ARRA Investments in Vaccine Development for AIDS-associated Malignancies
Public Health Burden
People infected with the human immunodeficiency virus (HIV) are at increased risk of developing cancer. It has been estimated that 30 to 40 percent of infected individuals are likely to develop cancer sometime during their lifetime. Cancer has been and remains a leading cause of death among HIV-infected persons.
AIDS-associated Malignancy Overview
Major advances in knowledge about HIV and its role in acquired immune deficiency syndrome (AIDS) and the development and application of treatments such as highly active antiretroviral therapy (HAART) have greatly increased the survival of people with HIV/AIDS. Accompanying this improvement in survival, however, has been an increase in the incidence of cancer among long-term HIV/AIDS survivors. Indeed, cancer is becoming the most frequent cause of death among HIV-infected populations. Because HIV suppresses the immune system, even in the presence of HAART, people with the virus are more susceptible than uninfected people to infection with other viruses that cause, or are strongly suspected of causing, cancer. These viruses include Kaposi sarcoma-associated herpesvirus (KSHV), which is associated with Kaposi sarcoma; Epstein-Barr virus (EBV), which can cause non-Hodgkin and Hodgkin lymphoma; human papillomavirus (HPV), which causes cervical cancer and is associated with anal, penile, vaginal, and vulvar cancers and some types of head and neck cancer; hepatitis C virus (HCV), which causes liver cancer; and Merkel cell polyomavirus (MCPyV), which is associated with Merkel cell carcinoma (MCC), a rare cancer of the skin.
ARRA funds are supporting efforts to develop vaccines to prevent or treat infections with these viruses (for HPV, vaccines to provide protection for types not represented in existing HPV vaccines) and HIV itself—to prevent or limit HIV infection in the host. These efforts will cover all phases of vaccine development, from basic science studies through animal model development to preclinical studies.
Vaccines that prevent or eliminate HIV infection would, by definition, reduce the incidence of all AIDS-associated malignancies. Several ARRA-supported projects are focused on this goal, including the following:
A study to evaluate a vaccine that targets CCR5, which is a host cell protein used by HIV to infect cells. The rationale is to induce antibodies against this self-protein that will attach to CCR5 on the surface of host cells and block HIV infection.
A study using a simian immunodeficiency virus (SIV)/macaque monkey model to develop a novel therapeutic approach for HIV/AIDS that involves two components: an antibody that blocks the activity of a protein called programmed death-1 (PD-1), which results in enhanced immune responses, and a vaccine designed to induce immune responses against SIV antigens.
A study to improve an anti-HIV vaccine that is based on the Full Length Single Chain (FLSC) region of gp120, which is a protein found on the outside of HIV particles that is necessary for viral infection. This vaccine induces a temporary immune response in a macaque model. Researchers will test whether combining the vaccine with Tat toxoid—a biologically inactive but highly immunogenic form of Tat, an HIV protein released from acutely infected cells that causes suppression of T cell immune responses—results in a more sustained immune response.
KSHV and EBV are both gamma herpesviruses that evade the host’s immune system and establish life-long infections. These infections are marked by prolonged periods of latency and intermittent periods of reactivation. KSHV and EBV are associated with the development of certain cancers and other conditions in people with HIV/AIDS. Several ARRA-supported research projects are aimed at developing vaccines against this class of viruses, as well as the individual viruses. For example:
A project to use a mouse model of gamma herpesvirus infection to test the efficacy of genetically engineered viruses as vaccines.
A project in which a mouse model of EBV-associated lymphoproliferative disease (EBV-LPD) will be used to systematically test the efficacy of vaccination with viral proteins to prevent EBV-LPD; the goal is to identify specific proteins for use in future clinical trials in humans.
A project to investigate how the immune system normally recognizes and suppresses infection by KSHV and the cancers it can cause, and then to develop new ways of using vaccines made from parts of the virus to boost the ability of HIV/AIDS patients to fight KSHV infection and prevent and/or treat the diseases caused by this virus.
Several HPV vaccines have been developed, but they protect against only a few specific types of the virus. ARRA funding is supporting research to address HPV infection more broadly. For example:
A project to develop a vaccine based on the HPV L2 capsid (outer coat) protein, which induces antibodies that protect against multiple cancer-causing HPV types.
HCV is the major cause of liver cancer in both HIV-uninfected individuals and people with HIV/AIDS. ARRA-funded research projects include the following:
A project to develop a vaccine against HCV based on synthetic structures, called peptoids that are recognized by already existing neutralizing monoclonal antibodies against HCV.
Approximately 80 percent of cases of MCC, a rare and highly lethal skin cancer, are associated with a newly discovered virus, MCPyV. ARRA-funded research projects include the following:
A project to define the immune responses against MCPyV in normal individuals and MCC patients, identify strategies by which MCC evades immune responses against it, and begin the process of developing a vaccine or immunotherapy interventions for this disease.
-- Evaluation of a CCR5 vaccine for HIV infection in the SIV/macaque model -- Chackerian, Bryce C (NM)
-- PD-1 blockade combined with vaccination as a therapy for SIV/AIDS -- Amara, Rama Rao (GA)
-- FLSC combined with TAT toxoid as an HIV prophylactic vaccine ¬-- Gallo, Robert C (MD)
-- Immunogenicity and efficacy of genetically engineered gamma-herpesvirus vaccines -- Blackman, Marcia A (NY)
-- Development of vaccine strategies to prevent EBV+ lymphoma in patients with HIV -- Baiocchi, Robert A (OH)
-- Strategies for therapeutic vaccination against KSHV -- Kedes, Dean H (VA)
-- Development of low cost and broadly protective human papillomavirus vaccines -- Roden, Richard B (MD)
-- A novel vaccine to prevent HCV infection and hence liver cancer -- Vitetta, Ellen S (TX)
-- Targeting MCPyV to overcome immune evasion in Merkel cell carcinoma -- Nghiem, Paul (WA)
Page Last Updated on June 30, 2018
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