2009/2010 H1N1 Vaccines for U.S. Distribution: Update 9.24.09

We have put together what the upcoming H1N1 vaccines will look like that will be distributed in the U.S. We wish to stress that some of this information is provisional and subject to change as more data become available. Such changes will be announced as updates in the title. The parental seed strain for the H1N1 vaccines is A/California/7/2009 (H1N1)v, however, several seed strains have been developed and sent to the WHO for distribution to the vaccine manufacturers to be tested for development as candidate vaccine H1N1 strains such as X‐179A, NIBRG-121, CBER-RG2 and IVR‐153. The following 4 vaccines have been approved by the FDA:

MedImmune's Monovalent H1N1 FluMist:
Description: FluMist is a live, attenuated vaccine administered intranasally manufactured on the same platform as their seasonal trivalent vaccine, FluMist. Each pre-filled sprayer is a single 0.2 mL dose that contains 10^6.5-7.5 FFU of the live attenuated influenza virus reassortant of the pandemic (H1N1) 2009 virus: A/California/7/2009 (H1N1)v, 0.188 mg/dose monosodium glutamate, 2.00 mg/dose hydrolyzed porcine gelatin, 2.42 mg/dose arginine, 13.68 mg/dose sucrose, 2.26 mg/dose dibasic potassium phosphate, 0.96 mg/dose monobasic potassium phosphate, and 0.015 mcg/mL gentamicin sulfate. The vaccine contains no preservatives.
Indications and Usage: FluMist is a vaccine indicated for the active immunization of individuals 2-49 years of age against influenza disease caused by pandemic (H1N1) 2009 virus. Children 2 through 9 years of age should receive two 0.2mL doses approximately 1 month apart. Children, adolescents and adults age 10 through 49 years should receive a single 0.2 mL dose.
Contraindications: Hypersensitivity to eggs, egg proteins, gentamicin, gelatin or arginine or life threatening reactions to previous influenza vaccination. Concomitant aspirin therapy in children and adolescents. Pregnant women, those with asthma and those with certain underlying immunocompromised disorders should not receive FluMist. Please consult the full package insert for other warnings and precautions.
Clinical Trials: Safety and immunogenicity in healthy adult (18-49 years old) is to evaluate the safety and immunogenicity of the H1N1 FluMist and is a randomised, placebo-controlled study. The anticipated study completion date is March, 2010 but the primary outcome data was completed in August, 2009. Safety and Immunogenicity in healthy children (2-17 years old) is to evaluate the safety and immunogenicity of the H1N1 FluMist and is a randomised, placebo-controlled study. The anticipated study completion date is March, 2010, but the primary outcome data was completed in August, 2009.
Safety and Efficacy: Clinical data from trials are not yet available.

CSL Limited's Monovalent H1N1 Injectable:
Description: The 2009 Monovalent H1N1 Vaccine is an inactivated split-virion vaccine manufactured on the same platform as their seasonal trivalent vaccine, Afluria. CSL H1N1 vaccine is prepared from influenza virus propagated in the allantoic fluid of embryonated chicken eggs. It is formulated to contain 15 mcg HA per 0.5 mL dose of influenza A/California/7/2009 (H1N1)v-like virus, contains 4.1 mg sodium chloride, 80 mcg monobasic sodium phosphate, 300 mcg dibasic sodium phosphate, 20 mcg monobasic potassium phosphate, 20 mcg potassium chloride, and 1.5 mcg calcium chloride. From the manufacturing process, each dose may also contain residual amounts of ≤ 10 ppm sodium taurodeoxycholate, ≤ 1 mcg ovalbumin, ≤ 0.2 picograms [pg] neomycin sulfate, ≤ 0.03 pg polymyxin B, and less than 25 nanograms beta-propiolactone. It is available in 0.5 mL preservative-free (thimerosal-free), single-dose, pre-filled syringes and 5 mL multi-dose vials containing ten doses. Thimerosal (an ethylmercury derivative), is added as a preservative to the 5 mL multi-dose vials only and each 0.5 mL dose contains 24.5 mcg (micrograms) of ethylmercury.
Indications and Usage: CSL H1N1 Monovalent Vaccine is indicated for adults 18 years of age and older against influenza disease caused by pandemic (H1N1) 2009 virus. Adults 18 years of age and older should receive a single 0.5 mL intramuscular dose.
Contraindications: Hypersensitivity to eggs or chicken protein, neomycin, or polymyxin, or life-threatening reaction to previous influenza vaccination. Please consult the full package insert for other warnings and precautions.
Clinical Trials: Safety and Immunogenicity in healthy children (6 months to less than 9 years old) is a randomised, observer-blinded study to evaluate the safety and immunogenicity of H1N1 Monovalent Vaccine. The anticipated study completion date is March, 2010, but the primary outcome data will be completed in October, 2009. Immunogenicity and dose response in healthy adults (18-64 years old) is a randomised, observer-blind study to assess the immunogenicity elicited by 15 mcg and 30 mcg of H1N1 HA doses. The anticipated study completion date is March, 2010, but the primary outcome data will be completed in September, 2009. Immunogenicity and dose response in healthy children (6 months-9 years old) is randomised, observer-blind study to assess the immunogenicity elicited by 7.5 mcg and 15 mcg of H1N1 HA doses. The anticipated study completion date is April, 2010, but the primary outcome data will be completed in October, 2009. Immunogenicity and dose response in healthy adults (≥18 years old) is randomised, observer-blind study to assess the immunogenicity elicited by 7.5 mcg, 15 mcg and 30 mcg of H1N1 HA doses. The anticipated study completion date is April, 2010, but the primary outcome data will be completed in October, 2009.
Safety and Efficacy: Preliminary data from the HHS report that 80% of healthy 18-60 year old adults demonstrated a robust immune response in 8-10 days from a single dose of H1N1 vaccine. Sixty percent of adults aged 65 and over demonstrated a robust immune response. The vaccine was well-tolerated.
Novartis' Monovalent H1N1 Injectable:
Description: The 2009 Monovalent H1N1 Vaccine is an inactivated sub-unit vaccine manufactured on the same platform as their seasonal trivalent vaccine, Fluvirin. Novartis H1N1 vaccine is a sub-unit (purified surface antigen) influenza virus vaccine prepared from virus propagated in the allantoic cavity of embryonated hens’ eggs inoculated with a specific type of influenza virus suspension containing neomycin and polymyxin. It is formulated to contain 15 mcg hemagglutinin (HA) per 0.5-mL dose of the following virus strain: A/California/7/2009 (H1N1)v-like virus. Each dose from the multidose vial or from the prefilled syringe may also contain residual amounts of egg proteins (≤ 1 mcg ovalbumin), ≤ 3.75 mcg polymyxin, ≤ 2.5 mcg neomycin, ≤ 0.5 mcg betapropiolactone and ≤0.015% w/v (weight/volume) nonylphenol ethoxylate. It is available in 0.5 mL single-dose, pre-filled syringes and contains trace amount of thimerosal (≤ 1 mcg mercury per 0.5-mL dose) left over from manufacturing. It is also available in 5 mL multi-dose vials containing ten doses. Thimerosal (an ethylmercury derivative), is added as a preservative to the 5 mL multi-dose vials only and each 0.5 mL dose contains 25 mcg (micrograms) of ethylmercury.
Indications and Usage: Novartis H1N1 Monovalent Vaccine is indicated for children and adults 4 years and older against influenza disease caused by pandemic (H1N1) 2009 virus. Children 4 through 9 years of age should receive two 0.5mL doses by intramuscular injection approximately 1 month apart. Children 10 years of age and adults should receive a single 0.5-mL intramuscular injection.
Contraindications: History of systemic hypersensitivity reactions to egg proteins, or any other component of Influenza A (H1N1) 2009 Monovalent Vaccine, or life-threatening reactions to previous influenza vaccinations. Please consult the full package insert for other warnings and precautions.
Clinical Trials: Safety and Immunogenicity and dose response of non-adjuvanted and adjuvanted H1N1 in healthy adults (≥ 18 years old) is a randomised, single-blind study to assess the immungenicity elicited by both adjuvanted and non-adjuvanted, one and two doses and high or low dose monovalent H1N1 HA. The anticipated study completion date is March, 2011, but the primary outcome data will be completed in October, 2009. There are numerous other trials that are planned and/or in process that can be viewed here although are not applicable to the current U.S. H1N1 vaccine recommendations.
Safety and Efficacy: Clinical data from trials are not yet available.

Sanofi Pasteur's Monovalent H1N1 Injectable: The 2009 Monovalent H1N1 Vaccine is an inactivated split-virus vaccine manufactured on the same platform as their seasonal trivalent vaccine, Fluzone. Sanofi Pasteur H1N1 vaccine is prepared from influenza viruses propagated in embryonated chicken eggs. The virus-containing allantoic fluid is harvested and inactivated with formaldehyde. It is formulated to contain 15 mcg hemagglutinin (HA) of influenza A/California/07/2009 (H1N1) v-like virus per 0.5 mL dose. 0.05% Gelatin is added as a stabilizer. Each 0.5 mL dose may contain residual amounts of ≤100 mcg formaldehyde, ≤0.02% polyethylene glycol p-isooctylphenyl ether, and ≤2.0% sucrose. It is available in 0.25 mL or 0.5 mL single-dose, pre-filled syringes, single dose 0.5 mL vials and contains no preservative (thimerosal). It is also available in 5 mL multi-dose vials containing ten doses. Thimerosal (an ethylmercury derivative), is added as a preservative to the 5 mL multi-dose vials only and each 0.5 mL dose contains 25 mcg (micrograms) of ethylmercury.
Indications and Usage: Sanofi Pasteur H1N1 Monovalent Vaccine is indicated for infants, children and adults 6 months old and older against influenza disease caused by pandemic (H1N1) 2009 virus. Children 6 through 35 months of age should receive two 0.25 mL intramuscular doses approximately 1 month apart. Children 36 months through 9 years of age should receive two 0.5 mL intramuscular doses approximately 1 month apart. Children 10 years of age and older and adults should receive a single 0.5 mL intramuscular dose.
Contraindications: Severe hypersensitivity to egg proteins or any component of the vaccine or life-threatening reactions after previous administration of any influenza vaccine. Please consult the full package insert for other warnings and precautions.
Clinical Trials: Sanofi H1N1 Influenza Vaccine Administered at Different Dose Levels With and Without AS03 Adjuvant in Healthy Adult and Elderly Populations is a randomised, double-blind study to assess the immunogenicity by both adjuvanted and non-adjuvanted and either 3.75 mcg, 7.5 mcg and 15 mcg of H1N1 HA doses. The anticipated study completion date is October, 2010. There are numerous other trials that are planned and/or in process that can be viewed here although are not applicable to the current U.S. H1N1 vaccine recommendations.
Safety and Efficacy: Update: Preliminary data from the HHS report that 76% of children aged 10-17 years old demonstrated a robust immune response in 8-10 days from a single dose of H1N1 vaccine with 15 mcg of HA. Thirty-six percent of 3-9 year olds demonstrated a strong response to a single (15 mcg- HA containing) dose and 25% of children, 6-36 months demonstrated a strong response to a single dose. Results from a second dose are pending. Preliminary data from the HHS report that 96% of healthy 18-60 year old adults demonstrated a robust immune response in 8-10 days from a single dose of H1N1 vaccine. Fifty-six percent of adults aged 65 and over demonstrated a robust immune response. The vaccine was well-tolerated.

The following vaccine has not yet been approved by the FDA:
GSK's Monovalent H1N1 Injectable: The The 2009 Monovalent H1N1 Vaccine is an inactivated split-virion vaccine (most likely) manufactured on the same platform as their Pandemrix vaccine, which incorporates the same manufacturing process as Fluarix. GSK H1N1 vaccine is a split-virion influenza vaccine that will probably be formulated to contain 15 mcg hemagglutinin (HA) per 0.5-mL dose of the following virus strain: A/California/7/2009 (H1N1)v-like virus. The virus is propagated in fertilised hens’ eggs. Each 0.5-mL dose also contains ≤0.120 mg octoxynol-10 (TRITON® X-100), ≤0.1 mg α-tocopheryl hydrogen succinate, and ≤0.380 mg polysorbate 80 (Tween 80). Each dose may also contain residual (≤0.0016 mcg) amounts of hydrocortisone, ≤0.15 mcg gentamicin sulfate, ≤1 mcg ovalbumin, ≤50 mcg formaldehyde, and ≤50 mcg sodium deoxycholate from the manufacturing process. It should be available in 0.5 mL single-dose, pre-filled syringes and contains no preservative (thimerosal). It may also be available in 5 mL multi-dose vials containing ten doses. Thimerosal (an ethylmercury derivative), is added as a preservative to the 5 mL multi-dose vials only and each 0.5 mL dose contains 5 mcg (micrograms) of ethylmercury.
Indications and Usage: GSK H1N1 Monovalent Vaccine is indicated for active immunization of adults (18 years of age and older) against influenza disease caused by pandemic (H1N1) 2009 virus. Adults 18 years of age and older should receive a single 0.5 mL intramuscular dose.
Contraindications: This vaccine should not be administered to anyone with known systemic hypersensitivity reactions to egg proteins (eggs or egg products), to chicken proteins, or to any component of FLUARIX or who has had a life-threatening reaction to previous administration of any influenza vaccine. Please consult the full package insert for other warnings and precautions.
Clinical Trials: Immunogenicity of the H1N1 candidate flu vaccine in infants (6-35 months old) is a randomised study to asses the immunogenicity of their H1N1 pandemic vaccine in infants using differing dosage schedules. The anticipated study completion date is June, 2011. Safety and immunogenicity of the H1N1 candidate vaccine in children and adolescents (3-17 years old) is a study to assess the immunogenicity elicited by a 3 dose schedule. The anticipated study completion date is April, 2011. Safety and immunogenicity of the H1N1 candidate vaccine in adults (≥18 years old) is a randomised, double-blind study to assess the safety and efficacy of 2 H1N1 vaccines. The anticipated study completion date is December, 2010. Safety and immunogenicity of the H1N1 candidate vaccine in infants and children (6 months to less than 9 years old) is a randomised, double-blind study to assess the safety and efficacy of 2 H1N1 vaccines. The anticipated study completion date is September, 2010.
Safety and Efficacy: Clinical data from trials are not yet available.

This vaccine will probably not be approved by the FDA for use during the 2009/2010 influenza season but is an interesting technology that doesn't require the use of eggs for production and instead a novel cell line. It is anticipated that their trivalent, seasonal recombinant influenza vaccine will be available in November, 2009:
Protein Sciences' PanBlok: The Monovalent H1N1 Candidate Vaccine is a recombinant hemagglutinin (rHA) virus cultured on a proprietary cell line that is non-transformed and non-tumourigenic (expressSF+Ⓡ insect cells), grown in serum-free medium. It would be manufactured on the same platform as their seasonal, trivalent rHA FluBlok vaccine. Protein Sciences PanBlok would be formulated to contain 45 mcg rHA of an H1N1 viral seed stock and stored in sterile, phosphate-buffered saline; there will be some trace excipients left over from the purification process. This vaccine does not contain adjuvants, antibiotics or any preservatives such as thimerosal.
Indications and Usage: It is not known, at this time, the age groups that this vaccine will be indicated for. A phase III trial for FluBlok TIV has been completed (see Clinical Trials) for adults 18-49 years old and the results can be found here.
Contraindications: Unknown at this time.
Clinical Trials: There are no clinical trials listed for PanBlok but the following trials have been listed for FluBlok: Immunogenicity and Safety of Trivalent Recombinant Hemagglutinin Influenza Vaccine in Healthy Adults is a study for safety and efficacy in adults (18-49 years old) which has been completed. The following four studies are listed as active but past estimated completion dates: Safety and Reactogenicity of FluBlok and Comparison of Immunogenicity, Efficacy and Effectiveness Against TIV is a study for safety and efficacy in older adults (50-64 years old). Immunogenicity, Safety, Reactogenicity, Efficacy, Effectiveness and Lot Consistency of FluBlok is a study for safety and efficacy in adults (18-49 years old). Comparison of the Immunogenicity, Safety and Reactogenicity of FluBlØk™, To a Licensed Vaccine In Elderly Adults is a study for safety and efficacy in older adults (≥65 years old). Safety and Immunogenicity of FluBlok in Pediatrics is a study for safety and efficacy in infants and children (6-59 months old).

As you can see, these vaccines are based upon widely used platforms with only an antigen change, just as is done every year with seasonal influenza. One concern is the association between Guillain-Barré syndrome (GBS) and the 1976 Swine Flu vaccine. In 2004, the Institute of Medicine (IOM) issued an Immunization Safety Review: Influenza Vaccines and Neurological Complications which concluded:

The committee concludes that the evidence favors acceptance of a causal relationship between 1976 swine influenza vaccine and Guillain-Barré syndrome in adults.

It has not been fully elucidated as to why there was an increased risk of GBS with receipt of the 1976 swine flu vaccine, however, there have been some postulations:

Although the 1976 influenza vaccine was produced under atypical conditions, with the four manufacturers given less time than usual while being asked to produce much larger quantities than in previous years, there is no evidence that the speed of manufacture or volume of production produced lapses that could have led to a faulty vaccine. The increased risk of GBS associated with the 1976 swine influenza vaccine appeared consistent for vaccine from the four different manufacturers, for the monovalent and bivalent vaccines, and for the whole- and split-virus vaccines.

The use of eggs to produce vaccine-strain influenza virus suggests the possibility that unrecognized antigens might have been present in the 1976 vaccine. C. jejuni infection is a recognized risk factor for GBS, possibly acting through molecular mimicry, and C. jejuni commonly infects chickens. Although the committee concluded that molecular mimicry is only theoretically possible as an immune mechanism by which influenza vaccines may cause GBS, the evidence that C. jejuni antigens can trigger GBS is strong, and the possibility cannot be excluded that C. jejuni antigens were present in swine influenza vaccine from all four manufacturers of the 1976 swine influenza vaccine.

Since this IOM report, there have been some studies conducted which have described the possible mechanism by which that particular vaccine could have facilitated GBS in the recipient. A study by Nachamkin et al. (2008) reports:

We found that commercial influenza vaccines containing A/NJ/1976 induced IgG and IgM antibodies to GM₁, but not to C. jejuni, after immunization in mice. Unexpectedly, this was not restricted to the 1976 vaccines but was also observed in both the 1991–1992 and 2004–2005 commercial vaccines. All tested 1976 vaccine lots retained HA activity and induced antibodies to HA in mice after the rather lengthy storage period. There was, however, variability in the HA titers among 1976 vaccine lots, which may represent some, but not complete, degradation of the product during storage.

One of the best‐studied examples of a precedent infection associated with GBS development is C. jejuni–mediated gastroenteritis. C. jejuni expresses ganglioside‐like mimicry in the core region of its bacterial surface LOS, and these structures can induce anti‐ganglioside antibodies, such as anti‐GM₁ [16, 27], and reproduce the disease in rabbits [14]. It is currently postulated that loss of tolerance to naturally occurring gangliosides in susceptible hosts is a mechanism for how these antibodies arise after C. jejuni infection and trigger autoimmune‐mediated disease [13, 33, 34]. Activation of autoreactive T cells to self‐glycolipids after infection may also play a role in the development and progression of disease [35]. Nonetheless, most patients infected with C. jejuni strains expressing ganglioside‐like mimicry do not develop GBS [32]; thus, host susceptibility factors may contribute to GBS development [36].

The vaccines produced in 1976, as well as the more contemporary formulations examined here, were produced in eggs and purified by physical and chemical procedures. These vaccine preparations contain not only HA but also other viral components—such as NA, nucleoprotein, and other viral structural proteins [37]—as well as egg proteins and other excipient remnants from production [18]. One hypothesis for why the 1976 vaccines elicited GBS was that bacterial antigens, such as those from C. jejuni, contaminated the eggs and/or were introduced during processing of the vaccine and thus elicited anti–C. jejuni immune responses in susceptible vaccinated individuals, leading to the development of GBS. However, this is an unlikely scenario, because C. jejuni is not transmitted vertically from hen to egg [38]. Alternatively, external egg contamination with C. jejuni through residual fecal material on the exterior of the eggs may have increased during the massive ramping up of swine flu vaccine production. We provide evidence, however, that C. jejuni contamination is probably not the cause of the anti‐GM₁ antibody production in animals immunized with A/NJ/1976 and other influenza vaccines. Importantly, antibodies to C. jejuni antigens were not detected in mice immunized with the various vaccine preparations, nor did any of the vaccines contain bacterial DNA.

On the other hand, we present preliminary evidence that influenza HA may be involved in eliciting anti‐GM₁ antibodies in mice, on the basis of 2 experiments. First, commercial monoclonal and polyclonal antibodies to GM₁ had low but detectable antibody activity against HA, and this was not detected with irrelevant monoclonal antibody or with mouse anti–C. jejuni polyclonal antibody. The specificity of the reaction was further underscored by the absence of HAI activity in an anti–asialo GM₁ (the related, nonsialyated form of GM₁) polyclonal antibody preparation. Serum samples from mice immunized with a C. jejuni isolate expressing GM₁ ganglioside mimicry, which contained anti‐GM₁ antibodies (figure 2), did not have HAI activity. This is likely explained by different fine specificities of the anti‐GM₁₁ response in animals immunized with ganglioside‐like structures borne on different chemical entities [13]. Second, experiments with recombinant HA of the H5 subtype also showed that immunized mice developed low but significant responses to GM ganglioside (figure 5).

Influenza viruses enter the host cell by binding to sialic acid receptors on cell surfaces; this is mediated by HA, a viral surface glycoprotein with a receptor‐binding pocket that can bind to specific sialylglycoproteins and cellular gangliosides [39–41] to facilitate host cell entry by influenza viruses. After intracellular viral replication, influenza viruses bud from the cell membrane but may become bound to the cell membrane through sialic acid receptors (e.g., a sialyated ganglioside [41]). Viral NA mediates virus release by removing sialic acid. It is unclear whether sialic acid is completely removed from the viral HA on virus release, and it is possible that sufficient sialic acid–associated HA occurs to mimic a GM₁ epitope. This is supported by our ability to detect GM₁ epitope mimicry in the egg‐grown virus preparation as well as in commercial vaccine preparations.

It had been reported elsewhere that influenza viruses and the commercial influenza vaccines derived from them contained varying amounts of viral NA and the A/NJ/1976 vaccine contained little to no detectable NA activity [37, 42], compared with other vaccine formulations. This leads us to speculate that the low levels of viral NA in the 1976 vaccine may have allowed for sufficient sialic acid to remain bound to viral HA, forming a sialic acid–HA complex that mimics GM₁ ganglioside. Higher levels of viral NA in other vaccines could be sufficient to reduce the amount of sialic acid–HA complex so that it is less immunogenic and therefore did not trigger GBS, as observed for the 1976 vaccine. Thus, given that the immunogenicity of HA differs among influenza virus strains [43], one possibility is that A/NJ/1976 HA had different immunogenic properties than other influenza vaccine HA, resulting in a more potent anti‐GM₁ (or other ganglioside) antibody response and GBS in susceptible hosts.

Several studies have examined the risk of GBS after various influenza immunization programs [1, 9, 44–47]. Compared with the risk associated with the A/NJ/1976 vaccines used in the 1976 vaccine program, the risk of GBS after immunization with other influenza vaccines, if there is one, is much smaller, perhaps contributing 1 excess GBS case per million individuals vaccinated. Thus, it has been difficult to establish a link between GBS and influenza vaccine–related GBS in recent years.

This study suggests that it may have been the ratio of HA to NA antigens present in the 1976 Swine flu vaccines that could have been responsible for provoking GBS in susceptible individuals, rather than the specific genetic sequences used in the vaccines. Since this has not been observed with subsequent influenza vaccines, the manufacturing processes that the current H1N1 vaccine producers employ are well tested, there is little reason to conjecture that the upcoming H1N1 vaccines will come with the same risk.