FLUAD TETRA Suspension for injection in pre-filled syringe Ref.[27852] Active ingredients: Influenza, inactivated, surface antigen

Pharmacotherapeutic group: Influenza vaccine
ATC code: J07BB02

Mechanism of action

Fluad Tetra provides active immunisation against four influenza virus strains (two A subtypes and two B types) contained in the vaccine. Fluad Tetra induces humoral antibodies against the haemagglutinins. These antibodies neutralise influenza viruses.

Specific levels of haemagglutination inhibition (HI) antibody titres post-vaccination with inactivated influenza vaccine have not been correlated with protection from influenza virus, but the HI antibody titres have been used as a measure of vaccine efficacy.

Antibody against one influenza virus type or subtype confers limited or no protection against another. Furthermore, antibody to one antigenic variant of influenza virus might not protect against a new antigenic variant of the same type or subtype.

Fluad Tetra contains the adjuvant MF59C.1 (MF59), which is designed to increase and broaden the antigen-specific immune response and to extend the duration of the immune response.

Annual revaccination is recommended because immunity declines during the year after vaccination and circulating strains of influenza virus change from year to year.

Pharmacodynamic effects

Immunogenicity

Adult population 50 to less than 65 years of age

Immunogenicity of Fluad Tetra in adults 50 to less than 65 years of age was evaluated in Study V118_23. This was a randomised, observer-blind, controlled, multi-centre clinical trial conducted in the US, Germany and Estonia, during the 2021-22 Northern Hemisphere season. In this study, adults 50 to less than 65 years of age who were healthy or had comorbidities that increased their risk of hospitalisation for influenza-associated complications, were enrolled to receive one dose of either Fluad Tetra (N=1027) or a non-adjuvanted quadrivalent comparator influenza vaccine (N=1017). The mean age of subjects enrolled in the Fluad Tetra group was 57.8 years and females represented 62% of subjects.

The immunogenicity endpoints assessed 3 weeks after vaccination were HI GMT and HI seroconversion rate (pre-vaccination HI titre <1:10 and post-vaccination HI titre ≥1:40 or at least a 4-fold increase in HI from pre-vaccination HI titre ≥1:10). As was seen in studies in older adults with aTIV (see below study V70_27), Fluad Tetra elicited higher immune responses compared to a nonadjuvanted quadrivalent comparator influenza vaccine although superiority of Fluad Tetra versus nonadjuvanted vaccine was not achieved for all four homologous strains. The HI GMT ratios (comparator/Fluad Tetra) ranged from 0.80 to 0.99 with the highest limit of the 95% CI of 1.07 and differences in HI seroconversion rates (comparator – Fluad Tetra) ranged from -4.5% to -1.8% with the highest limit of the 95% CI of 2.5%.

Elderly population (65 years and older)

The immunogenicity of Fluad Tetra was evaluated in clinical study V118_20, a multicentre, randomised, double-blind, comparator controlled study conducted during the 2017-2018 Northern Hemisphere influenza season. Elderly subjects 65 years of age and older were randomised (2:1:1) to receive Fluad Tetra, the licensed adjuvanted trivalent influenza vaccine (Fluad, aTIV-1) or an adjuvanted trivalent influenza vaccine containing the alternate B strain (aTIV-2).

Eligible subjects were men or women ≥65 years of age who were healthy or had comorbidities that increased their risk of influenza complications. The mean age of subjects at enrolment who received Fluad Tetra was 72.4 years. Female subjects represented 58.2% of the study population.

The immunogenicity endpoints assessed 3 weeks after vaccination were haemagglutination inhibition (HI) geometric mean antibody titre (GMT) and HI seroconversion rate (pre-vaccination HI titre <1:10 and post-vaccination HI titre ≥1:40 or at least a 4-fold increase in HI from pre-vaccination HI titre ≥1:10). Fluad Tetra met non-inferiority for all 4 influenza strains and superiority to the alternate B strain not included in the Fluad aTIV comparators. The non-inferiority data are summarised in Table 3.

Table 3. Post-vaccination GMT and seroconversion rates in elderly subjects 65 years of age and older:

Abbreviations: GMT= Geometric Mean antibody titre; CI= Confidence Interval; NA= Not Applicable.
aTIV-1: licensed MF59-adjuvanted trivalent subunit inactivated egg-derived influenza vaccine, FLUAD TIV containing B-Victoria; aTIV-2: MF59-adjuvanted trivalent subunit inactivated egg-derived influenza vaccine containing B-Yamagata
N = the number of vaccinated subjects with available data from the immunogenicity endpoint listed (Per Protocol Set).
^a Non-inferiority for the GMT ratio was defined as: the upper bound of the two-sided 95% CI for the ratio of the GMTs did not exceed 1.5.
^b Non-inferiority for the seroconversion difference was defined as: the upper bound of the two-sided 95% CI for the difference between the seroconversions did not exceed 10%.
^c Seroconversion was defined as pre-vaccination HI titre <1:10 and post-vaccination HI titre ≥ 1:40 or at least a 4-fold increase in HI from pre-vaccination HI titre ≥ 1:10.
^d aTIV-1 and aTIV-2 vaccine groups are pooled for the analysis of A/H1N1 and A/H3N2 strains. For B/Victoria
aTIV=aTIV-1, for B/Yamagata aTIV=aTIV-2.

Immunogenicity of aTIV

The immunogenicity of Fluad (trivalent formulation) is relevant to Fluad Tetra because both vaccines are manufactured using the same process and have overlapping compositions.

Study V70_27 was a large Phase 3, randomised, controlled, observer-blind, multicentre study to evaluate the immunogenicity and the safety of Fluad in comparison to non-adjuvanted vaccine and it was conducted in 2010-2011. Subjects were randomised in a 1:1 ratio to receive a single 0.5 ml dose of Fluad or a single dose of a non-adjuvanted influenza vaccine. All subjects were followed for approximately one year post-vaccination.

A total of 7082 subjects were randomised and vaccinated, including 3541 subjects in each of the pooled Fluad and non-adjuvanted vaccine groups. A total of 2573 subjects (1300 in Fluad and 1273 in non-adjuvanted vaccine group) were regarded as “high risk” subjects (underlying chronic diseases including congestive heart failure, chronic obstructive pulmonary disease, asthma, hepatic disease, renal insufficiency and/or neurological/neuromuscular or metabolic disorders including diabetes mellitus).

The primary objective of a superiority of Fluad versus non-adjuvanted vaccine was not achieved for all homologous strains. GMT ratios ranged from 1.15 to 1.61 with the lowest limit of the 95% CI of 1.08 and differences in seroconversion rates ranged from 3.2%-13.9% with the lowest limit of the 95% CI of 1.1%.

Fluad elicited higher antibody titres for A/H3N2 that persisted up to 12 months post-vaccination. The results were similar for high-risk subjects with predefined comorbidities.

Effectiveness

No effectiveness studies have been performed with Fluad Tetra. The observational effectiveness studies performed with Fluad (trivalent formulation) are relevant to Fluad Tetra because both vaccines are manufactured using the same process and have overlapping compositions.

Paediatric Population (6 months to less than 6 years)

Fluad Tetra is not indicated for use in children, see section 4.2. Efficacy, immunogenicity and safety of Fluad Tetra was evaluated in clinical study V118_05, a multicentre, randomised, observer-blinded, controlled study conducted in the 2013-14 (season 1) and 2014-15 (season 2) Northern Hemisphere seasons in children of 6 months to less than 6 years. Children less than 3 years of age received 0.25 ml vaccine, older children received 0.5 ml vaccine. Children naïve to prior influenza vaccination received two doses of vaccine, at least 4 weeks apart. 10,644 children were enrolled and randomised to receive Fluad Tetra or the non-adjuvanted comparator vaccine in a 1:1 ratio: 5,352 children were enrolled in the Fluad Tetra group and 5,292 children in the non-adjuvanted comparator vaccine group.

Immunogenicity

A subset of children enrolled in this study was evaluated for their immunological response to Fluad Tetra and the non-adjuvanted comparator. Immunogenicity assessments were performed prior to (each) vaccination and 3 weeks after the last vaccination. A total of 2886 children were included in the subset for immunogenicity evaluation (Fluad Tetra: N=1481; non-adjuvanted comparator vaccine: N=1405).

Fluad Tetra demonstrated a higher immune response compared to the non-adjuvanted comparator vaccine. In addition, in children naïve to influenza vaccination antibody titres 4 weeks after the first vaccination as well as 3 weeks after the second vaccination were greater in subjects who received Fluad Tetra.

At 12 months post-vaccination, persistence of the immune response was higher in the Fluad Tetra group compared to the non-adjuvanted comparator group.

Efficacy

Vaccine efficacy was assessed for the prevention of first-occurrence laboratory confirmed influenza associated with symptomatic influenza-like illness (ILI). Influenza-like illness was defined as fever of 37.8°C or above along with any of the following: cough, sore throat, nasal congestion, or runny nose occurring at ≥21 days and ≤180 days after the last vaccination or until the end of the influenza season, whichever was longer. Subjects with ILI had nasopharyngeal swabs collected and tested for influenza A (A/H1N1 and A/H3N2) and B (both lineages) by Reverse Transcription-Polymerase Chain Reaction (RT-PCR). A total of 508 cases of first-occurrence RT-PCR confirmed influenza occurred during the study; 10 during season one and 498 during season two. The majority of influenza cases were A/H3N2. Based on antigenic typing, more than ninety percent of A/H3N2 strains from season two were determined to be antigenically distinct from egg-propagated A/Texas/50/2012, the H3N2 vaccine strain.

Vaccine efficacy compared to the non-adjuvanted influenza comparator vaccine was assessed. The relative vaccine (rVE) efficacy between Fluad Tetra and the comparator vaccine group in subjects ≥6 to <72 months of age was -0.67 [95% CI: -19.81; 15.41]), which did not meet the primary objective of the study.

Safety

Safety data were collected up to 12 months after receipt of the last vaccination. A higher incidence of local and systemic reactions was reported in subjects who received Fluad Tetra compared to the non-adjuvanted comparator influenza vaccine.

The most commonly reported adverse reactions (>10%) were tenderness (43.2%), irritability (27.1%), sleepiness (26.3%), change in eating habits (22.5%), fever (19.1%), diarrhoea (12.3%) and vomiting (10.3%).

The European Medicines Agency has deferred the obligation to submit the results of studies with Fluad Tetra in one or more subsets of the paediatric population in prevention of influenza infection. See section 4.2 for information on paediatric use.