Annual immunization against influenza infection is one of the largest coordinated international public health efforts. Current flu vaccination strategies primarily elicit protection by the generating long lasting type-specific neutralizing IgG anti-hemagglutinin (HA) antibodies that bind to molecularly similar influenza subtypes. This phenomenon is termed antibody mediated heterosubtypic immunity (amHSI), and a major reason for the success of seasonal influenza vaccination. MF59 is a squaline-oil adjuvant recently approved for seasonal influenza vaccination in indivduals ?65 years of age. Our preliminary data suggests that MF59 increases amHSI in mice, ferrets and human subjects. Thus the primary goal of this Project is to elucidate and model the mechanisms of by which MF59 adjuvanted seasonal influenza vaccine increase B cell mediated amHSI at the immunoglobulin heavy chain DNA and protein repertoire level.
Aim 1 : To test the hypothesis that MF59 adjuvant increases the breadth, depth and molecular sequence diversity in the IgG repertoire after influenza vaccination.
Aim 2 : To build and validate an age-dependent branching process model of heterosubtypic immunity coverage induced by adjuvanted influenza vaccine.
Aim 3 : To model and identify the mechanisms responsible for MF59 adjuvanted influenza vaccine induced anti-HA IgG repertoire evolution and amHSI generation in human vaccine recipients. This proposal addresses a highly significant issue in public health, how to optimize the protection of the influenza vaccine using vaccine adjuvants to increase the cross-strain reactivity of the resulting mixture of IgG anti-HA antibodies. It also addresses a significant gap in scientific methods for reconstructing Ig sequence lineages resulting from hyperaccellerated somatic mutation within germinal center reactions. We will create age dependent branching process models that will provide mechanistic insight into how the adjuvant and intradermal vaccination alter the molecular diversity of antibody-mediated HSI. These models will be first developed using mice vaccinated with MF59 adjuvanted influenza vaccine in Aim 1, and then extended to human subjects in Aim 2. If successful, this work will provide a general framework for modeling the molecular processes involved in the generation of amHSI.

Public Health Relevance

Vaccination against influenza virus results in antibodies that bind to the virus and prevent infection. Currently, most vaccines produce a narrow range of antibodies that bind to the vaccine virus strain or very closely related influenza viruses. This project proposes to investigate how a new vaccine, which contains the adjuvant (immune system booster) MF59, increases the range of influenza antibodies binding to molecularly different influenza strains. We will use a combination of data from mice and human subjects, combined with mathematical modeling, to test hypotheses about how antibodies that bind different influenza strains arise.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI129518-05
Application #
10092077
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2017-02-01
Project End
2022-01-31
Budget Start
2021-02-01
Budget End
2022-01-31
Support Year
5
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Wang, Jiong; Hilchey, Shannon P; DeDiego, Marta et al. (2018) Broad cross-reactive IgG responses elicited by adjuvanted vaccination with recombinant influenza hemagglutinin (rHA) in ferrets and mice. PLoS One 13:e0193680
Nogales, Aitor; Piepenbrink, Michael S; Wang, Jiong et al. (2018) A Highly Potent and Broadly Neutralizing H1 Influenza-Specific Human Monoclonal Antibody. Sci Rep 8:4374
Zhu, Xu; Shen, Xiaomeng; Qu, Jun et al. (2018) Proteomic Analysis of Combined Gemcitabine and Birinapant in Pancreatic Cancer Cells. Front Pharmacol 9:84
Wang, Xue; Niu, Jin; Li, Jun et al. (2018) Temporal Effects of Combined Birinapant and Paclitaxel on Pancreatic Cancer Cells Investigated via Large-Scale, Ion-Current-Based Quantitative Proteomics (IonStar). Mol Cell Proteomics 17:655-671
Shen, Shichen; An, Bo; Wang, Xue et al. (2018) Surfactant Cocktail-Aided Extraction/Precipitation/On-Pellet Digestion Strategy Enables Efficient and Reproducible Sample Preparation for Large-Scale Quantitative Proteomics. Anal Chem 90:10350-10359
Clark, Amelia M; DeDiego, Marta L; Anderson, Christopher S et al. (2017) Antigenicity of the 2015-2016 seasonal H1N1 human influenza virus HA and NA proteins. PLoS One 12:e0188267
Huang, Junqiong; Hilchey, Shannon P; Wang, Jiong et al. (2017) IL-15 enhances cross-reactive antibody recall responses to seasonal H3 influenza viruses in vitro. F1000Res 6:2015