Presenter: Dr Julius Oyugi

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• James Rini• Dana Philpott

University of Nairobi• Walter Jaoko[PI]• Omu Onzala.• Julius Oyugi

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.

• 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.

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.

Team grant Themes

• Members of the TNFSF can enhance HIV specific CTL responses by their stimulatory effects on dendritic cells or CD4+ T cells.

• CTL vaccines based on DNA and pox virus vectors do not provide long lived memory T cell responses in humans.

Aim 1: Pre-clinical development of a canarypox (ALVAC) expressing HIV antigens and TNF-SF (tumor necrosis factor superfamily) molecules.

Plan• Develop ALVAC-SIV-gpe-TNSF vaccine construct• Carry out non-human primate studies

• 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].

Aim 2: Pre-clinical development of immunotherapeutic approaches targeting costimulatory and coinhibitory pathways to improve T cell function in HIV infection.

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].

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.

VZV based Vaccine as a vector

• 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].

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.

• 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.

Aim 5: To investigate the feasibility of blocking the HIV Env/ T cell integrin α4β7/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.

Team member Dr. Kaul has expertise in mucosal

immunology of gut / genital tract

PLAN:

• Assess expression of α4β7 and ligand MAdCAM 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

• 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.

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 Env clade A and C during early infection• KAVI personnel training at UT site

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.

ACKNOWLEDGEMENTS

• UOT TEAM: [Mario Ostrowski,Tania Watts,Jen Gommerman,Goetz Erhardt, Rupert Kaul, James Rini, Dana Philpott].

• UON TEAM [Walter Jaoko, Omu Onzala,Julius Oyugi].

• CIHR AND GHRI