Canadian HIV Vaccine Initiative funding recipients
Vaccines administered to individuals already infected with a pathogen are called therapeutic vaccines. In chronic human immunodeficiency virus (HIV) infection, therapeutic vaccines stimulate pre-existing and new immunity against HIV. If boosted immunity more effectively suppresses HIV replication, this could offer broader treatment options where antiretroviral drugs are not widely available and reduce dependence on antiretroviral drugs elsewhere. While therapeutic vaccines tend to focus on conserved portions of HIV or sequences known to be present in the infected individuals, we plan to test sequence variants that arise rarely in nature. Our hypothesis is that the immune system rapidly selects against variants that are more immunogenic than common sequences. Therefore, such sequences as rarely occur naturally in HIV may be more effective in therapeutic vaccines than the common sequences currently employed. Our research project aims to demonstrate this possibility and identify HIV peptide sequence variants with this characteristic for inclusion in future therapeutic HIV vaccines.
The development of a vaccine against HIV-1 represents the best hope of controlling the worldwide AIDS epidemics. To date, no vaccine has been shown to be clinically useful. However, in monkeys, an attenuated SIV (simian immunodeficiency virus) belonging to the same family of viruses and causing a similar disease as HIV-1, has been shown to be a very efficient vaccine against the challenging SIV. There is a general consensus that this represents the best available and the most potent vaccine against SIV. It is presumed that a similarly attenuated HIV-1 would also be very efficient as a vaccine. However, the mechanisms by which this attenuated SIV vaccine works do not seem to be through known immune responses (such as antibodies). Rather, protection is postulated to be mediated by evolutionary conserved mechanisms, designated innate immunity. Although such an attenuated SIV/HIV virus is dangerous and would never be used to vaccinate humans, knowing how it works would be very useful to design an HIV vaccine. The aim of our project is to study the mechanisms of protection by an attenuated HIV and SIV, in order to get insights on how to design a non-dangerous and potent HIV vaccine. We intend to carry out these experiments in the mouse because the same innate immunity as in monkeys and humans is likely to be effective, if indeed, this represents the mode of protection. Moreover, mice offer strong genetic tools to dissect this protective effect. Transgenic mice expressing the attenuated HIV or SIV will be challenged with HIV or SIV, in order to determine whether protection also arise in mice and by which mechanism.
Infection by the human immunodeficiency virus (HIV) can lead to a progressive deterioration of the body's immune system. AIDS (Acquired Immunodeficiency Syndrome) represents the stage when a HIV-infected individual's life is threatened by common pathogens that are normally destroyed by the immune system of healthy individuals. HIV is a retrovirus that has evolved to circumvent the human immune system in such ways that no cure or vaccine has yet been successfully developed. One of the virus' survival strategies is to cripple conventional adaptive immune responses that are essential for the effectiveness of most vaccines because the cells of the immune system themselves are its target. Nevertheless, there are several endogenous factors that can protect humans against the spread of HIV infection. One of these antiviral factors is a protein called APOBEC3G that is part of the innate component of the immune system. This protein can bind and heavily mutate HIV DNA, ultimately leading to the inactivation and destruction of the virus. Unfortunately, HIV encodes a protein called Vif that is dedicated to specifically induce the degradation of APOBEC3G. The overall aim of this catalyst grant proposal is to validate a new Vif-inhibiting technology that could lead to the development of a vaccine that could induce the inactivation infectious HIV particles in HIV/AIDS patients and also promote the elimination of HIV infected cells by recruiting the intrinsic antiviral properties of the innate immune system.
Most infections with HIV worldwide are sexually transmitted and women are the most frequently infected. In order to protect against HIV infection and AIDS, vaccines must be effective at blocking entry of the virus. In sexual transmission, HIV enters through the mucosal surfaces of the body. These surfaces can respond with a specific type of antibody, the IgA type. Thus, when developing new HIV vaccines, we must be able to measure the amount and quality of mucosal IgA antibody against HIV. Studies have shown that women who are able to resist HIV infection have IgA antibodies against HIV, while those that become infected have little or no IgA. Unfortunately, many such studies have conflicting results or are hampered by the difficulty in sampling and testing for these IgA antibodies, using fluid samples from the mucosal surfaces. A test in blood would be much more simple, reliable, and useful. We propose to use the circulating immune cells in blood responsible for IgA antibody production, as a reliable means to measure the amount and quality of mucosal IgA
The development of an effective vaccine against human immunodeficiency virus type-1 (HIV-1) has proven an enormous scientific challenge that is partly due to the lack of a suitable experimental cell system to investigate protective immune responses to HIV-1. Previous studies have shown that secondary lymphoid organs constitute preferred anatomical sites for HIV-1 replication and propagation. Given that secondary lymphoid organs are essential for the development of effective immune responses, we are proposing to test whether human lymphoid tissue cultured ex vivo could represent an appropriate experimental cell system to critically evaluate candidate HIV-1 vaccines.
Over 33 million individuals worldwide are infected with the Human Immunodeficiency Virus Type-1 (HIV-1), and yet there is no effective vaccine to prevent HIV-1 infection. The recent failure of the Merck vaccine, which was designed to elicit a type of immune response, called a killer T cell (or CTL) response resulted in no protection and even enhanced infection rates in volunteers, thus highlighting the challenges of HIV-1 vaccine development. Most successful vaccines that have been developed against viruses have been shown to induce another type of immune response after vaccination, called a neutralizing antibody response. The development of neutralizing antibodies with an HIV-1 vaccine has been one of the largest challenges in HIV-1 vaccine development. To date, no vaccine can induce antibodies that can neutralize a large variety of HIV-1 viruses circulating in the population. Part of the problem is due to the very nature of the surface protein of HIV-1, HIV-1 envelope. The HIV-1 envelope when given as a vaccine induced very poor neutralizing antibody responses. There are a number of molecules, called CD40L, BAFF or APRIL that have been shown to stimulate immune responses that make stronger antibodies. The current proposal will evaluate the construction of new HIV-1 envelope vaccines where we have combined these immune molecules with the HIV-1 envelope protein. We will test whether these new vaccines can stimulate the neutralizing antibody response more strongly. If we are successful these studies will lay the groundwork for developing a better vaccine against HIV-1.
7. A combined early and late HIV-1 protein-specific exosome-targeted T cell vaccine capable of stimulating HIV-1 specific CD8+ CTL responses in absence of CD4+ T cells and counteracting immune suppression (Jim XIANG, Jianhua, University of Saskatchewan) $89,482 for 1 year
CD4+ T cells are required for generation and maintenance of cytotoxic CD8+ T cells playing a critical role in control of human immunodeficiency virus type-1 (HIV-1) proliferation. However, CD4+ T cell depletion usually occurs in acquired immunodeficiency syndrome (AIDS) patients due to the viral cytopathic effect derived from binding of trimeric gp120 to CD4 of T cells. Therefore, how to stimulate efficient CD8+ cytotoxic T lymphocyte (CTL) responses in AIDS patients becomes one of the major challenges in AIDS patient therapy. Early HIV-1 proteins such as tat can broadern and enhance CD8+ CTL responses against late HIV-1 proteins such as gp120 and gag. Recently, we have developed a new vaccine by using dendritic cell-repeased exosome (EXO)-targeted active T (aTexo) cell vaccine capable of stimulating CD8+ CTL responses in absence of CD4+ T cells. In this proposal, we plan to develop a novel combined early and late HIV-1 protein-specific aTexo vaccine capable of overcoming CD4+ T cell deficiency and immune suppression and stimulating effective gp120-/gag-specific CD8+ CTL responses in AIDS patients with immune suppression and declined CD4+ T cells.
8. Attacking HIV protease cleavage sites with immunization - Explore the rapid mutation rate of HIV-1 (Luo, Ma Co-Investigators: Terry B Ball, Gary P Kobinger, Paul A. Sandstrom, University of Manitoba) $100,000 for 1 year
More than 25 years since HIV-1 was identified as the cause of AIDS, 60 million people have been infected and about half of them have died of HIV/AIDS. An effective vaccine is the only way to stop the epidemic, the failure of a series of vaccine trials based on the traditional approach demands novel ideas and avenues for HIV-1 vaccine development. The protease of HIV-1 is a small 99-amino acid aspartic enzyme that mediates the cleavage of Gag, Gag-Pol and Nef precursor polyproteins. The process is highly specific, temporally regulated and essential for the production of infectious viral particle. Since the protease cleavage sites of HIV-1 are much conserved among major subtypes of HIV-1, direct immune responses against these cleavage sites would yield two major advantages -1) The host immune response could destroy the virus before it can establish itself permanently in the host; and 2) the vaccine could force the virus to accumulate mutations at the protease cleavage sites and eliminating suitable substrates of the HIV protease thus eliminating viable virions. Unlike the traditional approach of antiprotease drug development, this strategy is to generate and direct host immune responses to target the 12 protease cleavage sites (p17/24, p24/p2, p2/p7, p7/p1, p1/p6, p7/TFP, TFP/p6, P6/PR, PR/RTp51, RT/RTp66, RTp66/INT, NEF) and eliminate virus by destroy viral infected cells and force the virus to mutate to its disadvantage. We propose to use Cynomolgus Macaques and SIVmac239 as an experimental model and a cocktail of peptides overlapping 12 protease cleavage sites as immunogens and deliver the peptides using two different approaches - 1). Deliver the peptides with a unique vector system (based on vesicular stomatitis virus) capable of targeting dendritic cells and generate robust immune responses; and 2). Deliver the peptide cocktail to the mucosal surface with a nanostructure delivery system.
1. The functional profile of NK cells in HIV exposed uninfected subjects: Association with carriage of NK receptor-HLA ligand genotypes (Nicole F. Bernard, The Research Institute of the McGill University Health Centre) $440,604 for 3 years
Natural killer (NK) cells are a key player in innate immunity to viruses such as HIV. NK cells can recognize virus infected cells very early after infection. They do so through cell surface receptors that recognize a cell surface molecule called HLA present on most cells in the body, including those that HIV enters in a new infection. The NK receptors and HLA molecules have many variants that differ from one person to another and influence the potency of NK cell activation when these cells see a virus infected target. Our previous work identified variants of NK receptors and HLA that are present more frequently in people who remain uninfected despite exposure to HIV (exposed uninfected or EU subjects) than in HIV susceptible individuals. There results led us to hypothesize that expressing the kind in NK receptor associated with protection from infection leads to activation of NK cells to either more readily kill HIV infected cells or prevent HIV from replicating and spreading. In this project we will study the anti-viral functions of NK cells from individuals carrying NK receptor HLA combinations associated with protection from HIV infection compared to that from subjects not carrying these combinations. Understanding how EUs are protected from infection is important because it may provide clues on how to manipulate the immune system in the context of vaccines to reduce the risk of HIV infection.
APOBEC3G is a host factor that is able to inhibit HIV-1 replication. A HIV-1 protein, so-called Vif, can protect the virus from the attack of APOBEC3G by binding to APOBEC3G and subsequently destroying it. Understanding the mechanism of how Vif protects HIV-1 from the inhibition by APOBEC3G may lead us to develop a novel therapeutic strategy for HIV-1 infection. The objective of this work is to explore the mechanism by which Vif abolishes anti-HIV activity of APOBEC3G.
As humans, we all share the same set of genes, however, we all possess slightly different versions of those genes and that is what makes us all unique as individuals. These genetic differences, called polymorphisms, also have been shown to be associated with differing susceptibility to disease, such as HIV. Our lab has previously demonstrated a link between increased susceptibility to HIV infection and a particular version of the gene that encodes the main host protein that HIV uses to enter into a cell, called CD4. Recent studies from our lab have shown that the genes that surround CD4 could also be linked to altered HIV susceptibility. We have termed this group of genes the CD4 pathogenicity island and this proposal seeks to explore the genetic linkages between these genes and also determine at a molecular level how they affect susceptibility to HIV infection. These studies could lead to be better understanding of the molecular events necessary to HIV to infect a cell which would provide a foundation for further anti-HIV drug development.
Human immunodeficiency virus type 1 (HIV-1) has claimed the lives of 25 million people since the beginning of the AIDS epidemic in the early 1980s and endangers the life of 33 million infected individuals. Finding an effective treatment or a cure for this deadly virus is the goal of AIDS research. The currently available antiretroviral drugs are potent enough to lower the viral load in patient below the detection level and thus can extend the patient's life for more than 25 years on average. Yet, the inevitable appearance and circulation of multi-drug resistance HIV-1 strains quickly exhausts the effectiveness of these HIV-1 inhibitors. Without an HIV-1 vaccine in hand, developing new antiretrovirals is essential to control this epidemic. Research proposed in this grant application is aimed to study one recently host factor named bone marrow stromal cell antigen 2 (BST2) that potently block HIV-1 production when viral Vpu is not expressed. Understanding how BST2 restricts HIV-1 production and how Vpu counteracts BST2 is expected to reveal new strategies for developing novel HIV-1 therapeutic approaches.
Despite current progress, the development of a safe and effective HIV-1 vaccine is still a major concern and an immense challenge. It has been previously demonstrated that virus-like particles (VLPs) are superior to conventional protein immunogens in the activation of immune responses. Unfortunately, HIV-1 has been reported to display a low immunogenicity by itself. To improve immunogenicity of HIV-1-based VLPs, we are proposing to incorporate constituents that can stimulate immune cells into VLPs. We propose that this experimental strategy could enhance and broaden immune responses, which are required for controlling HIV-1 infection.
Promising vaccine trials and recent advances in basic scientific understanding of HIV immunology suggest that a highly efficacious preventive vaccine will appear in the near future. However, it cannot be assumed that the availability of an efficacious vaccine will ensure a population's uptake, given the array of potential psychosocial, cultural and political barriers. Research that examines these barriers has tended to be conducted in North America. Moreover, communities of FSWs and MSM who encountered numerous barriers to health services are noticeably absent from this body of research. For this reason, the proposed project will examine the acceptability of a future HIV vaccine among highly stigmatized MSM and FSWs, as well as members of civil society organizations engaged in HIV prevention work within these communities. This project will be conducted at four culturally contrasting sites in Asia and Africa.
This project involves basic science HIV vaccine research. We propose to develop and test two vaccine candidates. Both vaccine projects will involve molecular biological techniques to construct the vaccines and test them for expression. The first project involves the construction of a Cytomegalovirus-based vaccine vector expressing green fluorescent protein and SIV gene inserts. The second project involves the development of a complex DNA vaccine based on a fusion protein of two trimerized proteins: one of gp140 and the other of a TNF superfamily molecule. Other innate immune molecules will also be tested for potential incorporation into the model. Small animal models and in vivo methods will be used to examine immunogenicity. Further testing involving immunological methods as well as molecular and retrovirology will be done in rabbits and nonhuman primates.
- Travel support to attend the AIDS Vaccine 2008 Partnership Development Forum in Cape Town, South Africa (Terry B. Ball, University of Manitoba) $9,500
- Comprehensive Development and Evaluation of Herpes Viruses as HIV Vaccine Vectors with Special Reference to Suitability and Application in Sub-Saharan Africa (Kelly S. Macdonald, Mount Sinai Hospital) $8,375
- Canadian African Prevention Trials Network Travel Grant (David M. Moore, University of British Columbia) $12,300
- Travel support to attend AIDS Vaccine 2008 Partnership Development Forum (Peter A. Newman, University of Toronto) $8,579
- Development of Novel Vaccine strategies against HIV-1 infection (Mario A. Ostrowski, University of Toronto) $2,000
- Herpes viruses as re-activating Vaccine Vectors: Protective Efficacy of a Varicella Zoster-HIV Vaccine in the SIV Macaque model (David O. Willer, Mount Sinai Hospital) $7,537
1. African Development of AIDS Prevention Trials capacities, Phase II (ADAPT2) (Neil Andersson, Kenneth Matengu, Beverly Shea, CIET Trust Johannesburg, South Africa, University of Namibia, Namibia, CIET Canada, Ontario) $1.8 million
The second African Development of AIDS Prevention Trials capacity initiative (ADAPT2) builds on the experience and networks created during ADAPT1 (2007 - 2009). This team was part of GHRI's HIV Prevention Trial Capacity Building Grants - Phase 1, funded by the Canadian International Development Agency in an amount of $3 million. ADAPT2 is an African-Canadian partnership that will increase the number and quality of HIV prevention trials led by African researchers through increasing capacities to conduct HIV prevention in 12 southern African countries. It will increase the institutional capacity of two African universities and a non-government organization to provide training in prevention trial methods; it will build a multi-country research framework for random controlled trials (RCTs); it will increase capacity of African policy makers and planners to interpret and use research findings; and it will develop fundable proposals and partnerships to increase sustainability.
ADAPT2 activities include a series of intensive short courses on epidemiology and RCT methods for researchers from 12 southern African countries. Training modules include research management, RCT analysis, research writing and presentation and proposal development. Short courses include strengthening of laboratory skills on analysis of dried blood spots, research ethics and executive training for policy makers on interpretation of research findings. ADAPT fellows will gain practical experience in ongoing HIV prevention trials in three countries in the region. The program will mentor researchers through evidence generation and use of research products. It will develop an HIV prevention trial module within a master's course for health planners at the University of Namibia. Several ADAPT2 researchers will undertake higher degrees at the University of Western Cape, an ADAPT2 partner.
2. The Canada-Africa Prevention Trials (CAPT) Network - Proposal to Build African Capacity for HIV/AIDS Prevention Trials (Pontiano Kaleebu, Guy de Bruyn, D. William Cameron, Clive Gray, David Moore, Uganda Virus Research Institute Entebbe, Uganda, Perinatal HIV Research Unit Wits Health Consortium, South Africa, University of Ottawa, at The Ottawa Hospital, Ontario, National Institute for Communicable Diseases, South Africa, BC Centre for Excellence in HIV/AIDS, British Colombia) $1.8 million
The Canada-African Prevention Trials (CAPT) Network was formed through GHRI's HIV Prevention Trial Capacity Building Grants - Phase 1 (2007-2009, which was funded by the Canadian International Development Agency in an amount of $3million. The network comprises eight African countries (4 Uganda, 1 Kenya, 3 South African) and seven Canadian partner institutions.
Under this project, the Network will enhance prevention research programs at each of its African sites through targeted workshops and training, while continuing to provide infrastructure support for research personnel. An African-led, multi-disciplinary research initiative will be developed using research platforms of high-risk populations developed during the first round of funding to promote African leadership and management capacity. To support these activities, the network will establish a research consortium, comprising three research
"hubs" in Uganda, South Africa and Canada. The consortium will be dedicated to providing administrative and research support to the sites in the design, execution and coordination of research studies. While fostering a streamlined and well-coordinated African-led research agenda, the research consortium will also develop the network's capacity to respond to HIV prevention funding opportunities. To complement the
"hands-on" experience in developing multi-centre HIV prevention trials, the network will undertake a multi-level training strategy, including merit-based academic scholarships for advanced research degrees, as well as yearly mentorship training opportunities. Through collaborative partnerships, practical experience and training opportunities the CAPT Network program of work will further develop the leadership and management capacity of its African partners.
Specifically, activities will include: infrastructure support for the research personnel at each site; support for academic and skill development through scholarships, mentorships and targeted training workshops; formalized research consortium to support the design, development, funding and execution of African-led prevention trials; and strong communication through annual meetings, an interactive website and the establishment of the research consortium.
3. The Canada-Sub-Saharan Africa (CANSSA) HIV/AIDS Network: Building Capacity for Prevention Trial Research and Clinical Care in Africa (Thumbi Ndung'u, Mark A. Brockman, University of Kwazulu Natal, Durban, South Africa, Simon Fraser University, British Colombia) $1.8 million
The goal of this project is to build a sustainable HIV/AIDS research network that utilizes existing expertise to enhance clinical, sociological, and biomedical research capacity throughout all of the linked sites in Africa. This will be accomplished through enhancing knowledge transfer (including staff training programmes and laboratory improvement strategies hosted through African "Sites of Excellence"); improving clinical and research infrastructure development (including support for laboratory equipment and data management); and collaborating on projects that develop cross-disciplinary approaches to HIV research. Activities will focus on the following five areas: developing an HIV/AIDS network that links developed and developing sites in Africa with expert support from investigators in Canada and the USA; transferring knowledge of advanced biomedical research and diagnostic techniques from Canada to South Africa; providing staff training opportunities in essential clinical, sociological, and biomedical skills; improving clinical and laboratory infrastructure through purchase of essential equipment and data management systems; and establishing collaborative, multi-site, cross-disciplinary pilot projects to explore shared interests.
4. Creating a Common Platform for HIV Vaccine Research and HIV Care and Treatment Program (Alash'le Abimiku, Gary E.Garber, Institute of Human Virology- Nigeria/Maryland, University of Ottawa, Ontario) $1.35 million
This HIV vaccine clinical trial capacity project will be implemented through a partnership between the Institute of Human Virology (Nigeria), a not-for-profit indigenous Nigerian organization and clinical research collaboration from the University of Ottawa. The program leads will implement the creation of an internationally-certified HIV clinical research site capable of conducting HIV vaccine clinical trials in populations with defined risk of HIV infection at the highest international standard.
The project will build on a large clinical and laboratory infrastructure developed in Nigeria. The three objectives for this capacity-building project are: clinical, research ethics and regulation capacity development; community mobilization and risk cohort development; and clinical research laboratory international certification. Research training under this project will benefit from collaboration with research training support from a University of Maryland grant. The synergies from this collaboration will result in a fully functional clinical trials unit with a well-engaged community, and robust ethics and regulatory infrastructure. The potential for addressing the epidemic by recombinant viruses unique to West Africa and 43% of the Sub-Saharan population through this study is significant.
5. The Kenya AIDS Vaccine Initiative (KAVI): A Centre of Excellence For HIV Vaccine/Prevention Trials In East Africa (Omu Anzala, Ruppert Kaul, University of Nairobi, Kenya, University of Manitoba, Manitoba) $1.8 million
The goal of the project is to establish KAVI as a Centre of Excellence for the training of health care professionals in Kenya and the East African region, on HIV vaccine and other prevention trials in East Africa. The project aims to: establish a Clinical Research Training Centre; enhance laboratory capacity to perform and offer training; build vaccine literacy and acceptance among local communities, policy makers and stakeholders; enhance the capacity of local ethics review boards to handle vaccine development; and enhance ability of KAVI to competitively bid for independent research funding for clinical trials.
The project will provide a wide-ranging, collaborative training programme that will build on productive and long-standing research collaborations with the Universities of Toronto and Manitoba. Specifically, activities will include: building local clinical trial expertise and capacity; improving local immune monitoring expertise and capacity; forging strong community ties and knowledge transfer exchange (KTE) capacity; building institutional capacity including within local research ethics boards, administrators and policy makers; and establishing the means for KAVI to sustain itself as a Centre of Excellence in the long term.
6. TanZamBo Capacity Building for HIV Prevention Research Network (Rosemary Musonda, John Shao, Modest Mulanga, Mark A. Wainberg, Botswana Harvard AIDS Institute Gaborone, Botswana, Kilimanjaro Christian Medical Centre, Tanzania, Tropical Diseases Research Centre, Zambia, McGill Aids Centre, McGill University) $1.35 million
The project will develop sustainable HIV/AIDS prevention trial expertise in Botswana, Tanzania and Zambia with an emphasis on
"learning by doing", using existing collaborations in Africa, Canada, and the USA. The project will improve the capacity of researchers to conduct various HIV/AIDS prevention trials including vaccines. The team members will use their comparative advantage in expertise and technology to strengthen the capacity of weaker institutions in HIV prevention interventions, through
"learning by doing". This project will recruit young scientists for MSc degrees in Clinical Research or Biostatics. In addition, the project will build capacity of postdoctoral fellows who will be co-managing the TanZamBo project at every site. Capacity building activities will also include short-term training in clinical trials design in Boston, and advanced laboratory techniques for virological markers for study endpoints at McGill. Networking activities will also include an undergraduate exchange programme for students in Tanzania, Zambia and Botswana to get exposed to HIV prevention research. This network will provide a platform for advocacy and dialogue with policy makers and communities in the TanZamBo countries to support HIV/AIDS prevention trials and vaccine research and development.
Specifically, activities will include: long-term training of research fellows for Master of Science degrees and postdoctoral fellows; short-term training; networking activities; infrastructure capacity improvement; community engagement and training in HIV prevention research; strengthening of review boards; creating platforms for dialogue with policy makers and researchers for advocacy on HIV/AIDS prevention research and trials; and monitoring and evaluation of the TanZamBo network.
7. West African Platform for HIV Intervention Research (WAPHIR) (Souleymane Mboup, Assan Jay, Université Cheikh Anta DIOP, (UCAD) Laboratoire de Bacteriologie Virologie, Dakar, Senegal, MRC Laboratories, Banjul, The Gambia) $1.8 million
The West African Platform for HIV Intervention Research (WAPHIR) Network Capacity Development Initiative will establish a West African driven partnership with Canadian and European collaboration to enhance HIV research and conduct Phase I and Phase II clinical trials in Senegal, Gambia and Guinea-Bisseau. The three sites, along with their Canadian and European partners, will develop and harness the resources of their regional HIV population cohorts to strengthen capacity in focused laboratory skills and clinical trials management. This will provide a shared unified database, an expanded HIV population and bio-bank resources, knowledge transfer, training in clinical trial support and the development of laboratory platforms to GCLP standards. Furthermore, it will strengthen capacity in maintaining laboratory equipment in the African sites through knowledge transfer of Biomedical Technology Management System.
A staff development programme will establish and ensure African scientific leadership through specialised work visits and "hands-on" training with Canadian and European collaborators who will provide support in specialized laboratory skills and clinical research trials. The existing collaborative research activities on clinical trial and laboratory work in HIV will be used as avenues to train young scientists in a post graduate apprenticeship 'sandwich' training programme.
8. Project under the Canadian HIV Technology Development Program: Design, Production and Evaluation of a Dendritic Cell Receptor-Targeted Multi-antigen Chimigen® HIV Prophylactic/Therapeutic Vaccine $491,500 (Akshaya Bio Inc.)
The company is using its proprietary Chimigen® Technology Platform to produce an effective prophylactic/therapeutic vaccine to prevent new HIV infections and to treat individuals who have been exposed to HIV. The technology is currently being used to develop therapeutic agents against various infectious diseases including chronic viral diseases, malaria and cancer. RNAi-based therapeutics for various disease conditions are also currently in development.
Sumagen Canada received approval from the United States Food and Drug Administration (FDA) in December 2011 to commence Phase I human clinical trials for a preventative HIV vaccine which is based on a genetically modified killed whole virus, SAV001. The HIV vaccine (SAV001) holds tremendous promise, having already proven to stimulate strong immune responses in preliminary studies with no adverse effects or safety risks. Financial support under The Canadian HIV Technology Development (CHTD) Program will assist Sumagen Canada to proceed more quickly to Phase I human clinical trials to test the safety of its SAV001 HIV/AIDS vaccine.
10. Project under the Canadian HIV Technology Development Program -"Identification of new targets for the development of immunotherapies to eradicate infected immune cells in HIV-1-infected patients" $464,407 (Alethia Biotherapeutics Inc)
The project will identify and validate new and highly-specific therapeutic targets for prevention and treatment of AIDS. The Research strategy will prioritize membrane-bound targets that are induced in target cells early upon exposure to HIV-1 with the objective of developing new vaccines and therapeutic mAbs.
ZBx Corporation develops rapid diagnostic platforms using its small-sample, whole-blood testing technology marketed under the trade name ZAP™. ZAP™ rapid tests operate on a simple platform technology requiring a single drop of whole blood from a finger prick with results in 10 to 15 minutes.
The objective of the project is to develop a point of care prototype to extract, detect and characterize HIV RNA from several millilitres of serum. The plan is to combine the extraction of nucleic acids, enrichment and detection into one instrument. The result of being able to effectively monitor the effectiveness of the drugs and the emergence of viral resistance will lead to better outcomes. The management of HIV infected patients is very complex. It is important to identify the strains and quantify the viral load. If this is successful it could be applied to other clinical applications. The focus will be to develop a prototype that will demonstrate proof of concept.
With the appearance of multi-drug resistance appearing to the present treatment using antiretroviral therapy, identification of new strains of Tuberculosis (TB), and the existing fact that numerous patients who have HIV also get tuberculosis, the aim of the project is to target two new mechanisms of action against the virus. These can interfere with both the formation of infectious particles and the un-coating process of the virus itself. The second class of compounds involve targeting receptors which activate seven trans-membrane G-protein-coupled receptors (7TM-GPCR). These receptors are shown to play a pivotal role in the entry of the HIV virus into the cell. The project is to produce new lead compounds for further development into preclinical candidates in collaboration with global partners.
The focus of this project is to produce monoclonal antibodies that are able to induce an anti-HIV immune response in an animal model. If successful this provides evidence that this approach could be used to develop a HIV vaccine.
This project is to develop and commercialize a test device for rapid Human Immunodeficiency Virus (HIV) p24 antigen detection for point-of-care application.
The overall goal is to develop a point-of-care (POC), CLIA-waived detection system for the determination of HIV-1 viral load in AIDS patients. During the 26-month project the development work consists of a non-infectious synthetic HIV RNA sample that will be reverse transcribed, isothermally amplified, and quantified electrochemically by a labtop platform reader. The labtop quantification system will be used as a basis to further develop a handheld platform system and disposable cartridge in subsequent years.
A new rapid flow-through HIV test platform that will capture both antigens and antibodies and provide an earlier diagnosis for patients exposed to HIV. This early detection reduces the risk of missing infected individuals that are in an early stage of the disease that is not yet detectable by other common testing methods.
Feasibility testing and pre-clinical toxicology studies, as well as human safety and efficacy clinical trials to examine the role of the Amp B delivery system in potentially treating patients with latent HIV reservoirs. Although current treatment regimes, such as highly active anti-retroviral therapy (“HAART”) have been very successful in managing and stabilizing HIV in patients, HIV can also persist by slowly replicating in tissue macrophages and blood monocytes. The long-lived HIV reservoirs enable long-term persistence of the infection during otherwise effective HAART and constitute a major roadblock to the complete eradication of HIV. To date, attempts to eliminate the virus from these reservoirs have been unsuccessful and the economic burden of HIV infection in the United States alone remains significant. The US Centre for Disease Control estimates the total lifetime treatment cost for HIV patients based on new diagnoses in 2009 at $16.6 billion. However, independent studies have demonstrated that Amphotericin B may be efficient at reactivating HIV-1 infection in THP89GFP cells, a model of HIV-1 latency in macrophages. Therefore, trans-reactivation strategies may hold the key to reactivating latent HIV-1 infections, in effect “flushing” the virus from the reservoirs and enhancing the effectiveness of existing therapies.
Support from the Canadian HIV Technology Development (CHTD) Program to support the production of antibodies that fight infection by disrupting the virus’s method of entry into human CD4+ lymphocytes (T-cells).
A dissemination strategy for the UNAIDS guidance document
"Good Participatory Practice Guidelines for Biomedical HIV Prevention Trials" was developed and implemented by UNAIDS. The guidelines, developed in English, were translated, laid out in graphic design and were printed in large quantities. Dissemination of the guidelines occurred through workshops, seminars, community mobilisation activities/initiatives (targeting specific vulnerable populations), conferences, UNAIDS and relevant stakeholder websites and NGO websites.
The Good Participatory Practice guidelines were intended to provide systematic guidance on the roles and responsibilities of entities funding and conducting biomedical HIV prevention trials towards participants and their communities. The objective of this project was to get the guidelines into the hands of those involved in HIV prevention trials, including clinical trials for HIV vaccines. As such the project was in line with one of the
"global access" guiding principle of the Canadian HIV Vaccine Initiative and it served to promote the community aspects of HIV vaccine research and delivery.
This project was intended to strengthen the ethical-legal framework for HIV vaccine trials and build the capacity of key actors in host countries to address the key ethical issues and challenges posed by these trials, including participation of adolescents. To meet these objectives, a range of research, training, advocacy and networking activities were carried out by the World Health Organization (WHO), UNAIDS and the African AIDS Vaccine Partnership. The project facilitated collaboration between partners in Canada and low and middle income countries to advance the legal, ethical and human rights dimensions of HIV vaccines.
The $2 million project is being implemented by the World Health Organization to support capacity-building activities intended to improve regulatory capacity in low-to-middle income countries, especially in countries where clinical trials are planned or are ongoing. The capacity-building activities, including workshops, training and guidelines development will increase the capacity of national regulatory agencies to assess HIV vaccine trial applications, to monitor approved clinical trials, and evaluate clinical trials data.
The objectives of the project are to: Strengthen National Regulatory Authorities (NRAs) in African countries targeted for vaccine clinical trials; support the integration of ethical review, regulation and registration of clinical trials in Africa; promote and strengthen collaboration between ethical and regulatory authorities in targeted African countries; and develop training materials, including e-learning tools for NRAs and Ethics Committees.
Expected outcomes from this project will include the establishment of a Secretariat for the African Vaccine Regulatory Forum (AVAREF) in Africa, as well as formalization and expansion of the network, currently comprised of NRAs and ECs from 19 African countries. The project will also contribute to harmonization of regulatory practices and standards for clinical trials; will strengthen Ethics Committees through training and financial support; and will work to establish national oversight bodies to monitor Institutional Review Boards.
Funding is being provided to support the AIDS Vaccine conferences and other Enterprise program activities, including: activities related to the renewal of the 2005 Scientific Strategic Plan (SSP); key priorities of the 2010 SSP; scientific workshops; and the young and early career investigator web portal.
The overall objectives of this contribution are to foster collaboration and to identify the latest scientific developments and gaps in HIV vaccine research. The overall outcomes of this contribution will further increase capacity for HIV vaccine research and development in developing countries; provide a venue for international scientific exchange on HIV and AIDS research; and accelerate the development of a preventative HIV vaccine.
The CHVI Regulatory Capacity Mentorship Program is designed to provide a one-on-one learning opportunity for national regulatory authorities (NRAs) who wish to strengthen their capacity in the context of vaccine and clinical trial regulation, to prepare for the future evaluation of an HIV vaccine application. Malawi is the Program’s first participant NRA and the mentorship relationship is expected to last 2-3 years. Initiated: February 2012.
Providing sponsorship to national regulatory authorities from low and middle income countries (LMICs) within Africa, Asia and South America; and offering training in the regulation of vaccines to help strengthen capacity in the regulation of HIV/AIDS vaccine clinical trials.
Support is being provided to the newly appointed African AIDS Vaccine Partnership, hosted at the Uganda Virus Research Institute, to establish an effective and functional African-based secretariat for sustainable and sound pan-African partnership of HIV vaccine stakeholders; to mobilize African and non-African resources; to advocate for African involvement as a key stakeholder in global HIV prevention, treatment and vaccine development efforts; to improve African ethical, legal and regulatory frameworks for HIV vaccine research; and to develop innovative capacity-building strategies to increase African research capacity.
Since 2011, support is being provided to the Canadian Association for HIV Research for their annual conferences in order to advance effective, evidence-based HIV prevention technologies by promoting greater involvement and collaboration among Canadian researchers and HIV community stakeholders.
Support was provided for the translation of the Ethical considerations in biomedical HIV prevention trials and Good participatory practice guidelines for biomedical HIV prevention trials (GPP). A “Guidance Point 20: People who inject drugs” was also developed and incorporated in the existing guidance document.
The objectives of the project are to provide training to a wide variety of community groups that address both domestic and international concerns and challenges regarding NPTs; diversify and increase the number of Canadians in prevention networks who access NPT information; and to raise awareness amongst students about NPT-related research opportunities in basic science, clinical or social science perspective.
On May 13, 2010, the Interagency Coalition on AIDS and Development (ICAD), the Canadian AIDS Society (CAS) and the Canadian AIDS Treatment Information Exchange (CATIE) hosted the Ancillary Event at the 19th Annual Canadian Conference on HIV/AIDS Research:
"Prevention technologies in the broader spectrum of HIV prevention". This day-long satellite session brought together 39 researchers, community and public health workers, community members and government stakeholders to explore how new HIV prevention technologies (NPTs), including vaccines, microbicides and pre-exposure prophylaxis, may fit within the broader continuum of HIV prevention strategies already in use.
The objectives of the event were: to explore how new prevention technologies may fit within the current landscape of HIV prevention strategies in Canada; to identify specific stakeholder needs and capacities in the area of NPTs; and to identify the major issues that are emerging in policy, programming, research and community advocacy, and which stakeholders need to be involved in each of these areas.
The objectives of the proposal are to build capacity of front-line workers and community-based organizations through a satellite presentation on vaccines and other prevention technologies and, to encourage individuals working primarily in HIV/AIDS to participate in the 6th Canadian HIV/AIDS Skills Building Symposium and NPT and vaccines satellite session by providing a scholarship to facilitate their attendance.
In order to promote global understanding, two participants from low and middle income countries will be supported to attend the conference, and the satellite session. They will also be invited to Ottawa to participate in site visits with host organizations namely, CAS and ICAD, and to give a presentation to officials at the Public Health Agency of Canada. The satellite session will increase knowledge within the HIV/AIDS community; provide a channel for key operators to inform and update their communities about progress made in the HIV vaccine and other prevention technologies; help build a stronger HIV/AIDS community network for ongoing engagement and, provide an opportunity for knowledge-sharing on new prevention technologies and vaccines.
The CAS project is currently underway. Under this project, CAS will undertake an analysis of trends, and lessons learnt from the deployment of vaccines and other public health measures in target populations. Community groups will be engaged through a best-practices symposium, and key informant interviews. The analysis will identify best practices for vaccine deployment in target populations and community resources that meet these needs, including methods for communicating with target communities, and tools such as fact sheets and guides based on the practices identified through the project. CAS has been championing the need for vaccines for six years by providing supports within the community-based AIDS movement to develop awareness and knowledge on this issue.
The project focuses on populations within Canada, as well as internationally. Research into best practices and findings around deployment of vaccines will serve to identify key thematic areas which will then be presented for discussion at a Best Practices Symposium, where participants will engage in a dialogue about the significance of the identified lessons and what they mean in a cultural context.
Results from this project will represent a synthesis of findings relevant to these communities. A background paper of findings and best practices will be developed. Through funding available in this proposal, the preliminary findings from this analysis will be presented and the research paper will be made available as part of a satellite presentation at the 2010 International AIDS Conference. The satellite session will be co-hosted by the Canadian AIDS Society, the Interagency Coalition on AIDS and Development, and the International AIDS Vaccine Initiative. Following the presentation at the 2010 International AID Conference, tool kits will be produced and sent to members of CAS and will be shared with the Canadian AIDS Treatment Information Exchange distribution centre.
ICAD will partner with the Southern African AIDS Trust in South Africa, and the New HIV and Microbicides Advocacy Society, in Nigeria, to share knowledge and expertise between Canadian and international collaborators; to build capacity within the three organizations; and facilitate broad dissemination of project materials.
The project will include a review of existing resources on HIV vaccines and other new prevention technologies. This information will form the basis for assembling a toolkit and a training package on HIV vaccines and prevention research, and for designing location-specific training workshops for community leaders and the media in Canada, Nigeria, and Southern Africa. The toolkit and training package will be pilot-tested in the three countries and upon finalizing the products, training will be delivered to community representatives, the media and journalists in the three countries. The three partners will disseminate the toolkit to their membership, networks, and the Canadian AIDS Treatments Information Exchange. ICAD will submit an abstract of the project to the International AIDS Conference in 2010.
6. Preparing the Canadian Public Health Community for New HIV Prevention Technologies: Understanding the Knowledge, Information Needs, and Potential Role of Public Health Workers in Canada and Learning from the Experiences in Southeast Europe (Canadian Public Health Association) $386,025
The Canadian Public Health Association (CPHA) represents over 25 public health disciplines ranging from nurses, dieticians, epidemiologists, to academics and public health officials. Its mandate is to constitute a special national resource in Canada that advocates for the improvement and maintenance of personal and community health according to the public health principles of disease prevention, health promotion and protection and healthy public policy. The CPHA addresses issues of significance in the domestic and international public health community, lending its expertise to more than 35 countries worldwide, including the Balkan Region of Southeast Europe which experiences similar rates of HIV infection as Canada, but with far fewer public health resources to deliver programs and services. This project aims to enhance understanding of the current knowledge, information needs, challenges and potential role of public health workers in Canada with respect to new HIV prevention technologies (NPTs) and contribute to the introduction and roll-out of NPTs in Canada. Through a partnership with non-government organizations in Southeast Europe, the project will also contribute to the beginning of a similar process in the Balkans region and will produce internationally relevant tools and materials as part of Canada's contribution to the development of global policies and frameworks in HIV vaccine delivery.
The CPHA will analyze the knowledge currently held by public health workers regarding HIV prevention technologies, and develop strategies to enhance the capacity of these workers to assist in the introduction and delivery of HIV vaccines and new prevention technologies as they become available.
To guide the project, a pan-Canadian advisory committee will be established. The committee will be comprised of federal and provincial/territorial representatives, public health workers, legal experts, HIV/AIDS organizations, representatives from Southeast Europe and people living with HIV/AIDS.
A national consultation will document community-based HIV prevention initiatives and best practices in Canada. An analysis will be conducted of the capacity of local health systems in Canada to deliver new HIV prevention technologies and next steps for trials. The roll-out in Canada will be identified and the CPHA will produce a report with recommendations for the introduction of new HIV prevention technologies in Canada.
The expected results of the project include: an analysis of the infrastructure and education required for the introduction of HIV vaccines and NPTs in Canada; an understanding of the potential role for public health workers with respect to HIV prevention technologies in Canada and in the Balkans; and the enhanced ability of public health workers to introduce and deliver an HIV vaccine and new prevention technologies, particularly to vulnerable populations in Canada.
The objectives of the project are to increase knowledge and understanding among frontline workers and policymakers about emerging biomedical approaches to HIV prevention; increase the capacity and readiness of front line organizations and policy makers to effectively participate in the research, development and implementation of new biomedical approaches to HIV; increase the capacity of researchers, frontline workers and policymakers to share and build knowledge for the integration of new biomedical prevention technologies into a national HIV prevention response, which includes current successful social and behavioural approaches, and provide an opportunity for frontline workers and policy makers to learn from the experiences of local, regional, national and international agencies already exploring the use of new prevention technologies.
The Alliance Coordinating Office (ACO), hosted at the International Centre for Infectious Diseases, will establish, lead, and promote the CHVI Research and Development Alliance which will be comprised of a network of public and private sector organizations, academic institutions with expertise in HIV/AIDS and vaccines fields as well as the international community. The Alliance will harness Canada' scientific excellence to make a significant contribution to global HIV vaccine efforts. Through the Alliance, innovative solutions, creative synergies and collaborations within the HIV vaccine development community and the broader vaccine community will be fostered. The ACO also provides administrative support to the CHVI Advisory Board.
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