Article

The HIV/AIDS Vaccine Candidate MVA-B Administered as a Single Immunogen in Humans Triggers Robust, Polyfunctional, and Selective Effector Memory T Cell Responses to HIV-1 Antigens

Centro Nacional de Biotecnología, CSIC, Madrid 28049, Spain.
Journal of Virology (Impact Factor: 4.44). 08/2011; 85(21):11468-78. DOI: 10.1128/JVI.05165-11
Source: PubMed

ABSTRACT

Attenuated poxvirus vectors expressing human immunodeficiency virus type 1 (HIV-1) antigens are considered promising HIV/AIDS vaccine candidates. Here, we describe the nature of T cell immune responses induced in healthy volunteers participating in a phase I clinical trial in Spain after intramuscular administration of three doses of the recombinant MVA-B-expressing monomeric gp120 and the fused Gag-Pol-Nef (GPN) polyprotein of clade B. The majority (92.3%) of the volunteers immunized had a positive specific T cell response at any time postvaccination as detected by gamma interferon (IFN-γ) intracellular cytokine staining (ICS) assay. The CD4(+) T cell responses were predominantly Env directed, whereas the CD8(+) T cell responses were similarly distributed against Env, Gag, and GPN. The proportion of responders after two doses of MVA-B was similar to that obtained after the third dose of MVA-B vaccination, and the responses were sustained (84.6% at week 48). Vaccine-induced CD8(+) T cells to HIV-1 antigens after 1 year were polyfunctional and distributed mainly within the effector memory (TEM) and terminally differentiated effector memory (TEMRA) T cell populations. Antivector T cell responses were mostly induced by CD8(+) T cells, highly polyfunctional, and of TEMRA phenotype. These findings demonstrate that the poxvirus MVA-B vaccine candidate given alone is highly immunogenic, inducing broad, polyfunctional, and long-lasting CD4 and CD8 T cell responses to HIV-1 antigens, with preference for TEM. Thus, on the basis of the immune profile of MVA-B in humans, this immunogen can be considered a promising HIV/AIDS vaccine candidate.

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Available from: Carmen Elena Gomez
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    • "[18]. Based on all these previous results, MVA-B entered in a phase I clinical trial (RISVAC02) in 30 human healthy volunteers in Spain and the results showed that MVA-B was safe, well tolerated and highly immunogenic, inducing broad, polyfunctional and long-lasting CD4+ and CD8+ T cell responses to HIV-1 antigens, with preference for effector memory T cells; and also induced antibody responses to Env in 95% of volunteers [19], [20]. "
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    ABSTRACT: Poxvirus vector Modified Vaccinia Virus Ankara (MVA) expressing HIV-1 Env, Gag, Pol and Nef antigens from clade B (termed MVA-B) is a promising HIV/AIDS vaccine candidate, as confirmed from results obtained in a prophylactic phase I clinical trial in humans. To improve the immunogenicity elicited by MVA-B, we have generated and characterized the innate immune sensing and the in vivo immunogenicity profile of a vector with a double deletion in two vaccinia virus (VACV) genes (C6L and K7R) coding for inhibitors of interferon (IFN) signaling pathways. The innate immune signals elicited by MVA-B deletion mutants (MVA-B ΔC6L and MVA-B ΔC6L/K7R) in human macrophages and monocyte-derived dendritic cells (moDCs) showed an up-regulation of the expression of IFN-β, IFN-α/β-inducible genes, TNF-α, and other cytokines and chemokines. A DNA prime/MVA boost immunization protocol in mice revealed that these MVA-B deletion mutants were able to improve the magnitude and quality of HIV-1-specific CD4(+) and CD8(+) T cell adaptive and memory immune responses, which were mostly mediated by CD8(+) T cells of an effector phenotype, with MVA-B ΔC6L/K7R being the most immunogenic virus recombinant. CD4(+) T cell responses were mainly directed against Env, while GPN-specific CD8(+) T cell responses were induced preferentially by the MVA-B deletion mutants. Furthermore, antibody levels to Env in the memory phase were slightly enhanced by the MVA-B deletion mutants compared to the parental MVA-B. These findings revealed that double deletion of VACV genes that act blocking intracellularly the IFN signaling pathway confers an immunological benefit, inducing innate immune responses and increases in the magnitude, quality and durability of the HIV-1-specific T cell immune responses. Our observations highlighted the immunomodulatory role of the VACV genes C6L and K7R, and that targeting common pathways, like IRF3/IFN-β signaling, could be a general strategy to improve the immunogenicity of poxvirus-based vaccine candidates.
    Full-text · Article · Jun 2013 · PLoS ONE
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    • "Another finding of our study was that the number of dextramer stained CD8+ T cells producing IFN-γ, TNF-α or the surface marker CD107a found in animals primed with Flu-M-ASP2 were approximately three times higher than those observed in other vaccinated groups. However, while the role of different T cell subpopulation to control the infection with some viruses, bacteria and Plasmodium was already well documented [47], [48], [49], [50], the biological relevance of CD8+ T cells subpopulations phenotypes to control the infection with T. cruzi remains elusive [51]. The IFN-γ production itself is known to be important for protection against Trypanosoma cruzi infection in many previous work of our and other groups [14], [52], [53], [54], [55]. "
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    ABSTRACT: In the present study we evaluated the protection raised by immunization with recombinant influenza viruses carrying sequences coding for polypeptides corresponding to medial and carboxi-terminal moieties of Trypanosoma cruzis amastigote surface protein 2 (ASP2). Those viruses were used in sequential immunization with recombinant adenovirus (heterologous prime-boost immunization protocol) encoding the complete sequence of ASP2 (Ad-ASP2) in two mouse strains (C57BL/6 and C3H/He). The CD8 effector response elicited by this protocol was comparable to that observed in mice immunized twice with Ad-ASP2 and more robust than that observed in mice that were immunized once with Ad-ASP2. Whereas a single immunization with Ad-ASP2 sufficed to completely protect C57BL/6 mice, a higher survival rate was observed in C3H/He mice that were primed with recombinant influenza virus and boosted with Ad-ASP2 after being challenged with T. cruzi. Analyzing the phenotype of CD8+ T cells obtained from spleen of vaccinated C3H/He mice we observed that heterologous prime-boost immunization protocol elicited more CD8+ T cells specific for the immunodominant epitope as well as a higher number of CD8+ T cells producing TNF-a and IFN-c and a higher mobilization of surface marker CD107a. Taken together, our results suggest that immunodominant subpopulations of CD8+ T elicited after immunization could be directly related to degree of protection achieved by different immunization protocols using different viral vectors. Overall, these results demonstrated the usefulness of recombinant influenza viruses in immunization protocols against Chagas Disease. Citation: Barbosa RPA, Filho BG, Santos LId, Junior PAS, Marques PE, et al. (2013) Vaccination Using Recombinants Influenza and Adenoviruses Encoding Amastigote Surface Protein-2 Are Highly Effective on Protection against Trypanosoma cruzi Infection. PLoS ONE 8(4): e61795.
    Full-text · Article · Apr 2013 · PLoS ONE
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    • "Moreover, MVA-B-infected DCs co-cultured with autologous T lymphocytes induced a highly functional HIV-1-specific CD8 + T cell responses including proliferation , secretion of different cytokines, and strong cytotoxic activity against autologous HIV-1-infected CD4 + T lymphocytes (Climent et al., 2011). Based on all these previous results, MVA-B entered in a phase I clinical trial (RISVAC02) in 30 human healthy volunteers in Spain and the results showed that MVA-B was safe, well tolerated , and highly immunogenic, inducing broad, polyfunctional, and long-lasting CD4 + and CD8 + T cell responses to HIV-1 antigens, with preference for effector memory T cells; and also induced antibody responses to Env in 95% of volunteers (Garcia et al., 2011; Gomez et al., 2011b). As a new step to move forward to support further exploration of MVA-B as an HIV-1 vaccine candidate, MVA-B is now entering into a phase I clinical trial in Spain with 30 HIV-1 infected patients on HAART, with suppressed viral replication, in order to evaluate the therapeutic benefit of this HIV/AIDS vaccine. "
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    ABSTRACT: MVA-B is an attenuated poxvirus vector expressing human immunodeficiency virus type 1 Env, Gag, Pol, and Nef antigens from clade B, and is considered a promising HIV/AIDS vaccine candidate. Recently, a phase I clinical trial in human healthy volunteers has shown that MVA-B is safe and highly immunogenic, inducing broad, polyfunctional, and long-lasting CD4(+) and CD8(+) T cell responses to HIV-1 antigens, with preference for effector memory T cells; and it also triggers the induction of specific antibodies to Env in most of the vaccines. While MVA recombinants expressing HIV-1 antigens are being used or plan to use in therapeutic clinical trials, little is known on the effect of HIV-1 highly active antiretroviral therapy in MVA life cycle. To define this role, here we have evaluated in established cell cultures and human dendritic cells to what extent different HIV-1 protease inhibitors affect virus replication and expression of HIV-1 antigens during MVA-B infection. The results obtained revealed that the most commonly used HIV-1 protease inhibitors (atazanavir, ritonavir, and lopinavir) had no effect on MVA-B virus growth kinetics, even at higher concentrations than those normally used on HAART. Furthermore, expression of gp120 and the fused Gag-Pol-Nef polyprotein in permissive and non-permissive cells infected with MVA-B were also not affected. These findings are relevant information for the therapeutic use of MVA-B as an HIV-1/AIDS vaccine.
    Full-text · Article · May 2012 · Virus Research
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