First U.S. Cell-Based Flu Vaccine Plant Awaits Pandemic

With the official dedication Dec. 12 of America’s first facility for making influenza vaccine in cell culture, the United States took a small but important step toward improved protection against the next flu pandemic, experts said.

But some question just how many weeks this new facility will shave off of the timeline for moving from a candidate pandemic vaccine strain to getting the vaccine into the arms of the American public. And by relying on an inherently old-fashioned approach to flu protection with limited effectiveness, some see this development as merely refining an archaic vaccine that is overdue for replacement by a newer and better method of immunoprotection against pandemic influenza.

"It’s a small, incremental step in preparedness, but the current hemagglutinin-antigen based vaccine really is inadequate for providing the kind of immunologic protection we need, and so anything you do to speed up the amount of [this type of] vaccine is only a marginal improvement in protecting against influenza," commented Michael T. Osterholm, Ph.D., professor in the school of public health and director of the Center for Infectious Disease Research and Policy at the University of Minnesota, Minneapolis.

"Just because you can make more of this [vaccine] faster, what does that mean? It’s better than nothing, absolutely, but that doesn’t mean it will be the answer for a very serious pandemic," Dr. Osterholm said in an interview.

"Having a new facility of substantial production capacity in the United States is a comfort," said Dr. William Schaffner, professor of medicine and chairman of preventive medicine at Vanderbilt University, Nashville, Tenn. "When you’re creating a pandemic vaccine, every week counts," and the cell culture–based technology that the new plant employs "is supposed to be somewhat faster" than conventional, egg-based production of flu vaccine, he noted. By not relying on chicken-based egg production that might conceivably be vulnerable to an avian flu pandemic, the new facility also sidesteps that potential danger.

"Having this facility in the United States is a significant step, as is having more vaccine," he said.

The new vaccine plant, in Holly Springs, N.C., culminates a 7-year project by Novartis working on contract with the Health and Human Services department, which funded 49% of the construction costs. The new plant brings cell-based flu vaccine production into the United States, and eventually onto the U.S. vaccine market for the first time, and also serves to beef up U.S.-based flu vaccine production of all types.

HHS officials first envisioned the new facility in 2004, when the American flu vaccine supply became threatened by many previous manufacturers going out of business, and when the supply from British-based Chiron temporarily went off line, said Robin Robinson, Ph.D., director of the HSS Biomedical Advanced Research and Development Authority. The facility uses cultured canine kidney cells to grow influenza vaccine.

Courtesy Novartis

The Holly Springs plant first became operational in late 2009, and now has produced several commercial-scale lots that have undergone testing in Phase III trials, Dr. Robinson said in an interview. The facility is positioned to immediately start making as much as 50 million doses of pandemic flu vaccine using cell-culture production, which could receive emergency-use FDA licensing and be available to the American public.

In the absence of a pandemic, the facility will primarily focus on making seasonal influenza vaccine (as well as certain other vaccines), but with much less urgency. The seasonal vaccine will undergo less speedy FDA licensing and will likely not appear on the U.S. market until 2013 or 2014, he said. Currently, U.S. residents received roughly 130 million doses of seasonal flu vaccine annually.

For pandemics, a major goal of cell-based flu vaccine production is to have "more vaccine available sooner," Dr. Robinson said. "The goal is 4 months" once a candidate vaccine strain is isolated during a new pandemic, but a more realistic expectation is that facility will send out significant amounts of vaccine after "4-5 months," he said. That compares with the 5 months it took to have the first egg-based vaccine appear during the H1N1 pandemic of 2009, he noted.

Courtesy Novartis

"If a pandemic happened now, and if everything went right, we’d cut the time to vaccine by about 1 month. That would have a huge impact. We hope it would eliminate the confusion" and the rationing that characterized the first weeks of pandemic vaccine availability in 2009, Dr. Robinson said.

Even saving just a couple weeks or so could make a difference, some experts said. "If the H1N1 vaccine had been available in quantity 1 month earlier, it would have made a difference in containing the [2009] pandemic," said Dr. W. Paul Glezen, a professor of molecular virology and microbiology at Baylor College of Medicine, Houston. "Using a tissue culture substrate to grow influenza viruses provides flexibility to vaccine production not available before using embryonated eggs. It should be safer as well, with less danger of contamination. Holly Springs is the beginning, and a good start. Most of the other manufacturers are also developing facilities for growing vaccine in tissue culture. The evidence suggests that all influenza vaccine should be produced in mammalian cells because adapting human influenza virus to grow in eggs alters important antigens that may result in vaccine that is less effective. The shorter production time also means the decision for [seasonal] vaccine constituents can be delayed to allow more time to assess the emergence of new variants to include in the vaccine."

"One month less" time to produce pandemic vaccine "is probably the best-case scenario. We might not get a full month, but it is supposed to be somewhat faster" than egg-based production, said Dr. Schaffner. "It could get the program going quicker, it could give the public a measure of confidence that the response is speedy and more optimistic. In 2009, it was perceived that the government over-promised and under-delivered. If we can start getting vaccine into the pipeline quicker, the public will think [the public health response] is on the ball."

But the reality may be more sobering. A Novartis cell-culture plant in Europe made H1N1 pandemic vaccine in 2009 that did not arrive any quicker than egg-based vaccine, Dr. Osterholm noted. Even if the 2009 European vaccine had glitches that could be avoided in America when the next flu pandemic strikes, what difference might a few weeks make for public health? "It means that vaccine would arrive at about the peak of the second [infection] wave, which is still really late," he said. "Even if you shaved a month off in 2009, it still would have had a limited impact. We need to do our best to have vaccine before the second wave."

Dr. Robinson agreed that even faster would be better. Next on the agenda for the Biomedical Advanced Research and Development Authority and HHS is to finish plans to make pandemic flu vaccine using recombinant technology. Dr. Robinson said this could produce vaccine within about 12 weeks, and that this capability is roughly 2 years away.

But recombinant vaccine may not be ideal either. Investigational recombinant vaccines have had effectiveness levels comparable to the 60% seen in trivalent inactivated vaccines. The answer, Dr. Osterholm said, lies in better understanding the immunity produced by natural flu infection and using that as a model to develop new vaccine antigens that reach much higher levels of effectiveness.

"Much of what we know about flu immunity is for hemagglutinin, and that’s not much," he said. "In 2009, there was clear evidence that 65- to 70-year-olds had residual protection to H1N1 from when that virus last circulated in the 1950s. These elderly people were entering immunosenescence, but they still had good protection. Yet we can’t get good protection from year to year with hemagglutinin-based vaccines. That shows something else going on immunologically that we should think about. Several possible target antigens have been identified, but so far they are not going anywhere because there has not been sufficient investment.

"Novel antigens are the ultimate flu vaccine goal. Is the Holly Springs plant a good thing for the short term? Sure, it’s an incremental increase in preparedness. But it’s not a major change in preparedness," Dr. Osterholm said.

Dr. Osterholm and Dr. Robinson said that they had no disclosures. Dr. Schaffner said that he has been a consultant to GlaxoSmithKline, Dynavax, Novartis, and Pfizer, and that he has served on data safety and monitoring boards for Sanofi-Pasteur and Merck. Dr. Glezen said that he has received a research grant from MedImmune.

With the official dedication Dec. 12 of America’s first facility for making influenza vaccine in cell culture, the United States took a small but important step toward improved protection against the next flu pandemic, experts said.

But some question just how many weeks this new facility will shave off of the timeline for moving from a candidate pandemic vaccine strain to getting the vaccine into the arms of the American public. And by relying on an inherently old-fashioned approach to flu protection with limited effectiveness, some see this development as merely refining an archaic vaccine that is overdue for replacement by a newer and better method of immunoprotection against pandemic influenza.

"It’s a small, incremental step in preparedness, but the current hemagglutinin-antigen based vaccine really is inadequate for providing the kind of immunologic protection we need, and so anything you do to speed up the amount of [this type of] vaccine is only a marginal improvement in protecting against influenza," commented Michael T. Osterholm, Ph.D., professor in the school of public health and director of the Center for Infectious Disease Research and Policy at the University of Minnesota, Minneapolis.

"Just because you can make more of this [vaccine] faster, what does that mean? It’s better than nothing, absolutely, but that doesn’t mean it will be the answer for a very serious pandemic," Dr. Osterholm said in an interview.

"Having a new facility of substantial production capacity in the United States is a comfort," said Dr. William Schaffner, professor of medicine and chairman of preventive medicine at Vanderbilt University, Nashville, Tenn. "When you’re creating a pandemic vaccine, every week counts," and the cell culture–based technology that the new plant employs "is supposed to be somewhat faster" than conventional, egg-based production of flu vaccine, he noted. By not relying on chicken-based egg production that might conceivably be vulnerable to an avian flu pandemic, the new facility also sidesteps that potential danger.

"Having this facility in the United States is a significant step, as is having more vaccine," he said.

The new vaccine plant, in Holly Springs, N.C., culminates a 7-year project by Novartis working on contract with the Health and Human Services department, which funded 49% of the construction costs. The new plant brings cell-based flu vaccine production into the United States, and eventually onto the U.S. vaccine market for the first time, and also serves to beef up U.S.-based flu vaccine production of all types.

HHS officials first envisioned the new facility in 2004, when the American flu vaccine supply became threatened by many previous manufacturers going out of business, and when the supply from British-based Chiron temporarily went off line, said Robin Robinson, Ph.D., director of the HSS Biomedical Advanced Research and Development Authority. The facility uses cultured canine kidney cells to grow influenza vaccine.

Courtesy Novartis

The Holly Springs plant first became operational in late 2009, and now has produced several commercial-scale lots that have undergone testing in Phase III trials, Dr. Robinson said in an interview. The facility is positioned to immediately start making as much as 50 million doses of pandemic flu vaccine using cell-culture production, which could receive emergency-use FDA licensing and be available to the American public.

In the absence of a pandemic, the facility will primarily focus on making seasonal influenza vaccine (as well as certain other vaccines), but with much less urgency. The seasonal vaccine will undergo less speedy FDA licensing and will likely not appear on the U.S. market until 2013 or 2014, he said. Currently, U.S. residents received roughly 130 million doses of seasonal flu vaccine annually.

For pandemics, a major goal of cell-based flu vaccine production is to have "more vaccine available sooner," Dr. Robinson said. "The goal is 4 months" once a candidate vaccine strain is isolated during a new pandemic, but a more realistic expectation is that facility will send out significant amounts of vaccine after "4-5 months," he said. That compares with the 5 months it took to have the first egg-based vaccine appear during the H1N1 pandemic of 2009, he noted.

Courtesy Novartis

"If a pandemic happened now, and if everything went right, we’d cut the time to vaccine by about 1 month. That would have a huge impact. We hope it would eliminate the confusion" and the rationing that characterized the first weeks of pandemic vaccine availability in 2009, Dr. Robinson said.

Even saving just a couple weeks or so could make a difference, some experts said. "If the H1N1 vaccine had been available in quantity 1 month earlier, it would have made a difference in containing the [2009] pandemic," said Dr. W. Paul Glezen, a professor of molecular virology and microbiology at Baylor College of Medicine, Houston. "Using a tissue culture substrate to grow influenza viruses provides flexibility to vaccine production not available before using embryonated eggs. It should be safer as well, with less danger of contamination. Holly Springs is the beginning, and a good start. Most of the other manufacturers are also developing facilities for growing vaccine in tissue culture. The evidence suggests that all influenza vaccine should be produced in mammalian cells because adapting human influenza virus to grow in eggs alters important antigens that may result in vaccine that is less effective. The shorter production time also means the decision for [seasonal] vaccine constituents can be delayed to allow more time to assess the emergence of new variants to include in the vaccine."

"One month less" time to produce pandemic vaccine "is probably the best-case scenario. We might not get a full month, but it is supposed to be somewhat faster" than egg-based production, said Dr. Schaffner. "It could get the program going quicker, it could give the public a measure of confidence that the response is speedy and more optimistic. In 2009, it was perceived that the government over-promised and under-delivered. If we can start getting vaccine into the pipeline quicker, the public will think [the public health response] is on the ball."

But the reality may be more sobering. A Novartis cell-culture plant in Europe made H1N1 pandemic vaccine in 2009 that did not arrive any quicker than egg-based vaccine, Dr. Osterholm noted. Even if the 2009 European vaccine had glitches that could be avoided in America when the next flu pandemic strikes, what difference might a few weeks make for public health? "It means that vaccine would arrive at about the peak of the second [infection] wave, which is still really late," he said. "Even if you shaved a month off in 2009, it still would have had a limited impact. We need to do our best to have vaccine before the second wave."

Dr. Robinson agreed that even faster would be better. Next on the agenda for the Biomedical Advanced Research and Development Authority and HHS is to finish plans to make pandemic flu vaccine using recombinant technology. Dr. Robinson said this could produce vaccine within about 12 weeks, and that this capability is roughly 2 years away.

But recombinant vaccine may not be ideal either. Investigational recombinant vaccines have had effectiveness levels comparable to the 60% seen in trivalent inactivated vaccines. The answer, Dr. Osterholm said, lies in better understanding the immunity produced by natural flu infection and using that as a model to develop new vaccine antigens that reach much higher levels of effectiveness.

"Much of what we know about flu immunity is for hemagglutinin, and that’s not much," he said. "In 2009, there was clear evidence that 65- to 70-year-olds had residual protection to H1N1 from when that virus last circulated in the 1950s. These elderly people were entering immunosenescence, but they still had good protection. Yet we can’t get good protection from year to year with hemagglutinin-based vaccines. That shows something else going on immunologically that we should think about. Several possible target antigens have been identified, but so far they are not going anywhere because there has not been sufficient investment.

"Novel antigens are the ultimate flu vaccine goal. Is the Holly Springs plant a good thing for the short term? Sure, it’s an incremental increase in preparedness. But it’s not a major change in preparedness," Dr. Osterholm said.

Dr. Osterholm and Dr. Robinson said that they had no disclosures. Dr. Schaffner said that he has been a consultant to GlaxoSmithKline, Dynavax, Novartis, and Pfizer, and that he has served on data safety and monitoring boards for Sanofi-Pasteur and Merck. Dr. Glezen said that he has received a research grant from MedImmune.

With the official dedication Dec. 12 of America’s first facility for making influenza vaccine in cell culture, the United States took a small but important step toward improved protection against the next flu pandemic, experts said.

But some question just how many weeks this new facility will shave off of the timeline for moving from a candidate pandemic vaccine strain to getting the vaccine into the arms of the American public. And by relying on an inherently old-fashioned approach to flu protection with limited effectiveness, some see this development as merely refining an archaic vaccine that is overdue for replacement by a newer and better method of immunoprotection against pandemic influenza.

"It’s a small, incremental step in preparedness, but the current hemagglutinin-antigen based vaccine really is inadequate for providing the kind of immunologic protection we need, and so anything you do to speed up the amount of [this type of] vaccine is only a marginal improvement in protecting against influenza," commented Michael T. Osterholm, Ph.D., professor in the school of public health and director of the Center for Infectious Disease Research and Policy at the University of Minnesota, Minneapolis.

"Just because you can make more of this [vaccine] faster, what does that mean? It’s better than nothing, absolutely, but that doesn’t mean it will be the answer for a very serious pandemic," Dr. Osterholm said in an interview.

"Having a new facility of substantial production capacity in the United States is a comfort," said Dr. William Schaffner, professor of medicine and chairman of preventive medicine at Vanderbilt University, Nashville, Tenn. "When you’re creating a pandemic vaccine, every week counts," and the cell culture–based technology that the new plant employs "is supposed to be somewhat faster" than conventional, egg-based production of flu vaccine, he noted. By not relying on chicken-based egg production that might conceivably be vulnerable to an avian flu pandemic, the new facility also sidesteps that potential danger.

"Having this facility in the United States is a significant step, as is having more vaccine," he said.

The new vaccine plant, in Holly Springs, N.C., culminates a 7-year project by Novartis working on contract with the Health and Human Services department, which funded 49% of the construction costs. The new plant brings cell-based flu vaccine production into the United States, and eventually onto the U.S. vaccine market for the first time, and also serves to beef up U.S.-based flu vaccine production of all types.

HHS officials first envisioned the new facility in 2004, when the American flu vaccine supply became threatened by many previous manufacturers going out of business, and when the supply from British-based Chiron temporarily went off line, said Robin Robinson, Ph.D., director of the HSS Biomedical Advanced Research and Development Authority. The facility uses cultured canine kidney cells to grow influenza vaccine.

Courtesy Novartis

The Holly Springs plant first became operational in late 2009, and now has produced several commercial-scale lots that have undergone testing in Phase III trials, Dr. Robinson said in an interview. The facility is positioned to immediately start making as much as 50 million doses of pandemic flu vaccine using cell-culture production, which could receive emergency-use FDA licensing and be available to the American public.

In the absence of a pandemic, the facility will primarily focus on making seasonal influenza vaccine (as well as certain other vaccines), but with much less urgency. The seasonal vaccine will undergo less speedy FDA licensing and will likely not appear on the U.S. market until 2013 or 2014, he said. Currently, U.S. residents received roughly 130 million doses of seasonal flu vaccine annually.

For pandemics, a major goal of cell-based flu vaccine production is to have "more vaccine available sooner," Dr. Robinson said. "The goal is 4 months" once a candidate vaccine strain is isolated during a new pandemic, but a more realistic expectation is that facility will send out significant amounts of vaccine after "4-5 months," he said. That compares with the 5 months it took to have the first egg-based vaccine appear during the H1N1 pandemic of 2009, he noted.

Courtesy Novartis

"If a pandemic happened now, and if everything went right, we’d cut the time to vaccine by about 1 month. That would have a huge impact. We hope it would eliminate the confusion" and the rationing that characterized the first weeks of pandemic vaccine availability in 2009, Dr. Robinson said.

Even saving just a couple weeks or so could make a difference, some experts said. "If the H1N1 vaccine had been available in quantity 1 month earlier, it would have made a difference in containing the [2009] pandemic," said Dr. W. Paul Glezen, a professor of molecular virology and microbiology at Baylor College of Medicine, Houston. "Using a tissue culture substrate to grow influenza viruses provides flexibility to vaccine production not available before using embryonated eggs. It should be safer as well, with less danger of contamination. Holly Springs is the beginning, and a good start. Most of the other manufacturers are also developing facilities for growing vaccine in tissue culture. The evidence suggests that all influenza vaccine should be produced in mammalian cells because adapting human influenza virus to grow in eggs alters important antigens that may result in vaccine that is less effective. The shorter production time also means the decision for [seasonal] vaccine constituents can be delayed to allow more time to assess the emergence of new variants to include in the vaccine."

"One month less" time to produce pandemic vaccine "is probably the best-case scenario. We might not get a full month, but it is supposed to be somewhat faster" than egg-based production, said Dr. Schaffner. "It could get the program going quicker, it could give the public a measure of confidence that the response is speedy and more optimistic. In 2009, it was perceived that the government over-promised and under-delivered. If we can start getting vaccine into the pipeline quicker, the public will think [the public health response] is on the ball."

But the reality may be more sobering. A Novartis cell-culture plant in Europe made H1N1 pandemic vaccine in 2009 that did not arrive any quicker than egg-based vaccine, Dr. Osterholm noted. Even if the 2009 European vaccine had glitches that could be avoided in America when the next flu pandemic strikes, what difference might a few weeks make for public health? "It means that vaccine would arrive at about the peak of the second [infection] wave, which is still really late," he said. "Even if you shaved a month off in 2009, it still would have had a limited impact. We need to do our best to have vaccine before the second wave."

Dr. Robinson agreed that even faster would be better. Next on the agenda for the Biomedical Advanced Research and Development Authority and HHS is to finish plans to make pandemic flu vaccine using recombinant technology. Dr. Robinson said this could produce vaccine within about 12 weeks, and that this capability is roughly 2 years away.

But recombinant vaccine may not be ideal either. Investigational recombinant vaccines have had effectiveness levels comparable to the 60% seen in trivalent inactivated vaccines. The answer, Dr. Osterholm said, lies in better understanding the immunity produced by natural flu infection and using that as a model to develop new vaccine antigens that reach much higher levels of effectiveness.

"Much of what we know about flu immunity is for hemagglutinin, and that’s not much," he said. "In 2009, there was clear evidence that 65- to 70-year-olds had residual protection to H1N1 from when that virus last circulated in the 1950s. These elderly people were entering immunosenescence, but they still had good protection. Yet we can’t get good protection from year to year with hemagglutinin-based vaccines. That shows something else going on immunologically that we should think about. Several possible target antigens have been identified, but so far they are not going anywhere because there has not been sufficient investment.

"Novel antigens are the ultimate flu vaccine goal. Is the Holly Springs plant a good thing for the short term? Sure, it’s an incremental increase in preparedness. But it’s not a major change in preparedness," Dr. Osterholm said.

Dr. Osterholm and Dr. Robinson said that they had no disclosures. Dr. Schaffner said that he has been a consultant to GlaxoSmithKline, Dynavax, Novartis, and Pfizer, and that he has served on data safety and monitoring boards for Sanofi-Pasteur and Merck. Dr. Glezen said that he has received a research grant from MedImmune.