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​Ho: Enhancing Innate Immune Activation

OVERVIEW

The Ho-led research consortium is exploring ways to enhance immune activation upon vaccine administration. Dendritic cells (DCs) are a type of immune system cell involved in the body’s innate response to pathogenic invaders. These cells ingest viral particles and display bits of them on their surfaces so that other immune cells, such as T-cells, can mount immune responses to the viruses. The Ho-led team is studying various approaches to harness the power of these dendritic cells to improve vaccine immunogenicity both in pre-clinical and clinical research efforts.

RESEARCH OBJECTIVES

The Ho-led research team will pursue several distinct vaccine approaches to direct HIV-1 antigens to dendritic cells or to induce type I interferon that can recruit and mature DCs. Each of these vaccine approaches has a modality to mature DCs, either co-administered exogenously or built-in.

The team will also evaluate both a novel vaccine adjuvant and a novel vaccine delivery platform. The adjuvant is a glycolipid compound that stimulates natural killer T cells, leading to DC maturation and improved immune responses to vaccines. The vaccine delivery platform will utilize the TriGridTM in vivo electroporation device to improve the immunogenicity of DNA-based vaccines by increasing the amount of vaccine delivered to cells.

These product development activities entail studies ranging from in vitro construction and characterization to animal experimentation, and to pilot human trials for select efforts.

PROGRESS

In previous years, researchers at the Aaron Diamond AIDS Research Center (ADARC) have reported results from the first Phase 1 clinical trial of ADVAX, a DNA-based HIV vaccine candidate delivered with the TriGridTM in vivo electroporation system, manufactured by Ichor Medical Systems, in healthy volunteers. Strong positive results indicate that in vivo electroporation is safe, tolerable, enhances the cellular immunogenicity of ADVAX, and is dose-sparing. Ancillary immunogenicity studies indicate that ADVAX delivered by electroporation not only enhances the magnitude of cellular immune responses to this DNA vaccine candidate, but also its breadth.

​In the past year, researchers have continued preclinical development of a promising new glycolipid-based vaccine adjuvant, 7DW8-5, which significantly enhances the immunogenicity of DNA and adenovirus-based vaccines in animals models. In partnership with the U.S. Naval Medical Research Center (NMRC) and the Tulane National Primate Research Center (TNPRC), we demonstrated that this glycolipid-based adjuvant can significantly boost the immunogenicity of an adenovirus-based vaccine candidate in monkeys without causing evident systemic reactogenicity. Clinical development plans for ADNY003 (the glycolipid adjuvant, 7DW8-5, in combination with the adenovirus-based vaccine candidate, AdPfCA) were presented to the US FDA in a Pre-IND meeting last year, and we conducted a GMP manufacturing campaign for 7DW8-5 and released the drug substance earlier this year. We are currently engaged in formulation and method development studies to manufacture the 7DW8-5 drug product, and have commenced genotoxicity studies in anticipation of a Phase 1 clinical trial that will begin enrollment next year.

 

Grant at a Glance

Principal Investigator

David Ho, MD

Grantee Institution

Aaron Diamond AIDS Research Center, New York, USA

Project Title

Harnessing Dendritic Cells & Innate Immune Activation Signals to Guide HIV-1 Vaccine Development

Grant Award

Up to $24.7 million, awarded July,​ 2006

Collaborating Institutions

  • Mount Sinai School of Medicine, USA
  • The Rockefeller University, USA

External Scientific Advisory Board

  • John Coffin, Tufts University
  • Ronald Desrosiers, Harvard Medical School
  • Stephen Goff, Columbia Universit
  • Beatrice Hahn, University of Alabama, Birmingham
  • Scott Hammer, Columbia Presbyterian Medical Center
  • George Shaw, University of Alabama, Birmingham
  • Joseph Sodroski, Dana-Farber Cancer Institute, Harvard Medical School

Progress to Date

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