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Vaccination with Ad5 vectors expands Ad5-specific CD8 T cells without altering memory phenotype or functionality.

Hutnick NA, Carnathan DG, Dubey SA, Cox KS, Kierstead L, Makadonas G, Ratcliffe SJ, Lasaro MO, Robertson MN, Casimiro DR, Ertl HC, Betts MR - PLoS ONE (2010)

Bottom Line: Adenoviral (Ad) vaccine vectors represent both a vehicle to present a novel antigen to the immune system as well as restimulation of immune responses against the Ad vector itself.Peripheral blood Ad5-specific CD8(+) T-cell numbers expanded after Ad5-HIV vaccination in all subjects, but differential expansion kinetics were noted in some baseline Ad5-neutralizing antibody (Ad5 nAb) seronegative subjects compared to baseline Ad5 nAb seropositive subjects.These data indicate that repeat Ad5-vector administration in humans expands Ad5-specific CD8(+) T-cells without overtly affecting their functional capacity or phenotypic properties.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Center for AIDS Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.

ABSTRACT

Background: Adenoviral (Ad) vaccine vectors represent both a vehicle to present a novel antigen to the immune system as well as restimulation of immune responses against the Ad vector itself. To what degree Ad-specific CD8(+) T cells are restimulated by Ad vector vaccination is unclear, although such knowledge would be important as vector-specific CD8(+) T cell expansion could potentially further limit Ad vaccine efficacy beyond Ad-specific neutralizing antibody alone.

Methodology/principal findings: Here we addressed this issue by measuring human Adenovirus serotype 5 (Ad5)-specific CD8(+) T cells in recipients of the Merck Ad5 HIV-1 vaccine vector before, during, and after vaccination by multicolor flow cytometry. Ad5-specific CD8(+) T-cells were detectable in 95% of subjects prior to vaccination, and displayed primarily an effector-type functional profile and phenotype. Peripheral blood Ad5-specific CD8(+) T-cell numbers expanded after Ad5-HIV vaccination in all subjects, but differential expansion kinetics were noted in some baseline Ad5-neutralizing antibody (Ad5 nAb) seronegative subjects compared to baseline Ad5 nAb seropositive subjects. However, in neither group did vaccination alter polyfunctionality, mucosal targeting marker expression, or memory phenotype of Ad5-specific CD8(+) T-cells.

Conclusions: These data indicate that repeat Ad5-vector administration in humans expands Ad5-specific CD8(+) T-cells without overtly affecting their functional capacity or phenotypic properties. This is a secondary analysis of samples collected during the 016 trial. Results of the Merck 016 trial safety and immunogenicity have been previously published in the journal of clinical infectious diseases [1].

Trial registration: ClinicalTrials.gov NCT00849680[http://www.clinicaltrials.gov/show/NCT00849680].

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Ad-specific CD8+ T-cells magnitude following vaccination.Five seronegative (Ad5 nAb titer ≤18, grey circles) and five seropositive subjects (Ad5 nAb titer >18, white circles) received Merck Ad5 gag/pol/nef as described in Methods. CD8+ T-cell responses were measured by flow cytometry following whole Ad5 vector stimulation. Black lines recommend the mean. Grey asterics represent a significant increase from baseline in seronegative subjects and black asterics represent a significant difference from baseline in seropositive subjects. Black bars represent a significant difference between the serogroups at that time point. A) Percentage of Ad-specific CD8+ T-cells. Seronegative subjects were significantly increased above baseline at week 8 (p<0.03), 26 (p<0.03), 42 (p<0.001), 52 (p<0.01), and 78 (p<0.001). Total Ad-specific CD8+ T-cells were increased above baseline in seropositive subjects at week 4 (p<0.0001), 8 (p<0.03), 30 (p<0.02), and 42 (p<0.04). Serogroups significantly differed at week 42 (p<0.02), 52 (p<0.01), and 78 (p<0.003). B) Percentage of Ad-specific Ki67+ CD8+ T-cells. C) Percentage of Ki67+ CD8+ T-cells. There was a significant increase above baseline in seronegative subjects at week 4 (p<0.01) and serpositive subjects at week 52 (p<0.12).
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pone-0014385-g002: Ad-specific CD8+ T-cells magnitude following vaccination.Five seronegative (Ad5 nAb titer ≤18, grey circles) and five seropositive subjects (Ad5 nAb titer >18, white circles) received Merck Ad5 gag/pol/nef as described in Methods. CD8+ T-cell responses were measured by flow cytometry following whole Ad5 vector stimulation. Black lines recommend the mean. Grey asterics represent a significant increase from baseline in seronegative subjects and black asterics represent a significant difference from baseline in seropositive subjects. Black bars represent a significant difference between the serogroups at that time point. A) Percentage of Ad-specific CD8+ T-cells. Seronegative subjects were significantly increased above baseline at week 8 (p<0.03), 26 (p<0.03), 42 (p<0.001), 52 (p<0.01), and 78 (p<0.001). Total Ad-specific CD8+ T-cells were increased above baseline in seropositive subjects at week 4 (p<0.0001), 8 (p<0.03), 30 (p<0.02), and 42 (p<0.04). Serogroups significantly differed at week 42 (p<0.02), 52 (p<0.01), and 78 (p<0.003). B) Percentage of Ad-specific Ki67+ CD8+ T-cells. C) Percentage of Ki67+ CD8+ T-cells. There was a significant increase above baseline in seronegative subjects at week 4 (p<0.01) and serpositive subjects at week 52 (p<0.12).

Mentions: We next examined the effect of Ad5 vector administration on the pre-existing Ad5-specific CD8+ T-cell response. After the initial vaccine administration, frequencies of Ad5-specific CD8+ T-cells in blood increased significantly above pre-vaccination frequencies in baseline Ad5 seropositive (p<0.0001) but not in baseline seronegative subjects as a group (Fig. 2A). On an individual basis, frequencies of Ad5-specific CD8+ T-cells increased in three of five seronegative subjects following the initial dose (data not shown). The remaining two seronegative subjects without Ad5-specific CD8+ T-cell expansion had large baseline responses.


Vaccination with Ad5 vectors expands Ad5-specific CD8 T cells without altering memory phenotype or functionality.

Hutnick NA, Carnathan DG, Dubey SA, Cox KS, Kierstead L, Makadonas G, Ratcliffe SJ, Lasaro MO, Robertson MN, Casimiro DR, Ertl HC, Betts MR - PLoS ONE (2010)

Ad-specific CD8+ T-cells magnitude following vaccination.Five seronegative (Ad5 nAb titer ≤18, grey circles) and five seropositive subjects (Ad5 nAb titer >18, white circles) received Merck Ad5 gag/pol/nef as described in Methods. CD8+ T-cell responses were measured by flow cytometry following whole Ad5 vector stimulation. Black lines recommend the mean. Grey asterics represent a significant increase from baseline in seronegative subjects and black asterics represent a significant difference from baseline in seropositive subjects. Black bars represent a significant difference between the serogroups at that time point. A) Percentage of Ad-specific CD8+ T-cells. Seronegative subjects were significantly increased above baseline at week 8 (p<0.03), 26 (p<0.03), 42 (p<0.001), 52 (p<0.01), and 78 (p<0.001). Total Ad-specific CD8+ T-cells were increased above baseline in seropositive subjects at week 4 (p<0.0001), 8 (p<0.03), 30 (p<0.02), and 42 (p<0.04). Serogroups significantly differed at week 42 (p<0.02), 52 (p<0.01), and 78 (p<0.003). B) Percentage of Ad-specific Ki67+ CD8+ T-cells. C) Percentage of Ki67+ CD8+ T-cells. There was a significant increase above baseline in seronegative subjects at week 4 (p<0.01) and serpositive subjects at week 52 (p<0.12).
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pone-0014385-g002: Ad-specific CD8+ T-cells magnitude following vaccination.Five seronegative (Ad5 nAb titer ≤18, grey circles) and five seropositive subjects (Ad5 nAb titer >18, white circles) received Merck Ad5 gag/pol/nef as described in Methods. CD8+ T-cell responses were measured by flow cytometry following whole Ad5 vector stimulation. Black lines recommend the mean. Grey asterics represent a significant increase from baseline in seronegative subjects and black asterics represent a significant difference from baseline in seropositive subjects. Black bars represent a significant difference between the serogroups at that time point. A) Percentage of Ad-specific CD8+ T-cells. Seronegative subjects were significantly increased above baseline at week 8 (p<0.03), 26 (p<0.03), 42 (p<0.001), 52 (p<0.01), and 78 (p<0.001). Total Ad-specific CD8+ T-cells were increased above baseline in seropositive subjects at week 4 (p<0.0001), 8 (p<0.03), 30 (p<0.02), and 42 (p<0.04). Serogroups significantly differed at week 42 (p<0.02), 52 (p<0.01), and 78 (p<0.003). B) Percentage of Ad-specific Ki67+ CD8+ T-cells. C) Percentage of Ki67+ CD8+ T-cells. There was a significant increase above baseline in seronegative subjects at week 4 (p<0.01) and serpositive subjects at week 52 (p<0.12).
Mentions: We next examined the effect of Ad5 vector administration on the pre-existing Ad5-specific CD8+ T-cell response. After the initial vaccine administration, frequencies of Ad5-specific CD8+ T-cells in blood increased significantly above pre-vaccination frequencies in baseline Ad5 seropositive (p<0.0001) but not in baseline seronegative subjects as a group (Fig. 2A). On an individual basis, frequencies of Ad5-specific CD8+ T-cells increased in three of five seronegative subjects following the initial dose (data not shown). The remaining two seronegative subjects without Ad5-specific CD8+ T-cell expansion had large baseline responses.

Bottom Line: Adenoviral (Ad) vaccine vectors represent both a vehicle to present a novel antigen to the immune system as well as restimulation of immune responses against the Ad vector itself.Peripheral blood Ad5-specific CD8(+) T-cell numbers expanded after Ad5-HIV vaccination in all subjects, but differential expansion kinetics were noted in some baseline Ad5-neutralizing antibody (Ad5 nAb) seronegative subjects compared to baseline Ad5 nAb seropositive subjects.These data indicate that repeat Ad5-vector administration in humans expands Ad5-specific CD8(+) T-cells without overtly affecting their functional capacity or phenotypic properties.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Center for AIDS Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.

ABSTRACT

Background: Adenoviral (Ad) vaccine vectors represent both a vehicle to present a novel antigen to the immune system as well as restimulation of immune responses against the Ad vector itself. To what degree Ad-specific CD8(+) T cells are restimulated by Ad vector vaccination is unclear, although such knowledge would be important as vector-specific CD8(+) T cell expansion could potentially further limit Ad vaccine efficacy beyond Ad-specific neutralizing antibody alone.

Methodology/principal findings: Here we addressed this issue by measuring human Adenovirus serotype 5 (Ad5)-specific CD8(+) T cells in recipients of the Merck Ad5 HIV-1 vaccine vector before, during, and after vaccination by multicolor flow cytometry. Ad5-specific CD8(+) T-cells were detectable in 95% of subjects prior to vaccination, and displayed primarily an effector-type functional profile and phenotype. Peripheral blood Ad5-specific CD8(+) T-cell numbers expanded after Ad5-HIV vaccination in all subjects, but differential expansion kinetics were noted in some baseline Ad5-neutralizing antibody (Ad5 nAb) seronegative subjects compared to baseline Ad5 nAb seropositive subjects. However, in neither group did vaccination alter polyfunctionality, mucosal targeting marker expression, or memory phenotype of Ad5-specific CD8(+) T-cells.

Conclusions: These data indicate that repeat Ad5-vector administration in humans expands Ad5-specific CD8(+) T-cells without overtly affecting their functional capacity or phenotypic properties. This is a secondary analysis of samples collected during the 016 trial. Results of the Merck 016 trial safety and immunogenicity have been previously published in the journal of clinical infectious diseases [1].

Trial registration: ClinicalTrials.gov NCT00849680[http://www.clinicaltrials.gov/show/NCT00849680].

Show MeSH
Related in: MedlinePlus