Modified vaccinia Ankara‐expressing Ag85A, a novel tuberculosis vaccine, is safe in adolescents and children, and induces polyfunctional CD4⁺ T cells

Abstract

Summary MVA85A is a new tuberculosis vaccine aimed at enhancing immunity induced by BCG. We investigated the safety and immunogenicity of MVA85A in healthy adolescents and children from a tuberculosis endemic region, who received BCG at birth. Twelve adolescents and 24 children were vaccinated and followed up for 12 or 6 months, respectively. Adverse events were documented and vaccine-induced immune responses assessed by IFN-γ ELISpot and intracellular cytokine staining. The vaccine was well tolerated and there were no vaccine-related serious adverse events. MVA85A induced potent and durable T cell responses. Multiple CD4+ T cell subsets, based on expression of IFN-γ, TNF-α, IL-2, IL-17 and GM-CSF, were induced. Polyfunctional CD4+ T cells co-expressing IFN-γ, TNF-α and IL-2 dominated the response in both age groups. A novel CD4+ cell subset co-expressing these three Th1 cytokines and IL-17 was induced in adolescents, while a novel CD4+ T cell subset co-expressing Th1 cytokines and GM-CSF was induced in children. Antigen-specific CD8+ T cells were not detected. We conclude that in adolescents and children MVA85A safely induces the type of immunity thought to be important in protection against tuberculosis. This includes induction of novel Th1 cell populations which have not been previously described in humans.

Immunological consequences of intragenus conservation ofMycobacterium tuberculosisT-cell epitopes

“…In this context, it is noteworthy that other studies also have reported reactivity to MTB-encoded antigens in HCs and NTM-infected/exposed individuals that is hypothesized to be as a result of exposure to NTMs (7,8,31). Furthermore, NTM exposure may explain the higher baseline reactivity to PPD that was found in MTB-naive young adults as compared with children (32). Other studies highlighted that the majority of small MTB-PPD reactions could be attributed to NTM exposure or disease (33).…”

Polyfunctional T cells in human tuberculosis

“…In humans, vaccination with a novel tuberculosis vaccine based on modified Vaccinia virus Ankara expressing Ag85A (MVA85A) induces T cells with complex phenotypic and polyfunctional cytokine-secreting profiles, including a less differentiated group that co-expresses IFN-g, TNF and IL-2, and with the ability to proliferate. Such cells are considered more likely than single cytokine secretors to be associated with protection [10,11]. Another novel TB vaccine, based on a recombinant replicationdeficient adenovirus (Ad35)-expressing TB antigens, also induces a robust polyfunctional CD4 1 T-cell response in adults [12].…”

Differential Cytokine Levels in Adults Induced by a Novel Candidate TB Boost Vaccine, MVA85A-According to Previous BCG Vaccination Status

“…Interestingly, in The Gambian study, the immunogenicity of MVA85A in BCG vaccinated (BCG+) and BCG naive (BCG-) adults was comparable, in contrast to studies in the UK where immunogenicity was higher in BCG vaccinated subjects [6]. Furthermore in South Africa, the immunogenicity of MVA85A in BCG vaccinated adults was also comparable to that seen in BCG naïve adults [8]. These findings suggest that MVA85A may boost cumulative mycobacterial exposure which is comprised of exposure to BCG, non-tuberculous mycobacteria and M.tb, and that the contribution of BCG to this cumulative mycobacterial exposure is less relevant in adults in TB endemic countries.…”

“…MVA85A was safe well tolerated and immunogenic when administered to adult volunteers in the UK, The Gambia and South Africa [6][7][8]. Interestingly, in The Gambian study, the immunogenicity of MVA85A in BCG vaccinated (BCG+) and BCG naive (BCG-) adults was comparable, in contrast to studies in the UK where immunogenicity was higher in BCG vaccinated subjects [6].…”