R01AI179141

Once bitten: Acquisition of malaria adaptive immunity (OBAMA - immunity) - Plasmodium falciparum control has stalled, and further progress reducing infections and deaths will require a highly-effective malaria vaccine.

Individuals exposed to malaria develop protective immune responses gradually over several infections. Studies of immune responses to P. falciparum have consistently demonstrated that targets which exhibit very high diversity are critical for these protective responses. However, immunity to these antigens is dominated by strain-specific responses, which confer partial but imperfect protection to heterologous strains.

This is a challenge for current vaccine candidates, including the first licensed malaria vaccine RTS,S, which are based on a single antigenic variant for a protein target and suffer from reduced efficacy to non-vaccine strains. There is evidence for strain-transcendent immunity in naturally exposed populations where individuals mount broadly protective responses after a few infections, despite the presence of dozens if not hundreds of different strains.

Understanding how to elicit strain-transcendent immunity towards key, diverse antigenic targets has the potential to transform the next generation of vaccine products. Prior longitudinal studies of infection and disease are unable to furnish this insight mainly because they suffer from the inability to distinguish protection from lack of exposure in naturally exposed populations. As a consequence, there is no clear phenotype of protection, producing an incomplete understanding of the acquisition of protective immunity.

Using our unique, longstanding cohort encompassing ~600 people in 75 households (initiated in 2017) in a high-transmission community in Western Kenya, we are able to pinpoint parasite transmission events to the individual-level, characterize the variant composition of multi-strain P. falciparum exposures, and document the outcome (no infection or protected vs. infected with or without symptoms) at the variant level.

By leveraging known exposures to clearly define protection phenotypes within a natural system that encompasses a high degree of parasite diversity, we are uniquely positioned to answer longstanding questions about protective immune responses. The goal of the proposed work is to use our unique system to advance multi-variant vaccine design.

In our first aim, we will quantify the strain-specific risk of malaria infection following a confirmed infectious bite (exposure). In the second aim, we will leverage peri-exposure and post-exposure samples to correlate strain-specific protection following an infectious bite with strain-specific immune responses in order to identify strain-transcendent responses, and then identify variants that most effectively promote strain-transcendent responses.

Our hypothesis is that a minimum set of strain-specific immune responses will be associated with strain-transcendent protection from infection after exposure. By exploring heterologous versus homologous strain-specific responses to elucidate a minimum set of antigenic variants required to confer strain-transcendent protection, we can facilitate the development and delivery of the next generation of P. falciparum vaccines.

Duke University

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]

Durham, North Carolina 277051104 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 277% from $870,556 to $3,285,014.