Summary of medicine characteristics - Aflunov
1. NAME OF THE MEDICINAL PRODUCT
AFLUNOV suspension for injection in pre-filled syringe.
Zoonotic influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted).
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Influenza virus surface antigens (haemagglutinin and neuraminidase)* of strain:
A/turkey/Turkey/1/2005 (H5N1)-like strain (NIBRG-23) (clade 2.2.1) 7.5 micrograms** per 0.5 ml dose
*
**
propagated in fertilised hens’ eggs from healthy chicken flocks expressed in microgram haemagglutinin.
Adjuvant MF59C.1 containing: squalene
polysorbate 80 sorbitan trioleate
9.75 milligrams per 0.5 ml
1.175 milligrams per 0.5 ml
1.175 milligrams per 0.5 ml
Excipient with known effect :
The vaccine contains 1.899 milligrams of sodium and 0.081 milligrams of potassium per 0.5 ml dose.
AFLUNOV may contain trace residues of egg and chicken proteins, ovalbumin, kanamycin, neomycin sulphate, formaldehyde and cetyltrimethylammonium bromide which are used during the manufacturing process (see section 4.3).
For the full list of excipients see section 6.1.
3. PHARMACEUTICAL FORM
Suspension for injection in pre-filled syringe.
Milky-white liquid.
4. CLINICAL PARTICULARS4.1 Therapeutic indications
Active immunisation against H5N1 subtype of Influenza A virus.
This indication is based on immunogenicity data from healthy subjects from the age of 18 years onwards following administration of two doses of the vaccine containing
A/turkey/Turkey/1/2005 (H5N1)-like strain (see sections 4.4 and 5.1).
AFLUNOV should be used in accordance with official recommendations.
4.2 Posology and method of administration
Posology
Adults and elderly (18 years of age and above):
One dose of 0.5 ml at an elected date.
A second dose of 0.5 ml should be given after an interval of at least 3 weeks.
AFLUNOV has been evaluated in healthy adults (18–60 years of age) and healthy elderly (over 60 years of age) following a 1, 22 day primary vaccination schedule, and booster vaccination (see sections 4.8 and 5.1).
There is limited experience in elderly over 70 years of age (see section 5.1).
In the event of an officially declared influenza pandemic due to A/H5N1 virus, persons previously vaccinated with one or two doses of AFLUNOV that contained haemagglutinin (HA) antigen derived from a different clade of the same influenza subtype as the influenza pandemic strain may receive a single dose of AFLUNOV instead of two doses that are required in previously unvaccinated individuals (see section 5.1).
Paediatric population
The safety and efficacy of AFLUNOV in subjects under 18 years of age have not yet been established.
Currently available data in subjects aged 6 months to 18 years of age are described in section 5.1 but no recommendation on a posology can be made.
No data are available in children aged less than 6 months.
Method of administration
Immunisation should be carried out by intramuscular injection into the deltoid muscle.
4.3 Contraindications
History of an anaphylactic (i.e. life-threatening) reaction to any of the constituents or trace residues (egg and chicken proteins, ovalbumin, kanamycin and neomycin sulphate, formaldehyde and cetyltrimethylammonium bromide) of this vaccine.
However, in a pandemic situation caused by the strain included in this vaccine, it may be appropriate to give this vaccine to individuals with a history of anaphylaxis as defined above, provided that facilities for resuscitation are immediately available in case of need.
4.4 Special warnings and precautions for use
Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Caution is needed when administrating this vaccine to persons with a known hypersensitivity (other than anaphylactic reaction) to the active substance, to any of the excipients listed in section 6.1 and to residues (eggs and chicken proteins, ovalbumin, kanamycin and neomycin sulphate, formaldehyde and cetyltrimethylammonium bromide).
As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of a rare anaphylactic event following the administration of the vaccine.
Immunization shall be postponed in patients with febrile illness or acute infection.
The vaccine should under no circumstances be administered intravascularly or intradermally.
There are no data with AFLUNOV using the subcutaneous route of administration. Therefore, healthcare providers need to assess the benefits and potential risks of administering the vaccine in individuals with thrombocytopenia or any bleeding disorder that would contraindicate intramuscular injection unless the potential benefit outweighs the risk of bleedings.
Protection against influenza
There is no immune correlate of protection established for influenza A (H5N1).
Based on humoral immune responses to the vaccine strain A/turkey/Turkey/1/2005 after two doses of AFLUNOV, a protective immune response may not be elicited in all vaccinees. In addition, antibody responses in patients with endogenous or iatrogenic immunosuppression may be insufficient to provide protection.
Some degree of cross-reactive immunity has been observed against H5N1 viruses of clades different to that of the vaccine strain. However, the degree of protection that may be elicited to H5N1 strains of other clades is unknown (see section 5.1).
Since a second dose is recommended, it should be noted that there are no safety, immunogenicity or efficacy data to support interchangeability of AFLUNOV with other H5N1 monovalent vaccines.
Syncope (fainting) can occur following, or even before, any vaccination as a psychogenic response to the needle injection. This can be accompanied by several neurological signs such as transient visual disturbance, paraesthesia and tonic-clonic limb movements during recovery. It is important that procedures are in place to avoid injury from faints
4.5 Interaction with other medicinal products and other forms of interaction
AFLUNOV may be co-administered with non-adjuvanted seasonal influenza vaccines, and immunisation should be carried out on separate limbs.
There are no data on co-administration of AFLUNOV with vaccines other than non-adjuvanted seasonal influenza vaccines. If co-administration with another vaccine is considered, immunisation should be carried out on separate limbs. It should be noted that the adverse reactions may be intensified.
The immunological response may be diminished if the patient is undergoing immunosuppressant treatment.
Following influenza vaccination, false positive serology test results may be obtained by the ELISA method for antibody to human immunodeficiency virus-1 (HIV-1), hepatitis C virus and, especially, human T-lymphotropic virus type 1 (HTLV-1). In such cases, the Western Blot method is negative. These transitory false positive results may be due to IgM production in response to the vaccine.
4.6 Fertility, pregnancy and lactation
Pregnancy
Limited data were obtained from women who became pregnant during the course of clinical trials with AFLUNOV or similar pandemic H1N1v vaccines adjuvanted with MF59C.1.
However, it is estimated that during the 2009 H1N1 pandemic more than 90,000 women were vaccinated during pregnancy with Focetria (an H1N1 pandemic vaccine similar to AFLUNOV) which contains the same amount of adjuvant MF59C.1 as AFLUNOV.
Post-marketing spontaneously reported adverse events and an interventional study do not suggest direct or indirect harmful effects of Focetria exposure on pregnancy.
In addition, two large observational studies designed to assess the safety of Focetria exposure in pregnancy showed no increase in the rates of gestational diabetes, preeclampsia, abortions, stillbirth, low birth weight, prematurity, neonatal deaths, and congenital malformations among almost 10,000 vaccinated pregnant women and their offspring compared with unvaccinated controls.
Since AFLUNOV is expected not to be used in an emergency situation, its administration during pregnancy might be deferred as a precautionary approach.
Healthcare providers need to assess the benefit and potential risks of administering the vaccine to pregnant women taking into consideration official recommendations.
Breast-feeding
There are no data regarding the use of AFLUNOV during breast-feeding. The potential benefits to the mother and risks to the infant should be considered before administering AFLUNOV during breast-feeding.
Fertility
There are no data concerning human fertility. A study in rabbits did not indicate reproductive or developmental toxicity of AFLUNOV (see section 5.3).
4.7 Effects on ability to drive and use machines
Some of the undesirable effects mentioned under section 4.8 may affect the ability to drive or operate machinery.
4.8 Undesirable effects
Summary of the safety profile
The incidence of adverse reactions has been evaluated in seven clinical trials in healthy subjects involving over 4300 adults and elderly receiving AFLUNOV (at least 7.5 ^g HA, adjuvanted). There were 3872 subjects 18–60 years of age, 365 subjects 61–70 years of age, and 89 subjects greater than 70 years of age. The safety profile across clinical studies using AFLUNOV containing either the A/turkey/Turkey/1/2005 or the A/Vietnam/1194/2004 strain is comparable.
Consistent with the data observed by trial for solicited reactions, there was a general trend towards decreased reports of local reactions after the second vaccination compared with the first injection. Irrespective of antigen dose, almost all systemic reactions were reported on the day of vaccination (day 1) or during the 3 days immediately following.
Data on safety of a booster dose of AFLUNOV are limited to three trials (V87P1, V87P2 and V87P1E1) that included 116 adults (18–60 years) and 56 elderly subjects (>61 years). No increase in reactions was reported when a booster dose was administered 6 months-18 months later, after the initial dosing series. A slight increase in reactions in adults was reported when a booster dose was administered 18 months after the initial dosing series. In the elderly, the reported reactions increased with the third booster dose only when compared with the second dose.
Tabulated list of adverse reactions
The adverse reaction rates reported after any vaccination doses (i.e. 1st, 2nd or booster) were similar and are listed according to the following MedDRA frequency convention and system organ class:
Very common (>1/10); Common (>1/100 to <1/10); Uncommon (>1/1,000 to <1/100); Rare (>1/10,000 to <1/1,000); Very rare (<1/10,000).
| MedDRA System Organ class | Very common (>1/10) | Common (>1/100 to <1/10) | Uncommon (>1/1,000 to <1/100) | Rare (>1/10,000 to <1/1,000) |
| Nervous system disorders | Headache | Convulsions | ||
| Gastrointestinal disorders | Nausea | |||
| Skin and subcutaneous tissue disorders | Sweating | Urticaria | Eye swelling | |
| Musculoskeletal and connective tissue disorders | Myalgia | Arthralgia | ||
| General disorders and administration site conditions | Injection site swelling, Injection site pain, Injection site induration, Injection site redness, Fatigue | Injection site ecchymosis, Fever, Malaise, Shivering | Influenza like illness | Anaphylaxis |
The majority of these side effects usually disappear within 1–2 days without treatment.
Clinical trials in special populations
Adverse reactions in special populations have been evaluated in two clinical trials, V87_25 and V87_26, involving adult (18–60 years) and elderly (> 61 years) subjects who were either healthy or with underlying medical conditions or immunosuppressive conditions.
| Study V87 25 | Study V87 26 | |||||||
| Medical conditions | Healthy | Immunocompromised | Healthy | |||||
| Adults (20–60 years) | Elderly (61–84 years) | Adults (19–60 years) | Elderly (61–79 years) | Adults (20–60 years) | Elderly (61–84 years) | Adults (18–59 years) | Elderly (61–91 years) | |
| No. of subjects | N=145 | N=149 | N=59 | N=58 | N=147 | N=148 | N=58 | N=62 |
*actual age range of population enrolled
Across studies V87_25 and V87_26, the safety of AFLUNOV in healthy adult and elderly subjects was consistent with existing safety data from previous clinical trials. However, in immunocompromised subjects 18 through 60 years of age, slightly higher rates of nausea (13.0%) were reported. In addition, higher rates of arthralgia (up to 23.3%) were reported in both adult and elderly subjects, who were immunocompromised or with underlying medical conditions.
The following solicited adverse reactions were additionally collected in these two studies and reported with the following frequencies across subjects who received AFLUNOV irrespective of age or health status: diarrhoea (up to 11.9%), loss of appetite (up to 10.9%) and vomiting (up to 1.7%). In both studies, subjects with underlying medical and immunosuppressive conditions reported higher frequencies of diarrhoea, loss of appetite and vomiting compared to healthy subjects (irrespective of age).
Post-marketing surveillance
No post-marketing surveillance data are available following AFLUNOV administration.
Description of selected adverse reactions
The following adverse events were reported from post-marketing surveillance with Focetria (an H1N1 pandemic vaccine similar to AFLUNOV) which contains the same amount of adjuvant MF59C.1 as AFLUNOV, approved for use in children 6 months of age and above, adults and the elderly:
Blood and lymphatic system disorders
Lymphadenopathy.
Immune system disorders
Allergic reactions, anaphylaxis including dyspnoea, bronchospasm, laryngeal oedema, in rare cases leading to shock.
Nervous system disorders
Headache, dizziness, somnolence, syncope. Neurological disorders, such as neuralgia, paraesthesia, convulsions and neuritis.
Cardiac disorders
Palpitation, tachycardia.
Respiratory disorders
Cough.
Gastrointestinal disorders
Gastrointestinal disorders such as nausea, vomiting, abdominal pain and diarrhoea.
Skin and subcutaneous tissue disorders
Generalised skin reactions including pruritus, urticaria or non-specific rash; angioedema.
Muscoskeletal, connective tissue and bone disorders
Muscular weakness, pain in extremities.
General disorders and administration site conditions
Asthenia.
The following additional adverse events were reported from post-marketing surveillance with seasonal non-adjuvanted trivalent vaccines in all age groups and a seasonal trivalent MF59-adjuvanted subunit influenza vaccine approved for use in elderly subjects 65 years of age and older:
Blood and lymphatic system disorders
Thrombocytopenia (in some cases reversible platelet counts less than 5000 mm3).
Nervous system disorders
Neurological disorders, such as encephalomyelitis, and Guillain Barré syndrome.
Vascular disorders
Vasculitis with transient renal involvement.
Skin and subcutaneous tissue disorders
Erythema multiforme.
General disorders and administration site conditions
Extensive swelling of injected limb lasting more than one week, injection-site cellulitis-like reaction (some cases of swelling, pain, and redness extending more than 10 cm and lasting more than 1 week).
Paediatric population
The incidence of AFLUNOV (A/Vietnam/1194/2004) adverse reactions has been evaluated in one clinical trial (V87P6) in children (6 months to 17 years old). Regardless of age, reactogencity was higher after the first dose than after the second vaccination. Reactogenicity after the third dose, administered 12 months following the first dose, was higher than after both first and second doses. The percentages of subjects reporting local reactions were higher in the older age groups, mainly due to the higher reports for pain. In toddlers, erythema and tenderness were the most commonly reported solicited local reactions; irritability and unusual crying were the most commonly reported solicited systemic reactions. In children and adolescents, pain was the most frequently reported solicited local reaction, and fatigue and headache were the most commonly reported solicited systemic reactions. Across all ages, low percentages of subjects reported fever.
| Injection 1 | Injection 2 | Injection 3 | |
| AFLUNOV | AFLUNOV | AFLUNOV | |
| Toddlers (6-<36 months) | N=145 | N=138 | N=124 |
| Any | 76% | 68% | 80% |
| Local | 47% | 46% | 60% |
| Systemic | 59% | 51% | 54% |
| Fever > 38°C (> 40°C) | 0% | 0% | 0% |
| Any Other Adverse Event | 54% | 49% | 35% |
| Children (3-<9 years) | N=96 | N=93 | N=85 |
| Any | 72% | 68% | 79% |
| Local | 66% | 58% | 74% |
| Systemic | 32% | 33% | 45% |
| Fever > 38°C (> 40°C) | 4% | 2% | 6% |
| Any Other Adverse Event | 36% | 31% | 19% |
| Adolescents(9-<18 years) | N=93 | N=91 | N=83 |
| Any | 91% | 82% | 89% |
| Local | 81% | 70% | 81% |
| Systemic | 69% | 52% | 69% |
| Fever > 38°C (> 40°C) | 0% | 1% | 2% |
| Any Other Adverse Event | 30% | 27% | 22% |
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important.
It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
4.9 Overdose
No case of overdose has been reported.
5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Influenza vaccine ATC Code J07BB02.
Clinical efficacy and safety
Clinical trials with AFLUNOV have been conducted with either the former
A/Vietnam/1194/2004 (H5N1) (clade 1) or the current A/turkey/Turkey/1/2005 (H5NI) vaccine strain (clade 2.2.1).
Immune response to AFLUNOV A/Vietnam/1194/2004 (H5N1) and A/turkey/Turkey/1/2005 (H5NI)
Adults (18–60 years)
A phase II clinical trial (V87P1) was conducted with AFLUNOV (A/Vietnam/1194/2004) in 312 healthy adults. Two doses of AFLUNOV were administered three weeks apart to 156 healthy adultsImmunogenicity was assessed in 149 subjects. In phase III clinical trial (V87P13) 2693 adult subjects were enrolled and 2566 received two doses of AFLUNOV (A/Vietnam/1194/2004) administered three weeks apart. Immunogenicity was assessed in a subset (n=197) of subjects. In a third clinical trial (V87P11) 194 adult subjects were enrolled and received two doses of AFLUNOV (A/turkey/Turkey/1/2005) administered three weeks apart. Immunogenicity was assessed in 182 subjects.
The seroprotection rate*, seroconversion rate** and the seroconversion factor*** for anti-HA antibody to H5N1 A/Vietnam/1194/2004 and to H5N1 A/turkey/Turkey/1/2005 in the adults measured by SRH assay was as follows:
| Anti-HA antibody (SRH) | Study V87P1 A/Vietnam/1194/2004 21 days after 2nd dose N=149 | Study V87P13 A/Vietnam/1194/2004 21 days after 2nd dose N=197 | Study V87P11 A/turkey/Turkey/1/2005 21 days after 2nd dose N=182 |
| Seroprotection rate (95%CI) | 85% (79–91) | 91% (87–95) | 91% (85–94) |
| Seroconversion rate (95%CI) | 85% (78–90) | 78% (72–84) | 85% (79–90) |
| Seroconversion factor (95%CI) | 7.74 (6.6–9.07) | 4.03 (3.54–4.59) | 6 (5.2–6.93) |
| Anti-HA antibody (SRH) | Study V87P13 A/Vietnam/1194/2004 21 days after 2nd dose N=69 | Study V87P13 A/Vietnam/1194/2004 21 days after 2nd dose N=128 | – |
| Baseline Serostatus | < 4 mm2 | > 4 mm2 | – |
| Seroprotection rate (95%CI) | 87% (77–94) | 94% (88–97) | – |
| Seroconversion rate (95%CI) | 87% (77–94) | 73% (65–81) | – |
| Seroconversion factor (95%CI) | 8.87 (7.09–11) | 2.71 (2.38–3.08) | – |
Seroprotection: SRH area > 25 mm2
Seroconversion was defined as an SRH area >25 mm2 for subjects who were seronegative at baseline (Day 1 SRH area <4 mm2) or a significant (at least 50%) increase in SRH area for subjects who were seropositive at baseline (Day 1 SRH area >4 mm2)
*** geometric mean ratios (GMRs) of SRH
MicroNeutralisation (MN) results against homologous A/Vietnam/1194/2004) indicate a seroprotection and seroconversion rate ranging from 67% (60–74) to 85% (78–90) and 65% (58–72) to 83% (77–89), respectively. Immune response to vaccination assessed by MN assay is in line with results obtained with SRH.
In Study V87P11 MN results against homologous A/turkey/Turkey/1/2005) indicate a seroprotection and seroconversion rate of 85% (79–90) and 93% (89–96), respectively. Immune response to vaccination assessed by MN assay is in line with results obtained with SRH.
Persistence of antibodies after primary vaccination in this population was assessed by hemagglutination inhibition (HI), SRH, and MN assays. Compared to the antibody levels obtained at day 43 after completion of primary vaccination schedules, antibody levels at day 202 were reduced by 1/5 to 1/2 from their prior levels.
Elderly (>61 years)
The seroprotection rate, seroconversion rate and the seroconversion factor*** for anti-HA antibody to H5N1 (A/Vietnam/1194/2004 and to A/ turkey/Turkey/1/2005) in subjects aged 61 years and older (limited number of subjects were above 70 years of age; n=123) measured by SRH assay assessed in three clinical studies were as follows:
| Anti-HA antibody (SRH) | Study V87P1 A/Vietnam/1194/2004 21 days after 2nd dose N=84a | Study V87P13 A/Vietnam/1194/2004 21 days after 2nd dose N=210b | Study V87P11 A/turkey/Turkey/1/2005 21 days after 2nd dose N=132c |
| Seroprotection rate (95%CI) | 80% (70–88) | 82% (76–87) | 82% (74–88) |
| Seroconversion rate (95%CI) | 70% (59–80) | 63% (56–69) | 70% (61–77) |
| Seroconversion factor (95%CI) | 4.96 (3.87–6.37) | 2.9 (2.53–3.31) | 3.97 (3.36–4.69) |
| Anti-HA antibody (SRH) | Study V87P13 A/Vietnam/1194/2004 21 days after 2nd dose N=66 | Study V87P13 A/Vietnam/1194/2004 21 days after 2nd dose N=143 |
| Baseline Serostatus | < 4 mm2 | > 4 mm2 |
| Seroprotection rate (95%CI) | 82% (70–90) | 82% (75–88) |
| Seroconversion rate (95%CI) | 82% (70–90) | 54% (45–62) |
| Seroconversion factor (95%CI) | 8.58 (6.57–11) | 1.91 (1.72–2.12) |
a Ages 62–88 years; b Ages 61–68 years; c Ages 61–89 years
Seroprotection: SRH area > 25 mm2
Seroconversion was defined as an SRH area >25 mm2 for subjects who were seronegative at baseline (Day 1 SRH area <4 mm2) or a significant (at least 50%) increase in SRH area for subjects who were seropositive at baseline (Day 1 SRH area >4 mm2)
GMRs of SRH
MN results against homologous A/Vietnam/1194/2004 indicate a seroprotection and seroconversion rate ranging from 57% (50–64) to 79% (68–87) and 55% (48–62) to 58% (47–69), respectively. MN results, similar to SRH results, demonstrated strong immune response after completion of priming vaccination series in a population of elderly subjects.
In Study V87P11, MN results against homologous A/turkey/Turkey/1/2005 indicate a seroprotection and seroconversion rate of 68% (59–75) and 81% (74–87), respectively. Immune response to vaccination assessed by MN assay is similar to SRH results.
Based on data obtained from trials V87P1, V87P11 and V87_13, persistence of antibodies after primary vaccination in elderly subjects as assessed by HI, SRH, and MN tests reduced
from 1/2 to 1/5th of their post-vaccination level at day 202 as compared to day 43 after completion of primary schedules. Up to 50% (n=33) of the elderly subjects aged 62 to 88 years immunised with AFLUNOV in trial V87P1 were seroprotected at six months.
A third (booster) dose of AFLUNOV was administered 6 months onwards after the primary vaccination. Results are shown by SRH.
The seroprotection rate, seroconversion rate and the seroconversion factor for anti-HA antibody to H5N1 A/Vietnam/1194/2004 measured by SRH assays were as follows:
| Study V87P1 Adults booster after 2nd dose | Study V87P2 Adults booster after 2nd dose | Study V87P1 Elderly booster after 2nd dose | |
| SRH | N=71 | N=13 | N=38 |
| Seroprotection rate (95%CI) | 89% (79–95) | 85% (55–98) | 84% (69–94) |
| Seroconversion rate (95%CI) | 83% (72–91) | 69% (39–91) | 63% (46–78) |
| Seroconversion factor (95%CI) | 5.96 (4.72–7.53) | 2.49 (1.56–3.98) | 5.15 (3.46–7.66) |
Seroprotection: SRH area > 25 mm2
Seroconversion was defined as an SRH area >25 mm2 for subjects who were seronegative at baseline (Day 1 SRH area <4 mm2) or a significant (at least 50%) increase in SRH area for subjects who were seropositive at baseline (Day 1 SRH area >4 mm2)
GMRs of SRH
Cross reactivity data in adults
Cross-reactive immune response elicited by A/Vietnam/1194/2004 against
A/turkey/Turkey/1/2005 and A/Indonesia/5/2005
Some heterologous immune response against A/turkey/Turkey/1/2005 (NIBRG23; clade 2.2.1) and A/ Indonesia/5/2005 (clade 2.1) was detectable both after the second and third vaccinations, indicating cross-reactivity of the clade 1 vaccine against clade 2 strains.
Seroprotection rate*, seroconversion rate** and the seroconversion factor*** for anti-HA antibodies to H5N1 A/turkey/Turkey/1/2005 after the 2nd dose in adults 18–60 years of age, measured by SRH and HI assays were as follows:
| Anti-HA antibody | Study V87P12 21 days after 2nd dose N=60 | Study V87P3 21 days after 2nd dose N=30 | Study V87P13 21 days after 2nd dose N=197 | |
| SRH | Seroprotection rate (95%CI) | 65% (52–77) | 90% (73–98) | 59% (52–66) |
| Seroconversion rate (95%CI) | 65% (52–77) | 86% (68–96) | 49% (42–56) | |
| Seroconversion factor(95%CI) * | 4.51 (3.63–5.61) | 7.67 (6.09–9.67) | 2.37 (2.1–2.67) | |
| N=60 | N=30 | N=197 | ||
| HI | Seroprotection rate (95%CI)° | 28% (17–41) | 24% (10–44) | 23% (18–30) |
| Seroconversion rate (95%CI)° | 28% (17–41) | 21% (8–40) | 19% (14–25) | |
| Seroconversion factor (95%CI)°° | 2.3 (1.67–3.16) | 1.98 (1.22–3.21) | 1.92 (1.64–2.25) |
Seroprotection: SRH area > 25 mm2
Seroconversion was defined as an SRH area >25 mm2 for subjects who were seronegative at baseline (Day 1 SRH area <4 mm2) or a significant (at least 50%) increase in SRH area for subjects who were seropositive at baseline (Day 1 SRH area >4 mm2)
*** GMRs of SRH
°
oo
measured by HI assay > 40
GMRs of HI
MN results for the three clinical studies in the Table above revealed a seroprotection rate and seroconversion rate against A/turkey/Turkey/2005 ranging from 10% (2–27) to 39% (32–46) and 10% (2–27) to 36% (29–43) respectively. MN results yielded a GMR against A/turkey/Turkey/2005 ranging from 1.59 to 2.95.
Cross-reactive immune response elicited by A/turkey/Turkey/1/2005 against A/Indonesia/5/2005 and A/Vietnam/1194/2004
Heterologous immune response against A/Indonesia/5/2005 (clade 2.1) was detectable in study V87P11 after the second vaccination, indicating cross-reactivity of the clade 2.2.1 vaccine against clade 2.1 strains.
Seroprotection rate*, seroconversion rate** and the seroconversion factor*** for anti-HA antibodies to H5N1 A/ Indonesia/5/2005 and A/Vietnam/1194/2004 after the 2nd dose in adults (18–60 years) and elderly (>61years), measured by SRH and HI assays were as follows:
| Anti-HA antibody | V87P11 Adults (18–60 years) N=186 | V87P11 Elderly (>61–89 years)a N=142 | |||
| A/Indonesia/ 5/2005 | A/Vietnam/ 1194/2004 | A/Indonesia/ 5/2005 | A/Vietnam/ 1194/2004 | ||
| SRH | Seroprotection rate (95%CI) | 83 (77–88) | 62 (54–69) | 61 52–69 | 45 (37–54) |
| Seroconversion rate (95%CI) | 79 (72–85) | 60 (53–68) | 64 (56–73) | 44 (35–53) | |
| Seroconversion factor (95%CI) | 6.24 (5.44–7.16) | 4.45 (3.85–5.14) | 3.87 (3.31–4.53) | 3.03 (2.56–3.58) | |
| N=194 | N=148 | ||||
| HI | Seroprotection rate (95%CI) ° | 50 (43–57) | 47 (40–55) | 34 (26–42) | 39 (31–48) |
| Seroconversion rate (95%CI) ° | 49 (42–56) | 44 (37–51) | 32 (25–41) | 34 (26–42) | |
| Seroconversion factor (95%CI) °° | 4.71 (3.74–5.93) | 4.25 (3.36–5.37) | 2.69 (2.18–3.32) | 2.8 (2.2–3.55) | |
a
***
°
oo
actual age range of population enrolled
Seroprotection: SRH area>25 mm2
Seroconversion was defined as an SRH area >25 mm2 for subjects who were seronegative at baseline (Day 1 SRH area <4 mm2) or a significant (at least 50%) increase in SRH area for subjects who were seropositive at baseline (Day 1 SRH area >4 mm2)
GMRs of SRH measured by HI assay > 40
GMRs of HI
MN results for A/Indonesia/5/2005 revealed a seroprotection rate of 38% (31–45) in adults (18–60 years) and 14% (8–20) in elderly (>61 years); a seroconversion rate of 58% (50–65) in adults and 30% (23–38) in elderly and finally a GMR of 4.67 (3.95–5.56) in adults and 2.19 (1.86–2.58) in elderly.
MN results for A/Vietnam/1194/2004 revealed a seroprotection rate of 10% (6–16) in adults (18–60 years) and 6% (3–11) in elderly (>61 years); a seroconversion rate of 19% (13–25) in adults and 7% (4–13) in elderly and finally a GMR of 1.86 (1.63–2.12) in adults and 1.33 (1.17–1.51) in elderly.
Long term booster immune memory:
A single vaccination with AFLUNOV (A/Vietnam/1194/2004) induced high and rapid serological response in subjects primed 6–8 years previously with two doses of a different surrogate H5N vaccine, having same formulation as AFLUNOV but using the strain H5N3.
In a phase I clinical trial (V87P3) adult subjects aged 18–65 years primed 6–8 years previously with 2 doses of MF59-adjuvanted H5N3 vaccine/A/Duck/Singapore/97, were administered 2 booster doses of AFLUNOV (A/Vietnam/1194/2004). SRH results after the first dose, that mimic prepandemic priming plus single heterologous booster dose, revealed seroprotection and seroconversion rates of 100% (74100) and an 18-fold increase in SRH area (GMR).
Alternative vaccination schedules :
In a clinical trial evaluating 4 different vaccination schedules in 240 subjects 18 to 60 years of age, where the second dose occurred either 1, 2, 3 or 6 weeks after the first AFLUNOV
(A/Vietnam/1194/2004) dose, all vaccine schedule groups after 3 weeks from the 2nd vaccination achieved high levels of antibodies as evaluated with SRH. SRH seroprotection rates ranged from 86% to 98%, seroconversion rated from 64% to 90%, and GMR ranged from 2.92 to 4.57. The magnitude of immune response was lower in the group who received the 2nd dose 1 week later and higher in the groups with longer interval schedules.
Subjects with underlying medical or immunosuppressive conditions:
Immunogenicity of AFLUNOV (A/turkey/Turkey/1/2005) in adults (18 to 60 years) and elderly (>61 years) subjects with underlying medical conditions (Study V87_25) or immunosuppressive conditions (mainly HIV-infected subjects) (Study V87_26) in comparison to healthy adults (18–60 years) and elderly (>61 years), was evaluated in two randomised, phase III controlled clinical trials (with a seasonal trivalent inactivated MF59-adjuvanted subunit influenza vaccine approved for use in elderly subjects 65 years of age and older as a comparator). In trial V87_25 and V87_26, 96 and 67 subjects, respectively, were over the age of 70 years. In both trials, immunogenicity of AFLUNOV was shown by HI, SRH and MN assays following both the first and second dose.
Geometric mean area, seroprotection rate*, seroconversion rate* and the seroconversion factor** for anti-HA antibody to H5N1 A/turkey/Turkey/1/2005 measured by SRH assays 21 days after the 2nd dose were as follows:
| Study V87 25 | ||||
| Adults (20– 60 years)a | Adults (19– 60 years)a | Elderly (61–84 years)a | Elderly (61–79 years)a | |
| Anti-HA antibody (SRH) | Medical Conditions N=140 | Healthy N=57 | Medical Conditions N=143 | Healthy N=57 |
| Geometrie Mean Area (95%CI) | 31.07 (27.43–35.19) | 58.02 (48.74–69.06) | 29.34 (26.07–33.01) | 27.78 (22.57–34.18) |
| Seroprotection rate (95%CI) | 65.00 (56.5–72.9) | 89.47 (78.5–96) | 58.74 (50.2–66.9) | 57.89 (44.1–70.9) |
| Seroconversion rate (95%CI) | 72.86 (64.7–80) | 98.25 (90.6–99.96) | 64.34 (55.9–72.2) | 66.67 (52.9–78.6) |
| Seroconversion factor (95%CI) | 3.33 (2.94–3.77) | 6.58 (5.53–7.83) | 2.37 (2.10–2.66) | 2.96 (2.41–3.64) |
| Study V87 26 | ||||
| Adults (20– 60 years)a | Adults (18–59 years)a | Elderly (61–84 years)a | Elderly (61–91 years)a | |
| Anti-HA antibody (SRH) | Immunocompromised N=143 | Healthy N=57 | Immunocompromised N=139 | Healthy N=62 |
| Geometric Mean Area (95%CI) | 26.50 (22.49–31.22) | 48.58 (40.01–58.99) | 26.85 (23.01–31.33) | 23.91 (18.89–30.26) |
| Seroprotection rate (95%CI) | 60.84 (52.3–68.9) | 87.72 (76.3–94.9) | 58.99 (50.3–67.3) | 53.23 (40.1–66) |
| Seroconversion rate (95%CI) | 61.54 (53–69.5) | 89.47 (78.5–96) | 64.75 (56.2–72.7) | 56.45 (43.3–69 |
| Seroconversion factor (95%CI) | 3.16 (2.69–3.73) | 7.10 (5.85–8.62) | 3.15 (2.70–3.68) | 2.83 (2.24–3.58) |
aactual age range of population enrolled
* measured by SRH assay seroprotection: SRH area >25 mm2, seroconversion: SRH area >25 mm2 for subjects with a baseline SRH area <4 mm2 or a minimum 50% increase in SRH area for subjects with >4 mm2.
** geometric mean ratios of SRH
HI results for the two clinical studies revealed lower values than those reported in previous studies. Seroconversion rates against homologous A/turkey/Turkey/1/2005 ranged from 37.50% to 43.10% in healthy adults, and from 19.18% to 26.47% in adults with immunosuppressive or underlying medical conditions, respectively; seroconversion rates ranged from 21.43% to 30.65% in healthy elderly subjects, and from 24.49% to 27.86% in elderly subjects with immunosuppressive or underlying medical conditions. Similar trends were observed for seroprotection rates in both studies.
MN results against homologous A/turkey/Turkey/1/2005 indicate a seroconversion rate of 66.67% in healthy adults, and ranging from 33.57% to 54.14% in adults with immunosuppressive or underlying medical conditions, respectively; seroconversion rates ranged from 24.39% to 29.03% in healthy elderly subjects, and from 31.65% to 39.42% in elderly subjects with immunosuppressive or underlying medical conditions. Similar trends were observed for seroprotection rates in both studies.
In both studies V87_25 and V87_26, the lower levels of antibodies (as measured by HI, SRH and MN assays) and reduced seroprotection rates in adults and elderly (> 61 years old) subjects with underlying medical or immunosuppressive conditions, suggest that AFLUNOV may not elicit the same level of protection against A/H5N1 strain as compared to healthy adults (see section 4.4). These studies provided limited immunogenicity data in subjects with some underlying medical (in particular, renal impairment and peripheral cardiovascular disease) and immunosuppressive conditions (in particular, transplant recipients and patients under cancer treatment). In these trials, lower levels of antibodies and reduced seroprotection rates against homologous H5N1 A/turkey/Turkey/1/2005 were also measured in healthy elderly subjects, as compared to healthy adults, though previous studies showed induction of sufficiently immunogenic responses against H5N1 strains (see above for information on elderly).
Available data in paediatric population
A clinical trial (V87P6) was conducted with AFLUNOV (A/Vietnam/1194/2004) in 471 children from 6 months to 17 years of age. Two doses of AFLUNOV were administered three weeks apart and a third dose 12 months following the first dose. After 3 weeks from the 2nd vaccination (day 43) all age groups (i.e. 6–35 months, 3–8 years and 9–17 years) achieved high levels of antibodies to (A/Vietnam/1194/2004) as evaluated with SRH and HI assays as presented in table below. In this trial no vaccine related SAEs were observed.
| Toddlers (6-<36 months) | Children (3-<9 years) | Adolescents (9-<18 years) | ||
| N=134 | N=91 | N=89 | ||
| HI | % SP (95% CI) Day 43 | 97% (92–99) | 97% (91–99) | 89% (80–94) |
| GMR Day 43 to Day 1 | 129 (109–151) | 117 (97–142) | 67 (51–88) | |
| % SC (95% CI)Day 43 | 97% (92–99) | 97% (91–99) | 89% (80–94) | |
| SRH | N=133 | N=91 | N=90 | |
| % SP (95% CI) Day 43 | 100% (97–100) | 100% (96–100) | 100% (96–100) | |
| GMR (95% CI) Day 43 to Day 1 | 16 (14–18) | 15 (13–17) | 14 (12–16) | |
| % SC (95% CI) Day 43 | 98% (95–100) | 100% (96–100) | 99% (94–100) | |
SP= seroprotection
SC= seroconversion
MN results against a A/Vietnam/1194/2004 indicate a seroprotection rate of 99% (95%CI: 94–100), a seroconversion rate ranging from 97% (95%CI: 91–99) to 99% (95%CI: 96–100) and a GMR ranging from 29 (95%CI: 25–35) to 50 (95%CI: 44–58).
The European Medicines Agency has deferred the obligation to submit the results of studies with AFLUNOV in one or more subsets of the paediatric population in active immunisation against H5N1 subtype of Influenza A virus. See section 4.2 for information on paediatric use.
Information from non-clinical studies
Efficacy against challenge with virus homologous and heterologous to vaccine strains was evaluated in the ferret model. AFLUNOV(A/Vietnam/1194/2004) and an AFLUNOV-like H5N1 vaccine (A/turkey/Turkey/1/2005-like) were tested. Animals received one or two doses of vaccine containing 3.75 or 7.5 micrograms of antigen, followed by challenge with a lethal dose of A/Vietnam/1203/04 virus.
All animals receiving 2 doses of AFLUNOV were protected, and 94% of animals receiving a single dose of AFLUNOV were protected. 87% of animals challenged with virus heterologous to the vaccine strain after 2 doses of vaccine were protected, and a single dose of heterologous vaccine protected 56% of the animals.
In a similar study, intranasal challenge was delayed until approximately 4 months after the second dose of vaccine was administered. In this study 100% of animals were protected against homologous challenge, and 81% of animals were protected against heterologous challenge. Vaccination protected animals from lethal challenge even when HI antibody titres were low or undetectable.
Efficacy against challenge with the heterologous virus A/Indonesia/5/2005 was also tested. Ferrets received one or two doses of vaccine (A/Vietnam/1194/2004). Two doses of vaccine protected 92% of animals, and a single dose of vaccine protected 50% of animals against challenge with the A/Indonesia/5/2005 virus. Lung damage was reduced in vaccinated groups. Viral shedding and viral titres in lungs were also reduced, suggesting that vaccination may reduce the risk of viral transmission.
5.2 Pharmacokinetic properties
Not applicable.
5.3 Preclinical safety data
Non-clinical data obtained with AFLUNOV and with seasonal influenza vaccine containing
MF59C.1 adjuvant reveal no special hazard for humans based on conventional studies of repeated dose toxicity, local tolerance, female fertility, and reproductive and developmental toxicity (through the end of the lactation period).
6. PHARMACEUTICAL PARTICULARS6.1 List of excipients
Sodium chloride,
Potassium chloride (E508),
Potassium dihydrogen phosphate (E340),
Disodium phosphate dihydrate (E339),
Magnesium chloride hexahydrate (E511),
Calcium chloride dihydrate (E509),
Sodium citrate (E311),
Citric acid (E330), Water for injections.
For the adjuvant, see section 2
6.2 Incompatibilities
In the absence of compatibility trials, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
Do not freeze.
Store in the original package in order to protect from light.
6.5 Nature and contents of container
0.5 ml in pre-filled syringe (type I glass) with plunger-stopper (bromo-butyl rubber).
Packs of 1 or 10 pre-filled syringes.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
The vaccine should be allowed to reach room temperature before use. Gently shake before use.
After shaking, the normal appearance of AFLUNOV is a milky-white suspension.
Visually inspect the suspension prior to administration. In case of any particles and/or abnormal appearance, the vaccine should be discarded.
Any unused vaccine and waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
Seqirus S.r.l.
Via del Pozzo 3/A, S. Martino
53035 Monteriggioni (SI)
Italy.
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/10/658/001–002
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 29 November 2010
Date of latest renewal: 17 July 2015