New technologies promise an end to shortages

By Henry I. Miller – washingtontimes.com 12/7/09

The H1N1 swine flu has sickened at least 22 million and killed almost 4,000 in the United States since April, according to the Centers for Disease Control and Prevention.

The shortage of the promised supplies of H1N1 flu vaccine has led to long waits in clinic lines for many Americans, frantic calls to doctors’ offices, and growing concern that immunization will arrive too late to prevent illness. In high-risk populations such as asthmatics, young children and expectant mothers, that anxiety is fueled by the possibility of life-threatening consequences should they become infected.

Overall, though, we were lucky this time around. Vaccine manufacturers have been able to produce substantial amounts of vaccine in record time and, as flu viruses go, the current H1N1 is tame. But the H1N1 immunization effort should be a wake-up call to health officials: We are woefully unprepared to deal with a true pandemic of a highly lethal virus. We need to modernize the technology used to make vaccines, so that they can be developed and manufactured more quickly. If large numbers of people were being killed by H1N1, shortages of vaccine would cause riots.

The trouble with our current vaccine production system is that it is not rapidly scalable to demand. It is an 80-year-old system that depends on harvesting the vaccine from fertilized chicken eggs. Manufacturers grow the virus in the eggs until there is a sufficiently high titer, and then the virus is harvested, killed and purified.

The entire process takes months. To harvest a suitable amount of vaccine for flu season requires millions of eggs. In 21st century America, we are waging war on a lethal infectious disease with World War I-era technology.

Fortunately, there are two newer, far superior ways to create vaccines.

The first is a process using recombinant DNA, or “gene-splicing,” technology to create a vaccine that induces the body to make its own antigen, and then to produce antibodies to that antigen. Researchers produce DNA of the target virus gene in a laboratory and introduce it into a circle of DNA called a plasmid, which acts as a carrier.

The plasmids containing the viral gene can easily and quickly be grown in large amounts. When the plasmids are injected into the muscle of a subject, they are taken up by cells that use the viral gene to make a viral protein, usually a protein that appears on the surface of the virus. (Sometimes, a second gene is present that directs the synthesis of an internal protein of the flu virus.) The viral protein – which is noninfectious and harmless – enters the bloodstream, where the immune system recognizes it as foreign and starts to make antibodies against it.

If the subject is later exposed to the flu virus, more antibodies are produced and bind to and neutralize the virus. Thus, the plasmid DNA that contains the viral gene is the vaccine.

The entire process, once the viral DNA is isolated, takes only a few days. This process is cost-effective and produces a vaccine with numerous advantages over the traditional versions.

DNA vaccines have a high heat tolerance, which means they can be transported over long distances without becoming inactivated, and can be stored in locations (such as developing countries) that lack refrigeration.

The vaccines are also easily altered in the lab, so that if the virus were to mutate, the genetic code could be changed accordingly and production could resume quickly. Another advantage is that because DNA vaccines do not contain whole viruses, there is no threat of viral infection from an immunization.

Another promising new vaccine process uses cell cultures of various kinds as a stand-in for the eggs in the traditional model. Manufacturers expose animal or insect cells grown in tissue culture to live virus, allow it to multiply and then harvest, inactivate and purify the virus particles.

This method saves time in scaling up to meet vaccine needs and avoids relying on eggs, which is cumbersome and could be vulnerable to infection if there were an outbreak of avian flu – thereby creating unacceptable and possibly lethal delays for the production process.

Federal health officials have already recognized the importance of these two cutting-edge approaches. A recent example is a contract from the U.S. Department of Health and Human Services (HHS) to the drug company Novartis, to support a new vaccine manufacturing facility that utilizes cell-based technology and other new processes to produce vaccine. And in June, HHS awarded a $35 million contract to Protein Sciences to develop and test a vaccine produced from gene-based technology.

These investments – and others like them – are good first steps, but we need to go further. Research and testing of DNA vaccines in particular must be expanded. Other vaccine manufacturers should be encouraged to branch into new technologies. The government should provide support for basic and proof-of-principle research. Even in the short term, expanding the use of gene and cell-based vaccine technologies could lead to a flu season without the threat of vaccine shortages.

Eventually, it might even yield the holy grail of flu vaccines – a “universal” vaccine based on the virus’ internal proteins, so that it is active on many different strains, year after year. Developing these new technologies for mass production is essential if we want to be prepared for the next pandemic.

Dr. Henry I. Miller, a physician and fellow at Stanford University’s Hoover Institution, was an official at the Food and Drug Administration from 1979 to 1994. He is the author of “To America’s Health: A Proposal to Reform the FDA” (Hoover Institution Press, 2000).

DNAWellnessinfo.com Resource: http://www.washingtontimes.com/news/2009/dec/07/better-vaccines-for-the-next-pandemic/

Better vaccines for the next pandemic is a post from: dnawellnessinfo.com

By Tom Fudge

September 23, 2009 – www.kpbs.org/

SAN DIEGO — Two San Diego companies are getting a lot of attention from the world of medicine and from investors. They’re doing it with a new kind of vaccine.

The conventional vaccine for swine flu should arrive next month and doctors expect it to be a good match for the H1N1 virus. Even so, two San Diego companies making alternative flu vaccines have seen their stock prices increase dramatically. The companies, Vical and Inovio, have shown good results in animal testing .

DNA vaccines use genetic sequencing to create a harmless, mock virus that gets an immune response. Joseph Kim, CEO of Inovio, said the conventional swine flu vaccines might work fine. But not if the virus mutates.

“That’s where we come in,” he said. “Our vaccine is specifically designed to work against a changing strain of virus.”

Neither company has FDA approval. But they say making DNA vaccines is faster, safer and the way of the future.

DNAWellnessinfo.com Resource:  http://www.kpbs.org/news/2009/sep/23/san-diego-companies-pioneer-dna-vaccines/

San Diego Companies Pioneer ‘DNA Vaccines’ is a post from: dnawellnessinfo.com

Denise Gellene 6/9/09

For a lesson in surviving tough times, look no further than San Diego’s Vical. (NASDAQ: VICL) The vaccine developer has endured two decades of red ink and by any sort of business logic should have folded its tent long ago. Instead, Vical is slowly but steadily advancing its “naked DNA” technology for use as a cancer vaccine (and with much fanfare against swine flu.) Last month, the company received a fresh $20 million infusion from investors, providing enough added cash for Vical to continue operations though the end of 2011.

By then, Vical will know the results of two key clinical studies. One is a late-stage trial of a therapeutic vaccine for metastatic melanoma to be completed in 2010. The second is a mid-stage test of a vaccine to prevent life-threatening cytomegalovirus infections in bone marrow transplant patients; interim results are expected this month. Positive outcomes from either trial would bring Vical a giant step closer to delivering a product while validating its faith in a pioneering technology.

When I recently asked CEO Vijay Samant for insight into Vical’s staying power, he first informed me that 20 years isn’t a long time to spend on something entirely new. He reminded me that one of San Diego’s most successful biotechnology companies, Idec – now Biogen Idec – worked on its first drug, a cancer medicine called Rituxan, for nearly 18 years.

“It takes time to understand the applications of the technology; it takes time to optimize the technology; it takes time to for regulatory agencies to understand the technology so they are comfortable with it; it takes time for clinicians and physicians to feel comfortable enough with the technology to inject people with it,” he said.

Traditional vaccines, such as those for flu, use actual virus to trigger an immune response. Vical instead uses genetic engineering techniques to produce sequences of virus DNA, which are injected into the body. Muscle cells take up the DNA and use it to produce virus proteins that stimulate the immune system. In essence, the body’s own muscle cells become vaccine mini-factories.

The beauty of Vical’s approach is that it can also be used for therapeutic cancer vaccines. Instead of virus DNA, the company’s experimental melanoma vaccine uses a genetic sequence that rarely occurs in Caucasians, who have a high incidence of skin cancer. Development partner AnGes of Japan wants to test the vaccine in head and neck cancer because the gene sequence is seldom seen in native Japanese, Samant said.

The early promise of Vical’s technology made it a biotech darling. The company’s market cap hovered around $1.5 billion in early 2000 — during what Samant calls the “rah-rah days” before the dot-com crash in April of that year. Vical’s current market cap approaches $90 million, much closer to earth for a company with no products.

Samant took charge of Vical in late 2000 after a stint as head of Merck’s vaunted vaccine group. He immediately faced numerous challenges. One was perception. Regulators considered Vical’s vaccines a form of gene therapy, a technology largely focused on using healthy genes to cure inherited disorders. Gene therapy companies typically use viruses to deliver genes, and face added regulatory scrutiny.

“It took us a long time, three or four years, to get out from under that gene therapy label,” Samant said.

Another was finding a way to intensify the immune response to Vical’s vaccines, which are designed to stimulate production of T cells in addition to antibodies. The solution was an adjuvant made of lipids, fatty molecules that naturally incite the immune system.

What other steps got Vical to this point? Samant shared some insights that offer useful tips to other innovation companies:

— Pick a market you can win. At least one Big Pharma player is working on a vaccine to prevent cytomegalovirus infections in healthy women; the virus can cause congenital disabilities when passed from pregnant women to fetuses. Lacking the resources to compete head-to-head, Vical targeted infections in bone marrow transplant patients, a narrow segment worth perhaps $100 million a year – too small to interest traditional vaccine makers. Successful results in transplant patients will position Vical to go after the larger market with a deep-pocketed partner.

— Validate your technology on someone else’s dime. Vical obtained government support for high-profile work on vaccines against avian flu and the H1N1 swine flu. The experimental avian flu vaccine promoted a robust immune response in nearly 70 percent of healthy volunteers; Vical is now looking for government money so it can move its swine flu vaccine from animal studies into human trials. Yet Samant was circumspect, even though Vical’s work on sequencing the swine flu virus was attention-grabbing. ”My goal is to demonstrate the value of our technology against a very difficult target,” he said. “If we’re lucky and the government places an order, that’s an upside.”

With its shares trading in penny stock territory, Vical clearly is not out of the woods. Last year, it closed a San Diego research facility and cut 29 jobs to save cash. And as with any vaccine, there is always concern about a strong or uncontrolled immune system response. A patient death in a mid-stage trial was classified as “probably related” to Vical’s melanoma vaccine, Allovectin-7, because the possibility could not be ruled out. The company does not believe the vaccine, which is injected directly into tumors, was a significant factor in the death.

Samant expressed confidence in the company’s science, which suggests a final bullet point—Believe. “We are close to validation on a variety of fronts,” he said. “We are ready for prime time.”

Former Los Angeles Times biotech reporter Denise Gellene is a regular contributor to Xconomy. You can email her at dgellene@xconomy.com

DNAWellnessinfo.com Resource:  http://www.xconomy.com/san-diego/2009/06/09/after-years-of-red-ink-vical-says-dna-based-vaccines-ready-for-prime-time/

After Years of Red Ink, Vical Says DNA-Based Vaccines ‘Ready for Prime Time.’ is a post from: dnawellnessinfo.com