title: Adenovirus type 35-vectored tuberculosis vaccine has an acceptable safety and tolerability profile in healthy, BCG-vaccinated, QuantiFERON(®)-TB Gold (+) Kenyan adults without evidence of tuberculosis.
abstract: In a Phase 1 trial, we evaluated the safety of AERAS-402, an adenovirus 35-vectored TB vaccine candidate expressing 3 Mycobacterium tuberculosis (Mtb) immunodominant antigens, in subjects with and without latent Mtb infection. HIV-negative, BCG-vaccinated Kenyan adults without evidence of tuberculosis, 10 QuantiFERON(®)-TB Gold In-Tube test (QFT-G)(-) and 10 QFT-G(+), were randomized 4:1 to receive AERAS-402 or placebo as two doses, on Days 0 and 56, with follow up to Day 182. There were no deaths, serious adverse events or withdrawals. For 1 AERAS-402 QFT-G(-) and 1 AERAS-402 QFT-G(+) subject, there were 3 self-limiting severe AEs of injection site pain: 1 after the first vaccination and 1 after each vaccination, respectively. Two additional severe AEs considered vaccine-related were reported after the first vaccination in AERAS-402 QFT-G(+) subjects: elevated blood creatine phosphokinase and neutropenia, the latter slowly improving but remaining abnormal until study end. AERAS-402 was not detected in urine or throat cultures for any subject. In intracellular cytokine staining studies, curtailed by technical issues, we saw modest CD4+ and CD8+ T cell responses to Mtb Ag85A/b peptide pools among both QFT-G(-) and (+) subjects, with trends in the CD4+ T cells suggestive of boosting after the second vaccine dose, slightly more so in QFT-G(+) subjects. CD4+ and CD8+ responses to Mtb antigen TB10.4 were minimal. Increases in Adenovirus 35 neutralizing antibodies from screening to end of study, seen in 50% of AERAS-402 recipients, were mostly minimal. This small study confirms acceptable safety and tolerability profiles for AERAS-402, in line with other Phase 1 studies of AERAS-402, now to include QFT-G(+) subjects.
authors.affiliation: United States Army Medical Research Unit-Kenya (USAMRU-K), Walter Reed Project, Kisumu 40100, Kenya. Electronic address: douglas.walsh@va.gov.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Walsh
authors.affiliation: United States Army Medical Research Unit-Kenya (USAMRU-K), Walter Reed Project, Kisumu 40100, Kenya.
authors.forename: Victorine
authors.initials: V
authors.lastname: Owira
authors.affiliation: United States Army Medical Research Unit-Kenya (USAMRU-K), Walter Reed Project, Kisumu 40100, Kenya.
authors.forename: Mark
authors.initials: M
authors.lastname: Polhemus
authors.affiliation: United States Army Medical Research Unit-Kenya (USAMRU-K), Walter Reed Project, Kisumu 40100, Kenya.
authors.forename: Lucas
authors.initials: L
authors.lastname: Otieno
authors.affiliation: United States Army Medical Research Unit-Kenya (USAMRU-K), Walter Reed Project, Kisumu 40100, Kenya.
authors.forename: Ben
authors.initials: B
authors.lastname: Andagalu
authors.affiliation: United States Army Medical Research Unit-Kenya (USAMRU-K), Walter Reed Project, Kisumu 40100, Kenya.
authors.forename: Bernhards
authors.initials: B
authors.lastname: Ogutu
authors.affiliation: United States Army Medical Research Unit-Kenya (USAMRU-K), Walter Reed Project, Kisumu 40100, Kenya.
authors.forename: John
authors.initials: J
authors.lastname: Waitumbi
authors.affiliation: Aeras, Observatory 7925, Cape Town, South Africa.
authors.forename: Anthony
authors.initials: A
authors.lastname: Hawkridge
authors.affiliation: Aeras, Rockville, MD 20850, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Shepherd
authors.affiliation: Crucell Holland B.V., 2333 CN Leiden, The Netherlands(5).
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Pau
authors.affiliation: Crucell Holland B.V., 2333 CN Leiden, The Netherlands(5).
authors.forename: Jerald
authors.initials: J
authors.lastname: Sadoff
authors.affiliation: Crucell Holland B.V., 2333 CN Leiden, The Netherlands(5).
authors.forename: Macaya
authors.initials: M
authors.lastname: Douoguih
authors.affiliation: Aeras, Rockville, MD 20850, USA.
authors.forename: J Bruce
authors.initials: JB
authors.lastname: McClain
mesh_terms: D000217:Acyltransferases / Q000276:immunology; D000328:Adult; D000907:Antibodies, Bacterial / Q000097:blood*; D057134:Antibodies, Neutralizing / Q000097:blood; D000942:Antigens, Bacterial / Q000276:immunology; D001500:BCG Vaccine / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D003402:Creatine Kinase / Q000097:blood; D016207:Cytokines / Q000276:immunology; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D000071497:Immunogenicity, Vaccine; D007371:Interferon-gamma / Q000276:immunology; D007630:Kenya / Q000453:epidemiology; D055985:Latent Tuberculosis / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D009503:Neutropenia / Q000209:etiology; D014376:Tuberculosis / Q000453:epidemiology / Q000517:prevention & control; D032581:Tuberculosis Vaccines / Q000009:adverse effects* / Q000276:immunology*; D014611:Vaccination; D019444:Vaccines, DNA; D055815:Young Adult
chemical_list: C000592463:AERAS-402; D000907:Antibodies, Bacterial; D057134:Antibodies, Neutralizing; D000942:Antigens, Bacterial; D001500:BCG Vaccine; D001426:Bacterial Proteins; D016207:Cytokines; D032581:Tuberculosis Vaccines; D019444:Vaccines, DNA; D007371:Interferon-gamma; D000217:Acyltransferases; C112580:antigen 85A, Mycobacterium tuberculosis; C121433:antigen 85B, Mycobacterium tuberculosis; D003402:Creatine Kinase
keywords: AERAS-402; Adenovirus-vectored; Immunity; Safety; Tuberculosis; Vaccine