ADJUPANRIX Emulsion and suspension for injectable emulsion

Pharmacotherapeutic group: influenza vaccines, ATC code J07BB02.‍​‍‍‍​‍‍‍‍‍‍‍‍​‍ Pharmacodynamic properties This section presents clinical experience obtained following administration of vaccines manufactured as part of pandemic preparedness. Vaccines manufactured as part of pandemic preparedness contain influenza antigens that differ from currently circulating influenza viruses. These antigens may be considered as "novel" antigens and simulate a situation in which the target vaccination population is immunologically naïve. Data obtained with a vaccine manufactured as part of pandemic preparedness will support the vaccination strategy that will likely be used for a pandemic vaccine: clinical immunogenicity, safety and reactogenicity data obtained with vaccines manufactured as part of pandemic preparedness are relevant for pandemic vaccines. Adults Adults aged 18–60 years In clinical studies evaluating the immunogenicity of a vaccine containing AS03 adjuvant and 3.75 micrograms of HA derived from strain A/Vietnam/1194/2004, the anti-haemagglutinin (anti-HA) antibody responses in subjects aged 18–60 years were as follows: Anti-HA antibody Immune response to strain A/Vietnam/1194/2004 Schedule 0, 21 days (D-Pan-H5N1-002) Schedule 0, 6 months (D-Pan-H5N1-012) 21 days after first dose n = 925 21 days after second dose n = 924 21 days after first dose n = 55 7 days after second dose n = 47 21 days after second dose n = 48 Seroprotection rate 1 44.5% 94.3% 38.2% 89.4% 89.6% Seroconversion rate 2 42.5% 93.7% 38.2% 89.4% 89.6% Seroconversion factor 3 4.1 39.8 3.1 38.2 54.2 1seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) antibody titre ≥ 1:40; 2seroconversion rate: proportion of subjects who were either seronegative before vaccination and had a protective post-vaccination titre ≥ 1:40, or who were seropositive before vaccination and had a four-fold increase in titre; 3seroconversion factor: ratio of post-vaccination geometric mean titre (GMT) to pre-vaccination GMT. After two doses administered at an interval of 21 days or 6 months, 96.0% of subjects had a four-fold increase in serum virus neutralising antibody titres and 98–100% had a titre of at least 1:80. In subjects in the D-Pan-H5N1-002 study, persistence of the immune response was monitored. The seroprotection rate at 6, 12 and 24 months after vaccination was as follows: Anti-HA antibody Immune response to strain A/Vietnam/1194/2004 6 months after first dose n = 256 12 months after first dose n = 559 24 months after first dose n = 411 36 months after first dose n = 387 Seroprotection rate 1 40.2% 23.4% 16.3% 16.3% 1seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) titre ≥ 1:40 In a clinical study (Q-Pan-H5N1-001), in which 140 subjects aged 18–60 years received two doses of a vaccine with AS03 adjuvant containing 3.75 micrograms of HA derived from strain A/Indonesia/05/2005 on day 0 and day 21, the anti-HA antibody responses were as follows: Anti-HA antibody Immune response to strain A/Indonesia/05/2005 Day 21 n = 140 Day 42 n = 140 Day 180 n = 138 Seroprotection rate 1 45.7% 96.4% 49.3% Seroconversion rate 2 45.7% 96.4% 48.6% Seroconversion factor 3 4.7 95.3 5.2 1seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) antibody titre ≥ 1:40; 2seroconversion rate: proportion of subjects who were either seronegative before vaccination and had a protective post-vaccination titre ≥ 1:40, or who were seropositive before vaccination and had a four-fold increase in titre; 3seroconversion factor: ratio of post-vaccination geometric mean titre (GMT) to pre-vaccination GMT. A four-fold increase in serum virus neutralising antibody titres was observed in 79.2% of subjects on day 21 after the first dose, in 95.8% of subjects on day 21 after the second dose and in 87.5% of subjects 6 months after the second dose. In a second study, 49 subjects aged 18–60 years received two doses of a vaccine with AS03 adjuvant containing 3.75 micrograms of HA derived from strain A/Indonesia/05/2005 on day 0 and day 21. On day 42, in terms of anti-HA antibodies, the seroconversion rate was 98%, seroprotection was achieved in all subjects and the seroconversion factor was 88.6. In addition, all subjects had virus neutralising antibody titres of at least 1:80. Cross-reactive immune response elicited by administration of a vaccine with AS03 adjuvant containing 3.75 micrograms of HA derived from strain A/Vietnam/1194/2004 (H5N1) Anti-HA antibody responses to strain A/Indonesia/5/2005 following administration of a vaccine with AS03 adjuvant containing 3.75 micrograms of HA derived from strain A/Vietnam/1194/2004 were as follows: Anti-HA antibody Immune response to strain A/Indonesia/5/2005 Schedule 0, 21 days (D-Pan-H5N1-002) Schedule 0, 6 months (D-Pan-H5N1-012) 21 days after second dose n = 924 7 days after second dose n = 47 21 days after second dose n = 48 Seroprotection rate* 1 50.2% 74.5% 83.3% Seroconversion rate 2 50.2% 74.5% 83.3% Seroconversion factor 3 4.9 12.9 18.5 *anti-HA ≥ 1:40 1seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) antibody titre ≥ 1:40; 2seroconversion rate: proportion of subjects who were either seronegative before vaccination and had a protective post-vaccination titre ≥ 1:40, or who were seropositive before vaccination and had a four-fold increase in titre; 3seroconversion factor: ratio of post-vaccination geometric mean titre (GMT) to pre-vaccination GMT. Regardless of the dosing schedule, more than 90% of vaccinees had a four-fold increase in serum virus neutralising antibody titres against strain A/Indonesia/5/2005 after administration of two doses. After administration of two doses at a 6-month interval, all subjects had a titre of at least 1:80. In subjects in the D-Pan-H5N1-002 study, persistence of anti-HA antibodies against strain A/Indonesia/5/2005 was observed. The seroprotection rate was 2.2% at 6 months; 4.7% at 12 months; 2.4% at 24 months and 7.8% at 36 months. In another study (D-Pan-H5N1-007), in 50 subjects aged 18–60 years, 21 days after the second dose of a vaccine with AS03 adjuvant containing 3.75 micrograms of HA derived from strain A/Vietnam/1194/2004, the anti-HA antibody seroprotection rate was 20% against strain A/Indonesia/5/2005, 35% against strain A/Anhui/01/2005 and 60% against strain A/Turkey/Turkey/1/2005. Cross-reactive immune response obtained following administration of a vaccine with AS03 adjuvant containing 3.75 micrograms of HA derived from strain A/Indonesia/5/2005 (H5N1) Following administration of 2 doses of a vaccine with AS03 adjuvant containing 3.75 micrograms of HA derived from strain A/Indonesia/05/2005 on day 0 and day 21 to 140 subjects aged 18–60 years, the anti-HA antibody responses to strain A/Vietnam/1194/2004 were as follows: Anti-HA antibody Immune response to strain A/Vietnam/1194/2004 Day 21 n = 140 Day 42 n = 140 Seroprotection rate 1 15% 59.3% Seroconversion rate 2 12.1% 56.4% Seroconversion factor 3 1.7 6.1 1seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) antibody titre ≥ 1:40; 2seroconversion rate: proportion of subjects who were either seronegative before vaccination and had a protective post-vaccination titre ≥ 1:40, or who were seropositive before vaccination and had a four-fold increase in titre; 3seroconversion factor: ratio of post-vaccination geometric mean titre (GMT) to pre-vaccination GMT. On day 180, the seroprotection rate was 13%. A four-fold increase in serum virus neutralising antibody titres against strain A/Vietnam/1194/2004 was observed in 49% of subjects 21 days after the first dose, 67.3% of subjects 21 days after the second dose and 44.9% of subjects 6 months after the second dose. Alternative schedules An extended dosing interval was investigated in study D-H5N1-012, in which a group of individuals aged 18–60 years received two doses of Adjupanrix vaccine at an interval of 6 or 12 months. Twenty-one days after the second dose, the seroprotection rate in individuals who received the vaccine at 6 months was 89.6% and the vaccine response rate was 95.7% against A/Vietnam/1194/2004. Twenty-one days after the second dose, the seroprotection rate in individuals who received the vaccine at 12 months was 92.0% and the vaccine response rate was 100.0%. Cross-reactive immune response against A/Indonesia/5/2005 was also monitored in this study. Twenty-one days after the second dose, the seroprotection rate in individuals who received the vaccine at 6 months was 83.3% and the vaccine response rate was 100.0%. Twenty-one days after the second dose, the seroprotection rate in individuals who received the vaccine at 12 months was 84.0% and the vaccine response rate was 100.0%. Administration of one dose of vaccine with AS03 adjuvant containing 3.75 micrograms of HA derived from strain A/Indonesia/05/2005 given after one or two doses of vaccine with AS03 adjuvant containing 3.75 micrograms of HA derived from strain A/Vietnam/1194/2004 In a clinical study (D-Pan-H5N1-012), subjects aged 18–60 years were vaccinated with one dose of a vaccine with AS03 adjuvant containing 3.75 micrograms of HA derived either from strain A/Vietnam/1194/2004 or from strain A/Indonesia/05/2005 6 months after they had been vaccinated with one or two primary doses of a vaccine with AS03 adjuvant containing 3.75 micrograms of HA derived from strain A/Vietnam/1194/2004 on day 0, or day 0 and 21, respectively. Anti-HA antibody responses were as follows: Anti-HA antibody Against strain A/Vietnam 21 days after booster with strain A/Vietnam n = 46 Against strain A/Indonesia 21 days after booster with strain A/Indonesia n = 49 After one primary dose After two primary doses After one primary dose After two primary doses Seroprotection rate 1 89.6% 91.3% 98.1% 93.9% Booster seroconversion rate 2 87.5% 82.6% 98.1% 91.8% Booster seroconversion factor 3 29.2 11.5 55.3 45.6 1seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) antibody titre ≥ 1:40; 2booster seroconversion rate: proportion of subjects who were either seronegative before the booster and had a protective post-vaccination titre ≥ 1:40 after the booster, or who were seropositive before the booster and had a four-fold increase in titre after the booster; 3booster seroconversion factor: ratio of geometric mean titre (GMT) before the booster and GMT after the booster. Regardless of whether one or two primary vaccination doses had been administered 6 months previously, the seroprotection rate against A/Indonesia after a dose of vaccine with AS03 adjuvant containing 3.75 micrograms of HA derived from strain A/Vietnam/1194/2004 was > 80% and the seroprotection rate against strain A/Vietnam after a dose of vaccine with AS03 adjuvant containing 3.75 micrograms of HA derived from strain A/Indonesia/05/2005 was > 90%. All subjects achieved virus neutralising antibody titres of at least 1:80 against each of these two strains regardless of the HA type in the vaccine(s) and regardless of the number of previous doses. In another clinical study (D-Pan-H5N1-015), 39 subjects aged 18–60 years received a booster dose of a vaccine with AS03 adjuvant containing 3.75 micrograms of HA derived from strain A/Indonesia/05/2005 14 months after they had received two doses of a vaccine with AS03 adjuvant containing 3.75 micrograms of HA derived from strain A/Vietnam/1194/2004 on day 0 and day 21. The seroprotection rate against strain A/Indonesia was 92% on day 21 after the booster and 69.2% on day 180. In another clinical study (D-Pan-H5N1-038), 387 subjects aged 18–60 years received a booster dose of a vaccine with AS03 adjuvant containing 3.75 micrograms of HA derived from strain A/Indonesia/05/2005 36 months after they had received two doses of a vaccine derived from strain A/Vietnam/1194/2004. At 21 days after the booster, the seroprotection rate was 100%, the booster seroconversion rate was 99.7% and the booster seroconversion factor against strain A/Indonesia/5/2005 was 123.8. Elderly individuals (60 years and older) In another clinical study (D-Pan-H5N1-010), 297 subjects over 60 years of age (divided into groups aged 61 to 70 years, 71 to 80 years and over 80 years) received either a single dose or a double dose of a vaccine with AS03 adjuvant containing 3.75 micrograms of HA derived from strain A/Vietnam/1194/2004 (H5N1) on day 0 and day 21. On day 42, the anti-HA antibody response was as follows: Anti-HA antibody Immune response to strain A/Vietnam/1194/2004 (D42) 61 to 70 years 71 to 80 years > 80 years Single dose n = 91 Double dose n = 92 Single dose n = 48 Double dose n = 43 Single dose n = 13 Double dose n = 10 Seroprotection rate 1 84.6% 97.8% 87.5% 93.0% 61.5% 90.0% Seroconversion rate 2 74.7% 90.2% 77.1% 93.0% 38.5% 50.0% Seroconversion factor 3 11.8 26.5 13.7 22.4 3.8 7.7 1seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) antibody titre ≥ 1:40; 2seroconversion rate: proportion of subjects who were either seronegative before vaccination and had a protective post-vaccination titre ≥ 1:40, or who were seropositive before vaccination and had a four-fold increase in titre; 3seroconversion factor: ratio of post-vaccination geometric mean titre (GMT) to pre-vaccination GMT. Although an adequate immune response on day 42 was achieved after administration of two single doses of a vaccine with AS03 adjuvant containing 3.75 micrograms of HA derived from strain A/Vietnam/1194/2004 (H5N1), a higher response was observed after administration of two double doses of the vaccine. Very limited data from seronegative subjects over 80 years of age (n = 5) indicate that none of the subjects achieved the seroprotection rate after two single doses of a vaccine with AS03 adjuvant containing 3.75 micrograms of HA derived from strain A/Vietnam/1194/2004 (H5N1). However, after two double doses of the vaccine, the seroprotection rate on day 42 was 75%. In subjects in the D-Pan-H5N1-010 study, persistence of the immune response was monitored. The seroprotection rate at 6, 12 and 24 months after vaccination was as follows: Anti-HA antibody Immune response to strain A/Vietnam/1194/2004 6 months after vaccination 12 months after vaccination 24 months after vaccination Single dose (n = 140) Double dose (n = 131) Single dose (n = 86) Double dose (n = 81) Single dose (n = 86) Double dose (n = 81) Seroprotection rate 1 52.9% 69.5% 45.3% 44.4% 37.2% 30.9% 1seroprotection rate: proportion of subjects with haemagglutination inhibition (HI) antibody titre ≥ 1:40 In addition, in 44.8% and 56.1% of subjects according to the respective dosing group, a four-fold increase in serum neutralising antibody titres occurred from day 0 to day 42, and on day 42, 96.6% and 100% of subjects, respectively, had a titre of at least 1:80. Twelve and twenty-four months after vaccination, virus neutralising antibody titres were as follows: Serum virus neutralising antibodies Immune response to strain A/Vietnam/1194/2004 12 months after vaccination 24 months after vaccination Single dose n = 51 Double dose n = 54 Single dose n = 49 Double dose n = 54 GMT 1 274.8 272.0 391.0 382.8 Seroconversion rate 2 27.5% 27.8% 36.7% 40.7% ≥ 1:80 3 82.4% 90.7% 91.8% 100% 1geometric mean titre; 2four-fold increase in serum virus neutralising antibody titres; 3percentage of subjects who had serum virus neutralising antibody titres of at least 1:80. In 297 subjects over 60 years of age, 42 days after the second dose of AS03-adjuvanted vaccine containing 3.75 micrograms of HA derived from strain A/Vietnam/1194/2004, the anti-HA antibody seroprotection rate was 23% and the seroconversion rate against strain A/Indonesia/5/2005 was 23%, and the seroconversion factor was 2.7. A virus neutralising antibody titre of at least 1:40 or at least 1:80 was achieved by 87% and 67%, respectively, of the 87 subjects tested. In subjects in the D-Pan-H5N1-010 study who received a single dose, persistence of anti-HA antibodies against strain A/Indonesia/5/2005 was monitored. The seroprotection rate was 16.3% at 12 months and 4.7% at 24 months. The virus neutralising antibody seroconversion rate against strain A/Indonesia/5/2005 was 15.7% at 12 months and 12.2% at 24 months. The percentage of subjects achieving a virus neutralising antibody titre > 1/80 was 54.9% at 12 months and 44.9% at 24 months. Paediatric population (children aged 6 months to < 18 years) Children aged 6 months to < 36 months In a clinical study Q-Pan-H5N1-023, 37 children aged 6 to < 36 months received two 0.125 ml doses containing strain A/Indonesia/2005 H5N1 on days 0 and 21. Anti-HA immune responses against the homologous strain (A/Indonesia/05/2005) in terms of seroconversion rate in this age group on day 42 (21 days after the second dose) were as follows: Anti-HA antibody Immune response to strain A/Indonesia/05/2005 (0.125 ml) 21 days after second dose (day 42) n 1 = 33 Seroconversion rate 2 100% Seroconversion factor 3 168.2 1according-to-protocol (ATP) immunogenicity cohort; 2seroconversion rate: proportion of subjects who were either seronegative before vaccination and had a protective post-vaccination titre ≥ 1:40, or who were seropositive before vaccination and had a 4-fold increase in titre; 3seroconversion factor: ratio of post-vaccination reciprocal HI titre to pre-vaccination reciprocal HI titre (on day 0). In children aged 6 to < 36 months vaccinated with the 0.125 ml dose (Q-Pan-H5N1-023), 100% of subjects (n = 31) had a vaccine response rate for A/Indonesia/05/2005, 96.9% of subjects (n = 32) had a vaccine response rate for the heterologous strain A/Vietnam/1194/2004 and 96.9% of subjects (n = 32) had a vaccine response rate for the heterologous strain A/duck/Bangladesh/19097/2013. Subjects enrolled in study Q-Pan-H5N1-023 were monitored for persistence of the anti-HA immune response against homologous strain A/Indonesia/05/2005 and heterologous strains A/duck/Bangladesh/19097, A/Vietnam/1194/2004 and A/gyrfalcon/Washington/41088-6/2014 at 12 months. The seroconversion rate at 12 months after the second dose in children aged 6 to < 36 months was as follows: Anti-HA antibody 0.125 ml Immune response to strain A/Indonesia/05/2005 Immune response to strain A/duck/Bangladesh/19097/2013 Immune response to strain A/Vietnam/1194/2004 Immune response to strain A/gyrfalcon/Washington/41088-6/2014 12 months after second dose n 1 = 33 12 months after second dose n 1 = 29 12 months after second dose n 1 = 29 12 months after second dose n 1 = 29 Seroconversion rate 2 78.8% 20.7% 27.6% 0% 1according-to-protocol (ATP) immunogenicity cohort on day 385 (persistence of immune response); 2seroconversion rate: proportion of subjects who were either seronegative before vaccination and had a protective post-vaccination titre ≥ 1:40, or who were seropositive before vaccination and had a 4-fold increase in titre. In study Q-Pan-H5N1-023, following primary vaccination with two 0.125 ml doses containing strain A/Indonesia/2005 (H5N1), one booster dose of the same Q-H5N1 vaccine was administered at month 12. The anti-HA immune response against strain A/Indonesia/05/2005 was evaluated 7 days after the booster dose. The seroconversion rate was as follows: Anti-HA antibody 0.125 ml Immune response to strain A/Indonesia/05/2005 Immune response to strain A/duck/Bangladesh/19097/2013 Immune response to strain A/Vietnam/1194/2004 Immune response to strain A/gyrfalcon/Washington/41088-6/2014 7 days after booster dose n 1 = 33 7 days after booster dose n 1 = 29 7 days after booster dose n 1 = 29 7 days after booster dose n 1 = 29 Seroconversion rate 2 100% 100% 100% 51.7% 1according-to-protocol (ATP) immunogenicity cohort on day 392 (after booster dose); 2seroconversion rate: proportion of subjects who were either seronegative before vaccination and had a protective post-vaccination titre ≥ 1:40, or who were seropositive before vaccination and had a 4-fold increase in titre. Children aged 36 months to < 18 years In a clinical study (D-Pan-H5N1-032), 312 children aged 3 to < 18 years were vaccinated with two 0.25 ml doses containing strain A/Indonesia/2005 H5N1 on days 0 and 21. The result presented below is from the group in which subjects received 2 doses (D0, D21) of H5N1 Indonesia vaccine, 1 booster dose (D182) of H5N1 Turkey vaccine (1.9 micrograms HA + AS03B) and 1 dose (D364) of Havrix. On day 42 (21 days after the second dose), the immune responses in terms of seroconversion rate against the homologous strain were as follows: Anti-HA antibody Immune response to strain A/Indonesia/05/2005 Immune response to strain A/Turkey/01/2005 21 days after second dose n 1 = 155 21 days after second dose n 1 = 155 3 to < 10 years n 2 = 79 10 to < 18 years n 2 = 76 3 to < 10 years n 2 = 79 10 to < 18 years n 2 = 76 Seroconversion rate 3 100% 98.7% 100% 97.4% Seroconversion factor 4 118.9 78.3 36.2 21.0 1according-to-protocol (ATP) immunogenicity cohort on day 42; 2age-specific according-to-protocol (ATP) immunogenicity cohort on day 42; 3seroconversion rate: proportion of subjects who were either seronegative before vaccination and had a protective post-vaccination titre ≥ 1:40, or who were seropositive before vaccination and had a 4-fold increase in titre; 4seroconversion factor: ratio of post-vaccination reciprocal HI titre to pre-vaccination reciprocal HI titre (on day 0). Subjects enrolled in study D-Pan-H5N1-032 were monitored for persistence of the anti-HA immune response against homologous strain A/Indonesia/05/2005 and heterologous strain A/Turkey/01/2005 at 6 months. The seroconversion rate on day 182 in children aged 3 to < 18 years was as follows: Anti-HA antibody Immune response to strain A/Indonesia/05/2005 Immune response to strain A/Turkey/01/2005 Vaccination schedule 0, 21 days Vaccination schedule 0, 21 days Day 182 n 1 = 155 Day 182 n 1 = 155 3 to < 10 years n 2 = 79 10 to < 18 years n 2 = 76 3 to < 10 years n 2 = 79 10 to < 18 years n 2 = 76 Seroconversion rate 2 83.5% 73.7% 55.7% 40.8% Seroconversion factor 3 10.2 8.1 6.2 5.1 1according-to-protocol (ATP) immunogenicity cohort on day 42; 2age-specific according-to-protocol (ATP) immunogenicity cohort on day 42; 3seroconversion rate: proportion of subjects who were either seronegative before vaccination and had a protective post-vaccination titre ≥ 1:40, or who were seropositive before vaccination and had a 4-fold increase in titre; 3seroconversion factor: ratio of post-vaccination reciprocal HI titre to pre-vaccination reciprocal HI titre (on day 0). Following primary vaccination with two 0.25 ml doses containing strain A/Indonesia/2005 (H5N1), one booster dose of D-H5N1 containing strain A/Turkey/2005/HA was administered at month 6 to children aged 3 to < 18 years (D-PAN-H5N1-032). Antibody immunogenicity following the booster dose against strain A/Indonesia/05/2005 was evaluated at 10 days (day 192) and antibody persistence at 6 months (day 364) after the booster dose. The seroconversion rates and factors at these time points were as follows: Anti-HA antibody Immune response to strain A/Indonesia/05/2005 1 Day 192 n 1 = 127 3 to < 10 years n 2 = 68 10 to < 18 years n 2 = 59 Seroconversion rate 5 100% 100% Seroconversion factor 6 142.6 94.4 Day 364 n 3 = 151 3 to < 10 years n 4 = 79 10 to < 18 years n 4 = 72 Seroconversion rate 5 100% 100% Seroconversion factor 6 42.4 30.4 1according-to-protocol (ATP) immunogenicity cohort at month 6; 2age-specific according-to-protocol (ATP) immunogenicity cohort at month 6; 3according-to-protocol (ATP) immunogenicity cohort at month 12; 4age-specific according-to-protocol (ATP) immunogenicity cohort at month 12; 5seroconversion rate: proportion of subjects who were either seronegative before vaccination and had a protective post-vaccination titre ≥ 1:40, or who were seropositive before vaccination and had a 4-fold increase in titre; 6seroconversion factor: ratio of post-vaccination reciprocal HI titre to pre-vaccination reciprocal HI titre (on day 0). Similar immunogenicity results for primary vaccination were obtained in a clinical study (D-PAN-H5N1-009) conducted in 102 children aged 3 to 5 years and 6 to 9 years who received two 0.25 ml doses of Adjupanrix vaccine containing strain A/Vietnam/1194/2004. This study also evaluated antibody persistence against homologous strain A/Vietnam/1194/2004 up to 24 months after the second dose. The seroconversion rate at month 24 was 38.3% in children aged 3 to 5 years and 22.9% in children aged 6 to 9 years. Cross-reactive antibody responses against heterologous strain A/Indonesia/05/2005 were also observed and, although declining, persisted up to 24 months after the second dose. Information from non-clinical studies: The ability of the vaccine to elicit protection against homologous and heterologous strains was evaluated in non-clinical studies using ferret challenge models. In each experiment, four groups of 6 ferrets were administered intramuscularly a vaccine with AS03 adjuvant containing HA derived from strain H5N1/A/Vietnam/1194/04 (NIBRG-14). Doses of 15, 5, 1.7 or 0.6 micrograms of HA were tested in the homologous strain experiment and doses of 15, 7.5, 3.8 or 1.75 micrograms of HA were tested in the heterologous strain experiment. Control groups included ferrets given adjuvant alone, vaccine without adjuvant (15 micrograms HA) or phosphate-buffered saline. Ferrets were vaccinated on day 0 and 21 and were then challenged intratracheally on day 49 with a lethal dose of strain H5N1/A/Vietnam/1194/04 or heterologous strain H5N1/A/Indonesia/5/05. Of the ferrets that received the adjuvanted vaccine, 87% and 96%, respectively, were protected against the lethal dose of homologous and heterologous strains. In vaccinated animals, virus shedding into the upper respiratory tract was also reduced compared to controls, suggesting a reduction in the risk of viral transmission. All animals in the control group that received vaccine without adjuvant or in the adjuvant-only control group died or had to be euthanised three to four days after the start of the challenge due to overall poor condition. This medicinal product has been authorised under "exceptional circumstances". This means that for scientific reasons it has not been possible to obtain complete information on this product. The European Medicines Agency will review any new information that may become available on an annual basis and this Summary of Product Characteristics (SmPC) will be updated as necessary.