Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Influenza vaccine, ATC code: J07BB02.
Mechanism of action
Vaxigrip Tetra provides active immunisation against four influenza virus strains (two A subtypes and two B types) contained in the vaccine.
Vaxigrip Tetra induces humoral antibodies against the haemagglutinins within 2 to 3 weeks. These antibodies neutralise influenza viruses.
Specific levels of haemagglutination-inhibition (HAI) antibody titer post- vaccination with inactivated influenza virus vaccines have not been correlated with protection from influenza illness but the HAI antibody titers have been used as a measure of vaccine activity. In some human challenge studies, HAI antibody titers of ≥1:40 have been associated with protection from influenza illness in up to 50% of subjects.
Since influenza viruses constantly evolve, the virus strains selected in the vaccine are reviewed annually by the WHO. Annual revaccination with Vaxigrip Tetra has not been studied. However, based on clinical experience with the trivalent vaccine, annual influenza vaccination is recommended given the duration of immunity provided by the vaccine and because circulating strains of influenza virus change from year to year.
Efficacy of Vaxigrip Tetra
Paediatric population
- Children from 6 to 35 months of age (active immunisation):
A randomized placebo controlled study was conducted in 4 regions (Africa, Asia, Latina America and Europe) over 4 influenza seasons, in more than 5,400 children from 6 to 35 months of age who received two doses (0.5 mL) of Vaxigrip Tetra (N=2,722), or placebo (N=2,717) 28 days apart to assess Vaxigrip Tetra efficacy for the prevention of laboratory-confirmed influenza illness caused by any strain A and/or B and caused by vaccine similar strains (as determined by sequencing).
Laboratory-confirmed influenza illness was defined as influenza like-illness (ILI) [occurrence of fever ≥ 38°C (that lasts at least 24 hours) concurrently with at least one of the following symptoms: cough, nasal congestion, rhinorrhoea, pharyngitis, otitis, vomiting, or diarrhoea] laboratory-confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) and/or viral culture.

Table 1: Influenza Attack Rates and Vaxigrip Tetra Efficacy against laboratory-confirmed influenza illness in children from 6 to 35 months of age
Vaxigrip Tetra      Placebo            Efficacy
(N=2,584)        (N=2,591) n Influenza n Influenza          % (2-sided 95% CI)
Attack           Attack
Rate (%)         Rate (%)
Laboratory-confirmed influenza illness caused by:
- Any influenza A or B type        122     4.72     255     9.84     52.03 (40.24; 61.66) - Viral strains similar to those          26     1.01      85      3.28       69.33 (51.93; 81.03) contained in the vaccine
N: Number of children analysed (full set) n: number of subjects fulfilling the item listed
CI: Confidence Interval
In addition, a predefined complementary analysis showed Vaxigrip Tetra prevented 56.6% (95% CI: 37.0; 70.5) of severe laboratory-confirmed influenza illnesses due to any strain, and 71.7% (95% CI: 43.7; 86.9) of severe laboratory- confirmed influenza illnesses due to vaccine-similar strains. Furthermore, subjects receiving Vaxigrip Tetra were 59.2% (95% CI: 44.4; 70.4) less likely to experience a medically attended influenza illness than subjects receiving placebo.
Severe laboratory-confirmed influenza illnesses were defined as ILI laboratory- confirmed by RT-PCR and/or viral culture with at least one of the following items: - fever > 39.5°C for subjects aged < 24 months or ≥ 39.0°C for subjects aged ≥ 24 months,
- and/or at least one significant ILI symptom which prevents daily activity (cough, nasal congestion, rhinorrhoea, pharyngitis, otitis, vomiting, diarrhoea), - and/or one of the following events: acute otitis media, acute lower respiratory infection (pneumonia, bronchiolitis, bronchitis, croup), inpatient hospitalization.
- Children from 3 to 8 years of age (active immunisation):
Based on immune responses observed in children 3 to 8 years of age, the efficacy of Vaxigrip Tetra in this population is expected to be at least similar to the efficacy observed in children from 6 to 35 months (see “Children from 6 to 35 months of age” above and “Immunogenicity of Vaxigrip Tetra“ below).
- Infants less than 6 months of age born to vaccinated pregnant women (passive protection):
Infants less than 6 months of age are at high risk of influenza, resulting in high rates of hospitalisation; however influenza vaccines are not indicated for active immunisation in this age group.
Efficacy in infants of women who received a single 0.5 mL dose of Vaxigrip Tetra during the second or third trimester of pregnancy has not been studied; however, efficacy in infants of women who received a single 0.5 mL dose of the trivalent inactivated influenza vaccine (Inactivated Influenza Vaccine (Split Virion) BP) during the second or third trimester has been demonstrated in clinical trials and can be extrapolated to Vaxigrip Tetra.
Efficacy of the trivalent inactivated influenza vaccine (Inactivated Influenza Vaccine (Split Virion) BP) in infants following vaccination of pregnant women during the first trimester has not been studied in these trials. Necessary influenza vaccination during the first trimester should not be postponed (see section 4.6).
In randomized, controlled phase IV clinical studies conducted in Mali, Nepal and South Africa, approximately 5,000 pregnant women received Inactivated Influenza Vaccine (Split Virion) BP (trivalent influenza thiomersal-free vaccine) and approximately 5,000 pregnant women received placebo or control vaccine (quadrivalent meningococcal conjugate vaccine) during the second or third trimester of pregnancy. Vaccine efficacy against laboratory confirmed influenza in pregnant women was evaluated as a secondary endpoint in all three studies.
The studies conducted in Mali and South Africa demonstrated the efficacy of Inactivated Influenza Vaccine (Split Virion) BP for the prevention of influenza in pregnant women following vaccination during these trimesters of pregnancy (see table 2). In the study conducted in Nepal, the efficacy of Inactivated Influenza Vaccine (Split Virion) BP for the prevention of influenza in pregnant women following vaccination during these trimesters of pregnancy was not demonstrated.

Table 2: Influenza Attack Rates and Inactivated Influenza Vaccine (Split Virion) BP Efficacy against Laboratory-confirmed influenza in pregnant women
Influenza Attack Rate           Inactivated Influenza
(Any influenza A or B type)      Vaccine (Split Virion) BP
% (n/N)                        Efficacy
% (95% CI)
TIV                     Control*
Mali                         0.5 (11/2,108)         1.9 (40/2,085)    70.3 (42.2 to 85.8) TIV                     Placebo
South Africa                 1.8 (19/1,062)         3.6 (38/1,054)    50.4 (14.5 to 71.2) * Meningococcal vaccine
N: Number of pregnant women included in analysis n: number of subjects with laboratory confirmed infuenza
CI: Confidence Interval

In the same randomized, controlled phase IV clinical studies conducted in Mali, Nepal and South Africa, 4530 of 4898 (92%) infants born to pregnant women who received Inactivated Influenza Vaccine (Split Virion) BP (trivalent influenza thiomersal free vaccine) and 4532 of 4868 (93%) infants born to pregnant women who received a placebo or control vaccine (quadrivalent meningococcal conjugate vaccine) (see table 3) during the second or third trimester of pregnancy, were followed up until approximately 6 months of age.
The studies confirmed the efficacy of Inactivated Influenza Vaccine (Split Virion) BP for prevention of influenza in infants from birth until approximately 6 months of age following vaccination of women during these trimesters of pregnancy.
Women in their first trimester of pregnancy were not included in these studies; Inactivated Influenza Vaccine (Split Virion) BP efficacy in infants born to mothers vaccinated during the first trimester could therefore not be evaluated.

Table 3: Influenza Attack Rates and Inactivated Influenza Vaccine (Split Virion) BP Efficacy against Laboratory-confirmed influenza in infants following vaccination in pregnant women
Influenza Attack Rate                  Inactivated Influenza
(Any influenza A or B type)             Vaccine (Split Virion) BP
% (n/N)                               Efficacy
% (95% CI)
TIV                    Control*
Mali                       2.4 (45/1,866)         3.8 (71/1,869)         37.3 (7.6 to 57.8) TIV                    Placebo
Nepal                     4.1 (74/1,820)         5.8 (105/1,826)         30.0 (5 to 48) South Africa              1.9 (19/1,026)         3.6 (37/1,023)          48.8 (11.6 to 70.4) * Meningococcal vaccine
N: Number of infants included in the analysis n: number of subjects with laboratory-confirmed influenza
CI: Confidence Interval
The efficacy data indicate a waning protection of the infants born to vaccinated mothers by time after birth.
In the trial conducted in South Africa, vaccine efficacy was highest among infants 8 weeks of age or younger (85.8% [95% CI, 38.3 to 98.4]) and decreased over time; vaccine efficacy was 25.5% (95% CI, -67.9 to 67.8) for infants >8 to 16 weeks of age and 30.4% (95% CI, -154.9 to 82.6) for infants >16 to 24 weeks of age.
In the trial conducted in Mali, there is also a trend of higher efficacy of the trivalent inactivated influenza vaccine in infants during the first 4 months after birth, with lower efficacy within the 5th month of surveillance and a marked fall within the 6th month where protection is no longer evident.
The prevention of influenza disease can only be expected if the infant(s) are exposed to strains included in the vaccine administered to the mother.
Immunogenicity of Vaxigrip Tetra
Clinical studies performed in adults from 18 to 60 years of age, in elderly over 60 years of age, in children from 3 to 8 years of age and from 6 to 35 months of age assessed Vaxigrip Tetra immune response for HAI Geometric mean antibody titer (GMT) at Day 21 (for adults) and at Day 28 (for children), HAI seroconversion rate (4-fold rise in reciprocal titer or change from undetectable [< 10] to a reciprocal titer of ≥ 40), and HAI GMTR (post-/pre-vaccination titers).
One clinical study performed in adults from 18 to 60 years of age and in children from 9 to 17 years of age described the immune response of Vaxigrip Tetra for HAI GMT at Day 21. Another clinical study performed in children from 9 to 17 years of age described the immune response of Vaxigrip Tetra.
One clinical study performed in pregnant women described the immune response of Vaxigrip Tetra for HAI GMT at Day 21, HAI seroconversion rate, and HAI GMTR after one dose administered during the second or third trimester of pregnancy. In this study, the transplacental transfer was evaluated using HAI GMTs of maternal blood, of cord blood and the ratio of cord blood/maternal blood, at delivery.
Vaxigrip Tetra induced a significant immune response to the 4 influenza strains contained in the vaccine.
Adults and elderly
A total of 832 adults from 18 to 60 years of age and 831 elderly over 60 years of age were assessed in terms of immune response after one dose of Vaxigrip Tetra.
Immunogenicity results are presented in the table below:
Table 4: Immunogenicity results in adults aged from 18 to 60 years and in elderly over 60 years of age
18 to 60 years of age                   over 60 years of age
Antigen Strain                          N=832                                  N=831 GMT (95% CI)
(a)(b)
A (H1N1)                            608 (563;657)                          219 (199; 241) A (H3N2)                            498 (459; 541)                         359 (329; 391) B (Victoria)                        708 (661; 760)                         287 (265; 311) B (Yamagata)                      1,715 (1607; 1830)                       655 (611; 701) (c)
SC % (95% CI)
(a)(b)
A (H1N1)                           64.1 (60.7; 67.4)                      45.6 (42.1; 49.0) A (H3N2)                           66.2 (62.9; 69.4)                      47.5 (44.1; 51.0) B (Victoria)                       70.9 (67.7; 74.0)                      45.2 (41.8; 48.7) B (Yamagata)                       63.7 (60.3;67.0)                       42.7 (39.3; 46.2) (d)
GMTR (95% CI)
(a)(b)
A (H1N1)                           9.77 (8.69; 11.0)                      4.94 (4.46; 5.47) A (H3N2)                           10.3 (9.15; 11.5)                      5.60 (5.02; 6.24) B (Victoria)                       11.6 (10.4; 12.9)                      4.61 (4.18; 5.09) B (Yamagata)                       7.35 (6.66;8.12)                       4.11 (3.73; 4.52) N=number of subjects with available data for the considered endpoint
GMT: Geometric Mean Titer; CI: Confidence Interval;
(a) N=833 for 18-60 years of age group
(b) N=832 for over 60 years of age group
(c) 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 ≥four-fold increase from pre- to post-vaccination titer
(d) GMTR: Geometric mean of individual titer ratios (post-/pre-vaccination titers) Pregnant women and transplacental transfer
A total of 230 pregnant women received Vaxigrip Tetra during the second or third trimester of pregnancy (from 20 to 32 weeks of pregnancy).
Immunogenicity results by HAI method, in pregnant women 21 days after vaccination with Vaxigrip Tetra are presented in table 5.

Table 5: Immunogenicity results by HAI method in pregnant women, 21 days post-vaccination with Vaxigrip Tetra
Antigen Strain                                                                    QIV N=216
GMT (95% CI)
A (H1N1)*                                                                     525 (466; 592) A (H3N2)*                                                                     341 (286; 407) B1 (Victoria)*                                                                568 (496; 651) B2 (Yamagata)*                                                                993 (870; 1134) ≥4-fold-rise n (%) (a)
A (H1N1)*                                                                    38.0 (31.5; 44.8) A (H3N2)*                                                                    59.3 (52.4; 65.9) B1 (Victoria)*                                                               61.1 (54.3; 67.7) B2 (Yamagata)*                                                               59.7 (52.9; 66.3) GMTR (95% CI) (b)
A (H1N1)*                                                                    3.81 (3.11; 4.66) A (H3N2)*                                                                    8.63 (6.85; 10.9) B1 (Victoria)*                                                               8.48 (6.81; 10.6) B2 (Yamagata)*                                                               6.26 (5.12; 7.65) *A/H1N1: A/Michigan/45/2015 (H1N1) pdm09-like virus; A/H3N2: A/Hong
Kong/4801/2014 (H3N2)-like virus;
B1: B/Brisbane/60/2008-like virus (B/Victoria lineage);
B2: B/Phuket/3073/2013-like virus (B/Yamagata lineage)
N: number of subjects with available data for the considered endpoint GMT: Geometric Mean Titer; CI: Confidence Interval
(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 ≥four-fold increase from pre- to post-vaccination titer
(b) GMTR: Geometric mean of individual titer ratios (post-/pre-vaccination titers) Immunogenicity descriptive assessment by HAI method, at delivery, in blood sample of mother (BL03M) and in cord blood sample (BL03B) and of the transplacental transfer (BL03B/BL03M) are presented in table 6.

Table 6: Immunogenicity descriptive assessment by HAI method of vaxigrip Tetra, at delivery
QIV
Antigen Strain                                              N=178
BL03M (Maternal blood)
GMT (95% CI)
A (H1N1)*                                                304 (265; 349) A (H3N2)*                                                178 (146; 218) B1 (Victoria)*                                           290 (247; 341) B2 (Yamagata)*                                           547 (463; 646) BL03B (Cord blood)
GMT (95% CI)
A (H1N1)*                                                            576 (492; 675) A (H3N2)*                                                            305 (246; 379) B1 (Victoria)*                                                       444 (372; 530) B2 (Yamagata)*                                                      921 (772; 1099) Transplacental transfer: BL03B/BL03M§ GMT
(95% CI)
A (H1N1)*                                                           1.89 (1.72; 2.08) A (H3N2)*                                                           1.71 (1.56; 1.87) B1 (Victoria)*                                                      1.53 (1.37; 1.71) B2 (Yamagata)*                                                      1.69 (1.54; 1.85) N: number of subjects with available data for the considered endpoint: women who received QIV, delivered at least 2 weeks after injection and with available cord blood and mother blood at the time of delivery.
*A/H1N1: A/Michigan/45/2015 (H1N1) pdm09-like virus; A/H3N2: A/Hong
Kong/4801/2014 (H3N2)-like virus;
B1: B/Brisbane/60/2008-like virus (B/Victoria lineage)
B2: B/Phuket/3073/2013-like virus (B/Yamagata lineage)
§ If a mother has X babies, her titers values is counted X times
At delivery, the higher level of antibodies in the cord sample compared to the maternal sample is consistent with transplacental antibody transfer from mother to the newborn following vaccination of women with Quadrivalent Influenza Vaccine (split virion, inactivated) 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 following vaccination of women during the second or third trimester of pregnancy with Inactivated Influenza Vaccine (Split Virion) BP in studies conducted in Mali, Nepal, and South Africa (see subsection Efficacy of Quadrivalent Influenza Vaccine (split virion, inactivated)).

Paediatric population
- Children from 9 to 17 years of age:
In a total of 429 children from 9 to 17 years of age who received one dose of Vaxigrip Tetra, the immune response against the 4 strains contained in the vaccine was similar to the immune response induced in adults from 18 to 60 years of age.
- Children from 6 months to 8 years of age:
A total of 863 children from 3 to 8 years of age received either one or two doses of Vaxigrip Tetra depending on their previous influenza vaccination history.
Children who received a one- or two-dose schedule of Vaxigrip Tetra presented a similar immune response following the last dose of the respective schedule.
In addition to the Vaxigrip Tetra efficacy, the immunogenicity of two 0.5 mL-dose of Vaxigrip Tetra was assessed 28 days after receipt of the last injection of Vaxigrip Tetra by HAI method in 341 children 6 to 35 months of age.
Immunogenicity results are presented in the table below:
Table 7: Immunogenicity results in children aged from 6 months to 8 years Antigen Strain                     6-35 months of age                      3-8 years of age N=341                                  N=863
GMT (95% CI)
A (H1N1)                              641 (547; 752)                       971 (896; 1,052) A (H3N2)                            1,071 (925; 1,241)                   1,568 (1,451; 1,695) B (Victoria)                          623 (550; 706)                      1,050 (956; 1,154) (a)
B (Yamagata)                        1,010 (885; 1,153)                   1,173 (1,078; 1,276) SC % (95% CI) (b)
A (H1N1)                             90.3 (86.7; 93.2)                     65.7 (62.4; 68.9) A (H3N2)                             90.3 (86.7; 93.2)                     64.8 (61.5; 68.0) B (Victoria)                         98.8 (97.0; 99.7)                     84.8 (82.3; 87.2) (a)
B (Yamagata)                         96.8 (94.3; 98.4)                     88.5 (86.2; 90.6) (c)
GMTR (95% CI)
A (H1N1)                             36.6 (30.8; 43.6)                     6.86 (6.24; 7.53) A (H3N2)                             42.6 (35.1; 51.7)                     7.49 (6.72; 8.35) B (Victoria)                          100 (88.9; 114)                      17.1 (15.5; 18.8) B (Yamagata) (a)                     93.9 (79.5; 111)                      25.3 (22.8; 28.2) N=number of subjects with available data for the considered endpoint
GMT: Geometric Mean Titer; CI: Confidence Interval;
(a) N=862 for 3-8 years of age group
(b) 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 ≥four-fold increase from pre- to post-vaccination titer
(c) GMTR: Geometric mean of individual titer ratios (post-/pre-vaccination titers) These immunogenicity data provide supportive information in addition to vaccine efficacy data available in this population (see Efficacy of Vaxigrip Tetra).

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Not applicable.