- Category: HIV Vaccines
- Published on Monday, 10 November 2014 00:00
- Written by Craig Rouskey
Microparticles containing conserved HIV epitopes may be able to prime antigen-presenting dendritic cells, which in turn activate antigen-specific CD8 killer T-cells, offering a potential new approach for developing T-cell-based preventive or therapeutic HIV vaccines, researchers with the open-access Immunity Project reported at the HIV Research for Prevention (HIV R4P) conference last week in Cape Town.
[Craig J. Rouskey is an immunology researcher working with the Immunity Project.]
It has been over 30 years since HIV was identified as the cause of AIDS. Since its explosion into a global pandemic, more than 60 million people have been infected and nearly half of them have died. There are currently more than 35 million people living with HIV worldwide, according to World Health Organization estimates, and only one-third have access to antiretroviral therapy. The lack of access to effective treatment is astonishing in light of the profits generated by large pharmaceutical manufacturers of HIV drugs. Surely there must be a way for crucial therapies to make their way into the hands of the sick populations around the world?
During the opening plenary of the HIV R4P meeting, Jared Baeten from the University of Washington in Seattle spoke about his hope for a future in which scientific innovations drive forward the prevention and treatment of HIV. While many share his hope, it must be said that scientific progress alone will not end the epidemic. To eliminate HIV/AIDS, there also must be a broad commitment from researchers and businesses to ensure that their work benefits affected communities. Technology must be opened up to provide low-cost alternatives to commercial medicines and to allow for the rapid enhancement of current therapeutics.
Today, researchers experimenting with open-access science offer innovative solutions in which scientists, academics, business people, and the public work collaboratively to develop the technologies needed for a better world. As a step forward in the movement towards open science, the Immunity Projectseeks to develop an open-access HIV-1 vaccine that promotes CD8 T-cell responses when delivered by biodegradable microparticles. If this research is successful, the Immunity Project aims to provide this vaccine free to the world.
Until recently, the central dogma around HIV vaccines has focused on protective antibody responses generated through B-cell or humoral immunity. This approach has resulted in 15 years of failed vaccine development and has cost billions of dollars. Now, a growing number of researchers are pushing back, stating that cytotoxic T-cell or cellular immunity is necessary to eliminate HIV from the body and to provide complete protection. Further, scientists are realizing that taking advantage of both the humoral and cellular arms of the immune response may be the "silver bullet" when seeking to prevent, treat, or possibly even cure HIV.
The technology platform used by the Immunity Project consists of poly-L-lactic-glycolic acid (PLGA) microparticles loaded with cytosine-phosphate-guanine (CpG), monophosphoryl lipid A (MPLA), and conserved HIV epitopes recognized by cytotoxic CD8 T-cells. The CpG and MPLA components serve as adjuvants designed to activate and promote maturation of dendritic cells, while directing CD8 T-cells toward human leukocyte antigen (HLA) class I presentation of viral epitopes, or key proteins that remain stable across specific virus strains.
HLA is a molecule on the surface of all cells that presents viral proteins to CD8 killer T-cells. Mature dendritic cells are the major antigen-presenting cells. Upon recognition of these viral antigens in conjunction with HLA class I, the killer T-cells are activated and effectively destroy cells presenting the viral proteins -- thereby eliminating the virus itself.
The Immunity Project’s vaccine candidates target antigen presentation. Variations of this method have been used by other researchers in vaccination and treatment for cancer and other viral pathogens.
In the research presented at HIV R4P, investigators tested PLGA microparticles containing conserved epitopes from the HIV-1 core structural Gag protein in vitro. We found that monocyte-derived dendritic cells exposed to the microparticles were more than 64% mature, based on cell surface markers. These dendritic cells induced upregulation of HLA class I antigen presentation. We observed both non-specific activation of CD4 helper T-cells (described as a "bystander effect") and epitope-specific activation and proliferation of CD8 killer T-cells. These primed CD8 T-cells effectively suppressed in vitro levels of p24, an antigen associated with early HIV replication.
"We are aware of the limitations of this in vitro study as a measure of in vivo efficacy of a possible therapeutic/prophylactic vaccine," the team concluded. "Nevertheless, our data suggest that the PLGA microparticles are effective antigen delivery vehicles and show promise as readily manufactured, stable, inexpensive T-cell vaccines against HIV-1."
The Controversy and the Promise
In a recent article in Nature News, Erika Check Hayden detailed the controversy surrounding the Immunity Project’s goals, funding approach, and technology. The article included a pointed criticism by immunologist Louis Picker of the Oregon Health and Science University in Portland. He stated that the Immunity Project is "preying on people who are desperate for a vaccine," and that "[t]he concept they're selling is an old concept that has been shown not to work, and can't work."
Contrary to these comments are positive results published by the Immunity Project, which is working to develop the biodegradable microparticle delivery platform for a broad range of viral and cellular diseases, as well as a philosophical shift within the HIV prevention field toward recognizing the benefits of CD8 T-cell vaccination. In an interesting twist, Picker himself just received $25.5 million from the Bill & Melinda Gates Foundation to conduct T-cell vaccine research.
The Immunity Project is a non-profit spinoff of Flow Pharma, Inc., a private, for-profit company that has provided an open license to the project for the indefinite use of its patented technology. (The Immunity Project is a fiscally sponsored project of the not-for-profit HIV charity "Until There's a Cure.") Though there is no expected direct financial gain for Flow Pharma, the benefit comes through validation of its delivery platform -- that is, by validating the platform through the Immunity Project's work, Flow Pharma will be able to develop and profit from other antiviral vaccines using the same technology, while keeping the HIV vaccine free for all.
The Immunity Project receives money through crowd-funding and from the technology start-up accelerator Y Combinator, better known for funding computer applications. This type of public-private partnership has the potential to transform the way medical therapies are developed and delivered to people in both wealthy and low-income countries.
Many traditional academic and industry scientists have pushed back against the Immunity Project's funding model. There is an unspoken social mandate in the scientific community that research funding provided through institutions such as universities and pharmaceutical companies is more legitimate than research performed without these institutions.
Yet large, established funding sources are laden with bureaucracy and politics, which can slow or curtail the research and development process. As such, we see an increasing number of scientists moving towards open-access, crowd-funded approaches. The Immunity Project seeks to develop these new funding mechanisms to deliver a tangible public benefit.
SS Killingbeck, S Zompi, V Paranjpe, et al. Eliciting Cytotoxic T-lymphocyte Responses to HIV by Human Dendritic Cell Driven in vitro T-cell Activation with Synthetic Peptide-containing Microspheres. HIV Research for Prevention (HIV R4P). Cape Town, South Africa, October 28-31, 2014. Abstract P41.11.