U01AI163090

Cytomegalovirus (CMV) Vaccine in Orthotopic Liver Transplant Candidates (COLT) - Project Summary:

Cytomegalovirus (CMV) has a major negative impact in solid organ transplant recipients (SOTXR) due to limitations in current preventive and therapeutic strategies, especially in CMV seronegative recipients (R-) of organs from seropositive donors (D+) [D+R-]. The D+R- subset comprises approximately 25% of all SOTXR but more than 80% of CMV disease and is independently associated with worse long-term survival after SOTX. The disproportionate impact in D+R- SOTXR results from an impaired ability to develop a primary immune response to donor-transmitted CMV infection in the context of immunosuppression.

Strategies that elicit or enhance CMV-specific immunity prior to SOTX could lead to more effective prevention/control of CMV after SOTX, minimizing the need for toxic CMV antiviral therapy (AVT). We have developed a modified vaccinia Ankara virus vaccine, Triplex, that expresses immunodominant CMV antigens PP65, IE-1, and IE-2 that are targets of protective T cell immunity. Triplex elicits robust, long-lasting, and functional CMV-specific CD4 and CD8 T cells. Triplex was safe, accelerated reconstitution of CMV protective immunity, and reduced significant CMV infection by approximately 50% in a phase 2 study of allogeneic hematopoietic cell TXR.

Our long-term goals are to harness vaccine-induced CMV-specific cellular immunity to reduce the impact of CMV in D+R- SOTXR and to define immune correlates of risk (COR) and for protection (COP) (i.e. immune correlates of Triplex vaccine efficacy [VE]). The central hypothesis is that pre-TX Triplex vaccination of CMV seronegative LTX candidates elicits functional CMV-specific CD4 and CD8 T cells, leading to improved immune control of CMV and significantly decreases the need for CMV AVT post-TX in D+R- LTXR who receive preemptive therapy (PET) for CMV prevention. We further hypothesize that there are specific immune COR for CMV outcomes and COP of Triplex vaccine.

We will leverage our established consortium and preliminary studies in a target population of D+R- LTXR with high unmet need (no FDA-approved available antiviral prophylaxis options, highly susceptible to valganciclovir toxicity, and significant CMV-associated morbidity, mortality, and cost). The objectives of this proposal are to assess the efficacy, safety, and immunogenicity of Triplex in D+R- LTXR in a phase 2 study and to define the immune COR and COP using state-of-the-art polyfunctional T cell assays and novel analytic approaches (combinatorial polyfunctionality analysis of antigen-specific T cell subsets [COMPASS]).

An effective pre-TX CMV vaccination approach would transform CMV prevention strategies in SOTX. The proposed studies will define immune COR for clinical outcomes, which will facilitate efficient evaluation of future immune-based strategies and lead to broader implementation of the more effective PET CMV prevention strategy in D+R- LTXR.

San Francisco Regents Of The University Of California

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

San Francisco, California 94143 United States

Single Zip Code

Change of Recipient Organization (Type 7 Parent Clinical Trial Optional) (PA-24-254)

Amendment Since initial award the total obligations have increased 576% from $2,295,742 to $15,523,610.