Organizations involved (a selected original developer):

U.S. Army – R&D; Tech.

Cross ref.: Besides this generic entry and the specific vaccine entries below, see also the Influenza H5N1 Vaccine Products entry concerning avian influenza vaccines and H1N1 Vaccine Products entry concerning swine flu vaccines.

Description: Influenza Virus Vaccines are formulations containing multiple strains of influenza virus for prevention of disease from infection with currently circulating strains of influenza virus (the flu). Approved vaccines generally contain three inactivated influenza virus strains, two from type A and one from type B influenza virus strains, selected each year to optimize prophylactic responses to expected epidemic strains, cultured separately in embryonated chicken embryos (fertile chicken eggs). For inactivated injectable vaccines, the virus is harvested, inactivated (killed), e.g., by exposure to formaldehyde or beta-propriolactone, and further purified. Most U.S. influenza virus vaccines are inactivated vaccines administered by intramuscular injection. A live attenuated intranasally administered vaccine, FluMist, is also marketed.

Most conventional influenza vaccines are split or subvirion (subunit) inactivated injectable vaccines, involving chemical disruption of the inactivated virus particles, e.g., with a surfactant such as polysorbate 80, and further purification, e.g., ether extraction and/or linear sucrose density gradient solution separation, and suspension. These subvirion influenza vaccines contain purified influenza virus surface antigens composed of purified hemagglutinin (HA) and neuraminidase (NA) envelope glycoproteins. Inoculation with HA and NA, whether from a whole or split or inactivated or live vaccine, induces specific neutralizing antibodies capable of providing protection from infection with influenza virus (presuming the HA and NA antigens are sufficiently similar in immunogenic response to those of the strain(s) to which one is exposed).

Annual Reformulations: Human influenza viruses are characterized by their immunogenic surface receptors hemagglutinin (HA: subtypes H1, H2, and H3), and neuraminidase (NA: subtypes N1 and N2). Infection with a virus of one subtype confers little or no immunity to an infection with another subtype. Antigenic variation (mutations) within strains of influenza virus and related changes in NA and HA are responsible for annual flu epidemics, New influenza virus strains to which persons have little or no immunity arise annually.

The annual recommendations for influenza vaccine formulation are based on antigenic and molecular analyses of recently isolated influenza viruses, epidemiologic data, and postvaccination serologic studies in humans. In recent years, generally, two type A influenza and one type B influenza strain have been selected for U.S. vaccines. In recent years, the recommendations for virus strains included in influenza vaccines have been the same as those specified by the World Health Organization (WHO, UN).

For the 2012/13 flu season, U.S. and most other countries’ influenza vaccines were formulated to contain A/California/7/2009 (H1N1)-like virus; A/Victoria/361/2011 (H3N2)-like virus; and B/Wisconsin/1/2010-like virus. While the H1N1 virus is the same as what was included in the 2011-2012 influenza vaccines, this year’s influenza H3N2 and B viruses differ from those in the 2011-2012 influenza vaccines.

For the 2009/2010 flu season, U.S. and most other countries’ influenza vaccines were formulated to contain an A/Brisbane/59/2007 (H1N1)-like virus; an A/Brisbane/10/2007 (H3N2)-like virus; and a B/Brisbane/60/2008-like virus. The A/Brisbane/59/2007 was in the prior year's vaccine. A/South Dakota/6/2007 (an A/Brisbane/59/2007-like virus) was in the prior year's live attenuated vaccines. A/Brisbane/10/2007 and A/Uruguay/716/2007 (an A/Brisbane/10/2007-like virus) were also in the prior year's vaccine. The B strain selected was new.

For the 2007-2008 flu season, U.S. and most other countries’ influenza vaccines are formulated to contain 45 µg hemagglutinin (HA) per 0.5 mL dose, in the recommended ratio of 15 µg HA of each of the following 3 strains: an A/Solomon Islands/3/2006 (H1N1)-like virus; an A/Wisconsin/67/2005 (H3N2)-like virus; and an A B/Malaysia/2506/2004-like virus.

For the 2006-2007 flu season, U.S. influenza vaccines were formulated to contain 45 µg hemagglutinin (HA) per 0.5 mL dose, in the recommended ratio of 15 µg HA of each of the following 3 strains: A/New Caledonia/20/99 (H1N1), A/New York/55/2004 (H3N2) (an A/California/7/2004-like strain), and B/Jiangsu/10/2003 (a B/Shanghai/361/2002-like strain).

For the 2005-2006 flu season, U.S. influenza vaccines contained an influenza A/California/7/2004 (H3N2) stain (replacing the Fujian strain), and two components used in the prior year – influenza virus B/Shanghai/361/2002-like and influenza virus A/New Caledonia/20/99 (H1N1)-like strains.

For the 2004-2005 flu season, U.S. influenza vaccines included influenza virus A/New Caledonia/20/99 (H1N1)-like, and two new/replacement viruses, influenza virus A/Fujian/411/2002 (H3N2-like) and influenza virus B/Shanghai/361/2002-like. For the A/Fujian component, manufacturers may alternatively use A/Wyoming/3/2003 (H3N2) or A/Kumamoto/102/2002 (H3N2). An available alternate for the B/Shanghai component is B/Jilin/20/2003.

For the 2002-2003 and 2003-2004 influenza seasons, the formulations were identical and standardized and included A/New Caledonia/20/99-like (H1N1), A/Panama/2007/99 (H3N2), and B/Hong Kong/330/2001-like virus strains.

Nomenclature: Influenza Virus Vaccine [FDA]; Inactivated Influenza Vaccine (Surface Antigen) [Eur. Pharm.]

Biological.: The genetic material (RNA) of influenza is associated with group-specific nucleoprotein, which is surrounded by a double membrane consisting of an inner layer of protein and an outer layer of host-derived lipid material. Two glycoproteins, hemagglutinin (HA) and neuraminidase (NA), appear as projections or spikes on the surface of the viral envelope, and together comprise about 36% of the total virus by weight. These two glycoproteins are the main immunogenic components of the virus and influenza vaccines. All other components, including other virus proteins, nucleic acids and lipids, are nonessential and undesired in inactivated influenza vaccines.

The influenza type A virus is about 80-120 nanometers in size and 5,000 to 5,550 kDa in weight. Hemagglutinin (HA units; haemagglutinin) comprises up to 28% of the virus, has a molecular weight of 210 kDa, forms a 14 nanometer long triangular rod of 4 nanometer width, and is located on the perimeter of the virus body attached to a lipid bi-layer membrane through a hydrophobic bond at the end of the HA rod. Neura-minidase (NA units) comprising up to 8% of the virus, have a weight of 270 kDa, form a cube with a 10 nanometer long rod extending from the center and terminating in a 4 nanometer diameter knob, and is located on the perimeter of the virus body among the HA units attached to the lipid bi-layer through a hydro-phobic bond at the NA knob. Polypeptides with a weight of 10 and 30 kDa are distributed in very small proportions among the HA and NA units. The remaining virus structure (~64% of the virus) consists primarily of nine distinct segments of polynucleotides (single-stranded RNA with a weight ranging from 100 to 1,000 kDa), lipid bi-layers encapsulating the RNA, polymerase, and nucleocapsid.

To infect a cell, the surface HA protein adsorbs to sialyl-oligo-saccharides in cell membrane glycoproteins and glycolipids. Following endocytosis of the virion in to the cell, a conformational change in the HA molecule occurs within the cellular endosome that facilitates membrane fusion and triggers uncoating. The nucle-o-capsid migrates to the cell nucleus where viral mRNA is transcribed as the essential initial event in infection. Transcription and replication of influenza RNA take place in the nucleus of infected cells, and assembly into virions occurs by budding out of or through the plasma membrane. With little RNA editing ability, influenza viruses can reassort (recombine) genes during mixed infections.

Replication of influenza virus RNAs is dependent on four viral gene products: PB1, PB2, PA, and NP. The three polymerase proteins, PB1, PB2, and PA, form a trimolecular complex in the nuclei of infected cells. Each protein has its own nuclear localization signal. PB1 appears to be primarily involved in the enzymatic polymerization process (the elongation step). It shares regions of amino acid homology with other RNA-dependent RNA polymerase proteins. The precise function of PA is unknown. The PB2 protein binds to the 5’-terminal cap structure present on host cell mRNAs; the mRNAs are then cleaved, producing a capped 9 to 15-mer oligoribo-nu-cleotide which serves as a primer for transcription of influenza mRNAs. The PB2 amino acid sequence contains a region of limited homology with the cellular cap-binding protein, eIF-4E. While PB2 is not absolutely required for replication of viral RNA, mRNAs transcribed from viral template in cells expressing only PB1, PA, and NP are uncapped and thus cannot be translated. At a later stage of infection, instead of making mRNAs, the polymerase proteins PB1, PB2, and PA are used to make new viral RNA genomes. The polymerase complex first transcribes cRNA, which then serves as template for production of more viral RNA.

Nucleocapsid assembly takes place in the nucleus. The virus matures by budding from the apical surface of the cell. The HA and NA glycoproteins are incorporated into the lipid envelope. In permissive cells, HA is post-translationally cleaved, but the two resulting chains remain associated by disulfide bonds.

History: The U.S. Army deserves much of the credit for sponsoring the research and development of inactivated influenza virus vaccines. In the 1940s (World War II), the Surgeon General of the U.S. Army commissioned research that resulted in development of the conventional inactivated influenza vaccine. Clinical trials using formalin-inactivated vaccine manu-factured by Sharp & Dohme (now Merck & Co., Inc.) began in 1943.

Eli Lilly & Co. was licensed to manufacture Influenza Virus Vaccine from Nov. 1945-April 1977; Merck & Co., Inc. (predecessors) from Nov. 1945-March 1995. Parke-Davis Div., Warner-Lambert Co., was licensed to manufacture Influenza Virus Hemagglutinating Antigen from March 1952-March 1973.

Influenza vaccine was not widely used in the general population until the 1960s when newer purification methods substantially reduced the vaccine’s reactogenicity (e.g., fever and swelling at site of injection). A rapid increase in Guillain-Barre syn-drome (GBS), a neuromuscular disease, was associated with influenza vaccine in 1967. manufacture and purification of influenza vaccines has substantially changed and improved since then. The incidence of vaccine-associated GBS has decreased since the 1970s to a level of about 1-2 cases/million doses administered (with the risk from not receiving the vaccine far outweighing the risk of vaccine-associated GBS). Split, subvirion, or HA/NA subunit vaccines were introduced in the late 1970s. These induce lower antibody titers than whole virus vaccines, but have a lower incidence of adverse reactions.

In early 1976, a new virulent strain of influenza A (swine flu) appeared. This was thought to be a threat perhaps comparable to the Spanish flu pandemic which caused global 21.5 million deaths in 1927 (now estimated to be 30 million or 50-100 million by some sources), including 675,000 deaths in the U.S. Fearing death of up to 1 million in the U.S. (although there were few documented deaths), the federal government (Ford administration) initiated a crash program to vaccinate every American. The program ran into problems from the start, including the selected virus strain growing poorly in chicken eggs (difficult to manufacture). One company used the wrong strain and had to restart manufacture. Insurance companies refused to insure the manufacturers, and Congress had to pass a law protecting them from liability. Single injections of some vaccine products did not protect children, requiring an inconvenient booster injection (which is normal/expected for influenza vaccines). Three elderly people in Pittsburgh died on the same day within hours of getting swine flu shots. Although considered a random event, this adversely affected public opinion. Despite these problems, what caused the final halt of the program was the finding in Dec. 1976 that persons having received the vaccine had a significantly increased risk for developing Guillain-Barre syndrome (GBS), a rare, usually reversible, but occasionally fatal form of paralysis. The incidence of GBS was about 1 in 1,000, about seven times higher than for unvaccinated individuals. The swine flu vaccine campaign was halted on Dec. 16, 1976. About 45 million people had received the vaccine (indicating at 1/1,000 that 450,000 likely developed GBS symptoms). The federal government eventually paid out $90 million in claims to people who developed GBS. The total cost of the program was more than $400 million.

Manufacture: The original methods for manufacture of influenza vaccine, as developed by Merck Sharp & Dohme, involved culture of the virus in the allantoic sac of embyronated (fertilized) hens eggs, extraction of the fluid, and purification by adsorption to and elution from human red blood cells, followed by inactivation with formaldehyde. By 1957, the manufacturing process involved culture for two days in the allantoic sac of embyronated, 11 day old, hens eggs; harvest of the allantoic fluid; formalin (formaldehyde) inactivation; precipitation of the virus with protamine; and further purification. In the late 1950s, Merck was the major manufacturer of influenza vaccines, supplying about 20 million doses annually, nearly one-half of U.S. consumption.

For manufacture of inactivated vaccine [a current composite example], 9 to 12-day old embryonated chicken eggs are pre-candled to eliminate spoiled and non-fertilized eggs. Remaining eggs are inoculated in the amniotic or allantoic cavity with a strain of live influenza virus. The eggs are incubated at a temperature of about 32-37˚ C for two or three days during which the virus replicates rapidly. The eggs are post-candled to eliminate eggs which spoiled or died during the incubation period. The eggs are refrigerated at about 5˚C for about 24 hours to attenuate the live virus before the egg fluids are aseptically harvested. Harvested allantoic fluid contains a high concentration of live influenza virus which is further purified, e.g., by density gradient centrifugation and selective membrane filtration (to eliminate undesirable particulate matter smaller and larger than the whole virus and undesirable dissolved solids). Individually cultured, purified, inactivated virus strains are pooled and inactivated with formalin/formaldehyde. The resulting inactivated purified mixed viruses may be formulated into whole virion vaccines, or further processed for manufacture of split, (subvirion) HA and NA purified vaccines.

Influenza virus splitting into HA and NA subunits, e.g., as described in U.S. patent 4,327,182 (1982) assigned to Connaught Labs. (now Sanofi Aventis), involves splitting or disrupting the virus with a nonionic surfactant, e.g., octoxynol (polyethylene glycol p-isooctylphenyl ether; Triton X-100 from Rohm and Haas) at room temperature for about 30-60 minutes. Once the HA and NA units have been split off from the virus particles, the resulting fluid is subjected to selective membrane filtration to separate the HA and NA units from remaining solids and the surfactants, e.g., using filtration membranes having a pore size which permit the HA and NA units to pass through but smaller than the remaining whole virus body and particulate matter in the same size range as the whole virus. A final selective filtration eliminates the surfactant by using a membrane selectively permeable to surfactant but impermeable to HA and NA units. Repeated washing may be carried out to remove the last traces of the surfactant.

Status: As of Aug. 2012, influenza vaccines approved in the U.S. are: Afluria, manufactured by CSL Limited; Fluarix, manufactured by GlaxoSmithKline Biologicals; FluLaval, manufactured by ID Biomedical Corporation (GSK); FluMist, manufactured by MedImmune Vaccines Inc.; Fluvirin, manufactured by Novartis Vaccines and Diagnostics Limited; and Fluzone, Fluzone High-Dose and Fluzone Intradermal, manufactured by Sanofi Pasteur.

At the start of each year, public health organizations in the U.S. and worldwide collaborate to determine the strains of virus to be used in the manufacture of the Influenza Virus Vaccine that will be manufactured by various companies worldwide and administered starting that fall. The recommendations are based on data provided from laboratories worldwide as influenza virus strains are continuously mutating.

Currently licensed vaccines contain three virus strains representing the strains predicted to be in U.S. circulation as recommended by the U.S. Public Health Service (FDA, CDC, NIH) for incorporation into the vaccine for the upcoming flu season (winter). These are usually the same strains recommended by the World Health Organization (WHO) for use in the Northern Hemisphere for the same time period. Generally, each seasonal vaccine contains two type A and one type B virus. Because of the necessity to have vaccines with the immunogenically similar to pathogenic virus strains currently in circulation, vaccines manufactured for the previous year are not reused the next year. Final recommendations for the three strains of influenza virus to be used in the manufacture of the next vaccine are usually agreed upon by or in March.

As soon as the strains are recommended, manufacturers begin to grow the virus strains in fertile hen’s eggs. The parent strains of vaccine, known as “seed strains,” used by each manufacturer are tested by Center for Biologics Evaluation and Research (CBER), FDA, to assure they are the same as the recommended strains. After the completion of manufacture of each lot of vaccine by each manufacturer, potency, sterility, endotoxin, and other tests are conducted to assure the safety and efficacy of the vaccine. manufacturers submit the results of their testing and samples from each lot to CBER for “lot release.” This consists of CBER’s review of the manufacturer’s test results, including tests on the lots of monovalent virus strains, and tests on the final trivalent product. CBER performs additional testing as appropriate. Although the manufacturing process and lot release is completed for some lots of vaccine in some years as early as July, the manufacturing of additional lots continues until September-October (or even later, if problems are encountered, as has occurred in recent years).

FDA regulations concerning the inactivated influenza vaccine “general safety test” performed in guinea pigs are described in the Code of Federal Regulations, Title 21, Vol. 7, Parts 610.11a and associated sections.

The vaccines prepared for the 2003-04 influenza season contained antigens from influenza A/New Caledonia/20/99-like (H1N1), A/Panama/2007/99 (H3N2), and B/Hong Kong/330/2001-like virus strains, exactly the same formulation as in the 2002-03 season. Early in the antigen selection process, there had been concern that the emerging “Fujian” influenza A (H3N2) strain posed an increased threat. The FDA’s Vaccines and Related Biological Products Advisory Committee voted to recommend use of Fujian/2002 as the H3N2 strain in the 2003-2004 formulation. However, this strain was found unable to replicate adequately in eggs, unless the vaccine had first been passaged in the MDCK cells, a canine (dog) kidney epithelial cell line. With no U.S. precedents for approval of such a mammalian cell passaged influenza strain for human vaccines, with the complex and lengthy testing that would be required for FDA approval, and with time running out for start of vaccine manufacturing, the decision was made not to swap in the Fujian strain (i.e., retain the Panama/1999 strain). In hindsight, this appears to have been a mistake, since the new Fujian strain caused significant morbidity, and the marketed vaccines (with the Panama/1999 strain) appeared to induce little or no immunity (neutralizing antibodies) against the Fujian strain (with reports of efficacy ranging from about 14%-60%, compared to the usual 60%-80%). A Fujian strain found capable of replication in eggs was reported in April 2003, but this was too late for approval and adoption for use in 2003-2004 vaccines.

In August 2003, with no vaccine shortages expected for the 2003-2004 flu season, the Centers for Disease Control and Prevention (CDC) suspended its guidelines for tiered vaccination (implemented in prior years to deal with shortages of vaccine), with all candidates encouraged to receive vaccination as soon as possible. In Oct. 2003, CDC reported that during the past 2002-2003 season, two-thirds of adults over 65 years had obtained vaccination, while only 36% of those 49-64 had received vaccination. CDC also issued recommendations that children aged 6 months to 23 months and their immediate families receive vaccine annually. Young children are much more likely than other segments of the population to contract and pass influenza (while elderly people are more likely to die after contracting the illness).

In April 2004, CDC announced it would purchase and stock-pile influenza vaccine to avoid the shortages that occurred in recent years. About 4 million doses will be purchased by CDC and set aside for children up to 18 years old. About $80 million is expected to be spent on the program in the next two years. Some adults may have access to the vaccine supply, if approved by Congress.

In April 2004, the Advisory Committee on Im-munization Practices (ACIP), Centers for Disease Control and Prevention (CDC), published recommendations that all children 6-23 months of age receive annual influenza vaccination, starting with the upcoming 2004-5 influenza season. In addition, household contacts and out-of-home caregivers of all children younger than 24 months of age are recommended to receive vaccination. These new recommendations are consistent with those previously issued by the American Academy of Pediatrics (AAP) and the American Academy of Family Physicians (AAFP). CDC continues to strongly recommend annual influenza vaccination for all children 6 months of age and older with chronic medical conditions, such as asthma or diabetes (although this may require two inoculations). Annual vaccination is also recommended for their household contacts and out-of-home caregivers. Recommendations for persons receiving live vaccine (FluMist) to avoid contact with severely immune suppressed patients was extended from 7 to 21 days; and only inactivated vaccine will be recommended for use by those (health care workers) expected to come into contact with immune suppressed patients.

For the 2005-2006 flu season, at the time, many expected the federal government to act to stabilize the market, to assure suppliers of sales of the vaccines they manufacture. The omnibus spending bill enacted for federal fiscal year 2006 included $100 million for government purchases of unsold vaccine. The Centers for Disease Control and Prevention (CDC) bought about 11.5 million of the 86 million doses produced by U.S. suppliers for the current 2005/6 season, for resale to the state health departments and public health programs it supplies.

The supply of influenza vaccines has been and remains somewhat tenuous. Manufacturing is complex and lengthy, and vaccines must be customized each year and manufactured in intense campaigns to prepare for each upcoming flu season. For example, as discussed in the Fluvirin entry, Chiron halted manufacture and supply of this vaccine to the U.S. market for the 2004/5 flu season due to quality control problems, effectively reducing the U.S. supply of vaccine by about half; and there have been other less severe supply disruptions. For example, Chiron experienced contamination problems with its Begrivac vaccine in 2005 and suspended manufacture of this vaccine used in European countries for the 2005/6 flu season.

As can been seen from the influenza vaccine product entries, several new seasonal vaccines and new manufacturers have recently entered the U.S. market. However, a disruption at one or several manufacturers can still disrupt supply.

In June 2005, the Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention (CDC), issued stronger recommendations that all U.S. healthcare workers should receive annual influenza vaccination. Annual influenza immunization has long been recommended for health care workers, but vaccination rates have remained dismally low at 36-38% overall.

In Feb. 2006, the Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention (CDC), issued new recommendations that all children two to five years old, as well as their caregivers and household contacts, should be vaccinated against influenza. Vaccination was already recommended for children between the ages of six months and two years, adults aged 65 years and older, and those who are pregnant or have chronic conditions. These recommendations means that public health programs will implement practices and insurers will essentially have to reimburse for the vaccine. ACIP/CDC made a strong recommendation, rather than simply “encourage” that two- to five-year-olds be immunized. Vaccination rates among children six and 23 months of age jumped to 48% from 17% after the initial recommendation was made in 2004.

On March 2, 2006, FDA issued its “Draft Guidance for Industry: Clinical Data Needed to Support the Licensure of Pandemic Influenza Vaccines.”

In June 2006, the Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention (CDC), updated its recommendations regarding seasonal influenza vaccination. Principal changes included (1) recommending vaccination of children aged 24-59 months and their household contacts and out-of-home caregivers; (2) highlighting the importance of administering two doses of influenza vaccine for children aged 6 months to ≤9 years who were previously unvaccinated; (3) advising healthcare providers, those planning organized campaigns, and state and local public health agencies to (a) develop plans for expanding outreach and infrastructure to vaccinate more persons than in the previous year and (b) develop contingency plans for the timing and prioritization of administering influenza vaccine, if the supply of vaccine is delayed and/or reduced; (4) reminding providers that they should routinely offer influenza vaccine to patients throughout the influenza season; (5) recommending that neither amantadine nor rimantadine (drugs approved for treatment of influenza) be used for the treatment or chemoprophylaxis of influenza A in the U.S. until evidence of susceptibility to these antiviral medications has been reestablished among circulating influenza A viruses. Other long-standing recommendations remained in place, with vaccination recommended for all persons at high risk for influenza-related complications and severe disease, including children aged 6 months to 59 months; women who will be pregnant during the influenza season; persons aged 50 years and older; persons of any age with certain chronic conditions, including cardiopulmonary disease (including asthma), metabolic diseases (including diabetes mellitus), renal insufficiency, hemoglobinopathies, immu-nodeficiency, conditions that can compromise respiratoryfunction or the handling of respiratory secretions, those who receive chronic aspirin therapy; persons who live with or care for persons at high risk should be vaccinated, including household contacts who have frequent contact with persons at high risk and who cantransmit influenza to those persons at high risk; out-of-home caregivers of persons at high risk; and all healthcare workers.

In Nov. 2006, a study published in Pediatrics reported that during the 2003-2004 flu season, only 12% of U.S. children between the ages of two and eight years who received flu shots for the first time went back for their second shot. Also, less than 25% of children in that age group received a second dose in the three flu seasons between 2001 and 2003. Children who received their first shot earlier, by mid-November, were more likely to go in for a follow-up dose. Children aged from six months to nine years need a second dose 28 or more days later in order to be protected. Researchers studied data on 126,000 children between the ages of six months and eight years across the country from the Vaccine Safety Datalink of the Centers for Disease Control and Prevention (CDC).

In Oct. 2007, the Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention (CDC), expanded recommendations for FluMist (see related entry) to all children aged six months to 18 years. Regardless of the vaccine used, ACIP, the American Academy of Pediatrics, and the American Academy of Family Physicians recommend that children aged <9 years who have not previously been administered an influenza vaccine should receive 2 doses separated by 4 or more weeks in the initial year. Children aged <9 years who did not receive the recommended second dose of influenza vaccine in the initial year that they received influenza vaccine should receive 2 doses separated by 4 or more weeks before or during the next influenza season. This applies only to the influenza season that follows the first season that a child aged <9 years receives influenza vaccine. C hildren aged <9 years who are being vaccinated two or more seasons after receiving an influenza vaccine for the first time should receive a single annual dose, regardless of the number of doses administered previously.

In 2009, H1N1 or swine flu strains that are pathogenic and communicable by contact and inhalation became the predominant influenza virus strain, causing as much or more disease, including deaths, as the seasonal strains then in circulation. The U.S. and many other governments worldwide responded by placing orders for H1N1 vaccines from various manufacturers, and multiple H1N1 vaccines have been approved in the U.S. and Europe. In the U.S., these were not treated as new, i.e., received supplemental BLA approvals, since they were considered simply just another influenza virus vaccine manufactured using the same processes as seasonal vaccines (which often vary from year-to-year).

Disease: Influenza infection is typified by rapid onset, high fever, respiratory symptoms, nonproductive cough, and muscular aches and pains lasting for several days. Serious complications are prevalent in elderly individuals and those with underlying health problems. High-risk groups may develop influenza pneumonia or secondary bacterial pneumonia leading to possible mortality. About 25-150 per 100,000 people over the age of 65 die from influenza-associated disease each year in the U.S. During the 2003-4 flu season, CDC reported 143 children died of influenza, which is about average.

According to the American Lung Association, each year there are more than 90 million cases of the flu in the U.S., resulting in over 69 million lost work days and 34,000 hospital stays. Influenza costs the U.S. $14.6 billion in direct health care costs and lost productivity each year.

In 1918-1919, the “Spanish flu” epidemic (or pandemic) killed up to 50-100 million people worldwide. Unlike most influenza epidemics/pandemics, the highest mortality (most deaths) were in young adults, generally the group least affected by influenza, not the young and elderly. This was the largest known outbreak of infectious disease in recorded human history. Recurrence of such a pandemic, involving the spread of a highly pathogenic strain of influenza to which few or no human have had preexposure/immunity, remains a possibility. This includes influenza virus H5N1 (avian or bird flu). The current manufacturing and distribution infrastructure is insufficient to handle such a contingency.

In the Jan. 8, 2003 issue of the J. Amer. Med. Assoc., the Centers for Disease Control and Prevention (CDC) reported new data showing that the incidence of influenza-related deaths in the U.S. had recently increased significantly since the 1970s. Mortalityincreased from 16,262 in 1976-1977 to 64,684 in 1998-1999. Influenza-related death now average 36,000/year, up from 20,000/year in earlier widely promulgated estimates. Influenza now kills more persons annually in the U.S. than HIV/AIDS. About 90% of influenza-associated deaths occurred among persons aged 65 years or older. Much of the increase is associated with the general aging of the population, with only about 65% of elderly persons usually receiving vaccine each year, and only 30% of high risk persons, e.g., those with diabetes or heart disease, receiving vaccination.

During the 2003-4 flu season, influenza A Fujian strain accounted for about 75% reported influenza cases. The influenza A-Fujian H3N2 antigen used in vaccines for that season turned out to be only partially effective, resulting in increased incidence of disease.

Newer recommendations for influenza vaccine use include use in children (see Status section above). Influenza puts children 6-24 months of age at significant risk for hospitalizations due to pneumonia, respiratory conditions, heart failure and inflammation of heart muscle (myocarditis). Influenza illness also increases the risk of a child developing otitis media, pneumonia, croup, and sepsis, and is a risk factor for the complication of bacterial superinfection. CDC reports that more than 120 influenza-related deaths occurred among children aged less than 18 years during the 2003-2004 influenza season.

For the 2008/9 flu season, CDC recommended the following groups receive annual influenza vaccination:

People at high risk for complications from the flu, including: children aged 6 months until their 5th birthday, pregnant women, people 50 years of age and older, people of any age with certain chronic medical conditions, and people who live in nursing homes and other long-term care facilities; and people who live with or care for those at high risk for complications from flu, including: household contacts of persons at high risk for complications from the flu, household contacts and out of home caregivers of children less

than 6 months of age (these children are too young to be

vaccinated), and healthcare workers.

Medical: Injectable influenza vaccine is administered intramuscularly, preferably into the deltoid muscle of adults and children, and the thigh of infants. Children under the age of nine should only be administered split-virion vaccine to lower the possibility of febrile (fever) reactions.

The effectiveness of vaccination decreases with the age of the adult vaccinee. Influenza vaccine decreases the occurrence of influenza by 70-90% in individuals younger than 65 years. Influenza illness may only be decreased by 30-40% in the elderly, but hospitalization for serious complications is cut by 80% in those vaccinated. For the elderly, the vaccine is most effective in preventing secondary infections, such as pneumonia, and decreasing hospitalization and mortality associated with an influenza infection at an older age. The data were obtained from Ontario, Canada, which in 2000 instituted universal influenza vaccination for all residents age 6 months and older.

In an article in the Nov. 2006 issue of the Archives of Internal Medicine, it was estimated that influenza vaccination raises the already very small risk of developing Guillain-Barre syndrome (GBS) by about 45% (from an already low risk), with one to two people per million vaccinated developing GBS as a result (“in the vicinity of being struck by lightning”). But, the risks from not being vaccinated are by far greater than being vaccinated.

Tech. transfer: With conventional egg-cultured influenza vaccines having been on the market for about 50 years, related technology is largely in the public domain.

MedImmune, Inc. (through its acquisition of Aviron) has licensed patents and effectively controls “reverse genetics” technology for rapidly generating influenza vaccine strains from pathogenic strains. This involves converting the RNA virus to its corresponding DNA sequence, deleting genes associated with pathogenicity, and converting the DNA back to an RNA virus clone, e.g., for large-scale egg culture and vaccine manufacture. This approach may provide a rapid method for generating culturable virus strains retaining their original HA, NA and other other epitopes. This technology has not yet been tested in clinical trials, although there has been some discussion that this method might be used in case of a serious influenza pandemic. MedImmune has already given the World Health Organization (WHO, UN) permission to develop and use such a vaccine in a pandemic situation; and will likely eventually apply this technology to annual reformulation of its FluMist intranasal vaccine.

MedImmune has acquired exclusive worldwide rights to certain intellectual property owned by Mount Sinai School of Medicine for reverse genetics, including U.S. patents 6,544,785 and 6,649,372. The company also owns or has exclusive rights to Mount Sinai School of Medicine Plasmid Rescue Portfolio (WO 01/04333); MedImmune Fundamental Reverse Genetics Portfolio (WO 91/03552); Wisconsin Alumni Research Foundation (University of Wisconsin) Plasmid Rescue Portfolio (WO 00/60050);a nd St. Jude Children’s Research Hospital Dual Promoter Plasmid Rescue Portfolio (WO 01/83794). In March 2007, Sanofi-Pasteur nonexclusively licensed reverse genetics technology from MedImmune to support the development and construction of new vaccine strains to produce human seasonal, pre-pandemic and pandemic influenza vaccines. In Spring 2007, MedImmune was analyzing results from a completed Phase I trial of a recombinant, intranasal, FluMist formulation of an H5N1 vaccine designed using reverse genetics.

Commercial users of reverse genetics-prepared vaccine seed strains will have to negotiate licenses with Medimmune, including royalty payments. MedImmune reports having offered licenses “for very reasonable terms.” This situation is unlike current influenza vaccine strains, which are provided free by CDC or other government authorities. In Europe (and, perhaps, the U.S.), reverse genetics-engineered viruses are classed as ‘genetically modified organisms,’ and vaccine production will require BSL-2+ or BSL-3 facilities that not all companies have. Regulatory agencies and populations will also have to accept reverse genetics (genetic engineering) for manufacture of pandemic vaccines. In the U,S,, in case of a pandemic, the government may exercise its right to compulsory licensing of reverse genetics-engineered seed strains for domestic production (based on original NIH funding of related research), but this will not address the intellectual property problems for non-U.S. companies that currently supply all non-seasonal vaccine-producing countries throughout the world (presuming they do not qualify for obtaining reverse engineered seek virus from WHO).

Market: As reported above, the world market/capacity for influenza vaccines is about 340 million, with over 100 million doses used in the U.S. Essentially all U.S.-Manufactured vaccine is used domestically, while European manufacturers supply most of the rest of the world. It has been reported (early 2007) that worldwide sales of human flu vaccine will be in excess of $2 billion (with this indicating an overall average price of about $3/dose) over the next year (including governments stocking up on H5N1 vaccines), and with a growing market for flu vaccines forecast to reach $3.7 billion by 2010. One company, Novartis, predicts a 14% compound annual growth rate for its sales of influenza vaccines.     

The global market for influenza vaccine is expected to grow by more than 13% annually through 2012. By 2012, worldwide sales are expected to exceed $4 billion. By 2011, global demand for seasonal influenza vaccine could be as large as 600 million doses---a reflection of expanding vaccination guidelines to include broader segments of the population.

GlaxoSmithKline plc (GSK), a major vaccine company, has estimated that the worldwide influenza vaccine market could more than double from its current value of £0.7-0.9 billion ($1.3-1.6 billion) to a 2010 value of £1.6-2 billion ($2.9-3.7 billion). .

Sanofi Pasteur Inc., formerly Aventis Pasteur Inc., currently holds the largest market share for influenza vaccines in the U.S., with about half or more of the total market. Aventis Pasteur, now Sanofi Pasteur, reported total influenza vaccine sales of $671.5 million in 2004, with the total market being on the order of double this. The former parent company Aventis S.A., which merged into Sanofi Aventis in last 2004, reported EUR 450 million sales of its influenza vaccines, Fluzone and Vaxigrip, in 2002, accounting for 22% of the company’s human vaccine sales. This was expected to double by 2010.

About 90-100 million doses of influenza vaccine are usually manufactured for the U.S. flu season.

Decision Resources Inc. reported in early 2001 that sales of influenza vaccines in the world’s major markets topped $550 million in 1999, with sales expected to exceed $1 billion in 2009, reflecting annual growth of 7%. In Nov. 2003, Decision Resources projected the total influenza pharmaceutical market will reach $2.5 billion in 2012, with 60% of this being FluMist, other intranasal, transdermal patches and other non-injected vaccines [am example how off-base market projections can be].

The approval of FluMist, a live recombinant influenza vaccine (#190 and #191) from MedImmune, administered by nasal spray was expected to change the market for influenza vaccines. Although introduced for the 2003/4 flu season at a premium price compared to conventional inactivated injected vaccines and facing consumer resistance to its higher price, its price for the 2004-5 flu season had been significantly reduced. However, 2004/5 and subsequentsales have been dismal, even after switching to CAIV-T, a next generation intransal influenza vaccine that can be stored refrigerated, not frozen. See the FluMist and CAIV-T entries in the Recombinant DNA Products section.

Prices for bulk influenza vaccine purchases, e.g., by CDC and other public health programs, directly from the manufacturer are significantly lower than those paid by non-bulk purchasers. Vaccinees in the U.S. often pay from $15-$25 to receive injectable vaccine. The nasal spray live influenza virus vaccine, FluMist, costs much more.

Too few Americans continue to receive annual influenza vaccinations. In Oct 2005, CDC reported analyses from the 2003/4 season. Only 65% of seniors were vaccinated, far below the 90% target. Rates among minorities are low. Just 48% of non-Hispanic blacks, and 45% of Hispanics in high-risk groups reported receiving vaccinations. Among persons aged 18 to 64 years with high-risk conditions, influenza vaccination coverage was 34.1%.” Only 13% of pregnant women were immunized, although they are also at risk of complications from influenza. Other studies have shown only 36% of health-care workers receive vaccinations, even though they are very likely to be infected, can pass the virus on to vulnerable patients and should know better. CDC attributes low coverage rates to lack of awareness of the benefits of vaccination.

In April 2005, the Centers for Disease Control and Prevention (CDC) reported that, based on an extensive survey, influenza vaccination coverage levels through Jan. 2005 among adults in priority groups nearly reached those in recent years, whereas coverage levels among adults not in priority groups were about half of levels in 2003. The results suggested that designation of the priority groups successfully directed the nation’s influenza vaccine supply to those at highest risk. [See the discussion of supply problems and shortages below]. Vaccination coverage among children aged 6-23 months was considered “notable” (48.4%), since 2004-05 was the first year this group was recommended for influenza vaccination. Among adults, influenza vaccination coverage through Jan. season was highest among persons aged ≥65 years (62.7%), followed by healthcare workers with patient contact (35.7%), and those aged 18-64 years with high-risk conditions (25.5%). Influenza vaccination coverage among healthy persons aged 18-64 years who were not healthcare workers or contacts of children aged <6 months was only 8.8%. An estimated 17.5 million persons (adults) not in priority groups reported not being vaccinated to save vaccine for people who needed it more. An estimated 63% of seniors and 46% of adults with chronic illnesses who tried to get the shot were able to. With long lines and considerable publicity about shortages, half of those in priority groups did not even try. Luckily, the 2004-05 influenza season was not severe and did not peak until mid-February.

Influenza vaccines have been covered by the Vaccines for Children (VFC) Program since March 1, 2003, with CDC purchasing vaccine supplies for distribution to its own and state-run immunization programs. The following groups are eligible to receive influenza vaccine through the VFC: all infants and children ages 6-23 months and children and adolescents 2-18 years of age who have risk factors or are household contacts of people with risk factors. Parents generally need to qualify based on low income or otherwise qualify for inclusion in public health programs.

In July 2005, influenza vaccines became eligible for compensation under the National Vaccine Injury Compensation Program (VICP; see the Vaccine Products entry), with retroactive coverage for those vaccinated in the previous eight years. The VICP, created by Congress in 1986 as an alternative to traditional civil litigation, provides financial compensation to eligible individuals thought to be injured by covered childhood vaccines. This complemented the addition of infants and children to those recommended to receive annual influenza vaccination. With this, influenza vaccine formally became a universal pediatric vaccine, although there are few or no regulations in place requiring annual pediatric influenza vaccine, e.g., as for other vaccines, including requirement for vaccination for children to attend school.

The system for manufacture and sales of influenza vaccines in Canada is much different than in the U.S. Canada’s public works ministry orders about 90% of the influenza vaccine the country uses each year. The government tells vaccine manufacturers how much to make, based on the share of the national total the firms have won by bidding on long-term contracts. The companies also make extra doses. This “on-spec” production is sold in the small, private market operating outside Canada’s national health system, or overseas on the world market. Thus, the vast bulk of vaccine is made without financial risk to the companies. Many desire or expect the U.S. to move towards adopting such a system.

U.S. Supply Problems, 2000-2003: A serious situation developed for the 2000-2001 flu season due to problems attaining sufficiently high titers (slower than normal replication) with culture of one of the component strains and regulatory compliance problems experienced by several manufacturers. Vaccine supplies were shipped starting a month or more later than usual. To help alleviate a potential shortage, the Centers for Disease Control and Prevention (CDC) contracted with Aventis Pasteur Inc. for manufacture of an additional nine million doses (of Fluzone). With this extra production, the U.S. supply of vaccine for 2000-2001 was brought up to approximately the same level as the previous year (~77 million doses).

CDC estimates 93 million doses of influenza vaccine were manufactured for U.S. consumption for the 2002-2003 flu season, and considerable surplus stocks remained at the end of 2002. An estimated 12 million doses went unused/unsold and were destroyed. Much of this over-production was in response to prior shortages of vaccine stocks and late shipping of vaccine which disrupted vaccination efforts. For the 1999-2000 flu season, a total of 77 million doses were manufactured in the U.S., just about enough to meet demand.

A total of 86.9 million doses of influenza vaccine were manufactured for use in the U.S. during the 2003-4 flu season, and about 83.1 million doses were distributed (sold/used; about the same as the prior 2002-3 season). Shortages of conventional injectable vaccine developed late in 2003. Many persons seeking vaccination could not find a source with any vaccine in stock (or reasonably-priced), despite there being no shortage of FluMist. As discussed in the FluMist entry, the U.S. launch in 2003 of FluMist was disastrous, with 80% of more of vaccine manufactured going unsold, despite implementation of rebates and even offers of free vaccine to public programs. For 2003-4 season, vaccination among those ages 18-49 at high risk was 23%; ages 50-64 at high risk was 44%; ages 50-64 total was 34%; ages ≥65 was 64%; among pregnant women was 12%; among health care providers was 38% and among household contacts was 18%.

2004/5 Supply Problems: As discussed further in the Influenza Vaccine/Chiron (Fluvirin) entry below, Chiron experienced bacterial contamination problems in the manufacture of its influenza vaccine for the 2004/5 flu season, and it vaccine was not released for marketing. Chiron had planned to supply the U.S. market with 46-48 million doses for the 2004/5 flu season. This left only one injectable vaccine to supply the entire U.S. market, Fluzone from Aventis Pasteur Inc. (now Sanofi Pasteur Inc.), and severe shortages occurred. It remains doubtful whether Chiron will be able to fix its problems with its vaccine manufacturing facility in the U.K. and receive FDA release (approval) of vaccine for the 2005/6 flu season, again leaving Sanofi Pasteur as the only supplier, which will be increasing its manufacturing for the 2005/6 season. However, even with this, there is likely to again be insufficient supply.

In response to the shortfall in the 2004-05 influenza vaccine supply, the Centers for Disease Control and Prevention (CDC) recommended in Oct. 2004 that vaccine be reserved for persons in certain priority groups, including persons aged ≥65 years and 6-23 months, persons aged 2-64 years with conditions that increased their risk for influenza complications, residents of chronic-care facilities, close contacts of infants aged <6 months, and healthcare workers with direct patient contact. In late Dec. 2004, based on declining demand among these groups, two additional groups – healthy persons aged 50-64 years and household contacts of all persons at high risk – were added to the list of vaccination priority groups.

Sanofi Pasteur provided about 60 million doses for U.S. use for the 2004/5 flu season. However, an estimated 3.5 million doses went unsold. MedImmune had manufactured 3 million doses of FluMist, but only sold about 1 million (see the Influenza Vaccine, rDNA entry in the Recombinant DNA Products section). These quantities of unsold vaccine demonstrate the unpredictability (risks) of the influenza vaccine market, with millions of unsold doses having to be trashed, even in a year of supply shortages.

2005/6 Supply Problems: A total of 86 million doses were sold in the U.S. for the 2005/6 season. Besides vaccines from Sanofi Pasteur (Fluzone) and Chiron (Fluvirin), vaccines from GlaxoSmithKline (Fluarix) and ID Biomedical/GSK (Fluviral) became available in the U.S. (see the related entries), although their market share was small. As is usual, Sanofi Pasteur (Fluzone) supplied an estimated 51% of vaccine doses. Chiron did not manufacture Fluvirin in prefilled syringes for general U.S. distribution for the 2005/6 flu season, but did manufacture vials.

2006/7 Supply Situation: The worldwide annual capacity for influenza vaccine manufacture is currently about 340 million doses, with the largest portion of this, generally over 100 million doses, manufactured and used in the U.S.

Manufacturers planned to produce up to 120 million doses of conventional influenza vaccine for the U.S. 2006/7 flu season, a record number. The increase was fueled by improved government reimbursement for vaccines and increased demand, e.g., an aging population and increasing vaccination of infants and children. Indications:, including record preordering, suggested that 2006/7 set a U.S. record for number of doses sold and administered.

Presuming no major manufacturing facilities go offline or significant stocks of vaccine are found to be contaminated (which has happened in recent years), manufacturers expected that there would be an adequate supply of vaccine to meet the nation’s needs for the 2006-2007 season. Vaccine manufacturers and distributors had learned lessors from recent supply disruptions and are requiring customers to prebook their orders earlier in the season, with this facilitating planning for production of the number of doses to be manufactured to fulfill demand (to avoid shortfalls and unsold surpluses).

In July 2006, Chiron Corp. reported it would not supply its new (in the U.S.) Begrivac influenza vaccine during the 2006/2007 flu season. As a new entrant, this did not significantly affect the U.S. supply. As discussed in the entry for Begrivac (#474), Chiron reduced its supply expectations for the vaccine after some lots of vaccine did not meet sterility specifications.

In Feb. 2006, Sanofi Pasteur Inc., the major source for influenza vaccine in the U.S., reported “unprecedented U.S. demand for influenza vaccine for 2006-2007 influenza season, with a record number of immunization providers contacting the company requesting its vaccine, Fluzone for the 2006-2007 season. The company planned to produce ~50 million doses of all Fluzone vaccine formulations for U.S. distribution by the end of October. Additional doses could be produced for delivery in Nov. or Dec., based on customer needs and production yields. During the first 30 minutes of accepting orders, the company received over 40,000 phone calls and more than 200,000 calls came in during the first eight hours, as many calls as the company normally receives in a six-month sales period. As a result of unprecedented demand, the company immediately committed (took orders for) all influenza vaccine doses planned for production for the 2006/7, except its preservative-free Fluzone vaccine in pediatric doses.

For the 2006/7 season, GSK supplied 25 million doses of the Fluarix and FluLaval in the U.S.

The U.S. government (CDC) also granted contracts for millions of doses of H5N1 avian influenza vaccine for addition to the national stockpile for use in the case of a deadly bird flu pandemic (see related entries below).

In Oct. 2006, a survey of 1,000 adults by the National Foundation for Infectious Diseases reported that only 48% of adults planned to get vaccinated for the 2006/7 flu season. About 43% said they did not think flu is serious, and 38% did not plan to get immunized because they do not think they are at risk.

Looking back (in mid-2007), there was no problem with supplies of influenza vaccine in the U.S. and, presumably, other developed countries in 2006/7. A total of about 115 million doses were manufactured for the U.S. market. Sanofi-Aventis produced 50 million doses, followed by Novartis with 40 million and GlaxoSmithKline with 25 million. There was even a surplus in the U.S., with some companies having to dispose of unsold or returned/unused vaccine. Novartis experienced a production problem, but this affected just 20,000 doses. Sanofi Pasteur similarly experienced a contamination problem, but this affected a relatively small number of doses. In contrast, the supply situation in Europe was tighter, with some early concerns that there would be insufficient vaccine.

2007/8 Supply Situation: As of mid-2007, no delays or problems in the manufacture of seasonal influenza vaccines for the U.S. market had been reported. Over 120 million doses were expected to be available in the U.S. The World Health Organization’s (WHO) estimated global production of influenza vaccine would be 350 million doses. Sanofi Pasteur, the largest manufacturer of influenza vaccines, reported its expected to manufacture 170 million doses.

For the 2007/8 season, GSK planned to supply the U.S. market with 30 million to 35 million doses of Fluarix and FluLaval.

After the season, CDC reported that 140.6 million doses had produced for the U.S. market.

2008/9 Supply Situation: The Centers for Disease Control and Prevention (CDC) reported that 135.9 million doses of flu vaccine were ultimately produced for the 2008/9 season following initial estimates of 143-146 million doses. Vaccine manufacturing and distribution occurred relatively early in the flu season. The total number of doses distributed2 (via both channels) was estimated to be 113.0 million doses – up slightly from 112.8 million in the previous season. The bulk of production (approximately 97%) was completed by Nov. 8, 2008 – before influenza’s typical peak in February. Approximately 22.9 million doses were not distributed. The number of “distributed doses” (those ordered by a distributor or provider and sent to a distributor or provider) does not necessarily reflect the number of doses administered to or demanded by patients. During the 2008-2009 season, the largest share of production, approximately 37% of doses, was produced by Sanofi Pasteur.

During the 2008-2009 influenza season, U.S. suppliers shipped about 50% of the flu vaccine supply directly to their customers (vs. selling through middle-men). Distributors delivered approximately half (the remaining 50%) of the vaccine supply – consistent with past seasons. Distributors serve approximately 200,000 points of care across the country, and more than 12,000 U.S. medical practices with six or fewer physicians.

By the end of the 2008–2009 vaccination season (March 2009), less than 40% of U.S. adults had been vaccinated against seasonal influenza, according to a Rand survey. Among those who were not vaccinated, the most commonly cited reason (25%) by individuals was that they “don’t need it,” followed by those who said they “didn’t get around to it.” Adults with a specific indication to receive the vaccine were more than twice as likely (78%) to have been vaccinated against influenza during the 2008–2009 season compared to those without a specific indication.

The emergence of a novel H1N1 pandemic influenza outbreak in April 2009 occurred at the conclusion of the 2008-2009 season, and did not significantly impact 2008-2009 roduction or distribution numbers. Although the H1N1 flu pandemic is likely to impact the regular 2009- 2010 influenza season, only a slight uptick in interest in seasonal vaccine was reported anecdotally by distributors and manufacturers at the conclusion of 2008-2009.

Competition: As reported by the World Health Organization (WHO), influenza vaccine manufacturers outside of the U.S. include CSL Ltd. (Australia), Baxter Vaccine AG (Austria), ID Biomedical Corp. (Canada), Typharm (China), Sanofi Pasteur S.A. (France), GlaxoSmithKline Biologicals (Germany), Chiron Vaccines (U.K., Germany and Italy), Istuto Vaccinogeno Pozzi (Italy), DENKA SEIKEN CO., Ltd. (Japan), BIKEN (The Research Foundation for Microbial Diseases of Osaka University; Japan), Kitasato Institute (Japan), Dong Shin Pharmaceutical Co, Ltd. (Korea), Solvay Pharmaceuticals (The Netherlands), Crucell NV (The Netherlands), Cantacuzino Institute (Romania), Berna Biotech Ltd. (Switzerland; now merged into Crucell N.V.).

Among the six influenza vaccines manufactured and marketed extensively in Europe, Vaxigrip from Sanofi Pasteur, Begrivac from Behring/Chiron and Fluarix/Influsplit from GSK are split-virion vaccines, i.e., sodium deoxycholate, ether or another agent is used to disintegrate, disrupt or split-up to whole virus prior to purification and either before or after viral inactivation, e.g., with formalin/formaldehyde or beta-propriolactone (BPL). The other three influenza vaccines in Europe, Influvac from Solvay (approved, but not marketed), Agrippal from Biocine/Chiron (Italy) and Fluvirin from Chiron, are subunit vaccines. These involve concentration and purification of viral surface antigens (HA and NA) using zonal centrifugation.

Chiron Vaccines manufactures Sandovac, an influenza vaccine at its facilities in Siena, Italy. The vaccine is exclusively sold to Novartis Pharma GmbH for purchase and distribution by the Austrian government. Chiron has supplied the vaccine since 1999.

In Oct. 2005, Sinovac Biotech Ltd. received approval in China (PRC) for its conventional split influenza vaccine, Anflu. Sinovac has capacity for 2 million doses/year.

R&D: Many companies are developing next-generation seasonal and pandemic, e.g., H5N1/bird flu, influenza vaccines. Since many of these are very similar, if not designed to be substantially identical to other vaccines, to some extent, and may even be approved based on comparative studies or abbreviated filings, these may be considered generic biopharmaceuticals (biogenerics, follow-on biologics, biosimilars, etc.). These include both conventional, seasonal/annual vaccines and vaccines for prevention of influenza virus H5N1 (bird flu; avian influenza).

Chiron Corp., now merged into Novartis AG, and PowderMed Ltd. (formerly PowderJect Pharmaceuticals plc, acquired by Chiron, and the spun-off in May 2004; acquired by Pfizer in Oct. 2006) are developing a Particle Mediated Epidermal Delivery (PMED needle-free injected powder influenza vaccine using influenza cultured in Madin Darby Canine Kidney (MDCK) cell lines. Phase I/II trials began in Oct. 2005. Chiron submitted an application for provisional/virtual European Union approval (if needed in emergency) in Feb. 2006. A DNA-based PMED vaccine from PowderMed entered Phase I trials in late 2006.

The National Institute of Infectious Diseases (Japan) in Oct. 2005 concluded an agreement with Hemispherx Biopharma, Inc. to test Ampligen as an adjuvant for a nasal influenza vaccine it is developing.

In April 2005, the Department of Health and Human Services (DHHS) awarded Sanofi Pasteur Inc. a five-year, $97 million contract for the development of using a cell culture-based, rather than an egg culture-based, influenza vaccine. The contract also calls for plans to establish a U.S.-based, cell cultured influenza vaccine manufacturing facility. Cell culture-based influenza vaccines are expected help meet surge capacity needs in the event of a shortage or pandemic, since cells may be frozen in advance and large volumes grown quickly. A cell cultured vaccine will also provide security against risks associated with egg-based production, such as the potential for egg supplies to be contaminated by various poultry-based diseases; and wil an option for people who are allergic to eggs and unable to receive the currently licensed vaccines. Sanofi Pasteur will develop plans for a U.S. manufacturing facility capable of producing at least 300 million doses of a pandemic influenza vaccine using this technology. This contract followed the August 2004 release of the draft National Pandemic Influenza Preparedness and Response Plan, which outlined a coordinated national strategy to prepare for and respond to an influenza pandemic. Positive results from a double-blind, placebo-controlled, dose-ranging Phase I/II trial in 451 healthy adults were reported in March 2006.

Coley Pharmaceutical Group and GlaxoSmithKline are developing an influenza vaccine using a CpG DNA adjuvant.

DelSite Biotechnologies Inc., a subsidiary of Carrington Laboratories Inc., is developing a GelVac intranasal powder influenza vaccines.

Protein Sciences Corp., formerly in collaboration with Aventis Pasteur (Sanofi Pasteur), now on its own, is developing a recombinant baculovirus vector, caterpillar cell expressed influenza virus hemagglutinin (rHA) vaccine (FluBlOk). The vaccine entered a U.S. Phase II/II trial in late 2004; and in June 2005, the company reported “excellent” efficacy results. In Feb. 2006, the company reported the successful production of rHA from from four potential pandemic strains of influenza (H5, H7, H9, and H2) at levels where manufacturing costs are expected to be equal to or less than that of traditional egg-based vaccines. Promising results from a trial were published in the April 11, 2007, issue of the Journal of the American Medical Association. In the study funded by the company of 460 healthy people ages 18 to 49, one-third of the participants received a smaller dose of the vaccine (75 µg), one-third received a larger dose (135 µg), and one-third received a placebo injection that didn’t include vaccine. Each of the “real” shots included vaccine designed to protect against the three strains of flu that had been predicted to be the greatest threat during the 2004-2005 winter, when the study was conducted. Both dosages caused an immune reaction generally considered effective for preventing influenza, with the larger dose inducing a stronger immune response. The side effects of the vaccine were the same as those usually reported from a typical flu shot – mainly mild arm pain. In the months that followed, there were seven cases of infleunza in the group that had not received the vaccine, compared to two cases in the group that received the smaller dose, and no cases in the group that received the larger dose. Together, the vaccine reduced the infection rate by 86%, about as good or better than conventional egg-cultured vaccines.

Intellivax International Inc. is developing an inactivated subunit “proteosome” influenza virus vaccine administered by intranasal spray.

At least three companies – Acambis plc (using CorVax antigen delivery technology from Apovia AG), BiondVax (Israel), and Dynavax Technologies – are developing “universal” cell cultured vaccines using conserved portions of influenza virus that remain relatively constant from year to year and found in essentially all epidemic strains.

Baxter AG had planned a major launch of VERO cell cultured, animal products-free vaccine, PrefluCel (InfluJect), in Europe in 2005. However, in Dec. 2004, Baxter voluntarily suspended enrollment in a Phase II/III study in Europe of PreFluCel due to a higher than expected rate of mild fever and associated symptoms in the trial participants, and put further trials (and regulatory filings) on hold. PreFluCel was based on culture of influenza viruses in Vero African green monkey kidney cell culture. This will be the first launch of a cell cultured influenza vaccine. Baxter has been constructing manufacturing facilities in Krems, Austria (near Vienna) and in Behu---mile, Czech Republic (near Prague), acquired from SEVAC (Czech gov’t). Baxter had projected FDA approval in 2007 (before the trial hold); and anticipated manufacturing 10-15 million doses in 2005, 40-50 million doses by 2007, with sales expected to reach $200-$400 million. PreFluCel is currently in Phase III trials.

Novavax Inc. is developing a recombinant, baculovirus-expressed, virus-like particle (VLP) seasonal influenza vaccine using its Novasome adjuvant. Promising early trial results were published in the Feb. 2007 issue of Vaccine.

Integrated BioPharma Inc. (Hillside, NJ) is collaborating with Fraunhofer USA Inc. (Plymouth, MI) to develop a recombinant plant system for influenza vaccine manufacture and associated vaccines.

VLP Biotech Inc., affiliated wih Tripep AB, is developing a universal influenza vaccine using influenza virus M2 protein formulated in virus-like particles (VLPs). Promising results have been reported in animal studies.

Vaxin Inc. is developing a cell cultured influenza vaccine for intranasal delivery using an adenovirus vector carrying influenza virus antigens, and is conducting Phase I and Phase II clinical trials in 2005 and 2006.

Acambis plc, in collaboration with the Flanders Interuniversity for Biotechnology (Belgium) is developing influenza A and B vaccines based on influenza virus M2e, the extracellular domain of the ion channel protein M2, which is specific to influenza A and is highly conserved. The vaccines are expected to not require annual changes to their formulation.

In April 2005, AlphaVax, Inc. received a 6.5 million, 3-year grant from the National Institute of Allergy and Infectious Diseases (NIAID), NIH, for development of development of an influenza vaccine using the company’s ArV (AlphaVax replicon Vector) system, involving use of alphavirus vectors, technology originally licensed from the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID).

In Nov. 2006, AerovectRx Corp. received a $750,000 contract from the Centers for Disease Control and Prevention (CDC) to develop a new intranasal vaccine delivery platform for influenza vaccination.

In March 2007, ImmuunoBiology Ltd. concluded an agreement with Eden Biodesign for manufacturing services for a “ next generation influenza vaccine.”

The Russian Influenza Research Institute (RAMS) is developing an intranasal seasonal influenza vaccine, similar in many respects to one that has long been manufactured and used in Russia. Korauban, which is related to cellulose and induces gamma interferon expression, is used as adjuvant. Clinical trials are expected to start in Fall 2008. The initial candidate vaccine will include antigens from three inactivated viruses (A1, A2, B). An undisclosed component, permitting 12-month tablet stability, will be used to develop a vaccine in oral tablet form.

HepaLife Technologies Inc. is developing cell culture-based influenza vaccines using a cell line licensed from Michigan State University.

Acambis (now part of Sanofi Pasteur) in Jan. 2008 reported positive results from a Phase I trial of ACAM-FLU-A, a recombinant influenza A M2e antigen linked to a Hepatitis B core protein vaccine with QS-21 Stimulon adjuvant from Antigenics.