R01AI158617

A Systems Immunology Approach for Predicting Poor Responses to Hepatitis B Vaccination - Project Summary

Vaccines are powerful tools for combating infectious diseases. However, there are cases where vaccination fails to induce robust antibody responses, even after multiple doses. Approximately 2-10% of all vaccinations in healthy individuals do not result in protective immunity. In the specific example of the Hepatitis B Virus (HBV) vaccine, chronic inflammatory states such as obesity are associated with 10-30% of individuals having poor antibody responses, leaving them unprotected.

Moreover, the prevalence of chronic inflammatory states such as obesity is steadily increasing worldwide, at a time where we depend more than ever on vaccines to prevent infectious diseases such as COVID-19. Therefore, there is an urgent need for a better understanding of the mechanisms behind poor humoral responses to vaccines.

Vaccine responses involve the induction of affinity-matured antibodies by B cells, which requires help from T follicular helper (TFH) CD4 cells in germinal centers. We have previously identified circulating TFH, termed cTFH, which provided help to B cells in vitro and had transcriptional and phenotypic similarities to lymphoid TFH. Additionally, cTFH responded to influenza vaccination in an antigen-specific way, giving us a "window" into lymphoid state and activity. However, our understanding of how cTFH and B cell responses to the HBV vaccine are established and change over time is limited, particularly in humans.

In this study, we propose to investigate the HBV vaccine response to understand factors associated with the strength of the protective antibody response. We will employ a systems immunology approach in a prospective clinical study of HBV vaccination in the setting of chronic inflammation induced by obesity.

In Aim 1, we will evaluate the effect of repeated antigen exposure by studying the TFH-B cell axis longitudinally for phenotype and repertoire. This will help us determine which characteristics are most predictive of the final antibody response.

In Aim 2, we will compare subjects receiving adjuvanted HBV vaccine to those receiving traditional HBV vaccine. This comparison will allow us to determine how the cTFH and B cell responses differ due to the adjuvant, using multi-modality single cell profiling.

Finally, in Aim 3, we will test mechanisms of how chronic inflammation in the host affects the HBV vaccine response. This will be done by performing direct lymph node biopsies for multiplex immunofluorescence studies.

Together, these experiments will explore the effects of repeated antigen exposure, adjuvants, and chronic inflammation on the cTFH-B cell axis. The findings from this study will suggest future strategies for improved vaccine design.

New York 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]

New York, New York 100168367 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Required) (PA-20-183)

Amendment Since initial award the total obligations have increased 439% from $727,613 to $3,925,255.