IDC Technology

Designing vaccine-based therapies requires an understanding of the cell types and molecular pathways that regulate the immune system. In the context of infectious disease, innate immune cells like granulocytes, macrophage, and natural killer cells destroy microbes, clear damaged tissue, and initiate wound repair. Acquired immune cells include B cells, which produce antibodies that inactivate microbes, and T cells, which help B cell responses and mediate cytolytic responses that kill infected cells. Vaccines attempt to mimic infection by delivering "antigens" isolated from microbes. This stimulates acquired immunity and a memory response resulting in a long-lived protection against the real disease.

Dendritic cells (DC) sit at the interface between innate and adaptive immunity, and provide a rapid defense against infection via production of pro-inflammatory signals and the mobilization of innate cell types. DC also integrate antigen-dependent acquired immune responses. The key features that distinguish DCs as targets for vaccine development involve the receptors involved in antigen uptake and presentation to lymphocytes, their maturation following microbe recognition, and where they locate before and after antigen capture.

Requirements for optimizing vaccine performance

Vaccines are typically optimized empirically and the ability to control the quality of the immune response is often limited. For instance, many vaccines can effectively induce neutralizing antibodies that prevent infection but are less capable in stimulating cytolytic T cells that stop the spread of infection. We believe that vaccine development can be accelerated by designing drugs that:

  • Regulate antigen uptake, expression, and presentation in DC
  • Direct DC activation and T cell priming
  • Deliver vaccines to DC-rich regions of the body

Immune Design Corp. is implementing the following technologies that address these principles.

DC-targeting Lentivectors

Lentivirus-based vectors are becoming increasingly popular as gene delivery vehicles for both pre-clinical and clinical applications. Several characteristics make lentivectors more versatile than other retroviruses or alternative viruses like adenovirus or adeno-associated virus. These include the ability to efficiently transduce non-replicating cells, like DC, and deliver a relatively large payload for gene expression. The cell-types that the vector can bind and internalize are easily manipulated by pseudotyping the vector with alternative envelope proteins from distinct viruses. The most widely used alternative env gene comes from the Vesicular Stomatitis Virus (VSV-G). This envelope protein enables lentiviral vectors to transduce a wide variety of target cells. Alternative proteins can also be incorporated into the vector preparation so as to restrict binding to specific cells. A striking example is the introduction of a mutant form of the Sindbis virus glycoprotein, allowing the specific infection of dendritic cells through the surface protein DC-SIGN. As recently reported by Yang, Baltimore, Wang and colleagues (2008), when delivered as a vaccine, these lentivectors specifically targeted DC in vivo and induced their maturation. The magnitude of the T cell response against antigen encoded in this lentivector appears unprecedented in terms of providing robust immunity against a tumor challenge. In addition to the vector reported by Yang et al, we are researching additional mechanisms for targeting lentivector to DCs, such as through the surface receptor DEC-205 (Yang L et al., 2006). We are evaluating the ability of these technologies to deliver robust and long lasting immunity against serious human infections.

TLR agonists as adjuvants

Adjuvants are compounds that boost the potency and longevity of immune responses to antigens, but cause minimal toxicity or long-lasting immune effects on their own (Reed, 20081). Adjuvants can be used to enhance immunogenicity, modulate the type of immune response, reduce the amount of antigen or the number of immunizations required, and improve the efficacy of vaccines in newborns or elderly. Adjuvants must be formulated appropriately to give both a maximum effect and long-term storage capacity. The criteria involved in selecting an adjuvant formulation for a given vaccine must be carefully considered.

Recent advances in our understanding of innate immunity and antigen presentation now permit a rational approach to designing and selecting compounds with adjuvant activity based on molecular interactions. The immune system has evolved to respond to foreign molecules, including viral, bacterial, fungal, or parasitic molecules, including cell wall components, lipoproteins, proteins, lipopolysaccharides, DNA and RNA. Such molecules are able to stimulate innate immune responses via pattern recognition receptors, including the toll-like receptors (TLR). TLRs play a pivotal role in DC-mediated activation of adaptive immunity and some of the most effective vaccine adjuvants function via TLR stimulation.

Immune Design Corp is developing vaccine adjuvants using proprietary synthetic TLRs and formulations. These adjuvants are being tested with commercial vaccines for several indications, and we are combining these adjuvants with licensed antigens to produce novel vaccines.

1Reed SG, Bertholet S, Coler RN, Friede M (2008) New horizons in adjuvants for vaccine development. Trends Immunol. 2008 Dec 5.