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Schlesinger: Dendritic Cells & Flavivirus Vectors

OVERVIEW

Advances in immunology, biochemistry, and biology have enabled scientists to rapidly identify the sequences and structures of antigens, the substances in vaccines that stimulate immune responses against disease. For an antigen to be valuable as a vaccine, however, scientists must find a way of giving it to individuals so that it predictably results in the desired immune response. Currently, scientists face roadblocks in producing vaccines that predictably raise protective immune responses against several diseases, notably HIV and malaria.

Dr. Schlesinger’s team is developing vaccines that stimulate the immune system’s dendritic cells, which are known to play an important role in stimulating protection against infectious diseases. Dr. Ralph Steinman and colleagues developed an approach to engineer vaccine antigens into monoclonal antibodies against receptors on the surface of dendritic cells. A secondary approach involves engineering genes for the antigens of interest into the yellow fever virus. The project will focus on creating experimental vaccines for a range of diseases, including HIV and malaria. If successful, this technology could identify a better way to create vaccines that stimulate multiple components of the body’s immune response, including those that have been difficult to target with existing vaccine approaches.

RESEARCH OBJECTIVES

The project team has engineered protein antigens into monoclonal antibodies that recognize endocyctic receptors on dendritic cells, selectively and efficiently target vaccine proteins to the dendritic cells in lymphoid tissues. They have chosen DEC-205 (CD-205) as the targeted dendritic cell receptor. The team has taken this approach into Phase I safety and immunogenicity testing of an HIV/AIDS vaccine. Their studies of this vaccine strategy for other diseases, including malaria and Epstein-Barr virus, have focussed on proof-of-concept in mouse models of infection.

PROGRESS

  • Investigators have developed a vaccination method with the potential to overcome obstacles to safe, protein-based vaccines that provide strong combined cellular and humoral immunity. This protein-based method is built on targeting to dendritic cells in vivo. It uses monoclonal antibodies that carry antigens to endocytic receptors (initially DEC-205) that are expressed selectively by dendritic cells in lymphoid tissues thereby greatly increasing the efficacy of antigen presentation on MHC class I and II products, compared to non-targeted antigens. Such dendritic cell targeting combined with stimuli for dendritic cell maturation enhances T cell and B cell immunity.
  • Investigators have completed enrollment of a 45 person dose-escalating, double-blinded Phase 1 proof of concept human clinical trial using a monoclonal antibody to DEC-205 engineered to express HIV gag protein administered in combination with poly ICLC (Hiltonol) as adjuvant.
  • Investigators are conducting three proof-of-concept studies in healthy human volunteers to evaluate the performance of different vaccine adjuvants. These adjuvants are poly ICLC, GLA and Flt3-ligand. The data from these studies will be used to select vaccine adjuvants and adjuvant combinations for future clinical vaccine trials.
 

Grant at a Glance

Principal Investigator

Sarah Schlesinger, MD

Grantee Institution

The Rockefeller University through the Foundation for the NIH

Project Title

Improved Vaccine Efficacy via Dendritic Cells and Flavivirus Vectors

Grant Award

$14M over 5 years, awarded in July 2005

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