Vaxigrip Mechanism of Action

Pharmacotherapeutic group: Influenza vaccine. ATC code: J07BB02.
Pharmacology: Pharmacodynamics: Mechanism of action: Vaxigrip provides active immunisation against three influenza virus strains (two A subtypes and one B type) contained in the vaccine.
Vaxigrip induces humoral antibodies 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 neutralizing antibodies.
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 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: Efficacy data of Vaxigrip are available in pregnant women and in infants less than 6 months of age born to vaccinated pregnant women (passive protection).
No efficacy studies were performed with Vaxigrip in children and adolescents from 9 to 17 years of age, in adults and in the elderly.
In children from 6 to 35 months of age and from 3 to 8 years of age (active immunisation), Vaxigrip efficacy is based on extrapolation of Quadrivalent Influenza Vaccine (split virion, inactivated) efficacy.
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 hospitalization; 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 during the second or third trimester of pregnancy has been demonstrated in clinical trials.
Efficacy of Vaxigrip 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 Use in Pregnancy & Lactation).
In randomized, controlled phase IV clinical studies conducted in Mali, Nepal and South Africa, approximately 5,000 pregnant women received Vaxigrip 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 Vaxigrip for the prevention of influenza in pregnant women following vaccination during these trimesters of pregnancy (see Table 1). In the study conducted in Nepal, the efficacy of Vaxigrip for the prevention of influenza in pregnant women following vaccination during these trimesters of pregnancy was not demonstrated.

Click on icon to see table/diagram/image

In the same randomized, controlled phase IV clinical studies conducted in Mali, Nepal and South Africa, 4,530 of 4,898 (92%) infants born to pregnant women who received Vaxigrip and 4,532 of 4,868 (93%) infants born to pregnant women who received a placebo or control vaccine (quadrivalent meningococcal conjugate vaccine) (see Table 2) during the second or third trimester of pregnancy, were followed up until approximately 6 months of age.
The studies confirmed the efficacy of Vaxigrip 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; Vaxigrip efficacy in infants born to mothers vaccinated during the first trimester could therefore not be evaluated. (See Table 2.)

Click on icon to see table/diagram/image

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 Vaxigrip in infants during the first 4 months after birth, with lower efficacy within the 5^th month of surveillance and a marked fall within the 6^th 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.
Children from 6 to 35 months of age (active immunisation): A randomized placebo controlled study was conducted in 4 regions (Africa, Asia, Latin 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 Quadrivalent Influenza Vaccine (split virion, inactivated) (N=2,722), or placebo (N=2,717) 28 days apart to assess Quadrivalent Influenza Vaccine (split virion, inactivated) 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. (See Table 3.)

Click on icon to see table/diagram/image

In addition, a predefined complementary analysis showed Quadrivalent Influenza Vaccine (split virion, inactivated) 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 Quadrivalent Influenza Vaccine (split virion, inactivated) 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 of Quadrivalent Influenza Vaccine (split virion, inactivated) observed in children 3 to 8 years of age, the efficacy of Vaxigrip 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 (active immunisation)" as previously mentioned and "Immunogenicity" as follows).
Immunogenicity: 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 described Vaxigrip (TIV) and Quadrivalent Influenza Vaccine (split virion, inactivated) (QIV) 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 Quadrivalent Influenza Vaccine (split virion, inactivated) and Vaxigrip for HAI GMT at Day 21. Another clinical study performed in children from 9 to 17 years of age described the immune response of Quadrivalent Influenza Vaccine (split virion, inactivated).
One clinical study performed in pregnant women described the immune response of Quadrivalent Influenza Vaccine (split virion, inactivated) and Vaxigrip 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.
Overall, Vaxigrip induced an immune response to the 3 influenza strains contained in the vaccine.
In children from 3 years of age, in adults including pregnant women and in the elderly, Vaxigrip was as immunogenic as Quadrivalent Influenza Vaccine (split virion, inactivated) for the strains in common.
Adults and elderly: In one clinical study, the immune response was described in adults from 18 to 60 years of age and elderly over 60 years of age who received one 0.5-mL dose of Vaxigrip or Quadrivalent Influenza Vaccine (split virion, inactivated).
The immunogenicity results by HAI method in adults from 18 to 60 years of age and elderly over 60 years of age are presented in Table 4. (See Table 4.)

Click on icon to see table/diagram/image

Pregnant women and transplacental transfer: In one clinical study, a total of 116 pregnant women received Vaxigrip and 230 pregnant women received Quadrivalent Influenza Vaccine (split virion, inactivated) 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 or Quadrivalent Influenza Vaccine (split virion, inactivated) are presented in Table 5. (See Table 5.)

Click on icon to see table/diagram/image

Immunogenicity descriptive assessment by HAI method, at delivery, in blood sample of mother (BL03M), in cord blood sample (BL03B) and of the transplacental transfer (BL03B/BL03M) are presented in Table 6. (See Table 6.)

Click on icon to see table/diagram/image

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 Vaxigrip or 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 Vaxigrip in studies conducted in Mali, Nepal, and South Africa (see Efficacy as previously mentioned).
Paediatric population: Children from 9 to 17 years of age: In a total of 55 children from 9 to 17 years of age who received one dose of Vaxigrip and 429 who received one dose of Quadrivalent Influenza Vaccine (split virion, inactivated), the immune response against the strains contained in the vaccine was similar to the immune response induced in adults 18 to 60 years of age.
Children from 3 years to 8 years of age: In one clinical study, the immune response was described in children from 3 to 8 years of age who received either one or two 0.5-mL doses of Vaxigrip or Quadrivalent Influenza Vaccine (split virion, inactivated), depending on their previous influenza vaccination history.
Children who received a one- or two-dose schedule of Vaxigrip or Quadrivalent Influenza Vaccine (split virion, inactivated) presented a similar immune response following the last dose of the respective schedule.
The immunogenicity results by HAI method 28 days after receipt of the last injection are presented in Table 7.
Children from 6 months to 35 months of age: In one clinical trial, the immune response was described in children from 6 to 35 months of age who received two 0.5-mL doses of Vaxigrip or Quadrivalent Influenza Vaccine (split virion, inactivated).
The immunogenicity results by HAI method, 28 days after receipt of the last injection are presented in Table 7. (See Table 7.)

Click on icon to see table/diagram/image

These immunogenicity data provide supportive information in addition to efficacy data available in children from 6 to 35 months of age (see Efficacy as previously mentioned).
Pharmacokinetics: Not applicable.
Toxicology: Preclinical safety data: Data in animals generated with Quadrivalent Influenza Vaccine (split virion, inactivated) (60 µg of total amount HA/dose) can be extrapolated to Vaxigrip (45 µg of total amount HA/dose): these data revealed no unexpected findings and no target organ toxicity.