VAXIGRIP Susp inj prefilled ser Trivalent influenza vaccine Ser/0,5ml+1needle

Injectable suspension (colourless and opalescent liquid, after gentle shaking).
Prefilled syringe of 0,5 ml of suspension, with attached needle, fitted with a plunger stopper. Box of 1.

For a dose of 0,5 mL:

Influenza virus (inactivated, split) of the following strains*:

• A/Missouri/11/2025 (H1N1)pdm09-like strain (A/Switzerland/6849/2025, IVR-278): 15 micrograms HA**
• A/Darwin/1454/2025 (H3N2)-like strain (A/Michigan/105/2025, SAN-049A): 15 micrograms HA**
• B/Tokyo/EIS13-175/2025-like strain (B/Tokyo/EIS13-175/2025, wild type): 15 micrograms HA**

* cultured on embryonated eggs from healthy chicken flocks
** haemagglutinin

This vaccine complies with the recommendations of the WHO (in the Northern Hemisphere) and the decision of the European Union for the 2026/2027 season.

VAXIGRIP may contain traces of egg, such as ovalbumin, traces of neomycin, formaldehyde and octoxinol-9, used during the manufacturing process (see section Contraindications).

Excipients:

VAXIGRIP is indicated for the prevention of influenza caused by the two viral subtypes of influenza A and the type of influenza B virus contained in the vaccine for:

• active immunisation of adults, including pregnant women, and children from the age of 6 months.
• passive protection of infants aged less than 6 months and born to women vaccinated during pregnancy (see sections Warnings and precautions, Fertility, pregnancy and breastfeeding and Pharmacodynamics).

VAXIGRIP must be used on the basis of official recommendations on vaccination against influenza.

Dosage

Adults: one dose of 0,5 mL

Paediatric population

• Children aged 6 months to 17 years: one dose of 0,5 mL.
  In children aged less than 9 years not previously vaccinated, a second dose of 0,5 mL shall be injected after an interval of at least 4 weeks.
• Infants aged less than 6 months: the safety and efficacy of administration of VAXIGRIP (active immunisation) have not been established. No data are available.
  
  Regarding passive protection: one dose of 0,5 mL administered to a pregnant woman may protect infants from birth to nearly 6 months of age (see sections Warnings and precautions, Fertility, pregnancy and breastfeeding and Pharmacodynamics).

Method of administration

This vaccine is preferably administered by the intramuscular route although it may also be administered by the subcutaneous route.

The intramuscular injection is preferably performed in the anterolateral part of the thigh (or the deltoid muscle if muscle mass is sufficient) in children aged 6 to 35 months, or in the deltoid muscle in children from 36 months and in adults.

Precautions to be taken before handling or administering the medicinal product

For instructions on preparation of the medicinal product before administration, see section Disposal and handling.

Hypersensitivity to the active substances, to any of the excipients listed in section Composition or to any constituent that may be present in trace amounts such as eggs (ovalbumin, chicken proteins), neomycin, formaldehyde and octoxinol-9.

Traceability:

In order to improve the traceability of biological medicinal products, the name and batch number of the administered product must be clearly recorded.

Hypersensitivity:

As with all injectable vaccines, it is recommended to have appropriate medical treatment available and to monitor the subject, in the event of an anaphylactic reaction following administration of the vaccine.

Concomitant disease:

Vaccination must be postponed in patients with acute febrile illness until the fever has resolved.

Precautions for use

VAXIGRIP must in no case be administered by the intravascular route.

Thrombocytopenia and coagulation disorders:

As with all other vaccines administered by the intramuscular route, the vaccine must be administered with caution in subjects with thrombocytopenia or coagulation disorders, as bleeding may occur following intramuscular administration in these subjects.

Syncope:

Syncope (fainting), as a psychogenic reaction to needle injection, may occur after, or even before, any vaccination. Measures must be put in place to prevent any injury due to fainting and to manage syncopal reactions.

Protection:

VAXIGRIP is intended to confer protection against the influenza virus strains from which the vaccine was prepared.

As with any vaccine, vaccination with VAXIGRIP may not protect all vaccinated persons.

Regarding passive protection, infants aged less than 6 months born to women vaccinated during their pregnancy may not all be protected (see section Pharmacodynamics).

Immunodeficiency:

The antibody response in patients with congenital or acquired immunosuppression may be insufficient.

Potassium and sodium content:

This medicinal product contains less than 1 mmol (39 mg) of potassium and less than 1 mmol (23 mg) of sodium per dose, that is to say it is essentially « without potassium » and « without sodium ».

VAXIGRIP could be administered at the same time as other vaccines if necessary. Data showing that VAXIGRIP can be administered at the same time as other vaccines are available for the following vaccines: a polysaccharide vaccine against pneumococcus, a diphtheria, tetanus, pertussis and poliomyelitis vaccine (dTcaP, Repevax) and a vaccine against herpes zoster. If VAXIGRIP is administered at the same time as another vaccine, separate injection sites and different syringes must be used.

The immune response may be reduced if the patient is under immunosuppressive treatment.

Pregnancy

Pregnant women are at high risk of complications due to influenza, including preterm labour and delivery, hospitalisation and death: pregnant women should receive an influenza vaccine.

VAXIGRIP may be used at all stages of pregnancy.

Safety data available for inactivated influenza vaccines are more extensive for the second and third trimesters than for the first trimester of pregnancy. Worldwide data on the use of inactivated influenza vaccines, including VAXIGRIP and VAXIGRIPTETRA (inactivated quadrivalent influenza vaccine), do not indicate abnormal outcomes for the foetus and for the mother attributable to the vaccine.

This is consistent with the results observed in a clinical study in which VAXIGRIP and VAXIGRIPTETRA were administered to pregnant women during the second or third trimester (116 exposed pregnancies and 119 live births for Vaxigrip and 230 exposed pregnancies and 231 live births for VAXIGRIPTETRA).

Data from four clinical studies conducted with VAXIGRIP administered in pregnant women during the second or third trimester (more than 5 000 pregnancies exposed and more than 5 000 live births followed up to approximately 6 months after delivery) do not indicate abnormal outcomes for the fetus, the newborn, the infant and the mother, attributable to the vaccine.

During the clinical studies conducted in South Africa and Nepal, there was no significant difference between the VAXIGRIP and placebo groups regarding events that may affect the fetus, the newborn, the infant and the mother (including miscarriages, stillbirths, premature births and low birth weight).

During a clinical study conducted in Mali, there was no significant difference between the VAXIGRIP and control groups (quadrivalent meningococcal conjugate vaccine) regarding the rate of premature births, the rate of stillborn children, and the rate of low birth weight children/small for gestational age children.

For more information, see the sections Adverse effects and Pharmacodynamics.

The results of a reproductive and developmental toxicity study in rabbits conducted with VAXIGRIPTETRA (60 μg of the total quantity of HA/dose) can be extrapolated to VAXIGRIP (45 μg of the total quantity of HA/dose): this study did not show any direct or indirect deleterious effects on pregnancy, embryo-fetal development or early postnatal development.

Breast-feeding

VAXIGRIP may be administered in case of breast-feeding.

Fertility

No data on fertility are available in humans. A study conducted in animals with VAXIGRIPTETRA did not show any deleterious effects on female fertility.

VAXIGRIP has no effect or only a negligible effect on the ability to drive vehicles and use machines.

Summary of the safety profile

The safety profile of VAXIGRIP is based on data from 46 clinical studies during which approximately 17 900 participants aged 6 months or more received VAXIGRIP or VAXIGRIPTETRA, and data from post-marketing surveillance.

Most adverse reactions generally occurred within 3 days following vaccination and resolved spontaneously within 1 to 3 days following their onset. The intensity of most of these effects was mild to moderate.

For all populations, including the entire group of children aged 6 to 35 months, the most frequently reported adverse reaction after vaccination was pain at the injection site.

Tabulated list of adverse reactions

Adverse events are classified according to their frequency using the following convention:

• 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).
• Frequency not known (cannot be estimated from the available data).

Adults and elderly

The safety profile is based on data from:

• clinical studies conducted in more than 8 000 adults (5 064 for VAXIGRIP, 3 040 for VAXIGRIPTETRA) and more than 5 800 elderly persons, over 60 years (4 468 for VAXIGRIP, 1 392 for VAXIGRIPTETRA),
• post-marketing surveillance worldwide in the general population.

In adults, the most frequently reported adverse reactions after vaccination were: pain at the injection site (52,8 %), headache (27,8 %), myalgia (23,0 %) and malaise (19,2 %).

In the elderly, the most frequently reported adverse reactions after vaccination were: pain at the injection site (25,8 %), headache (15,6 %) and myalgia (13,9 %).

Table 1: Adverse reactions reported in adults and the elderly

System organ classes (SOC)/Adverse reactions	Frequency
Blood and lymphatic system disorders
Lymphadenopathy(1)	Uncommon
Transient thrombocytopenia	Undetermined*
Immune system disorders
Allergic reactions such as hypersensitivity(2), atopic dermatitis(2), urticaria(2,3), oropharyngeal pain, asthma(1), allergic rhinitis(2), rhinorrhoea(1), allergic conjunctivitis(2), pruritus(2), hot flushes(5)	Uncommon
Allergic reactions such as angioedema(2,3), facial swelling, erythema, rash, flushing(5), oral eruption(5), oral paraesthesia(5), throat irritation, dyspnoea(2,3), sneezing, nasal obstruction(2), upper respiratory tract congestion(2), ocular hyperaemia(2), allergic dermatitis(2), generalised pruritus(2)	Rare
Allergic reactions such as erythematous rash, anaphylactic reaction, shock	Undetermined*
Metabolism and nutrition disorders
Decreased appetite	Rare
Nervous system disorders
Headache	Very common
Dizziness(4), somnolence(4)	Uncommon
Hypoesthesia(2), paresthesia	Rare
Neuralgia, convulsions, encephalomyelitis, neuritis, Guillain-Barré syndrome	Undetermined*
Vascular disorders
Vasculitides such as Henoch-Schönlein purpura, with transient renal involvement in some cases	Undetermined*
Gastrointestinal disorders
Diarrhea, nausea	Uncommon
Abdominal pain(2), vomiting	Rare
Skin and subcutaneous tissue disorders
Hyperhidrosis(1)	Uncommon
Musculoskeletal and systemic disorders
Myalgia	Very common
Arthralgia(1)	Uncommon
General disorders and administration site conditions
Injection site pain, malaise(6)	Very common
Fever(7), chills, injection site erythema, injection site induration, injection site swelling	Common
Asthenia(1), fatigue, injection site ecchymosis, injection site pruritus, injection site warmth, injection site discomfort	Uncommon
Influenza-like symptoms, injection site exfoliation(5), injection site hypersensitivity(2)	Rare

⁽¹⁾ Rare in the elderly

⁽²⁾ Reported in clinical studies in adults

⁽³⁾ Indeterminate in the elderly

⁽⁴⁾ Rare in adults

⁽⁵⁾ Reported in clinical studies in the elderly

⁽⁶⁾ Common in the elderly

⁽⁷⁾ Uncommon in elderly persons

^(*) Adverse effects reported after marketing of VAXIGRIP or VAXIGRIPTETRA

Paediatric population:

The safety profile is based on data from:

• from clinical studies conducted in 1 247 children aged 3 to 8 years (363 for VAXIGRIP, 884 for VAXIGRIPTETRA) and in 725 children/adolescents aged 9 to 17 years (296 for VAXIGRIP, 429 for VAXIGRIPTETRA),
• from a clinical study conducted in 1 981 children aged 6 to 35 months (367 for VAXIGRIP, 1 614 for VAXIGRIPTETRA),
• post-marketing surveillance worldwide in the general population.

Depending on their vaccination history, children aged 6 months to 8 year received one or two doses of VAXIGRIP or VAXIGRIPTETRA. Children/adolescents aged 9 to 17 years received one dose.

In children aged 6 months to 8 year, the safety profile was similar after the first and second injection, with a tendency towards a lower incidence of adverse effects after the second injection compared with the first in children aged 6 to 35 months.

In children/adolescents aged 9 to 17 years, the most frequently reported adverse effects after vaccination were: injection site pain (65,3 %), myalgias (29,1 %), headache (28,6 %), malaise (20,3 %), chills (13,0 %), injection site erythema (11,7 %) and injection site swelling (11,4 %).

In children aged 3 to 8 years, the most frequently reported adverse effects after vaccination were: injection site pain (59,1 %), malaise (30,7 %), injection site erythema (30,3 %), myalgias (28,5 %), headache (25,7 %), injection site swelling (22,1 %), injection site induration (17,6 %) and chills (11,2 %).

In children aged 6 to 35 months, the most frequently reported adverse effects after vaccination were: injection site pain/tenderness (29,4 %), fever (20,4 %) and injection site erythema (17,2 %).

• In the subpopulation of children aged 6 to 23 months, the most frequently reported adverse effects after vaccination were: irritability (34,9 %), abnormal crying (31,9 %), loss of appetite (28,9 %), somnolence (19,2 %) and vomiting (17,0 %).
• In the subpopulation of children aged 24 to 35 months, the most frequently reported adverse effects after vaccination were: malaise (26,8 %), myalgias (14,5 %), headache (11,9 %).

Table 2: Adverse effects reported in children and adolescents aged 6 months to 17 years.

System organ classes (SOC)/Adverse reactions	Frequency
	Children 6-35 months of age		Children 3-8 years of age	Children and adolescents 9-17 years of age
	6-23 months of age	24-35 months of age
Blood and lymphatic system disorders
- Lymphadenopathy	Undetermined*		Uncommon	Undetermined*
- Thrombocytopenia	Undetermined*		Uncommon	Undetermined*
Immune system disorders
- Allergic reactions such as:
Oropharyngeal pain	-		Uncommon	-
Hypersensitivity	Uncommon		-	-
Rash	-		Uncommon	Uncommon
Urticaria	Undetermined*		Uncommon	Uncommon
Pruritus	Undetermined*		Uncommon	Undetermined*
Generalised pruritus, papular rash	Rare		-	-
Erythematous rash, dyspnoea, anaphylactic reaction, angioedema, shock	Undetermined*		Undetermined*	Undetermined*
Metabolism and nutrition disorders
- Decreased appetite	Very common	Rare	-	-
Psychiatric disorders
- Abnormal crying	Very common	-	-	-
- Irritability	Very common	Rare	-	-
- Agitation	-		Uncommon	-
- Moaning	-		Uncommon	-
Nervous system disorders
- Headache	-	Very common	Very common	Very common
- Somnolence	Very common	-	-	-
- Dizzy sensation	-		Uncommon	Uncommon
- Neuralgia, neuritis and Guillain-Barré Syndrome	-		Undetermined*	Undetermined*
- Paresthesia, convulsions, encephalomyelitis	Undetermined*		Undetermined*	Undetermined*
Vascular disorders
- Vasculitides such as Henoch-Schönlein purpura with transient renal involvement in some cases	Undetermined*		Undetermined*	Undetermined*
Gastrointestinal disorders
- Diarrhea	Common		Uncommon	Uncommon
- Abdominal pain	-		Uncommon	-
- Vomiting	Very common	Uncommon	Uncommon	-
Musculoskeletal and systemic disorders
- Myalgia	Rare	Very common	Very common	Very common
- Arthralgia	-		Uncommon	-
General disorders and administration site conditions
Injection site reactions
- Pain/tenderness at the injection site, erythema at the injection site	Very common		Very common	Very common
- Swelling at the injection site	Common		Very common	Very common
- Induration at the injection site	Common		Very common	Common
- Ecchymosis at the injection site	Common		Common	Common
- Pruritus at the injection site	Rare		Uncommon	Uncommon
- Warmth at the injection site	-		Uncommon	Uncommon
- Discomfort at the injection site	-		-	Uncommon
- Rash at the injection site	Rare		-	-
Systemic reactions
- Malaise	Rare	Very common	Very common	Very common
- Chills	-	Common	Very common	Very common
- Fever	Very common		Common	Common
- Fatigue	-		Uncommon	Uncommon
- Asthenia	-		-	Uncommon
- Crying	-		Uncommon	-
- Influenza-like syndrome	Rare		-	-

(*) Adverse effects reported after marketing of VAXIGRIP or VAXIGRIPTETRA

Other special populations:

Although a limited number of subjects with comorbidities were included, the studies conducted in patients with comorbidities such as renal transplantation, or asthmatic patients showed no major difference in terms of the safety profile of VAXIGRIP and VAXIGRIPTETRA in these populations.

Pregnant women

During the clinical studies conducted with VAXIGRIP in South Africa and Mali in pregnant women (see sections Fertility, pregnancy and breastfeeding and Pharmacodynamics), the frequencies of solicited local and systemic reactions, reported within the 7 days following vaccine administration, were comparable to those reported for the adult population during the clinical studies. During the clinical study conducted in South Africa, local reactions were more frequent in the VAXIGRIP group than in the placebo group, both in the HIV-seronegative cohorts and in the HIV-seropositive cohorts. There were no other significant differences regarding the solicited reactions between the VAXIGRIP and placebo groups in both cohorts.

During a clinical study conducted with VAXIGRIP and VAXIGRIPTETRA in Finland in pregnant women (see sections Fertility, pregnancy and breastfeeding and Pharmacodynamics), the frequencies of solicited local and systemic reactions, were comparable to those reported for the adult population (excluding pregnant women) during the clinical studies conducted with VAXIGRIP and VAXIGRIPTETRA, even though they were higher for certain adverse reactions (injection site pain, injection site erythema, malaise, chills, headache, myalgia).

Reporting of suspected adverse reactions

Reporting of 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 report any suspected adverse reaction via the national reporting system: Agence nationale de sécurité du médicament et des produits de santé (ANSM) and network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr/.

Cases of administration of a higher dose than the recommended dose (overdose) have been reported with VAXIGRIP. When adverse reactions were reported, they corresponded to the safety profile of VAXIGRIP described in section Adverse effects.

Pharmacotherapeutic group: INFLUENZA VACCINES, ATC code: J07BB02.

Mechanism of action

VAXIGRIP confers active immunisation against three viral strains of influenza (two A subtypes and one B type) contained in the vaccine.

VAXIGRIP induces the production of humoral antibodies directed against the haemagglutinins within 2 to 3 weeks. These antibodies neutralise influenza viruses.

In infants less than 6 months of age born to women vaccinated with VAXIGRIP during pregnancy, protection is due to transplacental transfer of these neutralising antibodies.

There is no correlation between the specific rates of antibody titres after vaccination with inactivated influenza vaccines, measured by haemagglutination inhibition (HI) and protection against influenza, but HI antibody titres have been used as a measure of vaccine activity. In human studies, HI antibody titres ≥ 1/40 have been associated with protection against influenza in up to 50 % of subjects.

As influenza viruses are constantly evolving, the viral strains selected for the vaccines are reviewed every year by the WHO.

Annual vaccination against influenza is recommended due to the duration of immunity conferred by the vaccine and because circulating influenza virus strains may change from one year to another.

Efficacy

Efficacy data for VAXIGRIP are available in pregnant women and infants less than 6 months of age born to vaccinated pregnant women (passive protection).

No efficacy study has been conducted with VAXIGRIP in children and adolescents aged 9 years to 17 years, in adults and in the elderly.

In children aged 6 to 35 months and 3 to 8 years (active immunisation), the efficacy of VAXIGRIP is based on extrapolation of the efficacy of VAXIGRIPTETRA.

Infants less than 6 months of age born to women vaccinated during their pregnancy (passive protection)

Infants less than 6 months of age are at high risk of influenza, resulting in a high rate of hospitalisation. However, influenza vaccines are not indicated for active immunisation of this age group.

Efficacy in infants born to women who received a single dose of 0,5 mL of VAXIGRIP during the second or third trimester of pregnancy has been demonstrated during clinical studies.

The efficacy of VAXIGRIP in infants born to women vaccinated during the first trimester of pregnancy has not been studied during these studies. If influenza vaccination is considered necessary during the first trimester of pregnancy, it should not be postponed (see section Fertility, pregnancy and breastfeeding).

During phase IV, randomised and controlled clinical studies conducted in Mali, Nepal and South Africa, approximately 5 000 pregnant women received VAXIGRIP and approximately 5 000 pregnant women received a placebo or a control vaccine (quadrivalent meningococcal conjugate vaccine), during the second or third trimester of pregnancy. Vaccine efficacy in the prevention of laboratory-confirmed influenza in pregnant women was evaluated as a secondary endpoint in these three studies.

The studies conducted in Mali and South Africa demonstrated the efficacy of VAXIGRIP in the prevention of influenza in pregnant women following their vaccination during these trimesters of pregnancy (see table 3). In the study conducted in Nepal, the efficacy of VAXIGRIP in the prevention of influenza in pregnant women following their vaccination during these trimesters of pregnancy was not demonstrated.

Table 3: Attack rate of influenza and efficacy of VAXIGRIP against laboratory-confirmed influenza in pregnant women

	Attack rate of influenza (Any type A or B) % (n/N)		Efficacy of Vaxigrip % (CI at 95 %)
	Vaxigrip	Control*
Mali	0,5 (11/2 108)	1,9 (40/2 085)	70,3 (42,2 ; 85,8)
	Vaxigrip	Placebo
South Africa	1,8 (19/1 062)	3,6 (38/1 054)	50,4 (14,5 ; 71,2)

* Meningococcal vaccine

N: Number of pregnant women included in the analysis

n: number of subjects presenting with biologically confirmed influenza

CI: confidence interval

During the same phase IV, randomized and controlled clinical studies conducted in Mali, Nepal and South Africa, 4 530 of the 4 898 (92 %) infants born to women who received VAXIGRIP during the second or third trimester of pregnancy, and 4 532 of the 4 868 (93 %) infants born to women who received a placebo or a control vaccine (quadrivalent meningococcal conjugate vaccine) during the second or third trimester of pregnancy (see table 4) were followed up to approximately 6 months of age.

These studies confirmed the efficacy of VAXIGRIP in the prevention of influenza in infants born to women vaccinated during these trimesters of pregnancy, from birth up to approximately 6 months of age.

Women in the first trimester of pregnancy were not included in these studies; therefore, the efficacy of VAXIGRIP in infants born to women vaccinated during the first trimester of their pregnancy could not be evaluated.

Table 4: Influenza attack rate and efficacy of VAXIGRIP against biologically confirmed influenza in infants born to women vaccinated during their pregnancy

	Attack rate of influenza (Any type A or B) % (n/N)		Efficacy of Vaxigrip % (CI at 95 %)
	Vaxigrip	Control*
Mali	2,4 (45/1 866)	3,8 (71/1 869)	37,3 (7,6 ; 57,8)
	Vaxigrip	Placebo
Nepal	4,1 (74/1 820)	5,8 (105/1 826)	30,0 (5 ; 48)
South Africa	1,9 (19/1 026)	3,6 (37/1 023)	48,8 (11,6 ; 70,4)

* Meningococcal vaccine

N: Number of infants included in the analysis

n: number of subjects presenting with biologically confirmed influenza

CI: confidence interval

The efficacy data indicate a decrease over time, after birth, in the protection of infants born to women vaccinated during their pregnancy.

During the clinical study conducted in South Africa, vaccine efficacy was higher in infants aged 8 weeks or less (85,8 % [CI at 95 %: 38,3; 98,4]) and decreased over time; vaccine efficacy was 25,5 % (CI at 95 %: -67,9; 67,8) in infants aged 8 to 16 weeks and 30,4 % (CI at 95 %: -154,9; 82,6) in infants aged 16 to 24 weeks.

During the clinical study conducted in Mali, the efficacy of VAXIGRIP also tended to be higher in infants during the first four months following birth, with lower efficacy during the 5^th month and a marked decrease during the 6^th month where protection is no longer evident.

Prevention of influenza can only be expected if the infants are exposed to the strains included in the vaccine administered to the mother.

Children aged 6 to 35 months (active immunization)

A randomized placebo-controlled study was conducted in 4 regions (Africa, Asia, Latin America and Europe) during 4 influenza seasons, in more than 5 400 children aged 6 to 35 months who received two doses (0,5 mL) of VAXIGRIPTETRA (N = 2 722), or a placebo (N = 2 717) 28 days apart to evaluate the efficacy of VAXIGRIPTETRA in the prevention of biologically confirmed influenza, caused by an A and/or B strain, any strain, and caused by strains similar to those of the vaccine (determined by sequencing).

Biologically confirmed influenza was defined as an influenza-like illness [onset of fever ≥ 38 °C (which persists for at least 24 hours) at the same time as at least one of the following symptoms: cough, nasal congestion, rhinorrhea, pharyngitis, otitis, vomiting or diarrhea], biologically confirmed by reverse transcriptase polymerase chain reaction (RT-PCR [Reverse Transcriptase Polymerase Chain Reaction]) and/or viral culture.

Table 5: influenza attack rate and efficacy of VAXIGRIPTETRA against biologically confirmed influenza in children aged 6 to 35 months

	VAXIGRIPTETRA (N = 2 584)		Placebo (N = 2 591)		Efficacy
	N	Attack rate of influenza (%)	n	Attack rate of influenza (%)	% (bilateral CI at 95 %)
Biologically confirmed influenza caused by:
Any influenza of type A or B	122	4,72	255	9,84	52,03 (40,24 ; 61,66)
Viral strains similar to those contained in the vaccine	26	1,01	85	3,28	69,33 (51,93 ; 81,03)

N: number of children analysed (total population)

n: number of children meeting the listed criteria

CI: confidence interval

In addition, a predefined complementary analysis showed that VAXIGRIPTETRA prevented 56,6 % (CI at 95 %: 37,0; 70,5) of biologically confirmed severe influenzas due to any strain, and 71,7 % (CI at 95 %: 43,7; 86,9) of biologically confirmed severe influenzas due to strains similar to those in the vaccine. Furthermore, subjects who received VAXIGRIPTETRA had 59,2 % (CI at 95 %: 44,4; 70,4) lower risk of presenting influenza requiring a medical consultation than subjects who received placebo.

Biologically confirmed severe influenzas were defined as biologically confirmed influenza-like illnesses by RT-PCR and/or viral culture with at least one of the following:

• fever > 39,5 °C for subjects aged less than 24 months or ≥ 39,0 °C for subjects aged 24 months and older,
• and/or at least one significant symptom of an influenza-like illness preventing daily activity (cough, nasal congestion, rhinorrhoea, pharyngitis, otitis, vomiting, diarrhoea),
• and/or one of the following events: acute otitis media, acute lower respiratory tract infection (pneumonia, bronchiolitis, bronchitis, croup), hospitalisation.

Children aged 3 to 8 years (active immunisation) :

Based on the immune responses observed in children aged 3 to 8 years, the efficacy of VAXIGRIP in this population should be at least similar to the efficacy observed in children aged 6 to 35 months (see “Children aged 6 to 35 months” (active immunisation) above and “Immunogenicity of VAXIGRIP” below).

Immunogenicity

Clinical studies conducted in adults aged 18 to 60 years, in persons older than 60 years, in children aged 3 to 8 years and in children aged 6 to 35 months evaluated the immune response of VAXIGRIP (TIV) and VAXIGRIPTETRA (QIV) with regard to the geometric mean titre (GMT) of HI antibodies at Day 21 (for adults) and at Day 28 (for children), the HI seroconversion rate (multiplication by 4 of the reciprocal titre value or increase from an undetectable titre [< 10] to a reciprocal titre value ≥ 40), and the geometric mean of individual titre ratios (GMTR) HI (post-/pre-vaccination titres).

A clinical study conducted in adults aged 18 to 60 years and in children aged 9 to 17 years described the immune response of VAXIGRIP and VAXIGRIPTETRA with regard to the GMT of HI antibodies at Day 21. Another clinical study conducted in children aged 9 to 17 years described the immune response of VAXIGRIPTETRA.

A clinical study conducted in pregnant women described the immune response of VAXIGRIP and VAXIGRIPTETRA with regard to the GMT of HI antibodies at Day 21, the HI seroconversion rate and the HI GMTR, after a dose administered during the second or third trimester of pregnancy. In this study, transplacental transfer was evaluated using the GMTs of HI antibodies from maternal blood, cord blood and the cord blood/maternal blood ratio, at delivery.

In general, VAXIGRIP induced an immune response against the 3 influenza strains contained in the vaccine.

In children aged 3 years and older, in adults including pregnant women and in the elderly, VAXIGRIP was as immunogenic as VAXIGRIPTETRA for the common strains.

Antibody persistence was evaluated in adults, the elderly and children aged 6 months to 35 months. The duration of immunity induced by vaccination is at least 12 months.

Adults and elderly

In a clinical study, the immune response was evaluated in adults aged 18 to 60 years and elderly persons older than 60 years who received a 0,5 mL dose of VAXIGRIP or VAXIGRIPTETRA.

The immunogenicity results by the HI method in adults aged 18 to 60 years and elderly persons older than 60 years are presented in Table 6.

Table 6: immunogenicity results in adults aged 18 to 60 years and in elderly persons older than 60 years, 21 days after vaccination with VAXIGRIP or VAXIGRIPTETRA

	Adults aged 18 to 60 years			Elderly persons older than 60 years
Antigen strain	Alternative TIV(a) (B Victoria) N = 140	TIV authorized(b) (B Yamagata) N = 138	QIV N = 832	Alternative TIV(a) (B Victoria) N = 138	TIV authorized(b) (B Yamagata) N = 137	QIV N = 831
	GMT (CI at 95 %)
A (H1N1)(c)(d)	685 (587 ; 800)		608 (563 ; 657)		268 (228 ; 314)	219 (199 ; 241)
A (H3N2)(c)	629 (543 ; 728)		498 (459 ; 541)		410 (352 ; 476)	359 (329 ; 391)
B (Victoria)	735 (615 ; 879)	-	708 (661 ; 760)	301 (244 ; 372)	-	287 (265 ; 311)
B (Yamagata)	-	1 735 (1 490 ; 2 019)	1 715 (1 607 ; 1 830)	-	697 (593 ; 820)	655 (611 ; 701)
	% of SC (CI at 95 %)(e)
A (H1N1)(c)(d)	65,1 (59,2 ; 70,7)		64,1 (60,7 ; 67,4)		50,2 (44,1 ; 56,2)	45,6 (42,1 ; 49,0)
A (H3N2)(c)	73,4 (67,8 ; 78,5)		66,2 (62,9 ; 69,4)		48,5 (42,5 ; 54,6)	47,5 (44,1 ; 51,0)
B (Victoria)	70,0 (61,7 ; 77,4)	-	70,9 (67,7 ; 74,0)	43,5 (35,1 ; 52,2)	-	45,2 (41,8 ; 48,7)
B (Yamagata)	-	60,9 (52,2 ; 69,1)	63,7 (60,3 ; 67,0)	-	38,7 (30,5 ; 47,4)	42,7 (39,3 ; 46,2)
	GMTR (CI at 95 %)(f)
A (H1N1)(c)(d)	10,3 (8,35 ; 12,7)		9,77 (8,69 ; 11,0)		6,03 (4,93 ; 7,37)	4,94 (4,46 ; 5,47)
A (H3N2)(c)	14,9 (12,1 ; 18,4)		10,3 (9,15 ; 11,5)		5,79 (4,74 ; 7,06)	5,60 (5,02 ; 6,24)
B (Victoria)	11,4 (8,66 ; 15,0)	-	11,6 (10,4 ; 12,9)	4,60 (3,50 ; 6,05)	-	4,61 (4,18 ; 5,09)
B (Yamagata)	-	6,08 (4,79 ; 7,72)	7,35 (6,66 ; 8,12)	-	4,11 (3,19 ; 5,30)	4,11 (3,73 ; 4,52)

N = number of subjects for whom data on the endpoint considered are available

GMT: Geometric mean of the titers; CI: Confidence interval;

(a) Alternative TIV containing A/California/7/2009 (H1N1), A/Texas/50/2012 (H3N2) and B/Brisbane/60/2008 (Victoria lineage)

(b) TIV authorized in 2014-2015 containing A/California/7/2009 (H1N1), A/Texas/50/2012 (H3N2) and B/Massachusetts/2/2012 (Yamagata lineage)

(c) The pooled TIV group includes participants vaccinated with an alternative TIV or an authorized TIV, N = 278 for adults aged 18 to 60 years and N = 275 for persons aged more than 60 years

(d) N = 833 for the QIV group in adults aged 18 to 60 years; N = 832 for the QIV group in persons aged more than 60 years

(e) SC: seroconversion or significant increase: for subjects with a pre-vaccination titer < 10 (1/dil), proportion of subjects with a post-vaccination titer ≥ 40 (1/dil) and for subjects with a pre-vaccination titer ≥ 10 (1/dil), proportion of subjects with a multiplication by 4 or more of the pre- to post-vaccination titer

(f) GMTR: Geometric mean of the individual titer ratios (post-/pre-vaccination titers)

Pregnant women and transplacental transfer

During a clinical study, a total of 116 pregnant women received VAXIGRIP and 230 pregnant women received VAXIGRIPTETRA during the second or third trimester of pregnancy (between 20 and 32 weeks of pregnancy).

The immunogenicity results by the HI method, in pregnant women, 21 days after vaccination with VAXIGRIP and VAXIGRIPTETRA, are presented in Table 7.

Table 7: immunogenicity results by the HI method in pregnant women, 21 days after vaccination with VAXIGRIP or VAXIGRIPTETRA

	TIV (B Victoria)	QIV
Antigen strain	N = 109	N = 216
	GMT (CI at 95 %)
A (H1N1)*	638 (529 ; 769)	525 (466 ; 592)
A (H3N2)*	369 (283 ; 483)	341 (286 ; 407)
B1 (Victoria)*	697 (569 ; 855)	568 (496 ; 651)
B2 (Yamagata)*	-	993 (870 ; 1134)
	≥ 4 times more n (%)(a)
A (H1N1)*	41,3 (31,9 ; 51,1)	38,0 (31,5 ; 44,8)
A (H3N2)*	62,4 (52,6 ; 71,5)	59,3 (52,4 ; 65,9)
B1 (Victoria)*	60,6 (50,7 ; 69,8)	61,1 (54.3 ; 67,7)
B2 (Yamagata)*	-	59,7 (52,9 ; 66,3)
	GMTR (CI at 95 %)(b)
A (H1N1)*	5,26 (3,66 ; 7,55)	3,81 (3,11 ; 4,66)
A (H3N2)*	9,23 (6,56 ; 13,0)	8,63 (6,85 ; 10,9)
B1 (Victoria)*	9,62 (6,89 ; 13,4)	8,48 (6,81 ; 10,6)
B2 (Yamagata)*	-	6,26 (5,12 ; 7,65)

N = number of subjects for whom data on the endpoint considered are available

GMT : Geometric mean titer ; CI : Confidence interval

* A/H1N1 : A/Michigan/45/2015 (H1N1)pdm09 - analogous strain ;
A/H3N2 : A/Hong Kong/4801/2014 (H3N2) - analogous strain ;
B1 : B/Brisbane/60/2008 - analogous strain (B/Victoria lineage) : this strain was included in the composition of the TIV ;
B2 : B/Phuket/3073/2013 - analogous strain (B/Yamagata lineage) : this strain was not included in the composition of the TIV.

(a) SC : seroconversion or significant increase : for subjects with a pre-vaccination titer < 10 (1/dil), proportion of subjects with a post-vaccination titer ≥ 40 (1/dil) and for subjects with a pre-vaccination titer ≥ 10 (1/dil), proportion of subjects with a multiplication by 4 or more of the titer from pre- to post-vaccination

(b) GMTR : Geometric mean of the individual titer ratios (post-/pre-vaccination titers)

A descriptive analysis of immunogenicity by the HAI method, at delivery, in a sample of maternal blood (BL03M) and in a sample of cord blood (BL03B) and of transplacental transfer (BL03B/BL03M) is presented in Table 8.

Table 8 : Descriptive analysis of immunogenicity by the HAI method with VAXIGRIP or VAXIGRIPTETRA at delivery

	TIV (B Victoria)	QIV
Antigen strain	N = 89	N = 178
	BL03M (Maternal blood) GMT (CI at 95 %)
A (H1N1)*	411 (332 ; 507)	304 (265 ; 349)
A (H3N2)*	186 (137 ; 250)	178 (146 ; 218)
B1 (Victoria)*	371 (299 ; 461)	290 (247 ; 341)
B2 (Yamagata)*	-	547 (463 ; 646)
	BL03B (Cord blood) GMT (CI at 95 %)
A (H1N1)*	751 (605 ; 932)	576 (492 ; 675)
A (H3N2)*	324 (232 ; 452)	305 (246 ; 379)
B1 (Victoria)*	608 (479 ; 772)	444 (372 ; 530)
B2 (Yamagata)*	-	921 (772 ; 1 099)
	Transplacental transfer : BL03B/BL03MT** GMT (CI at 95 %)
A (H1N1)*	1,83 (1,64 ; 2,04)	1,89 (1,72 ; 2,08)
A (H3N2)*	1,75 (1,55 ; 1,97)	1,71 (1,56 ; 1,87)
B1 (Victoria)*	1,64 (1,46 ; 1,85)	1,53 (1,37 ; 1,71)
B2 (Yamagata)*	-	1,69 (1,54 ; 1,85)

N = number of subjects for whom data on the endpoint considered are available : women who received QIV or TIV, having delivered at least 2 weeks after the injection and with cord blood and maternal blood available at delivery.

GMT : Geometric mean titer ; CI : Confidence interval

* A/H1N1 : A/Michigan/45/2015 (H1N1) pdm09 - analogous strain ;
A/H3N2 : A/Hong Kong/4801/2014 (H3N2) - analogous strain ;
B1 : B/Brisbane/60/2008 - analogous strain (B/Victoria lineage) : this strain was included in the composition of the TIV ;
B2 : B/Phuket/3073/2013 - analogous strain (B/Yamagata lineage) : this strain was not included in the composition of the TIV

** If a mother has X babies, the values of her titers are counted X times

At delivery, the higher antibody level in the cord blood sample compared to the maternal blood sample is consistent with transplacental antibody transfer from the mother to the fetus following vaccination of women with VAXIGRIP or VAXIGRIPTETRA during the second or third trimester of pregnancy.

These data are consistent with the passive protection demonstrated in infants from birth to approximately 6 months of age born to women vaccinated during the second or third trimester of pregnancy with VAXIGRIP in studies conducted in Mali, Nepal and South Africa (see the subsection « Efficacy »).

Paediatric population

Children aged 9 to 17 years

In a total of 55 children aged 9 to 17 years who received one dose of VAXIGRIP and 429 children who received one dose of VAXIGRIPTETRA, the immune response directed against the strains contained in the vaccine was similar to the immune response induced in adults aged 18 to 60 years.

Children aged 3 to 8 years

In a clinical study, the immune response was described in children aged 3 to 8 years who received either one dose or two doses of 0,5 mL of VAXIGRIP or VAXIGRIPTETRA, depending on their influenza vaccination history.

Children who received a one- or two-dose regimen of VAXIGRIP or VAXIGRIPTETRA presented a similar immune response after the last dose of each of the regimens.

Immunogenicity results evaluated 28 days after the last injection using the IHA method are presented in table 9:

Children aged 6 to 35 months

In a clinical study, the immune response was described in children aged 6 to 35 months who received two doses of 0,5 mL of VAXIGRIP or VAXIGRIPTETRA.

Immunogenicity results evaluated 28 days after the last injection using the IHA method are presented in table 9.

Table 9: immunogenicity results in children aged 6 to 35 months and aged 3 to 8 years, 28 days after the last injection of VAXIGRIP or VAXIGRIPTETRA

	Children aged 6 to 35 months			Children aged 3 to 8 years
Antigen strain	Alternative TIV(a) (B Victoria) N = 172	TIV authorized(b) (c) (B Yamagata) N = 178	QIV N = 341	Alternative TIV(a) (B Victoria) N = 176	TIV authorized(b) (B Yamagata) N = 168	QIV N = 863
	GMT (CI at 95 %)
A (H1N1)(d)	637 (500 ; 812)	628 (504 ; 781)	641 (547 ; 752)	1 141 (1 006 ; 1 295)		971 (896 ; 1 052)
A (H3N2)(d)	1 021 (824 ; 1 266)	994 (807 ; 1 224)	1 071 (925 ; 1 241)	1 746 (1 551 ; 1 964)		1 568 (1 451 ; 1 695)
B (Victoria)(e)	835 (691 ; 1 008)	-	623 (550 ; 706)	1 120 (921 ; 1 361)	-	1 050 (956 ; 1 154)
B (Yamagata)(f) (g)	-	1 009 (850 ; 1 198)	1 010 (885 ; 1 153)	-	1 211 (1 003 ; 1 462)	1 173 (1 078 ; 1 276)
	% of SC (CI at 95 %)(e)
A (H1N1)(d)	87,2 (81,3 ; 91,8)	90,4 (85,1 ; 94,3)	90,3 (86,7 ; 93,2)	65,7 (60,4 ; 70,7)		65,7 (62,4 ; 68,9)
A (H3N2)(d)	88,4 (82,6 ; 92,8)	87,6 (81,9 ; 92,1)	90,3 (86,7 ; 93,2)	67,7 (62,5 ; 72,6)		64,8 (61,5 ; 68,0)
B (Victoria)(e)	99,4 (96,8 ; 100,0)	-	98,8 (97,0 ; 99,7)	90,3 (85,0 ; 94,3)	-	84,8 (82,3 ; 87,2)
B (Yamagata)(f) (g)	-	99,4 (96,9 ; 100,0)	96,8 (94,3 ; 98,4)	-	89,9 (84,3 ; 94,0)	88,5 (86,2 ; 90,6)
	GMTR (CI at 95 %)(f)
A (H1N1)(d)	35,3 (27,4 ; 45,5)	40,6 (32,6 ; 50,5)	36,6 (30,8 ; 43,6)	7,65 (6,54 ; 8,95)		6,86 (6,24 ; 7,53)
A (H3N2)(d)	44,1 (33,1 ; 58,7)	37,1 (28,3 ; 48,6)	42,6 (35,1 ; 51,7)	7,61 (6,69 ; 9,05)		7,49 (6,72 ; 8,35)
B (Victoria)(e)	114 (94,4 ; 138)	-	100 (88,9 ; 114)	17,8 (14,5 ; 22,0)	-	17,1 (15,5 ; 18,8)
B (Yamagata)(f) (g)	-	111 (91,3 ; 135)	93,9 (79,5 ; 111)	-	30,4 (23,8 ; 38,4)	25,3 (22,8 ; 28,2)

N = number of subjects for whom data on the endpoint considered are available

GMT: Geometric mean of the titers; CI: Confidence interval;

(a) Alternative TIV containing A/California/7/2009 (H1N1), A/Texas/50/2012 (H3N2) and B/Brisbane/60/2008 (Victoria lineage)

(b) TIV authorized in 2014-2015 containing A/California/7/2009 (H1N1), A/Texas/50/2012 (H3N2) and B/Massachusetts/2/2012 (Yamagata lineage)

(c) 0,5 mL dose in children aged 6 to 35 months

(d) For children aged 3 to 8 years: The pooled TIV group includes participants vaccinated with an alternative TIV or an authorised TIV, N = 344

(e) N = 169 for the Vaxigrip group (B Victoria) in children aged 3 to 8 years

(f) N = 862 for the QIV group in children aged 3 to 8 years

(g) For the alternative TIV group (B Victoria): N = 171 for children aged 6 to 35 months; N = 175 for children aged 3 to 8 years

(h) SC: seroconversion or significant increase: for subjects with a pre-vaccination titre < 10 (1/dil), proportion of subjects with a post-vaccination titre ≥ 40 (1/dil) and for subjects with a pre-vaccination titre ≥ 10 (1/dil), proportion of subjects with a multiplication by 4 or more of the post-vaccination titre

(i) GMTR: geometric mean of individual titre ratios (post-/pre-vaccination titres)

These immunogenicity data provide additional information supporting the efficacy data available in children aged 6 to 35 months (see subsection “Efficacy”).

Animal data generated with VAXIGRIPTETRA (60 μg of total HA quantity/dose) can be extrapolated to VAXIGRIP (45 μg of total HA quantity/dose): these data revealed no unexpected results or toxicity to target organs.

In the absence of compatibility studies, this vaccine must not be mixed with other medicinal products.

1 year.

Store in a refrigerator (between 2 °C and 8 °C). Do not freeze. Store the syringe in the outer carton in order to protect from light.

VAXIGRIP remains stable for a period of 72 hours at a temperature up to +25 °C ± 2 °C. This is not a recommended storage condition, but is intended solely to guide healthcare professionals in the case of a temporary temperature excursion.

The vaccine should be brought to room temperature before use.

Shake before use.

Preparation for administration:

The syringe containing the injectable suspension must be visually inspected before administration. In case of presence of foreign particles, leakage, premature activation of the plunger or defective tip, discard the prefilled syringe.

The syringe is intended for single use and must not be reused.

Any unused medicine or waste must be disposed of in accordance with current regulations.

List I

MA	CIP 3400930306000 (Ser/0,5ml+1aig).

Price:

11,75 euros (Ser/0,5ml+1aig).