The main barrier to prevention against influenza disease is the absence of a vaccine that can provide broad protection against antigenically distinct viruses. We recently showed that immunizing mice with influenza virus hemagglutinin in complex with IgG containing sialylated Fc domains leads to an antibody response with increased potency and breadth of response. We established that the mechanism for the enhanced antibody response involves co-engagement of CD23 by sialylated Fc domains with the B cell receptor (BCR), leading to upregulation of the inhibitory Fc?RIIB, which in turn suppresses the activation/proliferation signal triggered by HA interaction with low affinity, but nt high affinity, BCR. As a result, there is selection for the higher affinity antibody-producing cell. We plan to exploit this discovery in the projects outlined in this proposal by immunizing mice with an FDA approved, seasonal, inactivated influenza virus vaccine in complex with a mAb containing a sialylated Fc domain that will engage CD23. Based on our preliminary data, we expect that this will elicit a more potent, broadly neutralizing antibody response. Further, we wil define the determinants of enhanced IgG-mediated neutralization of influenza viruses achieved through CD23/BCR co-engagement. It is our hope that a viable strategy for enhancing the efficacy of approved influenza vaccines will result from completion of the proposed Aims. I am currently an Instructor of Clinical Investigation and a Postdoctoral Fellow in the Laboratory of Molecular Genetics and Immunology with Jeffrey Ravetch at The Rockefeller University. The Rockefeller University provides an outstanding academic environment and all resources that I could require for my scientific training and works are available to me. My overall career ambition is to become an independent investigator and an expert in the molecular and cellular bases of protective immune responses. My goal is to establish a research program that makes novel observations at a systems level, and then to dissect mechanisms underlying those observations at the cellular and molecular levels. I am particularly interested, at present, in developing new vaccination strategies to elicit neutralizing antibodies, which is the focus of this proposal. My plan for transition to independence is detailed in the attached application. Briefly, I will complee projects in progress and submit research manuscripts for publication. I will continue to learn from my colleagues in the lab and from the curriculum of the Clinical Scholars Program, which is designed to prepare physician-scientists for independent careers in clinical and patient-oriented translational research. I will also make time to identify and apply for independent research positions with an anticipated start date in 2016 or 2017.
The main barrier to prevention against influenza disease is the absence of a vaccine that can provide broad protection against antigenically distinct viruses. We recently showed that co-engagement of CD23 with B cell receptor during influenza vaccination leads to production of antibodies with increased breadth and potency of neutralizing activity. We will use this discovery to improve the vaccine response elicited by FDA approved, seasonal influenza vaccines and we will study the molecular basis of enhanced vaccine responses through CD23/BCR co-engagement.
|Maamary, Jad; Wang, Taia T; Tan, Gene S et al. (2017) Increasing the breadth and potency of response to the seasonal influenza virus vaccine by immune complex immunization. Proc Natl Acad Sci U S A 114:10172-10177|