CIHR team grant in HIV vaccine discovery: novel mechanisms and strategies of
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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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Presenter: Dr Julius Oyugi

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Presenter dr julius oyugi

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.


Presenter dr julius oyugi

  • 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.


Presenter dr julius oyugi

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.


Presenter dr julius oyugi

Plan

  • Develop ALVAC-SIV-gpe-TNSF vaccine construct

  • Carry out non-human primate studies


Presenter dr julius oyugi

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].


Presenter dr julius oyugi

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].


Presenter dr julius oyugi

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.


Presenter dr julius oyugi

  • 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].


Presenter dr julius oyugi

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.


Presenter dr julius oyugi

  • 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.


Presenter dr julius oyugi

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.


Presenter dr julius oyugi

  • 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.


Presenter dr julius oyugi

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.


Presenter dr julius oyugi

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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