Despite the fact that fungal diseases are an increasing clinical burden, particularly among immunocompromised patients, there are no anti-fungal vaccines approved for clinical use. The fungal opportunistic pathogen, Pneumocystis jirovecii is the causative agent of Pneumocystis pneumonia (PCP), which remains a serious AIDS-defining, opportunistic infection and is of increasing concern in persons receiving immunosuppressive therapies, including organ transplant recipients, cancer patients, individuals with inflammatory disease and in persons experiencing natural immunosuppression due to aging, congenital or acquired immunosuppressive states. In addition to causing PCP, several studies have shown an association between Pc colonization and chronic obstructive pulmonary disease (COPD) in both HIV-infected and non-HIV infected populations. Each of these patient populations would benefit from either a prophylactic PCP vaccine administered prior to immunosuppression (for example, prior to a clinical course of immunotherapy) or in populations at risk for HIV infection or individuals at the time of diagnosis of HIV infection. The overall goal of this research is to develop a vaccine for prevention of PCP and related pulmonary sequelae in HIV+ and other immunocompromised populations. Toward this end, we have identified and developed a vaccine candidate based on the Pneumocystis protein, kexin. We have produced a vaccine candidate based on Pneumocystis protein, kexin, and showed that immunization of non-human primates (NHP) prior to simian immunodeficiency virus (SIV) infection induces high level, kexin-specific plasma and lung immunoglobulin titers and protects against Pneumocystis pneumonia. The objective of this Phase I application is to complete lead optimization of the vaccine by testing the immunogenicity of the Pneumocystis jirovecii-derived kexin protein derivative. We will assess the immune response in NHPs following immunization and boost with the P. jiroveciii recombinant peptide in SIV-infected macaques and will evaluate the duration and quality of the specific memory responses in the immunosuppressed state. With the completion of this proof of concept study, we will focus efforts on preparation and evaluation of the vaccine for clinical trial.
Public Health Relevance Statement: Public Health Relevance: Pneumocystis jirovecii is the causative agent of Pneumocystis pneumonia (PCP), which remains a life-threatening, AIDS-associated infection and is of increasing concern in individuals with weakened immune systems. The research proposed in this application will further advance a vaccine candidate which has been shown to induce protective immune responses in experimental models of HIV- induced immunosuppression and Pneumocystis pneumonia. The successful completion of these studies will advance this vaccine candidate toward clinical trials.
Project Terms: Acquired Immunodeficiency Syndrome; Address; Adverse reactions; Aging; Amino Acids; Antibody titer measurement; Antifungal Agents; antiretroviral therapy; B-Lymphocytes; base; Biology; Cancer Patient; Chronic Obstructive Airway Disease; Clinical; Clinical Trials; commercialization; Development; Diagnosis; Disease; disorder control; Drug resistance; experience; Experimental Models; Formulation; Frequencies; Fungal Vaccines; Genomics; Goals; HIV; HIV diagnosis; HIV Infections; Human; Immune response; Immune system; Immunity; Immunization; Immunocompromised Host; immunogenicity; Immunoglobulin A; Immunoglobulin G; Immunoglobulins; Immunologic Memory; Immunologics; immunosuppressed; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Vitro; Incidence; Individual; Infection; Inflammatory; Inflammatory Response; lead optimization; Life; Lung; Macaca; Memory; Modeling; Morbidity - disease rate; mortality; natural antibodies; nonhuman primate; novel; Obstructive Lung Diseases; Opportunistic Infections; Organ Transplantation; Organism; pathogen; Pathogenesis; patient population; Persons; Phase; Plasma; Pneumocystis; Pneumocystis carinii; Pneumocystis carinii Pneumonia; Population; Populations at Risk; Preparation; prevent; Prevention; Primates; Production; prophylactic; Prophylactic treatment; Prospective Studies; protective efficacy; Protein Subunits; Proteins; public health relevance; recombinant peptide; Recombinants; Reporting; Research; research clinical testing; Resources; response; Risk; seropositive; SIV; Specificity; standard care; Testing; Therapeutic immunosuppression; Therapeutic Uses; Time; Tissues; Transplant Recipients; Treatment Failure; treatment guidelines; Trimethoprim-Sulfamethoxazole; Vaccinated; vaccination strategy; vaccine candidate; vaccine development; vaccine evaluation; Vaccine Therapy; Vaccines; Virus Diseases; Work
