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A Phase I Randomized Therapeutic MVA-B Vaccination Improves the Magnitude and Quality of the T Cell Immune Responses in HIV-1-Infected Subjects on HAART.

Gómez CE, Perdiguero B, García-Arriaza J, Cepeda V, Sánchez-Sorzano CÓ, Mothe B, Jiménez JL, Muñoz-Fernández MÁ, Gatell JM, López Bernaldo de Quirós JC, Brander C, García F, Esteban M - PLoS ONE (2015)

Bottom Line: MVA-B vaccine induced newly detected HIV-1-specific CD4 T cell responses and expanded pre-existing responses (mostly against Gag, Pol and Nef antigens) that were high in magnitude, broadly directed and showed an enhanced polyfunctionality with a T effector memory (TEM) phenotype, while maintaining the magnitude and quality of the pre-existing HIV-1-specific CD8 T cell responses.In addition, vaccination also triggered preferential CD8+ T cell polyfunctional responses to the MVA vector antigens that increase in magnitude after two and three booster doses.MVA-B vaccination represents a feasible strategy to improve T cell responses in individuals with pre-existing HIV-1-specific immunity.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.

ABSTRACT

Trial design: Previous studies suggested that poxvirus-based vaccines might be instrumental in the therapeutic HIV field. A phase I clinical trial was conducted in HIV-1-infected patients on highly active antiretroviral therapy (HAART), with CD4 T cell counts above 450 cells/mm3 and undetectable viremia. Thirty participants were randomized (2:1) to receive either 3 intramuscular injections of MVA-B vaccine (coding for clade B HIV-1 Env, Gag, Pol and Nef antigens) or placebo, followed by interruption of HAART.

Methods: The magnitude, breadth, quality and phenotype of the HIV-1-specific T cell response were assayed by intracellular cytokine staining (ICS) in 22 volunteers pre- and post-vaccination.

Results: MVA-B vaccine induced newly detected HIV-1-specific CD4 T cell responses and expanded pre-existing responses (mostly against Gag, Pol and Nef antigens) that were high in magnitude, broadly directed and showed an enhanced polyfunctionality with a T effector memory (TEM) phenotype, while maintaining the magnitude and quality of the pre-existing HIV-1-specific CD8 T cell responses. In addition, vaccination also triggered preferential CD8+ T cell polyfunctional responses to the MVA vector antigens that increase in magnitude after two and three booster doses.

Conclusion: MVA-B vaccination represents a feasible strategy to improve T cell responses in individuals with pre-existing HIV-1-specific immunity.

Trial registration: ClinicalTrials.gov NCT01571466.

No MeSH data available.


Related in: MedlinePlus

Functional profile of HIV-1-specific CD8 T cells.Frequencies of HIV-1-specific CD8 T cells (directed against Env+Gag+GPN) that mobilize CD107a and/or express IFN-γ and/or IL-2 and/or TNF-α in vaccinated (A) or placebo (B) groups before vaccination (W0), after two (W6) or three (W18) MVA-B or placebo doses or at time of HAART interruption (W24). All the combinations of the different functions contributing to the overall HIV-1-specific responses are shown on the x axis, whereas the percentages of the functionally distinct cell populations within cytokine-producing CD8+ T cells are shown on the y axis. Responses are grouped and color-coded on the basis of the number of functions. The boxes correspond to the individual data points and IQR at the different time points. The pie charts show the average proportion of the HIV-1-specific CD8 T cell responses according to the functions. Comparison of distributions was performed using a Student's T test and a partial permutation test as described [20]. All data are background-subtracted.
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pone.0141456.g006: Functional profile of HIV-1-specific CD8 T cells.Frequencies of HIV-1-specific CD8 T cells (directed against Env+Gag+GPN) that mobilize CD107a and/or express IFN-γ and/or IL-2 and/or TNF-α in vaccinated (A) or placebo (B) groups before vaccination (W0), after two (W6) or three (W18) MVA-B or placebo doses or at time of HAART interruption (W24). All the combinations of the different functions contributing to the overall HIV-1-specific responses are shown on the x axis, whereas the percentages of the functionally distinct cell populations within cytokine-producing CD8+ T cells are shown on the y axis. Responses are grouped and color-coded on the basis of the number of functions. The boxes correspond to the individual data points and IQR at the different time points. The pie charts show the average proportion of the HIV-1-specific CD8 T cell responses according to the functions. Comparison of distributions was performed using a Student's T test and a partial permutation test as described [20]. All data are background-subtracted.

Mentions: The functional and phenotypic profiles of HIV-1-specific CD4 and CD8 T cell responses were analyzed pre- and post-vaccination by polychromatic ICS assay. For functional analyses, we quantified the intracellular production of IFN-γ, IL-2 and TNF-α by HIV-1 Env-, Gag- and GPN-specific CD4 T cells and additionally evaluated the surface mobilization of CD107a by MVA-B immunogen-specific CD8 T cells. Pre-existing HIV-1-specific T cell responses were highly polyfunctional in both vaccinee and placebo groups, with more than 40% of the CD4 T cells and 60% of the CD8 T cells in the vaccinee group exhibiting at least two effector functions (Figs 5 and 6). Still, MVA-B immunization improved the functional profile of the HIV-1-specific CD4 T cells by further increasing the frequencies of T cells secreting simultaneously IFN-γ+IL-2+TNF-α (Fig 5A). Furthermore, MVA-B vaccination induced an increase in the frequencies of HIV-1-specific CD8 T cells secreting simultaneously CD107a+IFN-γ+TNF-α (Fig 6A). In the placebo arm, the functional profile of the HIV-1-specific CD4 and CD8 T cells was the same at pre- and post-vaccination times (Figs 5B and 6B).


A Phase I Randomized Therapeutic MVA-B Vaccination Improves the Magnitude and Quality of the T Cell Immune Responses in HIV-1-Infected Subjects on HAART.

Gómez CE, Perdiguero B, García-Arriaza J, Cepeda V, Sánchez-Sorzano CÓ, Mothe B, Jiménez JL, Muñoz-Fernández MÁ, Gatell JM, López Bernaldo de Quirós JC, Brander C, García F, Esteban M - PLoS ONE (2015)

Functional profile of HIV-1-specific CD8 T cells.Frequencies of HIV-1-specific CD8 T cells (directed against Env+Gag+GPN) that mobilize CD107a and/or express IFN-γ and/or IL-2 and/or TNF-α in vaccinated (A) or placebo (B) groups before vaccination (W0), after two (W6) or three (W18) MVA-B or placebo doses or at time of HAART interruption (W24). All the combinations of the different functions contributing to the overall HIV-1-specific responses are shown on the x axis, whereas the percentages of the functionally distinct cell populations within cytokine-producing CD8+ T cells are shown on the y axis. Responses are grouped and color-coded on the basis of the number of functions. The boxes correspond to the individual data points and IQR at the different time points. The pie charts show the average proportion of the HIV-1-specific CD8 T cell responses according to the functions. Comparison of distributions was performed using a Student's T test and a partial permutation test as described [20]. All data are background-subtracted.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4636254&req=5

pone.0141456.g006: Functional profile of HIV-1-specific CD8 T cells.Frequencies of HIV-1-specific CD8 T cells (directed against Env+Gag+GPN) that mobilize CD107a and/or express IFN-γ and/or IL-2 and/or TNF-α in vaccinated (A) or placebo (B) groups before vaccination (W0), after two (W6) or three (W18) MVA-B or placebo doses or at time of HAART interruption (W24). All the combinations of the different functions contributing to the overall HIV-1-specific responses are shown on the x axis, whereas the percentages of the functionally distinct cell populations within cytokine-producing CD8+ T cells are shown on the y axis. Responses are grouped and color-coded on the basis of the number of functions. The boxes correspond to the individual data points and IQR at the different time points. The pie charts show the average proportion of the HIV-1-specific CD8 T cell responses according to the functions. Comparison of distributions was performed using a Student's T test and a partial permutation test as described [20]. All data are background-subtracted.
Mentions: The functional and phenotypic profiles of HIV-1-specific CD4 and CD8 T cell responses were analyzed pre- and post-vaccination by polychromatic ICS assay. For functional analyses, we quantified the intracellular production of IFN-γ, IL-2 and TNF-α by HIV-1 Env-, Gag- and GPN-specific CD4 T cells and additionally evaluated the surface mobilization of CD107a by MVA-B immunogen-specific CD8 T cells. Pre-existing HIV-1-specific T cell responses were highly polyfunctional in both vaccinee and placebo groups, with more than 40% of the CD4 T cells and 60% of the CD8 T cells in the vaccinee group exhibiting at least two effector functions (Figs 5 and 6). Still, MVA-B immunization improved the functional profile of the HIV-1-specific CD4 T cells by further increasing the frequencies of T cells secreting simultaneously IFN-γ+IL-2+TNF-α (Fig 5A). Furthermore, MVA-B vaccination induced an increase in the frequencies of HIV-1-specific CD8 T cells secreting simultaneously CD107a+IFN-γ+TNF-α (Fig 6A). In the placebo arm, the functional profile of the HIV-1-specific CD4 and CD8 T cells was the same at pre- and post-vaccination times (Figs 5B and 6B).

Bottom Line: MVA-B vaccine induced newly detected HIV-1-specific CD4 T cell responses and expanded pre-existing responses (mostly against Gag, Pol and Nef antigens) that were high in magnitude, broadly directed and showed an enhanced polyfunctionality with a T effector memory (TEM) phenotype, while maintaining the magnitude and quality of the pre-existing HIV-1-specific CD8 T cell responses.In addition, vaccination also triggered preferential CD8+ T cell polyfunctional responses to the MVA vector antigens that increase in magnitude after two and three booster doses.MVA-B vaccination represents a feasible strategy to improve T cell responses in individuals with pre-existing HIV-1-specific immunity.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.

ABSTRACT

Trial design: Previous studies suggested that poxvirus-based vaccines might be instrumental in the therapeutic HIV field. A phase I clinical trial was conducted in HIV-1-infected patients on highly active antiretroviral therapy (HAART), with CD4 T cell counts above 450 cells/mm3 and undetectable viremia. Thirty participants were randomized (2:1) to receive either 3 intramuscular injections of MVA-B vaccine (coding for clade B HIV-1 Env, Gag, Pol and Nef antigens) or placebo, followed by interruption of HAART.

Methods: The magnitude, breadth, quality and phenotype of the HIV-1-specific T cell response were assayed by intracellular cytokine staining (ICS) in 22 volunteers pre- and post-vaccination.

Results: MVA-B vaccine induced newly detected HIV-1-specific CD4 T cell responses and expanded pre-existing responses (mostly against Gag, Pol and Nef antigens) that were high in magnitude, broadly directed and showed an enhanced polyfunctionality with a T effector memory (TEM) phenotype, while maintaining the magnitude and quality of the pre-existing HIV-1-specific CD8 T cell responses. In addition, vaccination also triggered preferential CD8+ T cell polyfunctional responses to the MVA vector antigens that increase in magnitude after two and three booster doses.

Conclusion: MVA-B vaccination represents a feasible strategy to improve T cell responses in individuals with pre-existing HIV-1-specific immunity.

Trial registration: ClinicalTrials.gov NCT01571466.

No MeSH data available.


Related in: MedlinePlus