While direct intramuscular injection of plasmid DNA can result in an immune response to the plasmid-encoded protein, for example a viral or bacterial antigen, adjuvants may be required to enhance immune response to a level that will provide immune protection against viral or bacterial infection. Vaxfectin^® is a novel proprietary cationic lipid-based formulation that has been shown to effectively enhance plasmid DNA-based (as well as protein- and peptide-based) vaccines. It is a commixture of a cationic lipid (GAP-DMORIE) and a neutral phospholipid (DPyPE) which, when combined in an aqueous vehicle, self-assemble to form liposomes.

Upon mixing with vaccines, these cationic liposomes associate through ionic, charge-based interactions with the vaccine and as a result provides an adjuvant effect, boosting the vaccines ability to stimulate immune responses.  In mechanism of action studies, Vaxfectin^® has been shown to increase a number of cytokines and chemokines, while Toll-like receptor signaling was contributory.

Vaxfectin^® was identified through an extensive screening of many different lipids, then optimized through an in vitro and in vivo development process, and finally validated through numerous studies using a wide variety of infectious disease models (including anthrax, HIV, influenza, malaria, measles, rabies, and tuberculosis). It has been extensively documented to enhance both antibody and cellular immune responses to vaccines at levels that provide protection in disease challenge models. Importantly, Vaxfectin^®-adjuvanted vaccines have advanced into several clinical trials and have shown promising safety and immunogenicity profiles.

Vical is developing several products that utilize Vaxfectin^® as an adjuvant. These include CyMVectin™, our prophylactic vaccine against cytomegalovirus infection, and our pandemic influenza vaccines. In addition, we are actively seeking partnerships for the licensure of Vaxfectin^® with other vaccines.

We entered into a worldwide, nonexclusive license with Bristol-Myers Squibb Company in September 2012 for both Vical's patented platform DNA immunization technology and our Vaxfectin^® adjuvant for use in the production of antibodies. Under the agreement, Bristol-Myers Squibb will use our technology to generate antibodies with potential therapeutic uses in humans. We will also provide Vaxfectin^® to Bristol-Myers Squibb from time to time.

Adjuvants

The advent of modern vaccines derived from genomics and proteomics has increased the need for safe and effective novel adjuvants. Since their first proposed use in the 1920s by the French veterinarian-scientist Gaston Ramon, only a handful of adjuvants have found successful use in commercial vaccines. These include the classic adjuvant alum (aluminum salts) and, starting in the late 1990s, several newer products approved in Europe (including the oil-in water emulsions MF59 and AS03). The first novel adjuvant-based vaccine licensed in the United States (in 2009) was the cervical cancer prophylactic vaccine Cervarix^®, which is adjuvanted with ASO4 (alum and monophosphoryl lipid A).

Over the past decade, advances in immunology coupled with a better understanding of the mechanism of action of traditional adjuvants has led to the rational design and testing of novel agents that can be tailored more specifically to obtain a desired immune response. These adjuvants, whether by direct stimulation of the innate immunity or an enhanced and more selective antigen delivery, are designed to boost the immunogenicity and duration of the desired immune response with a favorable safety profile.

Amongst the new generation of adjuvants in development, Vaxfectin^® is well positioned as it meets the desired requirements for an adjuvant with broad-based applications: it is a synthetic adjuvant with a straightforward scalable synthesis of the two constituting lipids; it formulates reproducibly with different types of vaccines by simple mixing; analytical assays have been developed to ensure lot-to-lot reproducibility; and it is cost-effective.

Vaxfectin^® has shown enhanced specific immune responses, dose-sparing effects, and protection against pathogen challenge with plasmid-, protein- and peptide-based vaccines in multiple preclinical models, together with a good safety profile. In addition, early testing in healthy subjects has shown promising safety and immunogenicity profiles for Vaxfectin^®-adjuvanted plasmid vaccines.