Safety and Immunogenicity of a New Tuberculosis Vaccine, MVA85A, in Mycobacterium tuberculosis–infected Individuals

Abstract

Rationale: An effective new tuberculosis (TB) vaccine regimen must be safe in individuals with latent TB infection (LTBI) and is a priority for global health care. Objectives: To evaluate the safety and immunogenicity of a leading new TB vaccine, recombinant Modified Vaccinia Ankara expressing Antigen 85A (MVA85A) in individuals with LTBI.Methods: An open-label, phase I trial of MVA85A was performed in 12 subjects with LTBI recruited from TB contact clinics in Oxford and London or by poster advertisements in Oxford hospitals. Patients were assessed clinically and had blood samples drawn for immunological analysis over a 52-week period after vaccination with MVA85A. Thoracic computed tomography scans were performed at baseline and at 10 weeks after vaccination. Safety of MVA85A was assessed by clinical, radiological, and inflammatory markers. The immunogenicity of MVA85A was assessed by IFNg and IL-2 ELISpot assays and FACS. Measurements and Main Results: MVA85A was safe in subjects with LTBI, with comparable adverse events to previous trials of MVA85A. There were no clinically significant changes in inflammatory markers or thoracic computed tomography scans after vaccination. MVA85A induced a strong antigen-specific IFN-g and IL-2 response that was durable for 52 weeks. The magnitude of IFN-g response was comparable to previous trials of MVA85A in bacillus CalmetteGuérin-vaccinated individuals. Antigen 85A-specific polyfunctional CD4 1 T cells were detectable prior to vaccination with statistically significant increases in cell numbers after vaccination. Conclusions: MVA85A is safe and highly immunogenic in individuals with LTBI. These results will facilitate further trials in TB-endemic areas. Clinical trial registered with www.clinicaltrials.gov (NCT00456183).

Induction and Regulation of T-Cell Immunity by the Novel Tuberculosis Vaccine M72/AS01 in South African Adults

“…These data thus provide compelling evidence of M72/AS01-mediated boosting of discrete T-cell populations primed by natural Mtb infection; moreover, they suggest that M72/AS01 may induce functionally distinct profiles of M72-specific T cells in Mtbinfected versus -uninfected individuals. These findings contrast with previously reported observations in a small clinical trial of adults vaccinated with MVA85A, in which no differences were found in the magnitude of Ag85A-specific IFN-g-producing T cells between Mtb-infected and BCG-vaccinated, Mtbuninfected participants after vaccination (39).…”

Evaluation of the Safety and Immunogenicity of Two Antigen Concentrations of the Mtb72F/AS02ACandidate Tuberculosis Vaccine in Purified Protein Derivative-Negative Adults

“…A role for CD8 ϩ T cells in the protection against TB has been demonstrated (15,23,27,32). Similar to results from an earlier study with Mtb72F/AS02 A (42) and studies with the MVA85a TB vaccine candidate (5,18,31), no vaccine-induced antigen-specific CD8 ϩ T cells could be detected by ICS using a short-term in vitro restimulation.…”

“…This is the first study which demonstrates the polyfunctionality of vaccine-induced CD4 ϩ T cells in PPD-negative subjects. Other studies of TB vaccine candidates have demonstrated polyfunctional CD4 ϩ T-cell responses in PPD-positive adults (2,5,18,31). Earlier work showed that the MVA85a TB vaccine candidate was immunogenic in PPD-negative British adults and that the magnitude of the IFN-␥ enzyme-linked immunospot assay response was positively influenced by BCG priming (26).…”

MTBVAC from discovery to clinical trials in tuberculosis-endemic countries

“…In general, these subunit candidates are intended to enhance preexisting immune responses to certain immunodominant antigens induced upon BCG vaccination at birth and or upon M. tuberculosis infection in BCG vaccinated individuals (infants, e.g. MVA85A vaccine trial in adolescents and adults) [35][36][37].…”