Trial answers some, not all, questions on cell-based flu vaccines

Oct 6, 2010 (CIDRAP News) – A new report says that a cell culture derived influenza vaccine and a conventional egg-based vaccine both proved effective in a large international clinical trial, offering support for those who contend that cell-based vaccines should become an important part of flu vaccine supplies in coming years.

But it remains to be seen whether cell culture production, which has been discussed for years, is the wave of the future for flu vaccines. Some doubts persist as to whether it offers sufficient advantages in effectiveness and production time to replace the traditional egg-based technology.

In the new study, the research team found that the cell-based vaccine was about 84% effective and the conventional vaccine about 78% effective against culture-confirmed infections with the three flu strains targeted by the vaccines, according to an early online report from Clinical Infectious Diseases. The vaccines provided about 70% and 63% protection against all circulating flu strains, compared with a placebo.

The trial involved close to 11,000 young adult volunteers and was conducted during the 2007-08 flu season in the United States, Poland, and Finland. Both vaccines were made by Novartis, which financed the study.

Cell culture technology—growing vaccine viruses in mammalian cells, such as canine kidney cells—is seen as more flexible and somewhat faster than the decades-old method of growing flu vaccines in chicken eggs.

In egg-based production, the time from receipt of a seed strain to large-scale production is generally about 4 to 6 months. Cell-culture technology is used to make certain other vaccines, such as polio and rabies. Some of the drawbacks of egg-based production were illustrated during the H1N1 pandemic by the low initial yields of vaccine for that virus.

Though the potential advantages of cell-based over egg-based flu vaccines have been cited for years, no cell-based flu vaccine has yet been approved in the United States. A few cell-based flu vaccines have been approved recently in Europe, but little information about their track record has been made available so far. Meanwhile, Novartis, with a large subsidy from the US government, has built a facility in North Carolina designed to produce cell-based flu vaccines and related products.

The cell-based vaccine used in the study, Optaflu, was approved by the European Union in 2007.

First study of its type
The authors write that their study is the first to evaluate the efficacy of a trivalent (three-strain) cell culture derived influenza vaccine (CCIV) against confirmed influenza and also is the largest randomized, controlled trial of the efficacy of inactivated flu vaccines generally. Their main aim was to assess the efficacy of the two vaccines as compared with a placebo, not to compare the two vaccines directly, the report says.

The team recruited 11,404 volunteers between the ages of 18 and 49, who were randomly assigned to receive either Optaflu; Agrippal, an egg-based, trivalent inactivated vaccine (TIV) used in Europe; or a placebo. All the participants were monitored for 6 months after vaccination, and nasal and throat swabs were collected for analysis from those with any flu-like illness.

A total of 10,844 volunteers completed the study, including 3,828 in the CCIV group, 3,676 in the TIV group, and 3,900 in the placebo group. The team diagnosed 231 flu cases of all strains, including 42 in the CCIV group, 49 in the TIV group, and 140 in the placebo group. Sixty of the 231 infections involved strains targeted by the vaccines.

For the CCIV, the authors calculated vaccine efficacy against all circulating strains to be 69.5% (lower limit of 97.5% confidence interval [CI], 55.0%). Efficacy for the egg-based vaccine was 63.0% (97.5% CI lower limit, 46.7%). Both numbers were significantly better than placebo. Most of the flu cases (134 of 231) were caused by type B strains that were not included in the vaccine, which lowered the vaccine efficacy against all strains.

For the flu strains targeted by the vaccines (vaccine-like strains), efficacy was estimated at 83.8% (97.5% CI lower limit, 61.0) for the cell-based vaccine and at 78.4% (97.5% CI lower limit, 52.1%) for the egg-based vaccine.

Both vaccines were found to be highly effective against circulating H1N1 viruses, but the results for H3N2 and influenza B were less consistent, the report says. Relatively few H3N2 infections were identified, making vaccine efficacy hard to evaluate, while most of the circulating B strains were not included in the vaccines. The measured efficacy against all B strains was about 50% for both vaccines, but the 97.5% CI lower limit was below 40%, which is the US Food and Drug Administration's minimum efficacy criterion.

By looking for antibodies in blood samples from a subsample of 1,045 volunteers in the US arm of the study, the team determined that both vaccines were highly immunogenic. Both vaccines were well tolerated and had similar safety profiles, and no one withdrew from the study because of adverse reactions.

Findings called reassuring
In an accompanying commentary, David I. Bernstein of Cincinnati Children's Hospital Medical Center said the findings provide further reassurance about the safety and efficacy of cell-based flu vaccines. "It appears that CCIVs will be useful and should begin to make up part of the vaccine supply shortly," he wrote.

He said that cell-based production has several advantages over egg-based, but that certain obstacles to its use remain.

Cell-based production does not depend on the availability of large supplies of eggs, and large quantities of cells can be provided fairly quickly, making the approach more flexible, Bernstein notes. In addition, cell-based production is not hampered by the fact that some flu viruses, such as H5 strains, kill chicken embryos. Further, flu viruses growing in cell culture are less likely to undergo genetic changes than viruses growing in eggs. And cell-based vaccines don't contain egg albumin, so they can be used in egg-allergic patients.

But Bernstein also noted some barriers and disadvantages: a lack of experience in using the technology, a need for more testing to ensure that vaccines are free of contaminants, and the need for new production facilities.

"The main impediment to the use of cell-culture systems is the identification of a cell suitable for use in the manufacture of vaccines," he wrote. It will be necessary to prove that vaccines are free of cell-derived contaminants and other viruses, an issue that was highlighted recently by the discovery of fragments of a porcine circovirus in the two rotavirus vaccines now in use, he noted. (No safety problems have been linked to the findings.)

An incremental improvement?
While Optaflu seemed to perform well in the study and cell-based flu vaccines may be gaining traction, some experts are doubtful that cell-based technology offers sufficient advantages to justify broad adoption. One is Michael T. Osterholm, PhD, MPH, director of the University of Minnesota Center for Infectious Disease Research and Policy, which publishes CIDRAP News.

"This is potentially an incremental improvement, and we need game-changers," Osterholm said.

"I think this is a really well-done study, and they ought to be applauded for the care they took in their methods," he said of the Optaflu trial. But he observed that the efficacy of both vaccines against all flu strains was only in the 60% range, and for the non-vaccine-like strains, efficacy for both vaccines was only about 50%, he added. "This is in healthy 18- to 49-year-olds, the group where it should work the very best."

Overall, he said, the results are consistent with the vaccine effectiveness seen in the 2009 H1N1 pandemic: about 65%, as reported at a recent flu conference in Hong Kong and in Centers for Disease Control and Prevention data that he has seen.

"This shows that what we really need are game-changing vaccines, to help the elderly, people with underlying problems. It points out the need for better vaccines even in healthy individuals," Osterholm said.

He also said it's not really clear how much time cell culture production saves, compared with egg-based. "The cell culture process surely is a potential advantage in providing a somewhat faster time period for production as well as increased production capacity, but it still is going to take substantial time, and how much we'll be able to shave off we really don't know."

"Cell culture vaccines work—it's not a surprise—but are we going to invest the many millions of dollars it'll take to convert current antigen–based production from egg to cell, when the real problem is we need better antigens?" Osterholm said.

He referred to hemagglutinin, the viral protein (antigen) targeted by existing vaccines, which constantly changes to evade the immune system. Flu experts hope that vaccines targeting more stable components of flu viruses will eventually be developed, so that the vaccine won't have to be reformulated every year.

Sanofi Pasteur, a major flu vaccine supplier for the United States, decided last year that cell-based production wasn't worth pursuing. Under a government contract, the company produced a cell-based vaccine on a pilot scale and conducted clinical studies. The vaccine worked, but it offered no real clinical advantage, a company official told CIDRAP News in November 2009. And while the technology offered a "modest" time savings in production, it was expensive, she said.

European experience
In response to CIDRAP News queries, the two companies that make cell-based flu vaccines used in Europe, Novartis and Baxter, released limited information about their experience with those vaccines.

Optaflu, the Novartis vaccine, was first supplied as a seasonal flu vaccine in January 2008, following its European approval in 2007, according to a company statement provided by spokeswoman Sarah Coles. From 2009 onward, "the process was dedicated to pandemic vaccine production" for the 2009 H1N1 vaccine, the company said.

Regarding production volume so far, "Novartis produced a number of seasonal doses and over 25 million doses of cell-based pandemic vaccine for the 2009 H1N1 pandemic, demonstrating a rapid response to the global health threat," the statement said.

As for production timelines, Novartis said it was the first company to report successful production of a batch of 2009 H1N1 vaccine when it did so on Jun 12, 2009, after receiving the seed strain from the World Health Organization at the end of May.

But the company did not share any specifics about how long it has taken to make commercial quantities of Optaflu. The firm said its production of Optaflu during the H1N1 pandemic "confirmed our ability to deliver large quantities of vaccine using flu cell culture technology."

Baxter Healthcare's cell-based 2009 H1N1 vaccine, Celvapan, received European Commission approval in October 2009. The company made the first commercial lots of the vaccine in late July, about 12 weeks after it received the seed strain in late May, according to company announcements at the time.

Baxter distributed Celvapan H1N1 in the United Kingdom, Ireland, Germany, Austria, France, and New Zealand, said a company statement released by spokesman Andrew Lewis. But he provided no information on how many doses were delivered. And other than the 12-week period for making the first lots, Lewis said he couldn't give any details on production times or whether the company encountered any production glitches.

"Baxter is pleased that our Vero Cell technology was successfully applied to address this global public health issue, and we are convinced that this technology will continue as a viable alternative to egg-based pandemic and seasonal vaccines," the company statement said.

Meanwhile, a cell-based seasonal flu vaccine made by Baxter, called Preflucel, was approved in Austria last week.

Novartis and Baxter declined to give any information on the prices of their cell-based vaccines.

Frey S, Vesikari T, Szymczakiewicz-Multanowska A, et al. Clinical efficacy of cell culture-derived inactivated subunit influenza vaccines in healthy adults. Clin Infect Dis 2010 Nov 1; early online publication [Abstract]

Bernstein DI. Cell culture-derived influenza vaccines: Has their time come? (Editorial) Clin Infect Dis 2010 Nov 1; early online publication [Full text]

See also:

November 24, 2009, CIDRAP News story "Novartis unveils US cell-based flu vaccine plant"

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