VecFlu - a viral vaccine vector for expression of foreign antigens.

VecFlu has an advantageous immunogenicity profile. It will be used for immunization against melanoma and tuberculosis. VecFlu, the company's vector program, is in an early stage. Research is being performed to optimize the vector and define the optimal antigens. The first two diseases targeted by VecFlu are melanoma and tuberculosis.

VecFlu - a viral vaccine vector

The application of viral vectors for delivery of foreign proteins and biologically active molecules is an attractive approach for gene therapy, treatment of cancer and prevention of infectious diseases. The establishment of reverse genetics methods to manipulate influenza virus genomes has allowed the generation of recombinant influenza viruses that can be used as vectors for the expressing of foreign sequences.

Strategies for the construction of influenza virus vectors include the insertion of foreign epitopes into influenza virus glycoproteins, the expression of polyproteins, and the rescue of bicistronic genes into infectious viruses. Influenza virus vectors have been obtained which express both B- and T-cell epitopes from different pathogens. These constructs have been shown to mount strong systemic and local antibody responses in immunized animals, and/or cytotoxic T-cell responses against the expressed epitope.The available evidence suggests that influenza virus vectors are attractive candidates for the development of effective vaccines for treatment of cancer and prevention of infectious diseases.

AVIR Green Hills Biotechnology has developed its proprietary influenza virus vector ( VecFlu ). In principle, this vector is based on replacing the NS1 gene by foreign sequences. More specifically, VecFlu comprises heterologous sequences inserted between modified splice donor acceptor sites of the NS segment. Most importantly, VecFlu allows stable and high expression levels of foreign proteins.

Due the replacement of the NS1 gene, VecFlu has similar immunogenic properties as the FluVacc - DNS1 vaccine (see FluVacc chapter[T1] <> ). The major difference is that the strong B- and T-cell responses induced by FluVacc - DNS1 are not only directed against influenza virus but also against the inserted foreign protein. Therefore VecFlu has great potential to effectively induce specific immune responses against cancer and infectious diseases. In a first step Avir Green Hills Biotechnology will use VecFlu as a vaccine against melanoma and tuberculoses.

VecFlu as vector for tumor antigens

The fact that VecFlu due to the lack of NS1 - stimulates a strong interferon response which in turn activates the immune system might be highly advantageous for a tumor vaccine. The specificity of tumor destruction is obtained by stimulating the response of T-cells and B-cells against antigens specific for tumor cells. Since AVIR Green Hills Biotechnology could demonstrate the selective expression of retroviral proteins in human melanomas as well as in metastases (see MelVir chapter[T2] <> ), these proteins represent promising candidates to be inserted as tumor antigens into the VecFlu vector. Therefore it is planned express these retroviral proteins by means of the VecFlu vector and thus create a therapeutic vaccine against melanoma.

VecFlu as vector for tuberculosis antigens

Since tuberculosis is an airborne disease, the intranasal route of vaccination might be preferable. Therefore VecFlu might be superior as a vector for mucosal immunization against M. tuberculosis. For proof of principle, several prototypes resembling VecFlu expressing the 6-kDa early secretory antigenic target protein (ESAT-6) of M. tuberculosis from the NS1 reading frame were generated. The potency to induce an M. tuberculosis-specific Th1 immune response in mice was demonstrated. Moreover, intranasal immunization of mice and guinea pigs with these vectors induced protection against mycobacterial challenge.