Progress in Understanding Ad Vector Immunity
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Progress in Understanding Ad Vector Immunity. Dan H. Barouch Beth Israel Deaconess Medical Center November 17, 2009. Importance of Studying Ad Vector Immunity.

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Progress in Understanding Ad Vector Immunity

Dan H. Barouch

Beth Israel Deaconess Medical Center

November 17, 2009


Importance of studying ad vector immunity l.jpg
Importance of Studying Ad Vector Immunity

  • The potential enhanced HIV-1 acquisition in the STEP study in Ad5 seropositive, uncircumcised men suggested the importance of understanding vector-specific immunity

  • A model was proposed in which individuals with baseline Ad5 NAbs may have higher Ad5-specific T lymphocyte responses that may expand following rAd5 vaccination and serve as increased “targets” for HIV-1 infection


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Four Interconnected Projects

  • Role of Ad5 vector-specific cellular immunity in the enhancement of HIV-1 acquisition in humans

  • Extent of mucosal inflammation and CD4+ T cell trafficking following rAd5 vaccination in nonhuman primates

  • Role of cross-reactive Ad vector-specific immunity in the enhancement of HIV-1 acquisition in humans

  • Capacity of cross-reactive Ad vector-specific cellular immunity to suppress alternative rAd vaccines in humans


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Four Interconnected Projects

  • Role of Ad5 vector-specific cellular immunity in the enhancement of HIV-1 acquisition in humans

  • Extent of mucosal inflammation and CD4+ T cell trafficking following rAd5 vaccination in nonhuman primates

  • Role of cross-reactive Ad vector-specific immunity in the enhancement of HIV-1 acquisition in humans

  • Capacity of cross-reactive Ad vector-specific cellular immunity to suppress alternative rAd vaccines in humans


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Role of Ad5 Vector-Specific Cellular Immunity in the Enhancement of HIV-1 Acquisition

Hypothesis: individuals with baseline Ad5 NAbs may have higher Ad5-specific T lymphocyte responses that may expand following rAd5 vaccination and serve as increased “targets”

Are anamnestic Ad5-specific T lymphocyte responses following rAd5 vaccination a safety concern in individuals with baseline Ad5 NAb titers?

116 subjects from Merck phase 1 studies of rAd5-Gag

Dose: 1010 or 1011 vp

Samples: week 0 (pre-vaccine) and week 8 (post-2nd vaccine) serum and PBMC

Assays: Ad NAb, ELISPOT, ICS assays with 104 MOI virus

O’Brien et al. Nat. Med. 2009; 15:873-875


Ad5 elispot responses are nearly universal and do not correlate with ad5 nab responses at baseline l.jpg
Ad5 ELISPOT Responses Are Nearly Universal and Do Not Correlate with Ad5 NAb Responses at Baseline

Baseline Serum and PBMC Samples

P=0.83

O’Brien et al. Nat. Med. 2009; 15:873-875


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Lower Ad5 ELISPOT Responses Following Vaccination in Individuals with Baseline Ad5 NAbs >18

P=0.91

P=0.95

P=2.3x10-3

P=8.3x10-3

P=8.9x10-5

P=0.043

P=4.2x10-3

P=0.53

>18

>18

< 18

< 18

Baseline Ad5 NAb

1010 vp Ad5-Gag

1011 vp Ad5-Gag

O’Brien et al. Nat. Med. 2009; 15:873-875


No increased activation or mucosal homing integrin expression on ad5 specific cd4 t lymphocytes l.jpg
No Increased Activation or Mucosal Homing Integrin Expression on Ad5-Specific CD4+ T Lymphocytes

Baseline Ad5 NAb

O’Brien et al. Nat. Med. 2009; 15:873-875


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Role of Ad5 Vector-Specific Cellular Immunity in the Enhancement of HIV-1 Acquisition

  • No correlation between Ad5 NAb titers and Ad5 T cell responses prior to vaccination

  • Ad5 T cell responses in Ad5 seropositive subjects lower than in Ad5 seronegative subjects following rAd5 vaccination

  • No increased CD4+ T lymphocyte activation or mucosal homing markers in Ad5 seropositive vs seronegative subjects

  • These data challenge the hypothesis that the potential enhancement of HIV-1 acquisition in the STEP study in subjects with baseline Ad5 NAbs >18 was due to anamnestic vaccine-elicited Ad5 T cell responses

  • Similar results published independently by another group (Hutnick, Betts et al. Nat. Med. 2009; 15: 876-878)

  • Caveat: mucosal vector-specific T cell responses not assessed

O’Brien et al. Nat. Med. 2009; 15:873-875


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Four Interconnected Projects Enhancement of HIV-1 Acquisition

  • Role of Ad5 vector-specific cellular immunity in the enhancement of HIV-1 acquisition in humans

  • Extent of mucosal inflammation and CD4+ T cell trafficking following rAd5 vaccination in nonhuman primates

  • Role of cross-reactive Ad vector-specific immunity in the enhancement of HIV-1 acquisition in humans

  • Capacity of cross-reactive Ad vector-specific cellular immunity to suppress alternative rAd vaccines in humans


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Assessment of Mucosal Inflammation Following rAd5 Vaccination in Rhesus Monkeys

  • Development of a rhesus monkey model to assess the extent and nature of cellular inflammation in the colorectal mucosa and prepuce (foreskin) following rAd5 vaccination

  • Protocol:

    • Induce Ad5 immunity by IN infection with replicating Ad5 vectors containing host range mutations (N=6)

    • Controls received IN saline (N=6)

    • Vaccinate all IM with replication-defective Ad5-gag/pol/nef

    • Assess inflammation, T cell activation, and vector-specific immunity in the colorectal mucosa and prepuce at week 2 following vaccination


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Ad5-Specific CD4+ T Cell Responses After Infection of Monkeys with rcAd5-Empty (Red) or Saline (Blue)

Ad5-specific NAb titers after rcAd5-Empty: 200-1000


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Ad5-Specific CD4+ T Cell Responses After Vaccination with Replication-Defective Ad5-Gag/Pol/Nef

Ad5-specific CD4+ T cell responses after rAd5 vaccination appear lower in monkeys with baseline Ad5-specific immunity (Red) compared with naïve monkeys (Blue), consistent with data obtained from the human samples


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Histopathology of the Colorectal Junction Replication-Defective Ad5-Gag/Pol/Nef

Following Vaccination

356-08 naïve

378-08 Pre-existing

  • Leukocyte populations (numbers, type) appear similar between groups

    • - Further evaluation by IHC

      • Ki67

      • CD3

      • CD4


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Immunohistochemistry of the Colorectal Junction: Replication-Defective Ad5-Gag/Pol/Nef

No Evidence for Increased Ki67 Cellular Activation

Ki67

Lamina Propria

Mean Objective Score

364-08 naive

Epithelium

350-08 pre-existing

Objective Score Criteria – Ki67

Epithelium

Lamina Propria


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Immunohistochemistry of the Colorectal Junction: Replication-Defective Ad5-Gag/Pol/Nef

No Evidence for Increased CD3+ T Lymphocytes

CD3

Lamina Propria

Mean Objective Score

Epithelium

369-08 Pre-existing

Objective Score Criteria – CD3

367-08 naive

Lamina Propria

Epithelium


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Immunohistochemistry of the Colorectal Junction: Replication-Defective Ad5-Gag/Pol/Nef

No Evidence for Increased CD4+ T Lymphocytes

CD4

Lamina Propria

Mean Objective Score

352-08 Pre-existing

Epithelium

Objective Score Criteria – CD4

355-08 Naive

Lamina Propria

Epithelium


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Assessment of Mucosal Inflammation Following rAd5 Vaccination in Rhesus Monkeys

  • We are developing an NHP model to assess the impact of rAd5 vaccination on the histopathology of mucosal sites

  • Following rAd5 vaccination of monkeys with or without pre-existing Ad5 immunity, there was no detectable increase in mucosal inflammation, CD4 T lymphocyte trafficking, or cellular immune activation in colorectal mucosa

  • Histopathology of foreskin currently being evaluated

  • These data further decrease the possibility that the potential increased HIV-1 acquisition in Ad5 seropositive vaccinees in the STEP study was mediated by anamnestic vector-specific T lymphocytes that trafficked to mucosal sites


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Four Interconnected Projects Vaccination in Rhesus Monkeys

  • Role of Ad5 vector-specific cellular immunity in the enhancement of HIV-1 acquisition in humans

  • Extent of mucosal inflammation and CD4+ T cell trafficking following rAd5 vaccination in nonhuman primates

  • Role of cross-reactive Ad vector-specific immunity in the enhancement of HIV-1 acquisition in humans

  • Capacity of cross-reactive Ad vector-specific cellular immunity to suppress alternative rAd vaccines in humans


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Ad Seroprevalence in the STEP Study Vaccination in Rhesus Monkeys

  • Substantial cross-reactive Ad-specific cellular immunity across related Ad serotypes

  • Aims:

    • To determine if baseline Ad5 NAbs correlate with NAbs to other Ad serotypes

    • To determine if baseline NAbs to other Ad serotypes correlate with enhancement of HIV-1 acquisition following rAd5 vaccination in the STEP study

  • Retrospective, case-controlled study using baseline STEP serum samples (81 cases, 324 non-cases)



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No Correlation Between Baseline Ad5 and Ad26/35/48 NAbs in rAd5 Vaccinees in the STEP Study

Ad26

Ad35

Ad48

P=0.46

P=0.44

P=0.77


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No Difference in Baseline Ad26/35/48 NAbs in Cases vs Non-Cases in rAd5 Vaccinees in the STEP Study

Ad26

Ad35

Ad48

P=0.97

P=0.46

P=0.47


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Ad Seroprevalence in the STEP Study Non-Cases in rAd5 Vaccinees in the STEP Study

  • NAbs to Ad5 and Ad26/35/48 are independent variables that do not co-segregate

  • Ad5 NAbs are not a surrogate marker for and do not predict NAbs to these other Ad serotypes

  • No increased HIV-1 acquisition in subjects with baseline Ad26/35/48 NAbs following rAd5 vaccination

  • Cross-reactive immunity against these Ad serotypes did not contribute to increased HIV-1 susceptibility in the STEP study

  • Ad NAb titers to other Ad serotypes in the STEP study and AIDSVAX studies in progress


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Four Interconnected Projects Non-Cases in rAd5 Vaccinees in the STEP Study

  • Role of Ad5 vector-specific cellular immunity in the enhancement of HIV-1 acquisition in humans

  • Extent of mucosal inflammation and CD4+ T cell trafficking following rAd5 vaccination in nonhuman primates

  • Role of cross-reactive Ad vector-specific immunity in the enhancement of HIV-1 acquisition in humans

  • Capacity of cross-reactive Ad vector-specific cellular immunity to suppress alternative rAd vaccines in humans


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A phase 1 randomized, double-blind, placebo controlled dose escalation clinical trial to evaluate the safety and immunogenicity of recombinant adenovirus serotype 26 HIV-1 vaccine (Ad26.ENVA.01) in healthy, HIV-1 uninfected adultsPI: Lindsey Baden, Brigham & Women’s Hospital

  • Late breaker presentation at the AIDS Vaccine 2009 Conference in Paris

  • Ad26 safe and immunogenic in humans at doses of 109, 1010, and 1011 vp

  • Humoral and cellular immune responses consistently observed

  • Ad26 appears a promising vector for further clinical development


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Baseline Ad26-Specific T Cell Responses Observed in Ad26 Seronegative Subjects and Correlate with Hexon-Specific Responses

R2=0.74

P<0.0001


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No Correlation Between Baseline Ad26 T Cell Responses and EnvA-Specific T Cell Responses Following rAd26-EnvA Vaccination

R2=0.01

P=0.87

R2=0.00

P=0.73


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No Correlation Between Baseline Ad26 T Cell Responses and EnvA-Specific Antibody Responses Following rAd26-EnvA Vaccination

R2=0.00

P=0.69

R2=0.00

P=0.78


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Conclusions EnvA-Specific Antibody Responses Following rAd26-EnvA Vaccination

  • Ad5-specific cellular immunity does not appear to explain the potential enhanced HIV-1 acquisition in the STEP study

    • No greater increase in Ad5-specific CD4 responses, activation status, or mucosal homing marker expression in Ad5 seropositive compared with seronegative humans following rAd5 vaccination

    • No increase in mucosal CD4 trafficking or immune activation in Ad5 seropositive vs seronegative monkeys following rAd5 vaccination

  • Cross-reactive Ad-specific immunity does not contribute to HIV-1 acquisition or suppression of vaccine responses

    • No increase in HIV-1 acquisition in vaccinees in the STEP study with baseline Ad26, Ad35, or Ad48 NAbs

    • Cross-reactive Ad-specific cellular immunity did not suppress rAd26 vaccine immunogenicity in our first-in-human rAd26 study


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Beth Israel Deaconess, Harvard Medical School EnvA-Specific Antibody Responses Following rAd26-EnvA Vaccination

Peter Abbink

Ritu Bradley

Sarah Clark

Rebecca Dilan

David Kaufman

Sharon King

Annalena La Porte

Jinyan Liu

Diana Lynch

Lori Maxfield

Kara O’Brien

Elizabeth Rhee

Ambryice Riggs

Betty Sun

Raphael Dolin

Michael Seaman

Brigham and Women’s, Harvard Medical School

Lindsey Baden

Acknowledgements

  • New England Primate Center

    • Angela Carville

    • Kate Hammerman

    • Keith Mansfield

  • Merck Research Laboratories

    • Michael Robertson

    • Danny Casimiro

    • John Shiver

  • HIV Vaccine Trials Network

    • John Hural

    • Julie McElrath

  • Ragon Institute of MGH, MIT, and Harvard

  • CAVD, Bill & Melinda Gates Foundation

  • DAIDS, NIAID, NIH

    • Michael Pensiero

    • Alan Fix


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