Influenza A H1N1 Monovalent Vaccine

Influenza A (H1N1) 2009 Monovalent Vaccine, for intramuscular injection, is a sterile, clear, colorless to slightly opalescent suspension with some sediment that resuspends upon shaking to form a homogeneous suspension. Influenza A (H1N1) 2009 Monovalent Vaccine is prepared from influenza virus propagated in the allantoic fluid of embryonated chicken eggs. Following harvest, the virus is purified in a sucrose density gradient using a continuous flow zonal centrifuge. The purified virus is inactivated with beta-propiolactone, and the virus particles are disrupted using sodium taurodeoxycholate to produce a “split virion”. The disrupted virus is further purified and suspended in a phosphate buffered isotonic solution.

Influenza A (H1N1) 2009 Monovalent Vaccine is formulated to contain 15 mcg hemagglutinin (HA) per 0.5 mL dose of influenza A/California/7/2009 (H1N1)v-like virus.

Thimerosal, a mercury derivative, is not used in the manufacturing process for the single dose presentations; therefore these products contain no preservative. The multi-dose presentation contains thimerosal, added as a preservative; each 0.5 mL dose contains 24.5 mcg of mercury.

A single 0.5 mL dose of Influenza A (H1N1) 2009 Monovalent Vaccine contains sodium chloride (4.1 mg), monobasic sodium phosphate (80 mcg), dibasic sodium phosphate (300 mcg), monobasic potassium phosphate (20 mcg), potassium chloride (20 mcg), and calcium chloride (1.5 mcg). A single 0.25 mL dose of Influenza A (H1N1) 2009 Monovalent Vaccine contains half of these quantities. From the manufacturing process, each 0.5 mL dose may also contain residual amounts of sodium taurodeoxycholate ( ≤ 10 ppm), ovalbumin ( ≤ 1 mcg), neomycin sulfate ( ≤ 0.2 picograms [pg]), polymyxin B ( ≤ 0.03 pg), and beta-propiolactone ( < 25 nanograms).

The rubber tip cap and plunger used for the preservative-free, single-dose syringes and the rubber stoppers used for the multi-dose vial contain no latex.

Influenza A (H1N1) 2009 Monovalent Vaccine is an inactivated influenza virus vaccine indicated for active immunization of persons ages 6 months and older against influenza disease caused by pandemic (H1N1) 2009 virus.

This indication is based on the immune response elicited by the seasonal trivalent Influenza Virus Vaccine manufactured by CSL (AFLURIA®). CSL's Influenza A (H1N1) 2009 Monovalent Vaccine and AFLURIA are manufactured by the same process. There have been no controlled clinical studies demonstrating a decrease in influenza disease after vaccination with AFLURIA (Clinical Studies).

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Mechanism Of Action

Influenza illness and its complications follow infection with influenza viruses. Global surveillance of influenza identifies yearly antigenic variants. For example, since 1977 antigenic variants of influenza A (H1N1 and H3N2) and influenza B viruses have been in global circulation. Specific levels of hemagglutination inhibition (HI) antibody titers post-vaccination with inactivated influenza virus vaccine have not been correlated with protection from influenza virus. In some human studies, antibody titers of 1:40 or greater have been associated with protection from influenza illness in up to 50% of subjects.3,4

Antibody against one influenza virus type or subtype confers limited or no protection against another. Furthermore, antibody to one antigenic variant of influenza virus might not protect against a new antigenic variant of the same type or subtype. Frequent development of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and the reason for the usual change to one or more new strains in each year's influenza vaccine.

Clinical Studies

CSL's Influenza A (H1N1) 2009 Monovalent Vaccine and seasonal trivalent Influenza Virus Vaccine (AFLURIA) are manufactured by the same process. Data in this section were obtained in clinical studies conducted with AFLURIA.

Immunogenicity In The Adult And Geriatric Populations

Three randomized, controlled clinical studies of AFLURIA have evaluated the immune responses by measuring HI antibody titers to each virus strain in the vaccine. In these studies, post-vaccination immunogenicity was evaluated on sera obtained 21 days after administration of AFLURIA. No controlled clinical studies demonstrating a decrease in influenza disease after vaccination with AFLURIA have been performed.

The US study (Study 1) was a randomized, double-blinded, placebo-controlled, multicenter study in healthy subjects ages 18 to less than 65 years. A total of 1,357 subjects were vaccinated (1,089 subjects with AFLURIA and 268 with a thimerosal-containing placebo). Subjects receiving AFLURIA were vaccinated using either a single-dose (preservative-free) or multi-dose (one of three lots) formulation. The evaluable efficacy population consisted of 1,341 subjects (1,077 in the AFLURIA group and 264 in the placebo group) with complete serological data who had not received any contraindicated medications before the post-vaccination immunogenicity assessment. Among the evaluable efficacy population receiving AFLURIA, 37.5% were men and 62.5% were women. The mean age of the entire evaluable population receiving AFLURIA was 38 years; 73% were ages 18 to less than 50 years and 27% were ages 50 to less than 65 years. Additionally, 81% of AFLURIA recipients were White, 12% Black, and 6% Asian.

In Study 1, the following co-primary immunogenicity endpoints were assessed: 1) the lower bounds of the 2-sided 95% confidence intervals (CI) for the proportion of subjects with HI antibody titers of 1:40 or greater after vaccination, which should exceed 70% for each vaccine antigen strain; and 2) the lower bounds of the 2-sided 95% CI for rates of seroconversion (defined as a 4-fold increase in post-vaccination HI antibody titers from pre-vaccination titers of 1:10 or greater, or an increase in titers from less than 1:10 to 1:40 or greater), which should exceed 40% for each vaccine antigen strain.

In subjects ages 18 to less than 65 years, serum HI antibody responses to AFLURIA met the pre-specified co-primary endpoint criteria for all three virus strains (Table 5). Clinical lot-to-lot consistency was demonstrated for the single-dose (preservative-free) and multi-dose formulations of AFLURIA, showing that these formulations elicited similar immune responses.

Table 5: Study 1 – Serum HI Antibody Responses in Subjects ≥ 18 to < 65 Years Receiving AFLURIA

The UK study (Study 2) was a randomized, controlled study that enrolled 275 healthy subjects ages 65 years and older. This study compared AFLURIA with a European-licensed trivalent inactivated influenza vaccine as an active control. The evaluable efficacy population consisted of 274 subjects (206 in the AFLURIA group and 68 in the control group). Among these subjects, 50% were men and 50% were women, with a mean age of 72 years (range: 65 to 93 years).

The co-primary immunogenicity endpoints for the seroconversion rate and the proportion of subjects with a minimum post-vaccination HI antibody titer of 1:40 are presented in Table 6.

Table 6: Study 2 – Serum HI Antibody Responses in Subjects ≥ 65 Years Receiving AFLURIA

A second UK study (Study 3) was a randomized, controlled study that enrolled 406 healthy subjects ages 18 years and older (stratified by age from 18 to less than 60 years and 60 years and older). This study compared AFLURIA with a European-licensed trivalent inactivated influenza vaccine as an active control. In a post-hoc analysis of different age ranges, among subjects ages 18 to less than 65 years receiving AFLURIA (146 subjects), 47% were men and 53% were women, with a mean age of 48 years for all subjects. Among subjects ages 65 years and older receiving AFLURIA (60 subjects), 53% were men and 47% were women, with a mean age of 71 years.

Analysis of serum HI antibody responses showed that the lower bound of the 95% CI for subjects with HI antibody titers of 1:40 or greater after vaccination exceeded 70% for each strain. HI antibody responses were lower in subjects, ages 65 years and older after administration of AFLURIA. Serum HI antibody responses to the active control were similar to those for AFLURIA in both age groups.

Immunogenicity In A Pediatric Population

An open-label, uncontrolled, multi-center study (Study 4) to evaluate the safety, tolerability and immunogenicity of AFLURIA in children 6 months to 9 years of age was conducted in Australia. The study subjects were subdivided into two groups dependent upon age at time of enrollment. A total of 298 subjects were enrolled, including 151 subjects, 6 months to less than 3 years (mean age 1.7 years with 51.0% females) and 147 subjects, 3 years to less than 9 years (mean age 5 years with 55.1% females).

Two doses of AFLURIA were administered to all subjects, with a 30 day interval between each dose. Children ages 6 months to less than 3 years received two 0.25 mL doses of AFLURIA. Children ages 3 years to less than 9 years were administered two 0.5 mL doses of AFLURIA. Sera for immunological assessment were taken 30 days (± 3) following each vaccination. Immunogenicity endpoints were the seroconversion rate and the proportion of subjects with a minimum post-vaccination HI antibody titer of 1:40. The results for each dose are presented in Table 7.

For both age groups, the vaccine met FDA acceptance criteria for immunogenicity developed for healthy adults for all three influenza strains following two doses. These criteria are: 1) that the lower bound of the 2-sided 95% CI for the seroconversion rate should be at least 40%; and 2) the lower bound of the 2-sided 95% CI for the proportion of subjects with a post-vaccination HI titer of ≥ 1:40 should be at least 70%.

Table 7: Study 4 – Serum HI Antibody Responses in Subjects ≥ 6 months to < 9 Years Receiving AFLURIA

REFERENCES

1. Centers for Disease Control and Prevention. Serum Cross-Reactive Antibody Response to a Novel Influenza A (H1N1) Virus After Vaccination with Seasonal Influenza Vaccine. MMWR 2009;58 (19): 521-524.

2. Centers for Disease Control and Prevention. Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2009;58 (RR-8):1-52.

3. Hannoun C, Megas F, Piercy J. Immunogenicity and Protective Efficacy of Influenza Vaccination. Virus Res 2004;103:133-138.

4. Hobson D, Curry RL, Beare AS, et al. The Role of Serum Hemagglutination-Inhibiting Antibody in Protection Against Challenge Infection with Influenza A2 and B Viruses. J Hyg Camb 1972;70:767-777.

CSL's Influenza A (H1N1) 2009 Monovalent Vaccine and seasonal trivalent Influenza Virus Vaccine (AFLURIA) are manufactured by the same process. The data in this section were obtained from clinical studies and postmarketing experience with AFLURIA.

Overall Adverse Reactions

Serious allergic reactions, including anaphylactic shock, have been observed during postmarketing surveillance in individuals receiving AFLURIA.

In adults, the most common local (injection-site) adverse reactions observed in clinical studies with AFLURIA were tenderness, pain, redness and swelling. The most common systemic adverse reactions observed were headache, malaise, and muscle aches.

In children, the most common local (injection-site) adverse reactions observed in a clinical study with AFLURIA were pain, redness and swelling. The most common systemic adverse reactions observed were irritability, rhinitis, fever, cough, loss of appetite, vomiting/diarrhea, headache, muscle aches and sore throat.

Safety Experience From Clinical Studies

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a vaccine cannot be directly compared to rates in the clinical studies of another vaccine and may not reflect the rates observed in clinical practice.

Clinical data for AFLURIA have been obtained in four clinical studies, three in adult populations and one in a pediatric population (see Clinical Studies). Safety data are provided for two of the adult studies and the pediatric study.

A US study (Study 1) included 1,357 subjects for safety analysis, ages 18 to less than 65 years, randomized to receive AFLURIA (1,089 subjects) or placebo (268 subjects) (see Clinical Studies for study demographics). There were no deaths or serious adverse events reported in this study.

A UK study (Study 2) included 275 subjects, ages 65 years and older, randomized to receive preservative-free AFLURIA (206 subjects) or a European-licensed trivalent inactivated influenza vaccine as an active control (69 subjects) (see Clinical Studies). There were no deaths or serious adverse events reported in this study.

An open-label, uncontrolled study in children, conducted in Australia (Study 4), included 298 subjects, ages 6 months to less than 9 years. All subjects received preservative-free AFLURIA administered as two doses, one month apart (see Clinical Studies). Subjects were subdivided into two age groups: children ages 6 months to less than 3 years (151 subjects) received two 0.25 mL doses of AFLURIA and children ages 3 years to less than 9 years (147 subjects) received two 0.5 mL doses of AFLURIA. There were no deaths or vaccine-related serious adverse events reported in this study.

The safety assessment was identical for the two adult studies. Local (injection-site) and systemic adverse events were solicited by completion of a symptom diary card for 5 days post-vaccination (Table 1). Unsolicited adverse events were collected for 21 days post-vaccination (Table 2). These unsolicited adverse events were reported either spontaneously or when subjects were questioned about any changes in their health post-vaccination. All adverse events are presented regardless of any treatment causality assigned by study investigators.

In the pediatric study, solicited adverse events were recorded for up to 7 days (Table 3) and unsolicited adverse events were recorded for 30 days post-vaccination (Table 4). Data are presented following each dose for each age group. All adverse events are presented regardless of any treatment causality assigned by study investigators.

Table 1: Proportion of Subjects With Solicited Local or Systemic Adverse Events* Within 5 Days After Administration of AFLURIA or Placebo, Irrespective of Causality† (Studies 1 and 2, Adult Populations)

Table 2: Adverse Events* Reported Spontaneously by ≥ 1% of Subjects Within 21 Days After Administration of AFLURIA or Placebo, Irrespective of Causality† (Studies 1 and 2, Adult Populations)

Table 3: Proportion of Subjects With Solicited Local or Systemic Adverse Events* Within 7 Days After Administration of AFLURIA, Irrespective of Causality† (Study 4, Pediatric Population)

Table 4: Adverse Events* Reported Spontaneously by ≥ 5% of Subjects Within 30 Days After Administration of AFLURIA, Irrespective of Causality (Study 4, Pediatric Population)

Postmarketing Experience

Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure. The adverse reactions described have been included in this section because they: 1) represent reactions that are known to occur following immunizations generally or influenza immunizations specifically; 2) are potentially serious; or 3) have been reported frequently. These adverse reactions reflect experience in both children and adults and include those identified during post-approval use of AFLURIA outside the US since 1985.

Transient thrombocytopenia

Allergic reactions including anaphylactic shock and serum sickness

Neuralgia, paresthesia, and convulsions; encephalopathy, neuritis or neuropathy, transverse myelitis, and GBS

Vasculitis with transient renal involvement

Pruritus, urticaria, and rash

Anaphylaxis has been reported after administration of AFLURIA. Although AFLURIA and Influenza A (H1N1) 2009 Monovalent Vaccine contain only a limited quantity of egg proteins, these proteins can induce immediate hypersensitivity reactions among persons who have severe egg allergy. Allergic reactions include hives, angioedema, asthma, and systemic anaphylaxis (see CONTRAINDICATIONS).

The 1976 swine influenza vaccine was associated with an increased frequency of GBS. Evidence for a causal relation of GBS with subsequent vaccines prepared from other influenza viruses is unclear. If influenza vaccine does pose a risk, it is probably slightly more than one additional case per 1 million persons vaccinated.

Neurological disorders temporally associated with influenza vaccination, such as encephalopathy, optic neuritis/neuropathy, partial facial paralysis, and brachial plexus neuropathy, have been reported.

Microscopic polyangiitis (vasculitis) has been reported temporally associated with influenza vaccination.