Ho Vaccine Discovery Consortium   

OVERVIEW: 

Most vaccines available today protect against disease by stimulating the body to produce antibodies against a specific infectious agent. To date, this strategy has failed to produce an HIV/AIDS vaccine that affords total protection. However, a number of ground-breaking strategies are being explored that could improve the traditional vaccine approach. 

The Ho-led VDC is pioneering one such strategy. Dendritic cells (DCs) are a type of immune system cell involved in the body’s innate response to pathogenic invaders. Discovered in 1973 by CAVD collaborator Ralph Steinman, 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 VDC 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 VDC is pursuing several distinct vaccine approaches, three of which direct HIV-1 antigens to dendritic cells. Two other strategies rely on the induction of type I interferon to recruit and mature DCs. Each of these vaccine approaches has a modality to mature DCs, either co-administered exogenously or built-in. 

The VDC is also developing 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. In a parallel effort, the TriGridTM in vivo electroporation device improves 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: 

The Ho VDC has two novel clinical trials in the human development stage, as well as a third in conjunction with the Steinman Grand Challenges in Global Health research project. A Phase I clinical trial to test the effect of in vivo electroporation on enhancing the immune response to ADVAX, a DNA-based candidate HIV vaccine, in healthy HIV-uninfected, low-risk volunteers, is nearly complete. This is the first demonstration that in vivo electroporation is safe, well-tolerated, and significantly improves cellular immune responses to DNA-based vaccines in healthy human volunteers.

Researchers are developing the use of adjuvants consisting of glycolipid analogues based on known structure-function correlates with alpha galactosyl ceramide. They have characterized and screened these glycolipids for NKT cell activation, cytokine secretion, and adjuvant effect with various vaccines. The most promising clinical lead is moving forward into clinical development, and GMP manufacturing is complete, in anticipation of a Phase 1 clinical trial in humans in the next year.

The researchers have evaluated the immune response to proteins fused to monoclonal antibodies targeting various dendritic cell (DC) receptors. The clinical development of DEC-205-Gag, the first DC-targeted vaccine candidate fused to HIV Gag, is proceeding under the Grand Challenges in Global Health program in collaboration with the CAVD.  

Researchers have created mouse monoclonal antibodies to other DC receptor targets, coupled to test antigens. The impact of targeting antigens via different DC receptors and different DC subsets on the quality and quantity of the immune response is being investigated in conjunction with various Toll-like receptor (TLR) ligands as vaccine adjuvants.

Other researchers have created yeast libraries to express novel human Fc sequences to optimize the activation: inhibition ratio. Researchers are testing HIV vaccine candidates fused to differing IgG subtypes to assess differences in immunogenicity. They have shown that varying the Fc sequence can have a significant effect on immunogenicity of HIV Gag.

Researchers have demonstrated that HIV-1 proteins fused to flagellin, in the absence of any adjuvant, can significantly enhance vaccine immunogenicity, and are now identifying novel flagellin variants with increased TLR5 binding affinity.

Researchers are developing Newcastle Disease Virus (NDV) as a potential vaccine vector. Codon-optimized gag inserts have been introduced into the optimal insertion sites in the vector, leading to further enhancements in immunogenicity.