature compared to BCG or placebo.<h4>Methods</h4>We analysed CD4+ T cell cytokine immune res ...[more]

PMID: 31120957

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Project description:BackgroundDevelopment 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.MethodsWe 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.ResultsDAR-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.ConclusionsA 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 registrationClinicalTrials.gov NCT02063555.

Dataset Information

CD4+ T cell cytokine responses to the DAR-901 booster vaccine in BCG-primed adults: A randomized, placebo-controlled trial.

Publications

CD4+ T cell cytokine responses to the DAR-901 booster vaccine in BCG-primed adults: A randomized, placebo-controlled trial.

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