U01AI165745

Baseline Host and Environmental Factors That Impact Pre-Erythrocytic Malaria Vaccine (Hypo)responsiveness in Endemic Regions - Abstract

An effective vaccine would complement other public health measures and is likely essential for putting an end to the high burden of malaria worldwide. Unfortunately, most malaria vaccines that entered late-stage clinical development have shown moderate efficacy in low and middle-income countries. Through a number of studies, vaccine efficacy was shown to vary from 20% to 100% when used in different countries and populations. Better understanding of factors that influence this variation is urgently needed.

Even within a country, significant differences in vaccine efficacy in rural and urban areas are present. This implies that exposure to environmental factors plays a major role besides genetic determinants. How and to what extent environmental exposures can influence immune profiles and, in turn, affect responses to vaccines? This question will be addressed in the current proposal.

Technological advances in "omics" platforms have improved our ability to examine the immune system in a more unbiased manner. Such platforms, involving transcriptomics, are being increasingly applied to understand vaccine responses, with promising results. However, for malaria vaccines, no harmonized approach to interrogate immunological reactivities and pathways across cohorts has been developed despite its public health importance and availability of cohorts assessed for a clinically relevant outcome (prevention of infection or disease). Even less has been done regarding integrated "omics," comparing populations living in different geographical locations and their response to vaccines. Moreover, there is very little data that link environmental exposures to in-depth changes in the immune system, and if available, the studies often address one environmental factor at a time.

We propose to address this and not only assess correlations in malaria vaccine cohorts but also to address the mechanisms underlying vaccine (hypo)responsiveness. We will build on available knowledge of immunological processes that can affect malaria vaccine responses and use samples from the cohorts where high-dimensional cytometry and RNAseq and antibody interrogations will help to refine and enrich the questions regarding malaria vaccine (hypo)responsiveness. In addition, by using human primary hepatocytes infected with P. falciparum, we will bring the research closer to mechanisms of tissue-specific responses and to extrapolate pre-erythrocytic immunity to malaria in the liver. This is of particular importance for pre-erythrocytic vaccines, where tissue-resident responses can play an important role.

By generating data on the same individuals, data integration approaches for high-dimensional mediation analysis will be used to pinpoint the specific immunological pathways and mechanisms that result in malaria vaccine (hypo)responsiveness. This information can be used to improve malaria vaccine efficacy and also to identify individuals who will not benefit from the vaccine regimens used so far. It can direct, in an evidence-based manner, alterations to the vaccination dose, intervals, and adjuvants.

Academisch Ziekenhuis Leiden

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]

Netherlands

Foreign

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 572% from $483,790 to $3,250,050.