Recombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humans

Abstract

Protective immunity against Mycobacterium tuberculosis depends on the generation of a T(H)1-type cellular immune response, characterized by the secretion of interferon-gamma (IFN-gamma) from antigen-specific T cells. The induction of potent cellular immune responses by vaccination in humans has proven difficult. Recombinant viral vectors, especially poxviruses and adenoviruses, are particularly effective at boosting previously primed CD4(+) and CD8(+) T-cell responses against a number of intracellular pathogens in animal studies. In the first phase 1 study of any candidate subunit vaccine against tuberculosis, recombinant modified vaccinia virus Ankara (MVA) expressing antigen 85A (MVA85A) was found to induce high levels of antigen-specific IFN-gamma-secreting T cells when used alone in bacille Calmette-Guerin (BCG)-naive healthy volunteers. In volunteers who had been vaccinated 0.5-38 years previously with BCG, substantially higher levels of antigen-specific IFN-gamma-secreting T cells were induced, and at 24 weeks after vaccination these levels were 5-30 times greater than in vaccinees administered a single BCG vaccination. Boosting vaccinations with MVA85A could offer a practical and efficient strategy for enhancing and prolonging antimycobacterial immunity in tuberculosis-endemic areas.

Immunisation with recombinant modified vaccinia virus Ankara expressing HIV‐1 gag in HIV‐1‐infected subjects stimulates broad functional CD4+ T cell responses

“…Here, we have shown that these augmented responses were directed not only at epitopes known to be frequently targeted by HIV-1-infected persons but also new epitopes that were also recognised by HIV-uninfected subjects given this vaccine [24,25]. While there is now substantial evidence that MVAvectored vaccines expressing antigens from pathogens other than HIV-1 can efficiently expand primed CD4 + T cells in HIV-uninfected human subjects [25,34,35], our data suggest that MVA.HIVA vaccination can stimulate HIV-1-specific T helper responses to a greater array of epitopes than those targeted by CD4 + T cells during chronic infection. In contrast, in earlier studies involving therapeutic vaccinations with an MVA vaccine expressing the HIV-1 nef gene, cellular responses to nef epitopes were boosted by immunisation but generated conflicting results with regard to amplification of T helper responses [36,37].…”

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

“…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). Our results are promising, since studies in mouse models showed that induction of polyfunctional T cells correlated with protection against tuberculosis (1,19) and that assessment in humans of T-cell polyfunctionality might allow more accurate identification of a protective T-cell population (9).…”

Mycobacterial Lipopeptides Elicit CD4+ CTLs in Mycobacterium tuberculosis-Infected Humans

“…Two vaccines improved classical BCG by inserting the secreted mycobacterial Ag85B (6) or by inserting listeriolysin to facilitate the escape of the bacilli from the phagosome into the cytoplasm (7). Another strategy follows the idea that secreted mycobacterial Ags from the Ag85 complex will induce protective memory T lymphocytes when given as fusion proteins (8 -10) or if expressed in a modified vaccinia virus Ankara (11). Even though the development of these vaccines is far advanced, it will take years until results on the efficacy in field trials will become available.…”