title: Prevention of tuberculosis in Bacille Calmette-Guérin-primed, HIV-infected adults boosted with an inactivated whole-cell mycobacterial vaccine.
abstract: OBJECTIVE
  To determine whether a multiple-dose series of an inactivated whole cell mycobacterial vaccine, Mycobacterium vaccae, can prevent HIV-associated tuberculosis.
  
  
  METHODS
  The DarDar trial was a randomized, placebo-controlled, double-blind trial. The study was carried in an outpatient facility in Dar es Salaam, Tanzania. HIV-infected patients with CD4 cell counts of at least 200 cells/microl and a Bacille Calmette-Guérin scar were chosen for the study. The intervention was carried out by random 1:1 assignment to five intradermal doses of M. vaccae or placebo. Tuberculin skin tests were performed, and patients with reactions of at least 5 mm were administered isoniazid for 6 months. The main outcome measures were disseminated (primary endpoint), definite, and probable tuberculosis (secondary endpoints).
  
  
  RESULTS
  Two thousand thirteen individuals were randomized (1006 to M. vaccae, 1007 to placebo) and followed every 3 months for a median of 3.3 years. The trial was terminated early because of slow accrual of cases of disseminated tuberculosis and significant protection against definite tuberculosis. Hazard ratios were disseminated tuberculosis 0.52 (95% confidence interval 0.21-1.34; seven cases in M. vaccae, 13 cases in placebo; log-rank P = 0.16), definite tuberculosis 0.61 (95% confidence interval 0.39-0.96; 33 cases in M. vaccae, 52 cases in placebo; P = 0.03), and probable tuberculosis 1.17 (95% confidence interval 0.76-1.80; 48 cases in M. vaccae, 40 cases in placebo; P = 0.46). Immunization was well tolerated, with no adverse effect on CD4 cell count or HIV viral load, and no increase in the rate of serious adverse events.
  
  
  CONCLUSIONS
  Administration of a multiple-dose series of M. vaccae to HIV-infected adults with childhood Bacille Calmette-Guérin immunization is safe and is associated with significant protection against definite tuberculosis. These results provide evidence that immunization with a whole cell mycobacterial vaccine is a viable strategy for the prevention of HIV-associated tuberculosis.
authors.affiliation: Infectious Disease and International Health, Dartmouth Medical School, Hanover, New Hampshire, USA. fvr@hitchcock.org
authors.forename: Charles F
authors.initials: CF
authors.lastname: von Reyn
authors.forename: Lillian
authors.initials: L
authors.lastname: Mtei
authors.forename: Robert D
authors.initials: RD
authors.lastname: Arbeit
authors.forename: Richard
authors.initials: R
authors.lastname: Waddell
authors.forename: Bernard
authors.initials: B
authors.lastname: Cole
authors.forename: Todd
authors.initials: T
authors.lastname: Mackenzie
authors.forename: Mecky
authors.initials: M
authors.lastname: Matee
authors.forename: Muhammad
authors.initials: M
authors.lastname: Bakari
authors.forename: Susan
authors.initials: S
authors.lastname: Tvaroha
authors.forename: Lisa V
authors.initials: LV
authors.lastname: Adams
authors.forename: Charles R
authors.initials: CR
authors.lastname: Horsburgh
authors.forename: Kisali
authors.initials: K
authors.lastname: Pallangyo
mesh_terms: D000328:Adult; D001500:BCG Vaccine / Q000276:immunology*; D018791:CD4 Lymphocyte Count; D004306:Dose-Response Relationship, Immunologic; D004311:Double-Blind Method; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000453:epidemiology / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D008297:Male; D013636:Tanzania / Q000453:epidemiology; D014376:Tuberculosis / Q000453:epidemiology / Q000276:immunology / Q000517:prevention & control*; D015164:Vaccines, Inactivated / Q000276:immunology
chemical_list: D001500:BCG Vaccine; D015164:Vaccines, Inactivated