HIV-Tat immunization induces cross-clade neutralizing antibodies and CD4(+) T cell increases in antiretroviral-treated South African volunteers: a randomized phase II clinical trial

Barbara Ensoli, Maphoshane Nchabeleng, Fabrizio Ensoli, Antonella Tripiciano, Stefania Bellino, Orietta Picconi, Cecilia Sgadari, Olimpia Longo, Lara Tavoschi, Daniel Joffe, Aurelio Cafaro, Vittorio Francavilla, Sonia Moretti, Maria Rosaria Pavone Cossut, Barbara Collacchi, Angela Arancio, Giovanni Paniccia, Anna Casabianca, Mauro Magnani, Stefano Buttò, Elise Levendal, John Velaphi Ndimande, Bennett Asia, Yogan Pillay, Enrico Garaci, Paolo Monini, SMU-MeCRU study group, Barbara Ensoli, Maphoshane Nchabeleng, Fabrizio Ensoli, Antonella Tripiciano, Stefania Bellino, Orietta Picconi, Cecilia Sgadari, Olimpia Longo, Lara Tavoschi, Daniel Joffe, Aurelio Cafaro, Vittorio Francavilla, Sonia Moretti, Maria Rosaria Pavone Cossut, Barbara Collacchi, Angela Arancio, Giovanni Paniccia, Anna Casabianca, Mauro Magnani, Stefano Buttò, Elise Levendal, John Velaphi Ndimande, Bennett Asia, Yogan Pillay, Enrico Garaci, Paolo Monini, SMU-MeCRU study group

Abstract

Background: Although combined antiretroviral therapy (cART) has saved millions of lives, it is incapable of full immune reconstitution and virus eradication. The transactivator of transcription (Tat) protein is a key human immunodeficiency virus (HIV) virulence factor required for virus replication and transmission. Tat is expressed and released extracellularly by infected cells also under cART and in this form induces immune dysregulation, and promotes virus reactivation, entry and spreading. Of note, anti-Tat antibodies are rare in natural infection and, when present, correlate with asymptomatic state and reduced disease progression. This suggested that induction of anti-Tat antibodies represents a pathogenesis-driven intervention to block progression and to intensify cART. Indeed Tat-based vaccination was safe, immunogenic and capable of immune restoration in an open-label, randomized phase II clinical trial conducted in 168 cART-treated volunteers in Italy. To assess whether B-clade Tat immunization would be effective also in patients with different genetic background and infecting virus, a phase II trial was conducted in South Africa.

Methods: The ISS T-003 was a 48-week randomised, double-blinded, placebo-controlled trial to evaluate immunogenicity (primary endpoint) and safety (secondary endpoint) of B-clade Tat (30 μg) given intradermally, three times at 4-week intervals, in 200 HIV-infected adults on effective cART (randomised 1:1) with CD4(+) T-cell counts ≥200 cells/µL. Study outcomes also included cross-clade anti-Tat antibodies, neutralization, CD4(+) T-cell counts and therapy compliance.

Results: Immunization was safe and well-tolerated and induced durable, high titers anti-Tat B-clade antibodies in 97 % vaccinees. Anti-Tat antibodies were cross-clade (all vaccinees tested) and neutralized Tat-mediated entry of oligomeric B-clade and C-clade envelope in dendritic cells (24 participants tested). Anti-Tat antibody titers correlated positively with neutralization. Tat vaccination increased CD4(+) T-cell numbers (all participants tested), particularly when baseline levels were still low after years of therapy, and this had a positive correlation with HIV neutralization. Finally, in cART non-compliant patients (24 participants), vaccination contained viral load rebound and maintained CD4(+) T-cell numbers over study entry levels as compared to placebo.

Conclusions: The data indicate that Tat vaccination can restore the immune system and induces cross-clade neutralizing anti-Tat antibodies in patients with different genetic backgrounds and infecting viruses, supporting the conduct of phase III studies in South Africa. Trial registration ClinicalTrials.gov NCT01513135, 01/23/2012.

Keywords: AIDS; CD4+ T cells; Clinical trials; Cross-clade antibodies; HIV; Neutralization; Tat; Therapy intensification; Vaccine; cART.

Figures

Fig. 1
Fig. 1
CONSORT flow diagram. The number of participants screened, enrolled, randomized, followed-up and analyzed is shown for vaccine and placebo groups. Two hundred participants were randomised to one of the two treatment groups and analyzed for safety (safety population). One subject who received only one immunization was excluded from the immunogenicity population (total = 199). Thirteen volunteers were excluded from the “Per protocol” analysis: four received

Fig. 2

Anti-Tat humoral immune response elicited…

Fig. 2

Anti-Tat humoral immune response elicited in study participants. a Percentage of responders for…

Fig. 2
Anti-Tat humoral immune response elicited in study participants. a Percentage of responders for anti-Tat Abs (see “Methods” section) in vaccinees (n = 99) or placebos (n = 100). The absolute number of vaccines/placebos developing anti-Tat Ig subclasses are reported on the top of each histogram. Statistical significant differences were detected between vaccinees and placebos for each Ig and for total response (p < 0.0001, Chi square test). b Percentage of responders for anti-Tat Abs stratified according to the presence of one or more Ab isotype in vaccinees (n = 99) or placebos (n = 100). The absolute number of vaccines/placebos developing one or more Ab isotype are reported on the top of each histogram. Statistical significant differences were detected between vaccinees and placebos (p < 0.0001, Chi square test). c IgM, IgG and IgA Ab mean titers (with standard error) in responders (vaccinees: n = 79 for IgM, n = 95 for IgG and n = 75 for IgA; placebos: n = 9 for IgM, n = 12 for IgG and n = 6 for IgA). Significant differences were detected between vaccinees and placebos for anti-Tat IgG Abs from week 12 to week 48 (Student’s t test)

Fig. 3

Anti-Tat Ab durability in responders.…

Fig. 3

Anti-Tat Ab durability in responders. a Kaplan–Meier estimates showing the cumulative probability of…

Fig. 3
Anti-Tat Ab durability in responders. a Kaplan–Meier estimates showing the cumulative probability of anti-Tat Ab durability during follow-up in responders (see “Methods” section) (vaccinees: n = 96; placebos: n = 18). Anti-Tat Abs persisted significantly longer in vaccinees as compared to the placebo group (p = 0.0019, log-rank test). b Kaplan–Meier estimates showing the cumulative probability of anti-Tat Ab durability during follow-up in vaccinees (left panel) or placebo (right panel) responders, according to the number of anti-Tat Ab isotypes (vaccinees: one subclass n = 10, two or three subclasses n = 86; placebo: one subclass n = 10, two or three subclasses n = 8)

Fig. 4

Increase of cross-clades anti-Tat Abs…

Fig. 4

Increase of cross-clades anti-Tat Abs elicited in vaccinees. a Baseline OD values of…

Fig. 4
Increase of cross-clades anti-Tat Abs elicited in vaccinees. a Baseline OD values of anti-Tat IgM, IgG and IgA against clades C, D and A in vaccinees prior to immunization (n = 29, 76 % C clade, 41 % A clade, 14 % D clade). b Changes from baseline of IgM, IgG and IgA Ab responses (OD) against Tat from other clades (C, D, A) after vaccination. Testing was performed at the peak of Ab responses (between 12 and 24 weeks). Statistical analysis was performed using the Wilcoxon signed-rank test. p values assess the increase from baseline

Fig. 5

Neutralization of Tat/Env complex entry…

Fig. 5

Neutralization of Tat/Env complex entry in DC. Baseline values ( left panels )…

Fig. 5
Neutralization of Tat/Env complex entry in DC. Baseline values (left panels) and changes from baseline after immunization (right panels) of B-clade Env entry in DC in the absence (a) or presence (b) of B-clade Tat in anti-Tat Ab-positive (n = 13) vaccinees, and anti-Tat Ab-positive (n = 6) or anti-Tat Ab-negative (n = 5) placebos at week 20 and 48 from the first immunization. Reduction of Env entry in DC by sera indicates neutralization. Student’s t test was applied to evaluate the changes from baseline within and between treatment groups

Fig. 6

Neutralization of B- and C-clade…

Fig. 6

Neutralization of B- and C-clade Tat/Env complex entry in DC in vaccinees. Neutralization…

Fig. 6
Neutralization of B- and C-clade Tat/Env complex entry in DC in vaccinees. Neutralization of B- (n = 13) and C- (n = 10) clade Env entry in DC in the presence or absence of (B- or C-clade) Tat by sera of Ab-positive vaccinees, measured at week 20 or week 48 after immunization. Data are presented as mean values with standard errors. Student’s t test for paired data was used for the analyses

Fig. 7

Changes from baseline of CD4…

Fig. 7

Changes from baseline of CD4 + T-cell number in vaccinees and placebos. Baseline…

Fig. 7
Changes from baseline of CD4+ T-cell number in vaccinees and placebos. Baseline values (left panel) and changes from baseline (right panel) of CD4+ T-cell counts in vaccinees (n = 99) and placebos (n = 100). Data are presented as mean values with standard errors. Longitudinal analysis for repeated measures by the generalized estimating equations method was applied for the analysis. p values assess the changes from baseline within and between treatment groups

Fig. 8

CD4 + T-cell numbers up…

Fig. 8

CD4 + T-cell numbers up to week 48 in vaccinees and placebo stratified…

Fig. 8
CD4+ T-cell numbers up to week 48 in vaccinees and placebo stratified by quartiles according to baseline values. Baseline values (left panels) and changes from baseline (right panels) of CD4+ T cells in a vaccinees (n = 98), b placebo (n = 100) and c anti-Tat Ab-negative placebo (n = 80). Data are presented as mean values with standard errors. Longitudinal analysis for repeated measures was used. p values assess the changes from baseline within each treatment group

Fig. 9

Changes from baseline of CD4…

Fig. 9

Changes from baseline of CD4 + T-cell number in vaccinees and placebos non…

Fig. 9
Changes from baseline of CD4+ T-cell number in vaccinees and placebos non compliant to therapy. Baseline values (left panel) and changes from baseline after immunization (right panel) of CD4+ T-cell counts in vaccinees (n = 18) and placebos (n = 5). Data are presented as box plots. Wilcoxon signed rank sum test for paired data and Wilcoxon–Mann–Whitney test were used for the analyses. p values assess the changes from baseline within and between treatment groups

Fig. 10

Plasma viremia up to week…

Fig. 10

Plasma viremia up to week 48 in vaccinees and placebo non compliant to…

Fig. 10
Plasma viremia up to week 48 in vaccinees and placebo non compliant to therapy. Percentage of vaccinees and anti-Tat Ab-negative placebos non-compliant to cART with detectable plasma viremia (upper panel), and plasma viremia values (log10 copies/mL) in patients with detectable viral load at each study visit (lower panel)
All figures (10)
Fig. 2
Fig. 2
Anti-Tat humoral immune response elicited in study participants. a Percentage of responders for anti-Tat Abs (see “Methods” section) in vaccinees (n = 99) or placebos (n = 100). The absolute number of vaccines/placebos developing anti-Tat Ig subclasses are reported on the top of each histogram. Statistical significant differences were detected between vaccinees and placebos for each Ig and for total response (p < 0.0001, Chi square test). b Percentage of responders for anti-Tat Abs stratified according to the presence of one or more Ab isotype in vaccinees (n = 99) or placebos (n = 100). The absolute number of vaccines/placebos developing one or more Ab isotype are reported on the top of each histogram. Statistical significant differences were detected between vaccinees and placebos (p < 0.0001, Chi square test). c IgM, IgG and IgA Ab mean titers (with standard error) in responders (vaccinees: n = 79 for IgM, n = 95 for IgG and n = 75 for IgA; placebos: n = 9 for IgM, n = 12 for IgG and n = 6 for IgA). Significant differences were detected between vaccinees and placebos for anti-Tat IgG Abs from week 12 to week 48 (Student’s t test)
Fig. 3
Fig. 3
Anti-Tat Ab durability in responders. a Kaplan–Meier estimates showing the cumulative probability of anti-Tat Ab durability during follow-up in responders (see “Methods” section) (vaccinees: n = 96; placebos: n = 18). Anti-Tat Abs persisted significantly longer in vaccinees as compared to the placebo group (p = 0.0019, log-rank test). b Kaplan–Meier estimates showing the cumulative probability of anti-Tat Ab durability during follow-up in vaccinees (left panel) or placebo (right panel) responders, according to the number of anti-Tat Ab isotypes (vaccinees: one subclass n = 10, two or three subclasses n = 86; placebo: one subclass n = 10, two or three subclasses n = 8)
Fig. 4
Fig. 4
Increase of cross-clades anti-Tat Abs elicited in vaccinees. a Baseline OD values of anti-Tat IgM, IgG and IgA against clades C, D and A in vaccinees prior to immunization (n = 29, 76 % C clade, 41 % A clade, 14 % D clade). b Changes from baseline of IgM, IgG and IgA Ab responses (OD) against Tat from other clades (C, D, A) after vaccination. Testing was performed at the peak of Ab responses (between 12 and 24 weeks). Statistical analysis was performed using the Wilcoxon signed-rank test. p values assess the increase from baseline
Fig. 5
Fig. 5
Neutralization of Tat/Env complex entry in DC. Baseline values (left panels) and changes from baseline after immunization (right panels) of B-clade Env entry in DC in the absence (a) or presence (b) of B-clade Tat in anti-Tat Ab-positive (n = 13) vaccinees, and anti-Tat Ab-positive (n = 6) or anti-Tat Ab-negative (n = 5) placebos at week 20 and 48 from the first immunization. Reduction of Env entry in DC by sera indicates neutralization. Student’s t test was applied to evaluate the changes from baseline within and between treatment groups
Fig. 6
Fig. 6
Neutralization of B- and C-clade Tat/Env complex entry in DC in vaccinees. Neutralization of B- (n = 13) and C- (n = 10) clade Env entry in DC in the presence or absence of (B- or C-clade) Tat by sera of Ab-positive vaccinees, measured at week 20 or week 48 after immunization. Data are presented as mean values with standard errors. Student’s t test for paired data was used for the analyses
Fig. 7
Fig. 7
Changes from baseline of CD4+ T-cell number in vaccinees and placebos. Baseline values (left panel) and changes from baseline (right panel) of CD4+ T-cell counts in vaccinees (n = 99) and placebos (n = 100). Data are presented as mean values with standard errors. Longitudinal analysis for repeated measures by the generalized estimating equations method was applied for the analysis. p values assess the changes from baseline within and between treatment groups
Fig. 8
Fig. 8
CD4+ T-cell numbers up to week 48 in vaccinees and placebo stratified by quartiles according to baseline values. Baseline values (left panels) and changes from baseline (right panels) of CD4+ T cells in a vaccinees (n = 98), b placebo (n = 100) and c anti-Tat Ab-negative placebo (n = 80). Data are presented as mean values with standard errors. Longitudinal analysis for repeated measures was used. p values assess the changes from baseline within each treatment group
Fig. 9
Fig. 9
Changes from baseline of CD4+ T-cell number in vaccinees and placebos non compliant to therapy. Baseline values (left panel) and changes from baseline after immunization (right panel) of CD4+ T-cell counts in vaccinees (n = 18) and placebos (n = 5). Data are presented as box plots. Wilcoxon signed rank sum test for paired data and Wilcoxon–Mann–Whitney test were used for the analyses. p values assess the changes from baseline within and between treatment groups
Fig. 10
Fig. 10
Plasma viremia up to week 48 in vaccinees and placebo non compliant to therapy. Percentage of vaccinees and anti-Tat Ab-negative placebos non-compliant to cART with detectable plasma viremia (upper panel), and plasma viremia values (log10 copies/mL) in patients with detectable viral load at each study visit (lower panel)

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