DNA immunization protocols
Inventors
Felber, Barbara • Pavlakis, George N.
Assignees
HEALTH AND HUMAN SERVICES GOVERNMENT OF United States, THE, Secretary of, Department of • US Department of Health and Human Services
Publication Number
US-8586055-B2
Publication Date
2013-11-19
Expiration Date
2027-01-12
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Abstract
This invention provides DNA vaccines for the treatment of patients undergoing anti-retroviral therapy. The vaccines are surprisingly effective at controlling viremia.
Core Innovation
This invention provides DNA vaccines for the treatment of patients undergoing anti-retroviral therapy (ART). The vaccines are surprisingly effective at controlling viremia and induce potent and long-lasting virus-specific immune responses which control viremia after ART cessation. The DNA vaccination regimens show evidence of triggering a Th1 response with prominent induction of cellular immune responses.
The invention addresses the problem that in HIV infection treated by ART, viremia rebounds rapidly upon treatment interruption because HIV remains in pharmacological sanctuaries. Chronic use of ART leads to toxicities and viral resistance, and therapy must be continued indefinitely, highlighting the need for improved immunizations that can control virus post-ART cessation.
The method involves administering an immunogenic composition comprising one or more expression vectors encoding fusion proteins including degradation polypeptides linked to immunogenic retroviral polypeptides, secreted fusion proteins with secretory polypeptides linked to viral polypeptides, and cytokines such as IL-15 and its receptor alpha, IL-12, and IL-2. The DNA vaccines are typically administered by electroporation multiple times, often three or more doses, to individuals undergoing or who have undergone ART, resulting in prolonged immune responses and control of viremia upon stopping ART.
Claims Coverage
The patent includes one independent claim focusing on a method of inducing an immune response in a retrovirus-infected individual using a specific immunogenic DNA vaccine composition administered by electroporation.
Immunogenic composition comprising multiple expression vectors encoding retroviral antigens linked to degradation or secretory signals
The method comprises administration of DNA expression vectors encoding a Gag polypeptide linked to a β-catenin destabilizing sequence, a Gag polypeptide linked to an MCP-3 secretory polypeptide, an Env polypeptide, an Env polypeptide linked to an MCP-3 secretory polypeptide, a Pol polypeptide linked to a LAMP degradation signal, and a polypeptide including Nef, Tat, and Vif antigens linked to a LAMP degradation signal.
Incorporation of cytokine components in the immunogenic composition
The immunogenic composition includes an IL-15 receptor alpha polypeptide and an IL-15 polypeptide linked to a secretory signal polypeptide, which may be encoded on the same or separate expression vectors. The IL-15 polypeptide may be linked to secretory signals such as tPA, IgE, or GM-CSF.
Administration regimen and result
The immunogenic composition is administered at least three times by electroporation into muscle, concurrently with ART, resulting in control of viremia upon cessation of ART. The components can be administered sequentially.
The independent claim recites a therapeutic method employing a multi-component DNA vaccine administered by electroporation to ART-treated retrovirus-infected individuals. The vaccine encodes fusion proteins with degradation and secretory signals, incorporates cytokines IL-15 and its receptor, and requires multiple administrations to achieve control of viremia post-ART.
Stated Advantages
The vaccines are surprisingly effective at controlling viremia in primates undergoing or post-ART.
The immunogenic compositions induce potent and long-lasting virus-specific immune responses controlling viremia after ART stopping.
DNA vaccination regimens trigger a Th1 response with prominent induction of cellular immune responses, including increased effector and central memory T cells.
Administration of IL-15/IL-15 receptor alpha enhances mobilization and function of lymphocytes, augmenting vaccine-induced antiviral immune responses.
DNA vaccines can be administered multiple times, with repeated administration boosting immune responses without adverse effects.
Documented Applications
Treatment of individuals infected with retroviruses, especially HIV, receiving or having received antiretroviral therapy.
Therapeutic vaccination protocols in primates chronically infected with SIV receiving ART to control viral rebound after ART cessation.
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