Project and Core Descriptions

Project 1, PI: Ravetch, J As basic mediators of humoral immunity, immunoglobulins have evolved to clear microbes and toxic molecules through coupling of antigen specificity to Fc-mediated effector functions. Effector functions conferred through the Fc domain include positive regulatory mechanisms such as the activation of antibody-dependent cellular cytotoxicity, phagocytosis, or pro-inflammatory cytokine production, as well as negative regulatory functions, such as inhibition of inflammatory immune responses. Whether activity mediated by the Fc region is pro- or anti-inflammatory in nature is determined by Fc protein sequence and by the precise composition of an N-linked, complex, biantennary glycan that regulates interactions with members of the IgG Fc receptor family (FcγRs) the SIGN family of molecules (mouse SIGNR1/human DC-SIGN) and CD23. The composition of the core Fc glycan can be altered by addition of saccharide units (fucose, N-acetylglucosamine, galactose and sialic acid) and these modifications directly alter the biological activity of IgG molecules. Though the precise saccharide composition of Fc glycans is a known determinant of the biological activity of IgGs, little is known about regulation of Fc glycan composition. Interestingly, vaccination of mice and of humans has been observed to cause various modulations in IgG Fc glycan composition. That Fc glycan composition can be modulated by vaccination is intriguing as it offers a system by which to study specific factors as they may or may not have a role in regulation; for example, glycan modifications might be determined by the nature/T cell dependence of the antigen, the route of antigen exposure, or host factors such as age. We propose to conduct the first systematic study of vaccine-elicited Fc glycan modifications in humans by immunization of volunteers with a panel of FDA vaccines. The experiments proposed in this application are designed to investigate two basic hypotheses: 1) that the composition of Fc glycans is actively regulated, and 2) that Fc glycan composition, either in the pre-existing IgG pool or on newly elicited IgGs directs the maturation of a humoral immune response.

Project 2, PI: Nussenzweig, M Most successful vaccines have been developed empirically, with little or no immunological insights. Continued existence of this gap has been a major barrier to the successful development of rationally designed vaccines. Due to their capacity to elicit and regulate immune responses, dendritic cells (DCs) are essential to any effort for vaccine development. The study of conventional DCs (cDCs) from humans has focused on cells in blood, which comprise BDCA-1+ myeloid DCs, BDCA-2+ plasmacytoid DCs, and a small subset of BDCA-3 high, myeloid DCs. The heterogeneity among DCs is of interest because of the specialized functional properties of each DC subset. But a comprehensive model that describes cDC genesis and the origins of cDC functional diversity in humans is lacking. To address this important gap in our understanding of this essential cell type, we propose to uncover the origin of human cDCs and to determine how adjuvants or vaccines alter cDC development. The hypothesis to be tested is that human cDC development, subset distribution, and their state of activation is altered by administration of adjuvants or vaccines. We will first elucidate the origin of cDCs in humans by identifying the human pre-DCs and by determining whether there are one or two lineages of pre-DCs corresponding to the two major myeloid cDC subsets (aim 1). Second, using clinical samples from individuals treated with increasing doses of Flt3L, we will determine if Flt3L administration might improve vaccine efficacy by mobilizing cDCs and their progenitors (aim 2). Lastly, we will define if adjuvants (i.e. TLR3 and TLR4 agonists) or vaccines (i.e. FDA-approved vaccines as well as a DC-targeted vaccine) administration impacts on cDC development in humans (aim 3). Taken together, these experiments should provide a comprehensive model of cDC development both in steady state and inflammatory condition. Understanding these processes will provide important insights into vaccine design.

Project 4, PI: Rice, C; Rosenberg, B Vaccines have been responsible for preventing millions of deaths and extending the average human lifespan. This remarkable record of success has not been unsullied and vaccine formulation, host genetic background, age, immune history and other factors influence immune responses to vaccination in ways that are underexplored. A better understanding of these factors and the correlates of vaccine success versus failure should provide a useful blueprint for improving current vaccines and developing new vaccines against prevalent and emerging pathogens. Essential in the innate immune control of viral infections, type I interferons (IFNs) are traditionally described as immunostimulatory and antiviral cytokines. However, emerging evidence suggests a paradoxical role for type I IFN in suppressing certain innate and adaptive immune functions. Chronic infection by hepatitis C virus (HCV) causes constitutive IFN stimulation, which may contribute to viral persistence in spite of immune defense mechanisms. Although not considered generally immunocompromised, chronic HCV patients demonstrate high failure rates to hepatitis B virus (HBV) vaccination. We hypothesize that this poor response is due to the immunomodulatory effects of persistent innate immune activation by chronic HCV infection. In collaboration with our clinical colleagues at Weill Cornell, our CCHI clinical core and complementing CCHI projects, we propose a comprehensive examination of HBV vaccine response in patients chronically infected with HCV. We will recruit chronic HCV patients and healthy controls for HBV vaccination, measure their innate immune status by interferon-stimulated gene expression in peripheral blood, and determine its association to HBV vaccine response. We will then characterize those immune mechanisms compromised in chronic HCV by assessing the HBV-specific adaptive immune response, and the innate inflammatory response to vaccine antigen and adjuvant. These studies will enhance our understanding of the immunomodulatory effects of chronic viral infection, establish determinants of effective vaccine responses, and help guide vaccination strategies for HCV patients and other individuals with chronic inflammatory disease.

Service Core, PI: Schlesinger, S The Clinical Immunology Services Core will serve all of the projects in the CCHI. It is at the center of all of the activities in the human immunology clinical trials. The major functions of the core are: Clinical and regulatory support for all of the scientific studies on the samples collected from human clinical immunology trials conducted under the auspices of these projects. The Core will support the consent for the scientific use of and the regulatory requirements associated with the use of human clinical samples that have been collected under previously conducted IRB approved protocols at The Rockefeller University Hospital. These samples are from the seven already IRB approved clinical protocols of experimental vaccines and vaccine adjuvants. The Core will also provide clinical and regulatory support for the conduct of ongoing and planned clinical trials of licensed influenza, pneumococcal, meningicoccal, and hepatitis B vaccines proposed in Projects 1 and 4. The Core will support all of the regulatory, human subjects’ protection, and clinical execution of these clinical trials. In addition the Clinical Immunology Services Core will also complete all of the data entry and management associated with these proposed protocols.

Pilot Core, PI: Schlesinger, S The Pilot Core will support small studies to generate preliminary data for the development and submission of future research applications for support from non-CCHI sources. The Core will rely on the long-standing collaborations and relationships developed through the Chris Browne Center for Immunology at The Rockefeller University to both solicit and review grants, as well as for the presentation of the resulting data.