title: Safety and immunogenicity of the M72/AS01 candidate tuberculosis vaccine in HIV-infected adults on combination antiretroviral therapy: a phase I/II, randomized trial.
abstract: OBJECTIVE
  Tuberculosis (TB) is highly prevalent among HIV-infected people, including those receiving combination antiretroviral therapy (cART), necessitating a well tolerated and efficacious TB vaccine for these populations. We evaluated the safety and immunogenicity of the candidate TB vaccine M72/AS01 in adults with well controlled HIV infection on cART.
  
  
  METHODS
  A randomized, observer-blind, controlled trial (NCT00707967).
  
  
  METHODS
  HIV-infected adults on cART in Switzerland were randomized 3 : 1 : 1 to receive two doses, 1 month apart, of M72/AS01, AS01 or 0.9% physiological saline (N = 22, N = 8 and N = 7, respectively) and were followed up to 6 months postdose 2 (D210). Individuals with CD4⁺ cell counts below 200 cells/μl were excluded. Adverse events (AEs) including HIV-specific and laboratory safety parameters were recorded. Cell-mediated (ICS) and humoral (ELISA) responses were evaluated before vaccination, 1 month after each dose (D30, D60) and D210.
  
  
  RESULTS
  Thirty-seven individuals [interquartile range (IQR) CD4⁺ cell counts at screening: 438-872 cells/μl; undetectable HIV-1 viremia] were enrolled; 73% of individuals reported previous BCG vaccination, 97.3% tested negative for the QuantiFERON-TB assay. For M72/AS01 recipients, no vaccine-related serious AEs or cART-regimen adjustments were recorded, and there were no clinically relevant effects on laboratory safety parameters, HIV-1 viral loads or CD4⁺ cell counts. M72/AS01 was immunogenic, inducing persistent and polyfunctional M72-specific CD4⁺ T-cell responses [medians 0.70% (IQR 0.37-1.07) at D60] and 0.42% (0.24-0.61) at D210, predominantly CD40L⁺IL-2⁺TNF-α⁺, CD40L⁺IL-2⁺ and CD40L⁺IL-2⁺TNF-α⁺IFN-γ⁺]. All M72/AS01 vaccines were seropositive for anti-M72 IgG after second vaccination until study end.
  
  
  CONCLUSIONS
  M72/AS01 was clinically well tolerated and immunogenic in this population, supporting further clinical evaluation in HIV-infected individuals in TB-endemic settings.
authors.affiliation: aDivision of Immunology and Allergy bService of Infectious Diseases, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland cGlaxoSmithKline Vaccines, Rixensart, Belgium. *The authors Eleonora G. Thacher and Matthias Cavassini contributed equally to the writing of this article. †Opokua Ofori-Anyinam and François Spertini are equal senior authors.
authors.forename: Eleonora G
authors.initials: EG
authors.lastname: Thacher
authors.forename: Matthias
authors.initials: M
authors.lastname: Cavassini
authors.forename: Régine
authors.initials: R
authors.lastname: Audran
authors.forename: Anne-Christine
authors.initials: AC
authors.lastname: Thierry
authors.forename: Anne
authors.initials: A
authors.lastname: Bollaerts
authors.forename: Joe
authors.initials: J
authors.lastname: Cohen
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Demoitié
authors.forename: Dawit
authors.initials: D
authors.lastname: Ejigu
authors.forename: Pascal
authors.initials: P
authors.lastname: Mettens
authors.forename: Philippe
authors.initials: P
authors.lastname: Moris
authors.forename: Opokua
authors.initials: O
authors.lastname: Ofori-Anyinam
authors.forename: François
authors.initials: F
authors.lastname: Spertini
mesh_terms: D000293:Adolescent; D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D000907:Antibodies, Bacterial / Q000097:blood; D023241:Antiretroviral Therapy, Highly Active; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004338:Drug Combinations; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D008050:Lipid A / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D008297:Male; D008875:Middle Aged; D010919:Placebos / Q000008:administration & dosage; D012503:Saponins / Q000008:administration & dosage / Q000009:adverse effects*; D016037:Single-Blind Method; D013557:Switzerland; D016176:T-Lymphocyte Subsets / Q000276:immunology; D016896:Treatment Outcome; D014376:Tuberculosis / Q000517:prevention & control*; D032581:Tuberculosis Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology*; D014611:Vaccination / Q000009:adverse effects / Q000379:methods; D055815:Young Adult
chemical_list: D044966:Anti-Retroviral Agents; D000907:Antibodies, Bacterial; D004338:Drug Combinations; D007074:Immunoglobulin G; D008050:Lipid A; D010919:Placebos; D012503:Saponins; D032581:Tuberculosis Vaccines; C000592464:adjuvant system 01