The team working on this project believes it has developed a vaccine vector that will give a better immune response than existing therapies for a variety of hard-to-treat viruses. Using attenuated vaccinia virus (Cowpox), the HIV genes are added to a patented mutation of the virus to draw the immune system’s attention to the target virus’s proteins, thus creating a strong immune response.
One of the reasons to work with vaccinia virus is its potential affordability: it is very cheap to grow, easy to administer (usually by scratching the skin), and doesn’t require a cold chain. Its relative safety for humans means that it can also be used as a delivery system for antigens for viruses. In addition to HIV vaccine applications, the approach is being used to develop a better smallpox vaccine which has the potential to be highly effective but will be a much safer vaccine than the one currently available, and the platform is also being used for hepatitis B.
The research revolves around understanding the molecular mechanisms of action of interferon, particularly as they concern control of gene expression at the level of translation. Interferons are a set of proteins secreted by vertebrate cells in response to virus infection or antigen stimulation. Interferon inhibits viral replication by inducing a double stranded RNA-activated protein kinase, PKR, which can phosphorylate, and inactivate eukaryotic protein synthesis initiation factor 2, thus preventing synthesis of viral proteins. It also acts to inhibit cell proliferation.
Numerous viruses, including vaccinia virus, have been shown to code for inhibitors of the interferon-induced protein kinase. These virus-encoded inhibitors allow the virus to circumvent one of the organism’s main defenses against virus protection and they also appear to prevent infected cells from committing suicide in response to infection. The project team aims to understand the molecular nature of the vaccinia viral kinase inhibitors and what role these inhibitors have in replication of these viruses in mammalian cells in culture and in infected animals. The goal is to use these studies in the development of safer, more effective vaccines for both humans and animals.
This project is aimed at preventing infection at the source, formulating trial vaccines to engage the body’s mucosal surfaces, the primary points of entry for the HIV contagion.
The process of HIV-1 viral replication is now fairly well understood. A central challenge facing researchers working on vaccines against retroviruses like HIV is how to derail the pathogen’s earliest invasive efforts. The HIV virus manages to integrate its genome into that of its host, initiating a chronic infection within days of primary exposure. This leaves only a narrow window of time to eliminate the virus completely. Further sabotaging efforts to combat HIV is the rapid, compulsive mutation of the virus which allows it to outpace the immune system’s efforts to generate an effective response.
In addition to mutation, HIV employs other tricks to evade immune detection, such as shielding critical protein components, camouflaging these in a thicket of surface glycans, while making use of sophisticated protein decoys to fool the body. Armed with this profile of the virus, Biodesign researchers are approaching the challenges of arresting the progression of HIV on the basis of four fundamental assumptions:
The research team is applying protein engineering efforts to the design of vaccine candidates consisting of a mucosal targeting component fused to a peptide corresponding to a section of gp41—an HIV-1 envelope protein. The specific region of gp41 is not only the target of two broad-spectrum neutralizing monoclonal antibodies, 2F5 and 4E10, but was also shown to be critical for the mucosal transmission of the virus.
In pre-clinical trial experiments, systemic and mucosal antibodies raised against this novel immunogen were shown to inhibit the crossing of a tight epithelial cell layer by an HIV-1 primary isolate, and also displayed some ability to neutralize infection of CD4+ (helper-T) cells, a leading component in effective immunodefense. The immunogen, as well as “next generation” vaccine candidates, are expressed in a variety of systems including bacteria, insect cells and plants.
The majority of those infected with HIV reside in poor countries and cannot afford existing antiretroviral drugs. This research offers hope for an effective, stable, and low-cost means of preventing HIV exposure from developing into a lethal AIDS infection.
The goals of the project (Plant Made Microbicides and Mucosal Vaccines for STIs) is to design and produce mucosal vaccines in plant expression systems for sexually transmitted viral diseases and to test these vaccines in pre-clinical animal trials and in human trials. A second proposed project is to produce mABs in plants which neutralize sexually transmitted viruses or which block viral receptors, and test them in human trials using vaginal delivery. While there is no programmatic overlap, both projects use transgenic plant technology as a common platform.
The research team leading this project has focused on the design of crops that will accumulate therapeutic compounds and vaccines in the leaves, fruits, grains, or storage tissue. They have been able to produce immunogenic proteins that can act as oral vaccines when ingested. They have conducted successful Phase I clinical trials with plant-derived vaccines against hepatitis B, enterotoxigenic E. coli, and Norwalk virus. These vaccines have shown particular utility in preventing diarrhea—still one of the two top causes for child mortality worldwide.
In addition to the obvious humanitarian benefits, vaccine production in crops affords other advantages including:
Disturbed cells, whether in HIV infection or cancer, make aberrant proteins-- proteins not produced at significant levels by normal cells. Since our strategy focuses on identifying proteins in the body that are only produced upon HIV infection, these proteins would be tested for their ability to specifically target and kill HIV infected cells. Once found, these proteins could be used as the basis to make a vaccine to prevent AIDS. Because this approach borrows from a process Biodesign has applied to cancer cells, the infrastructure for its execution is in place.
Each month, innovative research from the Biodesign Institute appears in the world’s premier scientific journals. Many such studies have graced the covers of these journals, showcasing Biodesign research ranging from water remediation to nanometer-scale structures built from DNA.
Air Toxics and Children’s Asthma: A Mixed Tale of Epidemiologic Evidence
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