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Aug 15, 2013

Getting Ready for the Flu

New methods advance flu vaccine production.

Getting Ready for the Flu

Authorities approve trivalent and quadrivalent vaccines while vaccine producers move beyond egg-based manufacturing. [Le Biplan - Fotolia.com]

  • Manufacturers have begun shipping flu vaccines for the 2013–2014 U.S. flu season. While some vaccines will be available in August, ample supplies, the CDC noted, should be available by September and October. The CDC recommends that everyone six months of age and older should get vaccinated early, ideally by October. Some of these vaccines will be manufactured in novel culture systems that don’t involve breaking any chicken eggs, the tried-and-true method of flu vaccine production that is slow, expensive, and hard to get up and running in response to a pandemic.

    As Nature News Blog put it, “After years of struggle, the production of seasonal flu vaccine in the United States has entered the modern era. On 20 November [2012], the FDA approved its first seasonal flu vaccine made in cell culture, rather than in fertilized chicken eggs.”

    According to the CDC, the 2012–2013 flu season was more severe than other recent seasons, with a higher percentage of flu-associated deaths, hospitalizations, and visits to physicians. Between September 2012 and May 2013, the proportion of deaths in the United States attributed to pneumonia or influenza peaked at 9.9%. In addition, the 2012–2013 flu season was particularly hard on older persons. The rate of hospitalization for flu-related illness among those 65 and older was 191 per 100,000 people, the highest rate of hospitalizations for this age group since the CDC began keeping track in 2005.

    The CDC has said that the flu vaccine affords the best protection against the flu for the coming season. Vaccinated individuals are 60% less likely to need treatment for the flu by a healthcare provider. Getting the vaccine has been shown to offer substantial other benefits including reducing illness, antibiotic use, time lost from work, hospitalizations, and deaths.

  • Trivalent and Quadrivalent Vaccines Available

    While the 2013–2014 trivalent influenza vaccine is made from three flu viruses—an A/California/7/2009 (H1N1)-like virus, an H3N2 virus antigenically like the cell-propagated prototype virus A/Victoria/361/2011, and a B/Massachusetts/2/2012-like virus—a quadrivalent vaccine containing a B/Brisbane/60/2008-like virus has also become available.

    Several new vaccines, including five approved this past July, are on the market. For example, according to an August 5 announcement by GlaxoSmithKline, the FDA approved the company’s Fluarix® Quadrivalent vaccine for shipment to CDC distribution centers and U.S. healthcare providers. Fluarix is the first quadrivalent vaccine available in the United States.

    Most influenza vaccines are trivalent, or designed to protect against three influenza viruses predicted to be the most common during the anticipated flu season. The three most common types of flu viruses commonly circulating among people today include influenza A (H1N1) viruses, influenza A (H3N2) viruses, and influenza B viruses. Each year, one flu virus of each kind is used to produce seasonal influenza vaccine. Since the late 1980s, however, scientists found that two influenza B virus strains circulate each year. “It is difficult to predict which one will cause the most illness in a particular influenza season,” said Leonard Friedland, M.D., vice president, scientific affairs and public policy, GlaxoSmithKline Vaccines, North America. “Fluarix Quadrivalent addresses this by protecting against both B strains.”

    For this influenza season, GlaxoSmithKline will supplement the supply of Fluarix Quadrivalent with its trivalent seasonal influenza vaccine. Fluarix Quadrivalent also is approved in Germany (marketed as Influsplit™ Tetra®) and the United Kingdom (as Fluarix™ Tetra).

    In its summary recommendations, the CDC described the vaccine products that are available, including the five newly approved vaccines. For many vaccine recipients, more than one type or brand of vaccine may be appropriate within indications and recommendations of the Advisory Committee on Immunization Practices (ACIP). Where more than one type of vaccine is appropriate and available, no preferential recommendation is made for use of any influenza vaccine product over another.

  • Concerns about Existing Approach to Vaccination

    But scientists remained concerned about how quickly new vaccine to meet new threats can be manufactured, and whether it is possible to produce a “universal” vaccine that will protect against any and all potential flu variations. In a 2012 interview with the New York Times, Gary Nabel, Ph.D, at the time a researcher at the NIH, said, “In the history of vaccinology, it’s the only one we update year to year.” (Dr. Nabel directed the Vaccine Research Center at the NIH’s National Institute of Allergy and Infectious Diseases before becoming chief science officer at Sanofi in December 2012.) Dr. Nabel said that experts foresee a time when seasonal shots become obsolete and will be replaced by long-lasting vaccines requiring only boosters.

    “That’s the goal: two shots when you’re young, and then boosters later in life. That’s where we’d like to go,” Dr. Nabel said. He predicted that scientists would reach that goal before long. “In our lifetime, for sure, unless you’re 90 years old.”

    The continual threat of pandemic influenza has prompted researchers to develop a number of novel approaches to providing immunity to this virus, focusing on target antigens that are highly conserved between different influenza A virus subtypes, said Sarah Gilbert, Ph.D., professor of vaccinology at the University of Oxford’s Jenner Institute. Several of these have now been taken into clinical development, focusing on target antigens which are highly conserved between different influenza A virus subtypes.

  • Alternatives to Egg-Based Manufacturing

    The right combination of antigens aside, alternatives to chicken egg-based manufacturing methods are needed, scientists say, to efficiently make enough vaccine to anticipate pandemics. It takes about one egg to make one dose of vaccine, meaning that around 100 million eggs are needed to create seasonal flu vaccines. And that’s one of the major limitations of the current process. If a strain of avian flu started infecting humans, for example, there might not be enough healthy chickens and healthy eggs to produce vaccines.

    Transitioning to alternative vaccine production methods using mammalian cell lines or other innovative methods, experts say, will cut vaccine production times in the event of an outbreak. Egg vaccine production won’t cut it for a pandemic, either. Current data suggest that egg-based production yields of hemagglutinin (HA) expressed by H5N1 viruses generated by reverse genetics are only 30–40% of the average HA yield for seasonal influenza viruses while virus yields are similar to those obtained usually. This could have serious implications for inactivated influenza vaccine production in the event of a pandemic. There are also long-standing concerns that growth of human influenza virus in eggs can lead to the selection of antigenic variants which may be less efficacious.

    But new vaccines produced in egg alternatives are entering the U.S. market, enabled largely by an inoculation of government capital. In 2012, the FDA approved Novartis’ Flucelvax®, manufactured in a mammalian cell line, the Madin-Darby canine kidney (MDCK) cell line, instead of chicken eggs.

    Novartis had partnered with the U.S. Department of Health and Human Services, Biomedical Advanced Research and Development Authority (HHS, BARDA) for the development of the cell culture manufacturing technology, to produce the vaccine, as well as for construction of the state-of-the-art facility in Holly Springs, NC. Public/private investment in the technology development and facility came to $1 billion.

    Next up was Protein Science Corporation’s Flublok®, approved by the FDA in January of this year. Flublok is described as the first trivalent influenza vaccine made using an insect virus (baculovirus) expression system and recombinant DNA technology. Flublok contains purified viral HA proteins produced in a continuous insect cell line (expresSF+®) derived from Sf9 cells of the fall armyworm, Spodoptera frugiperda, and grown in defined, serum-free medium.

  • Potential for Nanoparticle Vaccines

    Bypassing biological vaccine production systems altogether, nanoparticle vaccines may be in the works. Scientists working at NIAID and Medimmune reported that they had developed self-assembling influenza nanoparticle vaccines that elicit broadly neutralizing H1N1 antibodies. Dr. Nabel and his team at Sanofi in Cambridge developed vaccine nanoparticles using influenza HA and ferritin, an iron-transporting protein that naturally forms spherical clusters.

    The investigators fused these two proteins in such a way that the HA-ferritin complexes automatically assembled into a structure with a 24-piece ferritin core from which protruded eight three-piece HA spikes, mimicking the natural HA spikes in the flu virus coat. “We created an entirely new molecule,” said Dr. Nabel. “What’s cool is that the whole thing self-assembles.”

    When injected, the nanoparticles induced levels of anti-flu antibodies 34 times higher in mice and 10 times higher in ferrets compared with a traditional vaccine. Dr. Nabel thinks that this is because the HA molecules are much less densely packed on the nanoparticles than those on a real virus, and are not hidden by other coat proteins.

    Although further testing is needed, the HA-ferritin nanoparticle approach and other novel methods for vaccine production may eventually ease worries about vaccine supplies, as well as hold promise for development of more broadly protective vaccines for influenza as well as for other infectious diseases.


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