AFLUNOV suspension for injection in pre-filled syringe – Summary of Product Characteristics (SmPC) for healthcare professionals

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 micrograms haemagglutinin.

Adjuvant MF59C.1 containing:

squalene 9.75 milligrams per 0.5 ml polysorbate 80 1.175 milligrams per 0.5 ml sorbitan trioleate 1.175 milligrams per 0.5 ml

AFLUNOV may contain trace residues of egg and chicken proteins, ovalbumin, kanamycin, neomycin sulphate, formaldehyde, hydrocortisone 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 (injection).

Milky white liquid.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Active immunisation against H5N1 subtype of Influenza A virus in individuals 6 months of age and above.

AFLUNOV should be used in accordance with official recommendations.

4.2 Posology and method of administration

Posology

Two doses (0.5 ml each), at least 21 days apart.

Data on a third dose (booster) administered 6 months after the first dose are limited (see sections 4.8 and 5.1).

In the event of an officially declared influenza pandemic due to A/H5N1 virus, individuals 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 AFLUNOV instead of two doses that are required in previously unvaccinated individuals (see section 5.1).

Paediatric population

No data are available in children aged less than 6 months.

Elderly

There is limited experience in elderly over 70 years of age (see section 5.1).

Method of administration

The vaccine is administered by intramuscular injection, preferably in the anterolateral aspect of the thigh in infants or in the deltoid muscle region of the upper arm in older individuals.

The vaccine should under no circumstances be administered intravascularly or intradermally.

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, hydrocortisone and cetyltrimethylammonium bromide) of this vaccine.

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.

Hypersensitivity and anaphylaxis

Caution is needed when administrating this vaccine to individuals with a known hypersensitivity 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, hydrocortisone 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.

Concurrent illness

Immunisation should be postponed in patients with febrile illness until the fever is resolved.

Anxiety-related reactions

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 fainting.

Immunocompromised individuals

Immunocompromised individuals, whether due to the use of immunosuppressive therapy, a genetic defect, HIV infection, or other causes, may have reduced immune response to active immunisation.

Thrombocytopenia and coagulation disorders

As with other intramuscular injections, the vaccine should be given with caution in individuals receiving anticoagulant therapy or those with thrombocytopenia or any coagulation disorder (such as haemophilia) because bleeding or bruising may occur following an intramuscular administration in these individuals.

Protection against influenza

There is no immune correlate of protection established for influenza A (H5N1). A protective immune response may not be elicited in all vaccine recipients.

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).

That there are no safety, immunogenicity or efficacy data to support interchangeability of AFLUNOV with other H5N1 monovalent vaccines.

Excipients with known effect

Sodium

This vaccine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium free’.

Potassium

This vaccine contains potassium, less than 1 mmol (39 mg) per dose, that is to say essentially ‘potassium-free’.

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.

4.6 Fertility, pregnancy and lactation

Pregnancy

Limited data obtained from women who became pregnant during the course of clinical trials with AFLUNOV or similar pandemic H1N1v vaccines adjuvanted with MF59C.1 were insufficient to inform vaccine-associated risks in pregnancy.

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.

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). Male fertility has not been assessed in animals.

4.7 Effects on ability to drive and use machines

AFLUNOV has no or negligible influence on the ability to drive and use machines. However, some of the effects mentioned under section 4.8 may temporarily affect the ability to drive or operate machinery.

4.8 Undesirable effects

Summary of the safety profile

The safety of H5N1 vaccine combined with MF59C.1 adjuvant containing either the A/turkey/Turkey/1/2005 or the A/Vietnam/1194/2004 strain has been evaluated in nine clinical trials in healthy subjects involving 5055 adults and elderly (7.5 or 15 micrograms HA), and children (7.5 micrograms HA). There were 4041 adults subjects 18 to 60 years of age, 540 elderly subjects 61 years of age and above.

In the paediatric population, there were 214 subjects 6 to 35 months of age, 167 subjects 3 to 8 years of age and 93 subjects 9 to 17 years of age.

The overall safety profile was similar across the adult, elderly and paediatric populations.

Irrespective of antigen dose, or age group, most local and systemic adverse reactions after administration were of short duration, with onset close to the time of vaccination, and were mild or moderate in severity. The majority of these reactions usually disappeared within 3 days without treatment. Across all trials, there was a general trend towards decreased reports of local adverse reactions after the second vaccination compared with the first.

In adults 18 to 60 years, the most frequently reported (≥ 10%) adverse reactions were injection site pain (59%), myalgia (34%), headache (26%), injection site redness (24%), fatigue (24%), injection site induration (21%), injection site swelling (15%), chills (13%) and malaise (13%).

In elderly subjects (≥ 61 years), the most frequently reported (≥ 10%) adverse reactions were injection site pain (35%), myalgia (24%), injection site redness (17%), headache (16%), chills (12%), fatigue (10%) and malaise (10%).

In children and adolescents 3 to 17 years of age, the most frequently reported (≥10%) adverse reactions were injection site pain (95%), headache (61%), myalgia (60%), fatigue (41%), injection site redness (60%), injection site induration (34%), injection site swelling (34%), malaise (32%), nausea (25%), sweating (18%), chills (19%), diarrhoea (18%) and injection site ecchymosis (16%).

In infants and children 6 to 35 months of age, the most frequently reported (≥10%) adverse reactions were injection site redness (62%), irritability (57%), tenderness (55%), unusual crying (48%), sleepiness (45%), injection site induration (38%), injection site swelling (37%) change in eating habits (36%), diarrhoea (34%), fever (27%), injection site ecchymosis (19%), vomiting (10%), sweating, (10%) and unusual sweating (10%).

Tabulated list of adverse reactions

The solicited and unsolicited adverse reaction rates reported after any vaccination doses (i.e. first, second or booster) across subjects age, 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)

¹ Reported only in paediatric subjects 6-35 months

² Reported as Common in adults (18-60 years) and elderly (≥ 61 years)

³ Reported as Very common only in paediatric subjects 6 months-8 years. Reported as Common in adolescents and adults 9-60 years of age and Uncommon in eldery (≥ 61 years)

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.

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 to 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 experience exists for AFLUNOV.

In addition to the adverse events listed from clinical studies, the following adverse events were reported from post-marketing surveillance with H1N1v Focetria vaccine (licensed for use from 6 months of age during the 2009 influenza pandemic, and containing the same MF59 adjuvant and manufactured with the same process as AFLUNOV).

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

Dizziness, somnolence, syncope, presyncope, neuralgia, paraesthesia, convulsions and neuritis.

Cardiac disorders

Palpitation, tachycardia.

Respiratory, thoracic and mediastinal disorders

Cough.

Gastrointestinal disorders

Abdominal pain.

Skin and subcutaneous tissue disorders

Generalised skin reactions including pruritus non-specific rash; angioedema.

Muscoskeletal and connective tissue 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).

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

No case of overdose has been reported.

5 PHARMACOLOGICAL PROPERTIES

5.1 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:

* 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:

^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 (Studies V87P1 and V87P13) 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.

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:

* 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 second dose in adults 18-60 years of age, measured by SRH and HI assays were as follows:

factor (95%CI)°°

* 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 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 second dose in adults (18-60 years) and elderly (> 61years), measured by SRH and HI assays were as follows:

^a 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 memoryT:

A single vaccination with AFLUNOV (A/Vietnam/1194/2004) induced high and rapid serological response in subjects primed 6 to 8 years previously with two doses of a different surrogate H5 vaccine, having same formulation as AFLUNOV but using the strain H5N3.

In a phase I clinical trial (V87P3) adult subjects aged 18 to 65 years primed 6 to 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% (74- 100) 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 second 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 second 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 second dose were as follows:

^a actual 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).

Paediatric population

The immunogenicity of aH5N1 in the paediatric population was assessed in Studies V87P6 and V87_30.

Study 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 2^nd vaccination (day 43) all age groups (i.e. 6 to 35 months, 3 to 8 years and 9 to 17 years) achieved high levels of antibodies to (A/Vietnam/1194/2004) as evaluated with SRH and HI assays as presented in table below.

* Seroprotection defined as HI titre

1:40 ** Seroconversion defined as non-detectable titre to ≥1:40, or 4-fold increase from a detectable Day 1 titre

*** Geometric mean ratios of HI

°Seroprotection: SRH area ≥25 mm²

°°Seroconversion 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 of SRH

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).

Study V87_30 was a randomised, observer-blind, multicentre study to measure the immunogenicity of six formulations in terms of H5N1 A/turkey/Turkey/1/2005 and MF59 adjuvant ratio. In this study, 420 paediatric subjects 6 months to 8 years of age were divided into two age cohorts: 6 to 35 months of age (N=210) and 3 to 8 years of age (N=210).

The vaccine was administered in two separate injections given 3 weeks apart. Antibody levels against A/turkey/Turkey/1/2005 were measured by HI and MN assays three weeks after the second vaccination (Day 43). The immunological response for the the approved formulation (7.5 micrograms HA with 100% MF59 adjuvant, 0.5 ml dose) and the study formulation with half the antigen content (3.75 micrograms HA with 100% MF59 adjvant, 0.5 ml dose), are presented below.

* Seroprotection defined as HI titre

1:40 ** Seroconversion defined as non-detectable titre to ≥1:40, or 4-fold increase from a detectable Day 1 titre

*** Geometric mean titre ratios

Information from non-clinical studies

Efficacy against challenge with virus homologous and heterologous to vaccine strains was evaluated in the ferret model (Study 765-N106857).

AFLUNOV(A/Vietnam/1194/2004 clade 1) and an AFLUNOV-like H5N1 vaccine (A/turkey/Turkey/1/2005 clade 2.2.1) were tested. Animals received one or two doses of vaccine containing 3.75 or 7.5 micrograms of antigen, followed by intranasal challenge on Day 42 after the second vaccine dose 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 (Study 780-N007104). 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.

In Study 673-N106850, AFLUNOV containing 7.5 micrograms of antigen (A/Vietnam/1194/2004) was immunogenic, able to fully protect against mortality and to reduce virus shedding from nasal washes after a lethal homologous challenge. In Study CBI-PCS-008, AFLUNOV containing either 7.5 or 15 micrograms of antigen (A/Vietnam/1194/2004) was able to reduce the proportion of animals shedding virus as well as the amount of virus shedding after a non-lethal homologous challenge. Serological testing indicated both doses were immunogenic and induced cross-reactive antibodies against A/turkey/Turkey/1/2005 (Study VIV-PCS-001).

Efficacy against challenge with the heterologous virus A/Indonesia/5/2005 was also tested (Study 2810200). 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 PARTICULARS

6.1 List of excipients

Sodium chloride,

Potassium chloride,

Potassium dihydrogen phosphate,

Disodium phosphate dihydrate, Magnesium chloride hexahydrate, Calcium chloride dihydrate,

Sodium citrate,

Citric acid,

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. Discard if the vaccine has been frozen. 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

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 UK Ltd

Point, 29 Market Street

Maidenhead SL6 8AA

UK

8 MARKETING AUTHORISATION NUMBER(S)

PLGB 47991/0004

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

01/01/2021

10 DATE OF REVISION OF THE TEXT

06/03/2025