R01AI166358

The Impact of T Cell Selection on Vaccine Durability - Project Summary

An ongoing outbreak of a novel coronavirus infection (COVID-19) has claimed millions of lives and disrupted social infrastructures around the world. Fortunately, the new mRNA vaccines from Moderna or Pfizer/BioNTech are highly effective against SARS-CoV-2. However, much remains unknown about the longevity of memory responses generated by the new mRNA-based vaccine platform in humans. With the emergence of new viral variants, there is also the need to have a flexible type of immunologic memory that is not only long-lasting but can also respond to mutated viruses.

My lab studies human T cell memory. We have shown that the human pre-immune T cell repertoire for a novel pathogen is shaped by past antigen experiences and contains cross-reactive memory T cells that could compete with naïve T cells. Using a highly effective live attenuated yellow fever virus (YFV) vaccine as a model for novel infectious challenge, we tested how pre-immune repertoire impacts post-vaccine response. Multiple YFV-specific populations were identified longitudinally within the same individual using peptide-MHC (pMHC) tetramers. Extensive single-cell T cell receptor (TCR) sequencing on tetramer+ cells was used to follow progenies of the same parent cells over time. We found that the vaccine selectively recruits initially rare but more responsive T cells, leading to better repertoire fitness and higher TCR diversity after vaccination. Having a diverse TCR repertoire has been directly linked to protective T cell responses and host survival in mice. For fast-evolving pathogens, the diversity in T cell composition may additionally limit escape variants as mutations emerge.

Here, we will use the mRNA vaccines for COVID-19 (COVID vaccines) as a model to study the durability and the breadth of T cell responses elicited by mRNA-based vaccine strategies. We hypothesize that effective peripheral T cell selection is critical for maintaining durable immunity against actively mutating viruses. Here we will build on established biological insights, resources, and donor recruitment infrastructures to determine: (1) if COVID vaccine drives effective repertoire selection and diversification, (2) how boosting enhances CD4+ T cell diversity and variant recognition, and (3) how post-vaccine memory cells are maintained and change with time. The proposed experiments will map the entire trajectory of vaccine-induced response using precise molecular and cellular tools. Data from this study will provide vital knowledge on the quality, the breadth, and the longevity of CD4+ T cell response to the mRNA vaccines in humans. Beyond COVID, insights revealed by the proposed research will be relevant for understanding how immunological memory is generated and preserved. The proposed research will therefore have broad impact and could aid future development of improved vaccine strategies for other pathogens.

Trustees Of The University Of Pennsylvania

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]

Philadelphia, Pennsylvania 191044863 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 368% from $658,748 to $3,085,906.