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TOL-LIKE RECEPTOR TECHNOLOGY

DYNAVAX

A Flu Vaccine That confers Immunity to Widely Divergent Viral Influenza Strains

     The discovery of the Toll-like receptor’s relationship to the immune system’s stimulation and modulation might have begun to rewrite textbooks information about  the pathways to immune system function, infection/resistance, and immunization against viral and bacterial infection and diseases.  Today, it is the turn of one of the pioneers in the use of TLC receptor information, Dynavax (DVAX), in bringing news about early data showing that its influenza (flu) vaccine based on its proprietary TLR-9 agonist-based immunostimulatory sequence (ISS) technology confers immunity to widely divergent viral influenza strains and has potential as a universal flu vaccine. The vaccine is specifically designed to overcome the limitations of both development-stage pandemic vaccines and standard seasonal flu vaccines.

     In preclinical tests in mice, Dynavax's ISS-based flu vaccine has demonstrated the potential to confer cross-protective cellular and antibody- induced immunity against widely divergent flu strains. Co-administration in mice of Dynavax's flu vaccine plus a standard vaccine has shown to enhance the immune response to the standard vaccine, and may allow reduction of dosage while inducing comparable protective immunity. In addition, the enhanced immunogenicity and cross-protection of the Dynavax vaccine may provide immunity that can last for more than one year, potentially enabling the elimination of annual vaccination and stockpiling of vaccine for pandemic use.   

      According to Dynavax, its proprietary conjugation technology that chemically links the ISS molecule with highly conserved viral antigens confers a potent immunogenic and cross-protective effect regardless of the viral strain. The firm believes that its flu vaccine represents a potential breakthrough in the prevention of disease caused by serious, widespread viral outbreaks and may be a first line of defense against the event of a flu pandemic. Importantly, Dynavax approach may offer protection against any potentially pandemic strain, in contrast to other vaccines that specifically target an individual H5 or other strain.

     Standard flu vaccines are designed to generate neutralizing antibodies against viral surface proteins (hemagglutinin, or HA and neuraminidase, or NA). These proteins mutate rapidly and a match between vaccine and current circulating virus is required to generate immunity. In contrast, Dynavax's flu vaccine is produced by conjugating ISS with two highly conserved viral proteins, nucleoprotein (NP) and the extracellular domain of matrix protein 2 (M2e) so no expectation of mutation. The conjugates can be combined with the standard flu vaccine to confer cross-protective effect and to generate antigens capable of inducing potent immune responses.

* The NP-ISS conjugate induces strong type-1 helper T cell responses (Th1) and cytotoxic T cell responses (CTL) that can effectively kill virus-infected cells;

* The M2e-ISS conjugate induces strong cytotoxic antibody responses that can kill virus-infected cells.

* The ISS component of both conjugates enhances the response to standard flu vaccine.

Protection Against Antigenic Drift and Antigenic Shift  

     In these models, Dynavax's flu vaccine protects against both "antigenic drift" and "antigenic shift." Antigenic drift occurs when there are mutations in HA and NA viral surface proteins, leading to reduced efficacy of vaccines not precisely matched to these mutations. Antigenic shift occurs when there is exchange of genetic material between flu virus subtypes, creating an entirely new and potentially pandemic viral strain. Dynavax has previously presented data showing that immunization with NP-ISS induces potent NP-specific Th1 and cytotoxic T lymphocyte responses as well as enhanced responses to HA when co-delivered with conventional or split vaccine.  

     New data were presented by Dynavax on its NP-ISS and, for the first time, on its M2e conjugate.

Key new data presented are as follows.

* Mice immunized with the NP-ISS conjugate and then challenged with drift and shift virus strains demonstrated statistically significant lower viral titers and higher survival rates compared to mice immunized with NP alone or a PBS placebo.

* Mice immunized with an M2e-ISS conjugate generated an M2e-specific antibody response that was enhanced with NP formulations.

* Both NP-ISS and M2e-ISS have been shown to enhance responses to co- administered standard vaccine in mice.

* Primates (baboons) immunized with NP-ISS co-administered with standard vaccine (Fluzone® sanofi-aventis) demonstrated enhanced NP and Fluzone-specific antibody responses.      

    Dynavax's data were presented at the Conference on Novel Vaccines:Bridging Research, Development andProduction, sponsored by the Cambridge Healthtech Institute, Cambridge, MA. The presentation was entitled, "Use of Conserved Influenza Antigens Linked to Immunostimulatory DNA (ISS) to Generate Broad Immunity to Divergent and Potentially Pandemic Virus Strains," and were presented by Debbie Higgins, Senior Manager, Preclinical Programs, Dynavax Technologies. Preclinical data were generated by Dynavax and collaborators at The Influenza Research Center, Baylor College of Medicine. 

    In 2003, Dynavax was awarded a $3.0 million grant over three and a half years to fund research and development of a pandemic influenza vaccine under a cooperative research program administered by the National Institute of Allergy and Infectious Disease (NIAID), a division of the National Institutes of Health.   

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