Next generation of flu vaccines coming of age: Cell-based technology may replace egg-based flu vaccines
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* Teddi Dineley Johnson

With the reliability of a finely tuned clock, seasonal influenza returns each year, causing about 36,000 U.S. deaths and incalculable misery. Not as reliable has been the availability of the most important tool for controlling flu: vaccines.

Delays, shortages and distribution problems that have stymied immunization efforts in recent years have raised questions about the nation’s commitment to preparedness and sparked interest in the government’s efforts to develop new and better flu vaccines. Without compromising efficacy and safety, greater innovation is needed in the area of vaccine development, said a December Institute of Medicine report.

“Developing and manufacturing most vaccines involves using living organisms and presents unique technical and regulatory challenges,” said the report, “Priorities for the National Vaccine Plan.”

Both industry and regulators are “risk averse,” the report said, noting that progress in regulatory science in general has been slow and as a result, a “tried and true paradigm” characterizes some aspects of vaccine development and regulation.

One such paradigm, the half-century-old egg-based method of producing flu vaccine, has major limitations, experts say, including a lengthy six- to nine-month manufacturing process and the need to forecast and select the virus strains to be used in the vaccine at least six months ahead of the flu season, not to mention the annual demand for hundreds of millions of fertilized chicken eggs. Also, decisions about which viral strains to include in the vaccine may not always be correct, and midcourse corrective action is virtually impossible because of the long lead time required to acquire eggs. Also concerning is the fact that people who are allergic to eggs cannot receive the vaccine.

“We need a better technology for making flu vaccine,” Arthur Reingold, MD, a member of the IoM report’s authoring committee, told *The Nation’s Health.* “People have recognized that, and there is good work going on.”

The Institute of Medicine released its report on the same day that the National Institutes of Health hosted an educational seminar for the media on new flu vaccine technologies. In an event speech, Health and Human Services Secretary Kathleen Sebelius told attendees that the process used to make the egg-based flu vaccine is “cumbersome and outdated.”

“We couldn’t have had a better indication of the need for new flu vaccine technology than our experience with the 2009 H1N1 virus this fall,” Sebelius said. “It will be several more years before we are able to wean ourselves away from egg-based vaccine, but we are committed to move ahead with 21st century vaccine development.”

Demonstrating her commitment to new flu vaccine technologies, Sebelius was present in late November when Novartis Vaccines and Diagnostics cut the ribbon on the nation’s first large-scale U.S. facility to manufacture cell-based vaccine for seasonal and pandemic flu. In place of eggs, the nearly $1 billion Holly Springs, N.C., plant is using laboratory-grown mammalian cells that are capable of hosting a growing virus. Cell culture-based vaccines are already approved for use in some European countries.

![Figure1](http://www.thenationshealth.org/http://www.thenationshealth.org/content/nathealth/40/1/1.1/F1.medium.gif)

[Figure1](http://www.thenationshealth.org/content/40/1/1.1/F1)

Workers run tests on flu vaccine manufacturing equipment at the new Novartis facility in Holly Springs, N.C., in November.

Photo by Jim R. Bounds, courtesy Bloomberg/Getty Images

Because cell-based influenza vaccine can be made faster and in greater quantities than traditional vaccine, the new facility is expected to increase the nation’s capacity to make pandemic influenza vaccine by at least 25 percent, according to HHS, which awarded Novartis a $487 million multi-year contract to support the initiative’s domestic manufacturing capacity.

The plant is expected to be running at full-scale commercial production in 2013 and will also be producing the company’s proprietary adjuvant. When injected together with a vaccine, adjuvants expand and compound the strength of the response to allow for a lesser dose of the vaccine.

Marking another bold move into the future, HHS in June awarded Protein Sciences of Meriden, Conn., an initial $35 million contract to develop a so-called recombinant influenza vaccine. Under the technology, a gene is extracted from a flu virus and placed into an insect virus called baculovirus, which does not affect people but can multiply quickly to high levels in insect cells. The cells are purified to become a basic part of a human vaccine. Using this method, vaccine production may be available faster than by using traditional egg-based production methods, and because the basic cells can be frozen and stored indefinitely, manufacturing large quantities of a vaccine would also be faster, according to a statement released in June by HHS.

Other new technologies for producing influenza vaccines include DNA-based approaches and the development of broadly protective “universal” vaccines based on influenza virus proteins that are shared by multiple strains.

One strategy to produce improved influenza vaccine is at the finish line and will likely be available for the 2010–2011 flu season. In December, the Food and Drug Administration approved Sanofi Pasteur’s license application for a high-dose flu vaccine aimed at seniors. According to a company statement, the vaccine is specifically designed to generate a more robust immune response in people 65 and older, an age group that “typically does not respond as well to the standard dose of influenza virus vaccines as younger individuals because they have weakened immune systems.”

Transitioning to newer methods has been slow, partly because the development and production of vaccine is fundamentally a private-sector issue, said Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases. Incentives for private companies to invest in the transition from the established methodology of developing flu vaccines in eggs have been few, especially because vaccine — and flu vaccine in particular — is not a big profit maker for companies.

“There is a risk when you’re dealing with needing to grow the virus in the medium of eggs that something could go wrong, namely the virus can grow slow, the situation can require a surge of many more doses than you thought you would need, and it is difficult to, on a dime, start surging with more doses because you have to preorder the chickens, preorder the eggs, preinoculate the eggs, etc.,” Fauci told *The Nation’s Health.* “So there was always the realization that this was a fragile system. It worked and it has worked for decades but the incentive to transition into a more modern, reliable and surgable technique was not there.”

Recent threats, such as H5N1 avian influenza — which continues to smolder — reinforced the need for the federal government to partner with private sector companies and help them shift development to new cell culture technologies, Fauci said.

“However, that process doesn’t happen overnight,” Fauci said, noting that it takes years to build factories and show that a virus can grow in cells and that a vaccine is safe and effective. “That process was already ongoing when we became aware that we needed to make a vaccine for H1N1. It was ongoing but not quite ready for prime time, so right now we are seeing that transition get closer and closer to reality.”

The transition from eggs to cells speeds the vaccine manufacturing process by several weeks, Fauci said, and offers more flexibility in terms of being able to “surge up” with many more doses. But the new technology is not the final frontier by any means.

![Figure2](http://www.thenationshealth.org/http://www.thenationshealth.org/content/nathealth/40/1/1.1/F2.medium.gif)

[Figure2](http://www.thenationshealth.org/content/40/1/1.1/F2)

A researcher in Wuhan, China, does preparation work for producing H1N1 flu vaccine using eggs in June 2009.

Photo by Zhou Chao, courtesy ChinaFotoPress/Getty Images

“I don’t consider, nor do many of my colleagues consider, that that’s the end game solution,” Fauci said, pointing to what he calls the “ultimate holy grail” — a universal vaccine that would theoretically provide protection against any strain of influenza without needing to be updated or administered every year to protect against newly emerging annual or pandemic strains, but “that is years away,” he said.

The IoM report, “Priorities for the National Vaccine Plan” is online at [www.iom.edu](http://www.iom.edu). To watch the Dec. 11 NIH media seminar online, visit [http://videocast.nih.gov](http://videocast.nih.gov).

*   Copyright The Nation’s Health, American Public Health Association