U01AI165455

Collective Responses to Malaria Vaccination - Summary

The overall project goal is to identify key characteristics of immune responses to vaccination with attenuated Plasmodium falciparum sporozoites (APFSPZs) which result in sterilizing immunity. We hypothesize that this immunity is due to cellular and humoral responses specific to PF antigens (AGs) that are presented during the liver stage (LS) of infection. We propose a detailed longitudinal analysis of innate and adaptive immune responses using cutting-edge immunological analyses, associated informatics, and systems immunology.

We will identify ASPZ vaccine-induced cellular and humoral responses that correlate with protection in malaria-naïve and malaria-experienced subjects. Complementary orthogonal analytical tools and approaches will identify relevant immune cell subsets, AG receptor (AR) repertoires, lineages, and specificities to protective AGs. The functional characteristics of the immune cells and products, including antibodies, that correlate with protection will be identified and validated.

This will be accomplished by:

Aim 1: Identifying ASPZ vaccine-induced cellular and humoral responses that are associated with protection. Unbiased and AG-specific cellular profiling will characterize the kinetics of protection-associated responses to vaccination and controlled human malaria infection (CHMI). Follow-on analyses will profile identified AG-specific adaptive and innate cellular responses by mass cytometry (CYTOF), multiplexed PMHC/AG multimer staining, and multi-omic single-cell sequencing to determine protection-associated gene and protein expression signatures and functional antibody responses, which will be extended in later aims.

Aim 2: Identify protection-associated T and B cell AG receptor (AR) repertoires at key times after vaccinations and CHMI. Natively paired and single AR chains from T and B cells will be sequenced to determine repertoire attributes and identify vaccine-induced PF AG-specific ARs. Cellular transcriptomic profiles and AG specificities will be linked by joint single-cell and TCR/BCR sequence analyses. Novel AR-AG and antibody specificities will be identified by yeast display methods. This aim will identify T and B cell ARs and antibody AG specificities that are correlated with protection.

Aim 3: Identifying functional characteristics of cellular and antibody responses that confer protection. Sorted reactive T cells will be assayed by AG-specific CYTOF-based intracellular cytokine staining (ICS), activation-induced marker (AIM), and single-cell sequence-based multi-omics analyses. The biophysical and functional analyses of monoclonal antibodies will be used to assess B cell roles in protection.

The comprehensive project data will undergo integrated multi-factorial bioinformatic analysis, curation, and sharing using established platforms. Overall, this project will identify key characteristics of the intricate immune responses to the complex antigenic composition of ASPZ PF vaccination and the effector processes that correlate with protection. It will provide a set of immune correlates of protective immunity against malaria to guide vaccine development.

Seattle Children's Hospital

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]

Washington United States

State-Wide

A Multidisciplinary Approach to Study Vaccine-elicited Immunity and Efficacy against Malaria (U01 Clinical Trial Not Allowed) (RFA-AI-20-064)

Amendment Since initial award the total obligations have increased 297% from $700,000 to $2,779,001.