Vical Incorporated announced a breakthrough with preliminary clinical trial data demonstrating that DNA vaccines can safely achieve significant immune responses against H5N1 pandemic influenza in humans. DNA vaccines are fundamentally different from conventional vaccines because they do not contain any part of the virus itself, and may offer compelling advantages in response to a pandemic outbreak because of significantly reduced development and manufacturing times.

Specifically, preliminary human safety and immunogenicity data obtained in a 100-subject phase 1 trial of the company's Vaxfectin-formulated H5N1 pandemic influenza DNA vaccines demonstrated for the first time that DNA vaccines have achieved potentially protective levels of antibody responses (defined as hemagglutination inhibition, or HI, titers of at least 40; responses ranged from 40 to 640) in up to 67 per cent of evaluable subjects in the higher dose cohorts. No significant safety issues were observed at any of the Vical vaccine doses tested. These results support further development of Vaxfectin-formulated DNA vaccines, and could position them as potential alternatives to conventional vaccines.

"The preliminary results from this phase 1 trial indicate for the first time that an adjuvanted DNA vaccination against H5N1 influenza is well-tolerated and can induce impressive antibody responses even against this relatively weak immunogen," said Robert B. Belshe, M.D., Dianna and J. Joseph Adorjan Endowed Professor of Infectious Diseases and Immunology, Saint Louis University School of Medicine, who was the lead external safety monitor for the study. "Successful development of a safe and effective DNA vaccine will help address the potential public health threat of pandemic influenza."

Vijay B Samant, Vical's president and chief executive officer, said, "Our preliminary phase 1 pandemic influenza vaccine results clearly demonstrate the potential of Vaxfectin-formulated DNA vaccines to achieve antibody responses in the same range as conventional vaccines. The ability to manufacture DNA vaccines in weeks rather than the months required for conventional vaccines may provide a significant advantage when dealing with an emerging infectious disease such as pandemic influenza. This trial is also important because it marks the first successful safety evaluation in humans for our Vaxfectin adjuvant, which has potential applications with both DNA vaccines and conventional protein-based vaccines."

The double-blind, placebo-controlled, dose-escalation trial was conducted in approximately 100 healthy volunteers age 18 to 45 at three U.S. clinical sites. The trial was designed to assess safety and immunogenicity following intramuscular vaccination with needle and syringe or with the Biojector 2000 needle-free injection system in different cohorts, and to evaluate monovalent and trivalent Vaxfectin-formulated DNA vaccines at various doses.

In the phase 1 trial, subjects were injected at Days 0 and 21. Primary evaluation of antibody responses was by HI antibody titers, the accepted standard correlate of protection for influenza vaccines. Responders were those subjects achieving H5 HI titers of at least 40 and achieving at least a four-fold increase from baseline HI titers. By Day 56, at least 50% and up to 67% of evaluable subjects were responders in each of the three cohorts receiving 0.5 mg or 1 mg H5 DNA doses, and there were no responders in the placebo cohort. More than 90% of the responders had sustained HI titers through the last measurement to date (Day 84). Neutralizing antibody production against H5 was demonstrated separately by microneutralization assays. For comparison, the protein-based pandemic influenza vaccine currently stockpiled by the US government was approved with HI titers of 40 or more in 44% of subjects by Day 56.

Even at the lowest dose tested (0.033 mg H5 DNA), one of the six subjects was a responder by Day 56. Some subjects who received the highest H5 DNA dose were responders at Day 21 after a single vaccine injection. Preliminary analyses also showed cross-strain immune responses against a strain of H5N1 from a clade not matching the vaccine. Cross-strain protection could be important against emerging strains of pandemic influenza that may not match vaccine stockpiles.

Additional assays are ongoing to further evaluate antibody responses, breadth and magnitude of T-cell immune responses, cross-strain responses, and the relative advantages of monovalent vs. trivalent vaccines and needle vs. needle-free injection.

"These results are important to Vical for three reasons," added Samant. "First, they encourage further development of pandemic influenza DNA vaccines, for which we are currently exploring funding or partnering options. Second, they support advancement of additional Vaxfectin( formulated DNA vaccines toward clinical testing. Third, they provide new incentives for potential commercial partners and collaborators to explore additional applications for our Vaxfectin adjuvant for DNA vaccines as well as protein and peptide-based vaccines. We are excited by these strong preliminary antibody results, and we look forward to evaluating more detailed immunogenicity data as they become available."

DNA vaccines may offer both technical and economic advantages compared with conventional vaccine approaches. DNA vaccines encode certain proteins associated with a target pathogen, rather than using any part of the pathogen itself, and can prime the immune system as well as induce potent antibody and T-cell immune responses. DNA vaccines contain no viral particles, are non-infectious, and can be administered on a repeat basis without unwanted immune responses. Additionally, DNA vaccines have the potential to achieve proof of concept more quickly and cost-effectively than conventional vaccines, and can be manufactured using uniform methods of fermentation and purification, allowing significantly faster development and production.

Vical's monovalent vaccine contains a plasmid (a closed loop of DNA) encoding the hemagglutinin (HA) surface protein from the H5N1 influenza virus strain, A/Vietnam/1203/04. It is designed primarily to elicit antibody responses against the H5 protein but could elicit T-cell responses against H5 as well. Vical's trivalent vaccine contains the H5 plasmid plus separate plasmids encoding consensus sequences of two highly conserved influenza virus proteins: nucleoprotein (NP) and ion channel protein (M2). The trivalent vaccine is designed to elicit a combination of T-cell and antibody responses against all three proteins. Both vaccines are formulated with the company's Vaxfectin adjuvant, which has demonstrated effectiveness with a variety of DNA vaccines in multiple animal models as well as dose-sparing and immune-enhancing ability in animals with a conventional seasonal influenza vaccine.

Vical researches and develops biopharmaceutical products based on its patented DNA delivery technologies for the prevention and treatment of serious or life-threatening diseases. Potential applications of the company's DNA delivery technology include DNA vaccines for infectious diseases or cancer, in which the expressed protein is an immunogen; cancer immunotherapeutics, in which the expressed protein is an immune system stimulant; and cardiovascular therapies, in which the expressed protein is an angiogenic growth factor.