Safety and Immunogenicity of Adenovirus 35 Tuberculosis Vaccine Candidate in Adults with Active or Previous Tuberculosis. A Randomized Trial.

Abstract

RATIONALE:

Administration of tuberculosis (TB) vaccines in participants with previous or current pulmonary TB may have the potential for causing harmful postvaccination immunologic (Koch-type) reactions.

OBJECTIVES:

To assess the safety and immunogenicity of three dose levels of the AERAS-402 live, replication-deficient adenovirus 35-vectored TB candidate vaccine, containing three mycobacterial antigens, in individuals with current or previous pulmonary TB.

METHODS:

We performed a phase II randomized, placebo-controlled, double-blinded dose-escalation study in an HIV-negative adult South African cohort (n = 72) with active pulmonary TB (on treatment for 1-4 mo) or pulmonary TB treated at least 12 months before study entry and considered cured. Safety endpoints included clinical assessment, flow volume curves, diffusing capacity of the lung for carbon monoxide, pulse oximetry, chest radiograph, and high-resolution thoracic computerized tomography scans. Cytokine expression by CD4 and CD8 T cells, after stimulation with Ag85A, Ag85B, and TB10.4 peptide pools, was examined by intracellular cytokine staining.

MEASUREMENTS AND MAIN RESULTS:

No apparent temporal or dose-related changes in clinical status (specifically acute, Koch phenomenon-like reactions), lung function, or radiology attributable to vaccine were observed. Injection site reactions were mild or moderate. Hematuria (by dipstick only) occurred in 25 (41%) of 61 AERAS-402 recipients and 3 (27%) of 11 placebo recipients, although no gross hematuria was reported. AERAS-402 induced robust CD8+ and moderate CD4+ T-cell responses, mainly to Ag85B in both vaccine groups.

CONCLUSIONS:

Administration of the AERAS-402 candidate TB vaccine to participants with current or previous pulmonary TB induced a robust immune response and is not associated with clinically significant pulmonary complications. Clinical trial registered with www.clinicaltrials.gov (NCT 02414828) and in the South African National Clinical Trials Register ( www.sanctr.gov.za DOH 27-0808-2060).

• Authors: Richard N van Zyl-Smit, Aliasgar Esmail, Mary E Bateman, Rodney Dawson, Jonathan Goldin, Eva van Rikxoort, Macaya Douoguih, Maria Grazia Pau, Jerald C Sadoff, J Bruce McClain, Margaret Ann Snowden, Jacqueline Benko, David A Hokey, Kathryn Tucker Rutkowski, Andrew Graves, Barbara Shepherd, Sadritdin Ishmukhamedov, Benjamin M N Kagina, Brian Abel, Willem A Hanekom, Thomas J Scriba, Eric D Bateman
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 195 Issue 9 Pg. 1171-1180 (05 01 2017) ISSN: 1535-4970 [Electronic] United States
• PMID: 28060545 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial)

Chemical References

• AERAS-402
• Cytokines
• Tuberculosis Vaccines
• Vaccines, Attenuated
• Vaccines, DNA
• Vaccines, Synthetic

Topics

• Adenoviridae
• Adult
• Cytokines (metabolism)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Female
• Humans
• Lung (diagnostic imaging)
• Lung Volume Measurements
• Male
• Middle Aged
• Oximetry
• Radiography, Thoracic
• Tomography, X-Ray Computed
• Tuberculosis Vaccines (administration & dosage, adverse effects, immunology, therapeutic use)
• Tuberculosis, Pulmonary (diagnostic imaging, immunology, therapy)
• Vaccines, Attenuated (adverse effects, immunology, therapeutic use)
• Vaccines, DNA
• Vaccines, Synthetic
• Young Adult