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Jun 1, 2009 (Vol. 29, No. 11)

Ramping Up Flu Vaccine Efforts

Goal Is to Move Products through Clinical Trials Quickly and Safely

  • One year ago, a new technology predicted that significant outbreaks of the H1N1 flu virus would occur within 6 to 12 months. One year later, the H1N1 flu virus triggered a stage 5 pandemic alert from the World Health Organization.

    While the ability to accurately predict influenza outbreaks and their locations is extraordinary, the same technology can be used to develop flu vaccines.

    The predictions, made by Replikins, were based on correlations of flu virus specimen and Pub Med documentation of major outbreaks during the past 90 years, focusing on concentrations of, and spacings between, replikins—the lysine and histidine residues in the hemagglutinin unit genetic sequences of the eight major genes in the influenza virus.

    Sam Bogoch, M.D., Ph.D., chairman of Replikins, says those replikins are strain-specific and determine the virus’ rate of replication. High counts (e.g., seven replikins per 100 amino acids) indicate an outbreak is imminent. Lower counts (four per 100 amino acids) indicate the virus will remain dormant indefinitely. The analysis showed a point-for-point correlation between high replikin counts and outbreaks.

    Dr. Bogoch notes that the company’s PanFlu™, a vaccine that interferes with replikins, is ready for clinical trials. A similar vaccine has proved effective in blocking H5N1 transmission among chickens, and has conferred 91% protection against the lethal Taura syndrome in shrimp populations, he points out, adding that because the replikins are conserved, this strategy has the potential to become a broad-spectrum flu vaccine. That vaccine can be manufactured in seven days, he explains.

    Novavax plans to create a virus-like particle-based (VLP) vaccine against the H1N1 strain, according to Rahul Singhvi, Sc.D., president and CEO. “Our recombinant VLP technology obviates the need for a live virus seed for manufacturing,” he says. Therefore, “We can cut the cycle time from strain identification to production of the first vaccine to just 10 to 12 weeks.”

    The VLPs contain the proteins that make the virus’ outer shell and the surface proteins, without the RNA required for replication. “There’s no genetic material in these VLPs, and they are unable to replicate,” Dr. Singhvi emphasizes.

    The vaccine includes three immunologically important proteins (hemagglutinin, neuraminidase, and matrix1) and is matched to the wild-type virus that causes influenza in humans.

  • Robust Response

    In tests against the Indonesian strain of H5N1 flu, “there was a robust immunogenic response,” Dr. Singhvi says. Phase II results shows that 64% of patients had a hemagglutinin inhibition titer above 1:40 at a 90 mcg dose, and 94% of patients showed a neutralizing antibody response against the H5N1 virus above 1:20 at a 90 mcg dose. Importantly, in preclinical studies, a VLP vaccine candidate against the 1918 H1N1 flu virus conferred protection against that strain and, when administered intranasally, also protected animals against a highly pathogenic strain of the H5N1 influenza.

    Phase III trials of the seasonal flu vaccine were planned for 2010, but Novavax stands ready to accelerate trials to combat pandemics, Dr. Singhvi says.

    Medicago received the genetic sequence for the H1N1 influenza virus strain in late April to begin testing using its virus-like particle technology. This August, it plans to begin a Phase I trial using its technology to target the H5N1 influenza virus. The goal is to prove the safety of a vaccine produced using Medicago’s plant-based technology.

    The company relies on a transient expression system to produce recombinant vaccine antigens in the Nicotiana benthamiana plant, according to Frederic Ors, vp, business development. It has the potential to deliver a vaccine for testing one month after the genetic materials from a virus strain are identified and sequenced, he says.

    “We immerse the leaves of the plant into a liquid containing the gene sequence in agrobacterium and apply a vacuum for one minute. This removes the air between the cells. The leaf acts like a sponge, drawing in the agrobacterium. The cells produce the protein for four to six days before leaves are harvested,” explains Ors.

    Medicago’s VLP technology has the potential to produce pandemic vaccines before a pandemic strikes and will be in a position to supply large volumes of vaccines to the global market once human trials are completed, claims Ors.

    In preclinical trials, the vaccine conferred cross protection against several strains of the H5N1 influenza virus, including those from Indonesia, Vietnam, China, and Turkey. “We also are developing a seasonal vaccine to follow our H5N1 vaccine candidate,” Ors says.

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