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Homeland Security

Flu Pandemic Mitigation - Vaccine

The single best way to prevent influenza is to get vaccinated. Although it resides in the respiratory tract, it is by no means the only virus likely to be lurking there and may not be the major source of flu-like aches and fever. If not, then immunization against influenza, even assuming that the vaccine fits the strain and that it actually immunizes, safeguards nobody from identical symptoms caused by other viruses.

Inoculation takes two weeks to bring immunity. The possibility that there would be sufficient vaccine early in a pandemic to vaccinate the majority of the population or sufficient antiviral drugs to provide prophylaxis for highrisk persons is extremely remote. "A vaccine probably would not be available in the early stages of a pandemic. Once a potential pandemic strain of influenza virus is identified, it will take [six to nine] months before a vaccine will be widely available." [U.S. Centers for Disease Control, "Pandemic Influenza, Q&A," December 2005]

The best method of preventing and reducing the severity of the flu is the timely development, distribution, and administration of influenza vaccine. Influenza vaccination is used during interpandemic years to reduce deaths and disease. Seasonal influenza vaccine production begins as early as 6-9 months before the beginning of vaccine distribution. Even with this early start, it isn't possible to complete the entire production and distribution process prior to the vaccination season, particularly given the limited number of influenza vaccine manufacturing plants in the United States and the large number of doses that are produced each year. Instead, influenza vaccine distribution takes place in a phased fashion over a number of months. It begins in late summer for some manufacturers and vaccine products and usually completes near the end of November or early in December. Manufacturers and distributors work to try to get some vaccine to as many providers as possible as soon as possible so that they can begin vaccinating their high-risk patients.

Vaccine is unlikely to be available in time or in sufficient quantities for use during the initial wave of a pandemic. The US-based vaccine production capacity was assumed at 3 to 5 million 15g doses per week with 3 to 6 months needed before the first doses are produced. Two doses per person were assumed to be required for protection. Subsequent results of an NIH clinical trial of influenza A (H5N1) vaccine suggest that higher doses of antigen will be needed to elicit a good immune response; thus, these assumptions could potentially substantially overestimate the amount of vaccine that would be produced. Priority would be given to vaccine and antiviral manufacturers and others essential to manufacturing and critical support (~40,000). Priority would also be given to medical workers and public health workers (8-9 million) who are involved in direct patient contact, other support services essential for direct patient care, and vaccinators.

Currently, influenza vaccines licensed by the U.S. Food and Drug Administration (FDA) are made in specialized chicken eggs using a process that has changed little in over 50 years. In place of eggs, cell-based vaccine production uses laboratory-grown cells that are capable of hosting a growing virus. The virus is injected into the cells where it multiplies. The cells' outer walls are removed, harvested, purified, and inactivated. Using this technology, a vaccine can be produced in a matter of weeks.

The surge capacity that will be needed for a pandemic response cannot be met by egg-based vaccine production alone, as it is impractical to develop a system that depends hundreds of millions of 11-day old specialized eggs on a standby basis. In addition, because a pandemic could result from an avian influenza strain that is lethal to chickens, it is impossible to ensure that eggs will be available to produce vaccine when needed.

In contrast, cell culture manufacturing technology can be applied to influenza vaccines as they are with most viral vaccines (e.g., polio vaccine, measles-mumps-rubella vaccine, chickenpox vaccine). In this system, viruses are grown in closed systems such as bioreactors containing large number of cells in growth media rather than eggs. The surge capacity afforded by cell-based technology is insensitive to seasons and can be adjusted to vaccine demand, as capacity can be increased or decreased by the number of bioreactors or the volume used within a bioreactor. In addition to supporting basic research on cell-based influenza vaccine development, HHS is currently supporting a number of vaccine manufacturers in the advanced development of cell-based influenza vaccines with the goal of developing US-licensed cell-based influenza vaccines produced in the United States.

About 100 million US residents were inoculated in the 2006-2007 season. For the 2006-2007 season, there were only four manufacturers of influenza vaccine for the United States: GlaxoSmithKline (GSK), Sanofi Pasteur, Novartis, and MedImmune. And only one of those, Sanofi Pasteur, actually produced the vaccine domestically. In all, those manufacturers produced about 120 million doses of vaccine for the 2006-2007 season, of which about 100 million were distributed.

The "standard dose" of antigen for flu vaccine is 15 micrograms (mcg) of flu-virus proteins. (Seasonal vaccines comprise three doses of 15 mcg-two from the influenza A family and one representing influenza B-in a single shot.)

Vaccinating the entire U.S. population does not guarantee everyone will be protected from influenza-related illness and death. It is uncertain how well vaccines can help prevent or control the spread of a pandemic influenza virus. Vaccines against various strains differ in their ability to produce antibodies to neutralize the virus, and each person's immune system may respond somewhat differently. Limited studies have shown that when the vaccine provides a good antibody response to the virus, approximately 70 to 90 percent of healthy young adults may be protected from influenza. This protection drops to about 30 to 40 percent for the elderly and those suffering from chronic illness or disease.

According to the National Strategy for Pandemic Influenza [01 Nov 2005] "The Federal Government has established two primary vaccine goals: (1) establishment and maintenance of stockpiles of pre-pandemic vaccine adequate to immunize 20 million persons against influenza strains that present a pandemic threat; and (2) expansion of domestic influenza vaccine manufacturing surge capacity for the production of pandemic vaccines for the entire domestic population within 6 months of a pandemic declaration. ... Priority recommendations will reflect the pandemic response goals of limiting mortality and severe morbidity; maintaining critical infrastructure and societal function; diminishing economic impacts; and maintaining national security."

"... since populations have no baseline immunity to strains of influenza with pandemic potential, it is highly probable that more vaccine antigen will be required per person to induce protective immunity. The amount of vaccine antigen that is currently manufactured is matched to the usual requirements for seasonal influenza vaccine, and not the requirements for a pandemic vaccine, which may require significantly more hemagglutinin per person than a seasonal vaccine to induce an effective immune response. Furthermore, in the event of a pandemic it is likely that bulk influenza vaccine manufactured outside the United States (and accounting for about 40 percent of annual domestic supply) will be unavailable. Thus, the measures taken by the Federal Government over the past several years to ensure a secure egg supply and support the expansion and diversification of influenza vaccine manufacturing capacity will require significant enhancement and acceleration."

"The use of pre-pandemic vaccine will be targeted to maintain critical societal functions through the protection of critical infrastructure personnel and to protect those who are at greater risk of early exposure and infection during a pandemic, such as health care providers or first responders."

Current estimates of global vaccine production capacity vary wildly. Rear Admiral Anne Schuchat, MD, interim deputy director of the CDC's Science and Public Health Program, told Congress Thursday 30 April 2009 that US manufacturing capacity would allow for the production of 600 million doses, or two shots for every US resident. The funding for vaccine manufacturing has produced "phenomenal expansion in manufacturing capacity," Dr. Anne Schuchat, an interim deputy director at the Centers for Disease Control and Prevention, told a Senate hearing on 30 April 2009. Asked if the United States could produce 300 million doses domestically now, Schuchat said officials were "very optimistic," but added: "This virus can surprise us, and even with all those investments it may just technically be difficult." If all goes well, broader production would start in the fall. "We think 600 million doses is achievable in a six-month time frame" from that fall start, HHS Assistant Secretary for Preparedness and Response Rear Admiral W. Craig Vanderwagen said during a hearing on Thursday 30 April 2009 before the House Energy and Commerce Health subcommittee. Vanderwagen said it would take at least two months to develop the vaccine.

By one estimate [Pandemic Vaccines May be Too Little, Too Late By Todd Neale, Staff Writer, MedPage Today Published: April 28, 2009], using egg-based technology, an influenza pandemic vaccine would require at least 6 months to produce, and the current egg-derived flu vaccine manufacturing process can take up to nine months to complete. At the end of April 2009 Klaus Stohr, D.V.M., vice president and global head of Novartis Vaccines and Diagnostics said the earliest the public would see a vaccine against the disease would be September 2009. He said it would take about two weeks for vaccine strain preparation, and seed virus preparation would take another three or four weeks, putting the start of bulk production at the end of June 2009. Standardizing reagents would not be available for another eight weeks, and quality control would tack on an additional one to two weeks. Then, in early September, Novartis and other vaccine makers could start distributing vaccine.

By another estimate, it might take six to eight weeks [about two months] to develop and test the first "seed lot." Under a best-case scenario, the first batch of pandemic vaccine would be distributed about 12 weeks [about three months] later. Thus a decision by the end of May 2009 to produce a vaccine would result in initial vaccine distribution by the end of October 2009.

In an influenza pandemic, a course of immunization would consist of two doses for each person. Very limited supplies of vaccine could be available in the early days of the pandemic - perhaps only enough to vaccinate 3 million persons per month starting 3-6 months after the pandemic begins, or up to 18-27 million persons in first year of the pandemic. [SOURCE] The Congressional Budget Office noted in September 2008 that "When all .. factors - uncertain availability of imports, higher content per dose, and more doses per course - are taken into consideration, current U.S. capacity to produce pandemic vaccine is only about 12.5 million courses. That estimate could be high; in the past, manufacturers have had difficulty growing pandemic-influenza strains."

The worldwide capacity for making a pandemic vaccine is 2 billion doses. About 70 percent of the world's flu vaccine is made in Europe. The United States has preexisting contracts that would allow it to buy at least 600 million doses. According to Robin Robinson, head of the Biomedical Advanced Research and Development Authority of the Department of Health and Human Services, "We have the contractual mechanisms to purchase pandemic or other influenza vaccines ... "We believe the U.S. needs could be satisfied by the capacity that is out there from these contracts." The contracts are with Sanofi Pasteur, GlaxoSmithKline and Novartis.

The possibility of the virus mutating before returning to the northern hemisphere in a much deadlier strain in autumn was one reason not to rush into mass production of a vaccine.

Vaccine may be in extremely short supply through the first wave of a pandemic and even longer. Under the July 2008 Guidance on Allocating and Targeting Pandemic Influenza Vaccine, the highest priority Tier 1 groups for receiving the first dose of vaccine would include 700,000 deployed and mission-critical military personnel with essential roles in national and homeland security. There are a total of 24 million people in this highest priority Tier 1, but as of 2009 it is estimated that there would only be enough vaccine available for half this number.

The HHS Pandemic Preparedness Plan, issued in November 2005, called for the expansion of domestic pandemic vaccine manufacturing surge capacity for 300 million persons within six months of the onset of an influenza pandemic. At that time, manufacturing capacity for the only licensed pandemic-influenza vaccine in the United States was about 25 million doses, or enough vaccine to protect about 12.5 million people.

Sanofi Pasteur has two vaccine plants in Swiftwater, PA. An older one makes about 50 million doses of seasonal vaccine each year, and a new one, which got final approval 06 May 2009 from the Food and Drug Administration, has a capacity of about 100 million doses. In 2008 the French company had completed construction of the $150 million building to double its vaccine production capacity.

HHS has made large investments in domestic vaccine manufacturing capacity by supporting vaccine research with contracts that require manufacturers to establish vaccine-producing facilities within US borders. Through these contracts, one US facility has expanded its manufacturing capacity and a second facility was established in the United States. In June 2007 HHS awarded two cost-reimbursable contracts totaling $132.5 million to sanofi pasteur and MedImmune over five years to retrofit existing domestic vaccine manufacturing facilities on a cost-sharing basis and to provide warm-base operations for manufacturing pandemic influenza vaccines.

By 2011 Sanofi Pasteur is working to triple its production capacity. The company will spend $102 million to retrofit an existing facility, and it added a second facility, at a cost of $150 million, to its complex in Swiftwater, Pennsylvania. When both facilities are approved by the FDA - expected by 2011 - the company's annual production capacity for seasonal-influenza vaccine would triple, from 50 million to 150 million 45 microgram doses. That would allow the manufacturer to produce 75 million doses of its licensed pandemic-influenza vaccine, or enough vaccine for about 38 million people (at 90 micrograms per dose for a two-dose course).

By 2011, MedImmune is expected to have emergency capacity to produce 50 million doses of pandemic vaccine. MedImmune will retrofit its California facility to produce bulk quantities of pandemic-influenza vaccine in case of an emergency. MedImmune's manufacturing facility in the UK produces bulk seasonal-influenza vaccine for the US market, but it prepares the seasonal seed strain at its facility in California.

Because cell-based influenza vaccine can be made faster and in greater quantities than traditional vaccine, a new facility is expected to increase the U.S. capacity to make pandemic influenza vaccine by at least 25 percent. Cell-based vaccine production could more easily meet surge capacity needs because cells could be frozen and stored in advance of an epidemic or developed rapidly in response to an epidemic. Cell-based vaccine production also dramatically reduces the possibility for contamination and promises to be more reliable, flexible, and expandable than egg-based methods. HHS awarded Novartis a $220 million contract in May 2006 to speed the development of cell-based flu vaccines. This contract was for development of cell-based flu vaccines. Most of the vaccine development has been done in a plant in Marburg, Germany.

The company announced plans for the North Carolina production facility in July 2006. Novartis projects that the facility will have an annual production capacity of up to 50 million doses of seasonal trivalent flu vaccine. If an influenza pandemic occurred, the plant could ramp up to 150 million doses within six months. Novartis broke ground at the site on Aug. 23, 2007. Once complete, it will be the first cell-culture-derived influenza vaccines manufacturing facility in the United States. On 15 January 2009 the US Department of Health and Human Services (HHS) announced a $487 million multiple year contract with Novartis Vaccines and Diagnostics, Inc., to build the first US facility to manufacture cell-based vaccine for seasonal and pandemic flu. The overall timetable for the facility calls for its completion in late 2009 or early 2010.



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