The alphavaccine technology is based on AlphaVax’s proprietary replicon vector platform derived from attenuated strains of the alphavirus, Venezuelan equine encephalitis (VEE) virus. Among alphaviruses, attenuated strains of VEE virus are particularly attractive for the generation of replicon vaccines due to their natural tropism for lymphatic tissues and dendritic cells, relative resistance to interferon, high expression levels, lack of pre-existing anti vector immunity in most human and animal populations, and efficient production of virus-like replicon particle (VRP) vaccines in cell lines with an accepted regulatory pedigree. In addition, these alphavirus derived replicon particle vectors are notably resistant to anti-vector immune responses, and remain immunogenic in recipients with vector-specific immune responses.
AlphaVax has successfully optimized the alphavaccine technology, developed a strategic intellectual property portfolio, a robust, scalable, manufacturing process, and has advanced five alphavaccine candidates into human clinical trials. AlphaVax’s alphavaccine technology is the only alphavirus-based vector system to have advanced into clinical testing.
Key Advantages of the Alphavaccine System
AlphaVax’s proprietary vector design improvements, combined with the inherent properties of the parent virus and the ability to manufacture at scale in a regulatory-compliant environment, provide a viral vector system with significant advantages over other platform technologies:
- High Levels of Disease Target Gene Expression – The replication of RNA and synthesis of messenger RNA in recipient cells is very efficient, resulting in expression levels of antigen proteins that are typically much higher than competing vaccine vectors, such as poxvirus and adenovirus vectors. Combined with the tropism to dendritic cells and lymphatic tissues, this is believed to contribute significantly to the vector’s immunogenicity.
- Efficient Generation of Immune Responses – In direct comparison with other vectors, the immune responses (both antibody and T cell responses) achieved by alphavaccines have been favorable, even when the competing systems have been used in heterologous prime-boost combinations.
- Broad Flexibility for Disease Targets – VRP vaccines have been produced that express a wide array of disease antigen genes, from over 12 different virus families, multiple species of bacteria, different types of cancer, and several parasites. Alphavaccines have provided complete protection both in diseases in which antibody responses are the most important immune response and those in which cellular responses are critical immune effectors.
- Lack of Inhibition by Anti-Vector Immunity – A very significant alphavaccine advantage over many competing vector systems is the absence of significant pre-existing anti-vector immunity in human populations, since most humans have never been exposed to VEE virus. Furthermore, preclinical animal studies have demonstrated that the anti-vector immunity that develops after initial vaccination with VRP (or even vaccination to VEE virus itself) does not significantly hinder efficacy in repeated or simultaneous vaccinations with VRP. This is in direct contrast to the experience with most virus vectors. Thus, it is possible to efficiently boost immune responses using the same VRP vaccine used to prime, and heterologous prime-boost vaccination regimens that have significantly improved the response to some vector systems have not been necessary with alphavaccines. In addition, a universal vaccination indication for a vector such as adenovirus-5 (Ad5) would effectively eliminate that vector as a vaccine solution for any other disease, or for a disease such as influenza where annual vaccinations are needed.
- VRP-based Adjuvants – AlphaVax scientists have discovered that this vector platform can also be used as a potent adjuvant by expressing cytokines and immunomodulatory molecules in the packaged replicon. Such “VRP Adjuvants” can be used in dose sparing strategies for protein-based vaccines or in combination with antigen-expressing VRP to augment immunogenic responses.
- Ability to Break Tolerance against Self Antigens in Cancer Models – An essential prerequisite for any vaccine approach in a tumor immunotherapeutic setting is the ability to break tolerance to tumor-associated antigens that the immune system does not normally recognize, allowing cancer cells to multiply and spread throughout the body. Alphavaccines have been shown to break immunological tolerance in several stringent tumor challenge models, and now in humans against CEA in patients with Stage IV CEA+ colon cancer.
These characteristics make the alphavaccine vector system uniquely suited for cancer immunotherapy. As such, the Company will advance its current trio of cancer immunotherapy vaccine products into three key clinical trials for safety and immunogenicity/efficacy evaluation in patients with CEA-expressing colon cancer, Her-2-positive breast cancer and melanoma.