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CIHR team grant in HIV vaccine discovery: novel mechanisms and strategies of protection University of Toronto KAVI University of Nairobi. Presenter: Dr Julius Oyugi. HIV Vaccine Team. University of Toronto Mario Ostrowski [PI] Tania Watts Jen Gommerman Goetz Erhardt Rupert Kaul

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CIHR team grant in HIV vaccine discovery: novel mechanisms and strategies of protectionUniversity of TorontoKAVI University of Nairobi

Presenter: Dr Julius Oyugi

hiv vaccine team
HIV Vaccine Team

University of Toronto

  • Mario Ostrowski[PI]
  • Tania Watts
  • Jen Gommerman
  • Goetz Erhardt
  • Rupert Kaul
  • James Rini
  • Dana Philpott

University of Nairobi

  • Walter Jaoko[PI]
  • OmuOnzala.
  • Julius Oyugi
principles
PRINCIPLES
  • Need for “Back to Basics” approach.
  • Focus on mucosal sites.
  • Target HIV immune responses via T cells, B cells and Innate cells.
nature of research collaboration
Nature of research collaboration.
  • Grant uses an iterative approach
  • Yearly meetings of all members
  • Cross-fertilization of trainees
  • Project is primarily discovery and pre-clinical
  • Industrial partners to be based on promising discoveries.
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Team grant Themes

Theme 1: Optimizing CD8 T cell memory for prophylactic or therapeutic immunization.

  • An ALVAC strategy[weakly immunogenic and potentially efficacious].
  • A VZV strategy [a persistently reactivating immunogen].

Theme #2: Optimizing and targeting mucosal

antibody responses.

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Aim 1: Pre-clinical development of a canarypox (ALVAC) expressing HIV antigens and TNF-SF (tumor necrosis factor superfamily) molecules.
  • CTL vaccines based on DNA and pox virus vectors do not provide long lived memory T cell responses in humans.
  • Members of the TNFSF can enhance HIV specific CTL responses by their stimulatory effects on dendritic cells or CD4+ T cells.
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Plan
  • Develop ALVAC-SIV-gpe-TNSF vaccine construct
  • Carry out non-human primate studies
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Aim 2: Pre-clinical development of immunotherapeutic approaches targeting costimulatory and coinhibitory pathways to improve T cell function in HIV infection.
  • CTL are exhausted in chronic virus infections.
  • Build on team members Watts, Ostrowski work:
    • Tim-3 upregulation and TRAF-1 downregulation are markers of CD8 dysfunction during chronic viral infection
  • Evaluation of candidate co-stimulatory molecules to improve T cell function including CD40L, 41-BBL, Tim-3 blockade[mice model].
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Aim 3: Determining the feasability of a persistent replicating virus vector for HIV vaccine development: the role of pre-existing vector immunity on mucosal T cell immunity and activation.
  • Current DNA/virus vector primer are limited in maintaining long term effector CTL.
  • Emerging evidence suggests that virus vectors that can continue to induce persistent effector CTL may be preferable[Louis Picker et al, 2011].
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VZV based Vaccine as a vector

Goal is to determine whether a VZV based vaccine could;

  • Induce mucosal T cell immunity even in the presence of VZV sero-positivity.
  • To assess the activation state of mucosal sites post VZV vaccination, particularly in those who are VZV sero-positive.
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Team member McDonald has developed preclinical HIV vaccine candidates based on persistent CMV and VZV vectors.
  • Plan:
  • Field work in Kenya evaluating T cell systemic and mucosal immune responses after administration of a licensed VZV vaccine[Team member Walter Jaoko].
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Aim # 4: Exploring B cells as key cellular players in controlling HIV propagation within mucosal tissues
  • It is uncertain if B cells are actively recruited to sites of viral replication in the mucosa, and if so, what types of B cells congregate around active foci of viral replication.
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Team member Gommerman is B cell immunologist
  • PLAN:
    • Evaluating B cell subsets in human gut and genital mucosa tissues
    • Evaluating TNF/iNOS-producing plasma cells at mucosal sites and their role in viral control
    • Evaluating B cell exhaustion and how to reverse it.
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Aim 5: To investigate the feasibility of blocking the HIV Env/ T cell integrinα4β7/b1 interaction as a strategy to reduce mucosal acquisition of HIV.
  • The role of α4β7 in HIV pathogenesis
  • Homing marker for effector T cells to the gut.
  • It is capable of binding HIV gp120.
  • Its expression is associated with increased susceptibility to HIV infection.
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Team member Dr. Kaul has expertise in mucosal
  • immunology of gut / genital tract
  • PLAN:
  • Assess expression of α4β7 and ligandMAdCAM in genital tissues (cervix, foreskin).
  • Assess importance of α4β7: HIV target cell susceptibility at mucosal sites.
  • Work with team member Rini to develop small molecule inhibitors.
aim 6 nod agonists as vaccine adjuvants
Aim 6: Nod agonists as vaccine adjuvants

Team member Philpott is Nod expert

Test ability of candidate NLR agonists to enhance antibody responses at the mucosal level.

Progress: Have begun testing Nod 2 agonist (MDP) and a novel nod agonist (AHL) in a DNA vaccine and protein vaccine approach using gp120 in Balb/C mice.

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Aim 7: Development and standardization of mucosal immune assays focused on B cell responses to be applied to vaccination studies in the Kenyan cohort.
  • Team member Dr Oyugi and Prof Anzala

PLAN:

    • Assess B cell immunity at the mucosal surface
    • Development of HIV Ab ELISA using envelopes from early infection, IgG, IgA
    • B cell ELISpot assay from mucosal surfaces: IgG, IgA

Progress: Obtained Envclade A and C during early infection

  • KAVI personnel training at UT site
obstacles so far
Obstacles so far
  • Purchasing equipment and transporting to UN is problematic
  • Protocol development requires REB approval at both sites
  • No indirect costs permitted by funder on funds sub-contracted to UN site.
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ACKNOWLEDGEMENTS
  • UOT TEAM: [Mario Ostrowski,Tania Watts,
  • Jen Gommerman,GoetzErhardt,
  • Rupert Kaul, James Rini,
  • Dana Philpott].
  • UON TEAM [Walter Jaoko, OmuOnzala,
  • Julius Oyugi].
  • CIHR AND GHRI
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