ADACEL Suspension for injection

Pharmacotherapeutic group: Combinations of bacterial and viral vaccines.‍​‍‍‍​‍‍‍‍‍‍‍‍​‍ Vaccines against diphtheria, tetanus, pertussis and poliomyelitis. ATC code: J07CA02 Clinical studies Immune responses in children aged 3 to 6 years, adolescents and adults observed one month after vaccination with Adacel Polio are presented in the table below. Table 2: Immune responses 4 weeks after vaccination with Adacel Polio Antibody Criterion Children aged 3-5 years 1 (n = 148) Children aged 5-6 years 2 (n = 240) Adults and adolescents 3 (n = 994) Diphtheria (SN, IU/ml) ≥0.1 100% 99.4% 92.8% Tetanus (ELISA, IU/ml or EU/ml) 4 ≥0.1 100% 99.5% 100% Pertussis (ELISA, EU/ml) Pertussis toxoid Filamentous haemagglutinin PertactinFimbriae, types 2 and 3 ≥5 5 99.3%99.3%100%100% 91.2%99.1%100%99.5% 99.7%99.9%99.6%99.8% IPV (SN, titre)Type 1Type 2Type 3 ≥1:8 100%100%100% 100%100%100% 99.9%100%100% ELISA: Enzyme Linked Immunoassay; EU: ELISA units; IPV: inactivated poliomyelitis vaccine; IU: international units; n: number of participants who received Adacel Polio; SN: seroneutralisation. 1 Studies U01-Td5I-303 and U02-Td5I-402 were conducted in the United Kingdom in children who had previously been vaccinated with DTwP and OPV at the age of 2, 3 and 4 months. Study U01-Td5I-303 included children aged 3.5-5 years. Study U02-Td5I-402 included children aged 3 to 3.5 years. 2 The Sweden 5.5 study was conducted in Swedish children aged 5–6 years who had been vaccinated with DTaP and IPV at the age of 3, 5 and 12 months. 3 Studies TD9707 and TD9809 were conducted in Canada. Study TD9707 included adolescents aged 11-17 years and adults aged 18-64 years. Study TD9809 included adolescents aged 11-14 years. 4 Tetanus units differed according to the testing laboratory. Results were in IU/ml for the Sweden 5.5 study and in EU/ml for the other studies. 5 Antibody levels ≥5 EU/ml were considered possible surrogate markers of protection against pertussis according to Storsaeter J. et al, Vaccine 1998;16:1907-16. The use of Adacel Polio in children aged 3 to 6 years is based on studies in which Adacel Polio was administered as the fourth dose (first booster dose) of diphtheria, tetanus, pertussis and poliomyelitis vaccines. Robust immune responses were observed after administration of a single dose of Adacel Polio in children vaccinated in infancy with either whole-cell pertussis vaccine (DTwP) and OPV (United Kingdom study; aged 3–5 years) or acellular pertussis vaccine (DTaP) and IPV (Swedish study; aged 5-6 years). The safety and immunogenicity of Adacel Polio in adults and adolescents were shown to be comparable to the safety and immunogenicity observed with a single booster dose of adsorbed Td or TdPolio vaccines containing similar amounts of tetanus and diphtheria toxoids and inactivated polioviruses types 1, 2 and 3. The lower response to diphtheria toxoid likely reflected the inclusion of some study participants with uncertain or incomplete vaccination history. Serological correlates of protection against pertussis have not yet been established. Based on a comparison of data from the Sweden I pertussis vaccine efficacy studies conducted between 1992 and 1996, which demonstrated 85% protective efficacy against pertussis disease following primary vaccination with the paediatric DTaP vaccine containing the acellular pertussis vaccine from Sanofi Pasteur, it can be concluded that Adacel Polio induced a protective immune response in clinical trials in children, adolescents and adults. Antibody persistence Pivotal studies conducted with Adacel provided follow-up serological data at 3, 5 and 10 years in individuals previously immunised with a single booster dose of Adacel. Persistence of seroprotection against diphtheria and tetanus and seropositivity to pertussis are summarised in Table 3. Table 3: Rate (%) of persistence of seroprotection/seropositivity in children, adolescents and adults at 3, 5 and 10 years following administration of a dose of Adacel (Tdap component of Adacel Polio) (PPI population 1 ) Children(4-6 years) 2 Adolescents(11-17 years) 3 Adults(18-64 years) 3 Time since Adacel dose 5 years 3 years 5 years 10 years 3 years 5 years 10 years Participants n=128-150 n=300 n=204-206 n=28-39 n=292 n=237-238 n=120-136 Antibody % seroprotection/seropositivity Diphtheria(SN, IU/ml) ≥ 0.1 86.0 97.0 95.1 94.9 81.2 81.1 84.6 ≥ 0.01 100.0 100.0 100.0 100.0 95.2 93.7 99.3 Tetanus(ELISA, IU/ml) ≥ 0.1 97.3 100.0 100.0 100.0 99.0 97.1 100.0 Pertussis(ELISA, EU/ml) Seropositivity 4 63.3 97.3 85.4 82.1 94.2 89.1 85.8 PT FHA 97.3 100.0 99.5 100.0 99.3 100.0 100.0 PRN 95.3 99.7 98.5 100.0 98.6 97.1 99.3 FIM 98.7 98.3 99.5 100.0 93.5 99.6 98.5 ELISA: Enzyme Linked Immunoassay; EU: ELISA units; IU: international units; n: number of participants with available data; PPI: per-protocol immunogenicity; SN: seroneutralisation. 1 Eligible participants for whom immunogenicity data were available for at least one antibody at the specified time point. 2 Study Td508 was conducted in Canada in children aged 4–6 years. 3 Study Td506 was conducted in the United States in adolescents aged 11-17 years and adults aged 18-64 years. 4 Percentage of participants with antibodies ≥ 5 EU/ml for PT, ≥ 3 EU/ml for FHA and PRN and ≥ 17 EU/ml for FIM at 3-year follow-up; ≥ 4 EU/ml for PT, PRN and FIM and ≥ 3 EU/ml for FHA at 5-year and 10-year follow-up. Follow-up studies conducted with Adacel Polio provide serological data at 1, 3, 5 and 10 years in individuals previously immunised with a single booster dose of Adacel Polio. Persistence of seroprotection against diphtheria and tetanus, seropositivity to pertussis and seroprotective antibody levels (dilution ≥1:8) against each poliovirus (types 1, 2 and 3) are summarised in Table 4. Table 4: Rate (%) of persistence of seroprotection/seropositivity in children, adolescents and adults at 1, 3, 5 and 10 years following administration of a dose of Adacel Polio (ITT population 1 ) Children(3.5-5 years) 2 Adolescents(11-17 years) 2 Adults(18-64 years) 2 Time since Adacel Polio dose 1year 3years 5 years 1year 3years 5years 10 years 1year 3years 5years 10years Participants n=36-37 n=36 n=38-48 n=6 4 n=117 n=108 n=97-107 n=3 2 n=135-136 n=127 n=67-79 Antibody % seroprotection/seropositivity Diphtheria(SN,IU/ml) ≥ 0.1 89.2 72.2 75.0 71.9 85.2 77.1 68.5 62.5 55.6 35.2 32.9 ≥ 0.01 100 100 100 100 99.1 96.2 99.1 90.6 91.9 79.2 84.8 Tetanus(ELISA,IU/ml) ≥ 0.1 100 100 100 100 100 100 97.2 100 97.8 98.4 93.7 Pertussis(ELISA,EU/ml) Seropositivity 3,4 89.2 61.1 55.3 98.4 96.6 99.1 87.6 100 97.1 97.6 91.0 PT FHA 100 94.4 100 100 99.1 99.1 98.1 100 100 100 100 PRN 97.3 91.7 95.7 100 99.1 100 88.8 100 99.3 98.4 93.7 FIM 100 100 95.7 98.4 98.3 98.1 100 93.8 94.1 93.7 98.7 IPV(SN, titre) ≥ 1:8 Type 1 100 100 97.9 98.4 100 100 NA 100 100 100 NA Type 2 100 100 100 100 100 100 NA 100 100 100 NA Type 3 100 97.2 95.7 98.4 100 98.2 NA 100 100 100 NA ELISA: Enzyme Linked Immunoassay; EU: ELISA units; IPV: inactivated poliomyelitis vaccine; ITT: intention to treat; IU: international units; n: number of participants with available data; NA: not analysed; SN: seroneutralisation. 1 ITT population: Study U01-Td5I-303-LT: Eligible participants for whom immunogenicity data were available for at least one antibody at the specified time point and at Year 5. Study TD9707-LT: Eligible participants for whom immunogenicity data were available for at least one antibody at the specified time point. 2 Study U01-Td5I-303-LT conducted in the United Kingdom in children aged 3.5-5 years; study TD9707-LT conducted in Canada in adolescents aged 11-17 years and adults aged 18-64 years. 3 For study U01-Td5I-303-LT: percentage of participants with antibodies ≥ 5 EU/ml for PT, ≥ 3 for FHA and ≥ 4 for PRN and FIM at 1-year follow-up; ≥ 4 EU/ml for PT, FIM and PRN and ≥ 3 EU/ml for FHA at 3-year and 5-year follow-up. 4 For study TD9707-LT: percentage of participants with antibodies ≥ 5 EU/ml for PT, ≥ 3 EU/ml for FHA and PRN and ≥ 17 EU/ml for FIM at any follow-up time point except 10 years; ≥ 4 EU/ml for PT, FIM and PRN and ≥ 3 EU/ml for FHA at 10-year follow-up. Immunogenicity after repeat vaccination The immunogenicity of Adacel after repeat vaccination was evaluated 10 years after the previous dose of Adacel or Adacel Polio. One month after vaccination, ≥ 98.5% of study participants achieved seroprotective antibody levels (≥ 0.1 IU/ml) against diphtheria and tetanus and ≥ 84% achieved a booster response to pertussis antigens. (A positive booster response to pertussis was defined as a post-vaccination antibody concentration that is ≥ 4 times the LLOQ (lower limit of quantification) if the pre-vaccination baseline level is < LLOQ; ≥ 4 times the baseline antibody level if the baseline level was ≥ LLOQ but < 4 times the LLOQ; or ≥ 2 times the baseline antibody level if the baseline value was ≥ 4 times the LLOQ). Based on follow-up serological data and repeat vaccination data, Adacel Polio can be used instead of dT vaccine or dT-IPV vaccine to boost immunity against pertussis in addition to diphtheria and tetanus. Immunogenicity in unvaccinated individuals After administration of a single dose of Adacel Polio to 330 adults aged ≥40 years who had not received any diphtheria and tetanus vaccine in the preceding 20 years: ≥95.8% of adults were seropositive (≥ 5 IU/ml) for antibodies against all pertussis antigen-containing vaccines, 82.4% and 92.7% were protected against diphtheria with a threshold of ≥0.1 and ≥0.01 IU/ml, respectively, 98.5% and 99.7% were protected against tetanus with a threshold of ≥0.1 and ≥0.01 IU/ml, respectively, and ≥98.8% were protected against polio (types 1, 2 and 3) with a dilution threshold of ≥1:8. After administration of two additional doses of a vaccine containing diphtheria, tetanus and polio to 316 subjects one to six months after the first dose, the seroprotection rate against diphtheria was 94.6% and 100% (≥0.1 and ≥ 0.01 IU/ml, respectively), against tetanus 100% (≥0.1 IU/ml) and 100% against polio (types 1, 2 and 3) (dilution ≥1:8) (see Table 4). Table 5: Serological immune status (seroprotection/serological response rate and GMC/GMT) before vaccination and after each dose of a 3-dose vaccination regimen including Adacel Polio (dose 1) followed by 2 doses of REVAXIS 1 and 6 months later (doses 2 and 3) in subjects vaccinated per protocol (FAS) Antigen Criterion Before vaccination After dose 1Adacel Polio After dose 2REVAXIS After dose 3REVAXIS n=330 n=330 n=325 n=316 Diphtheria GMC 0.059 0.813 1.373 1.489 (SN, IU/ml) 95%CI [0.046; 0.077] [0.624; 1.059] [1.100; 1.715] [1.262; 1.757] ≥0.1 44.5% 82.4% 90.5% 94.6% 95%CI [39.1; 50.1] [77.9; 86.4] [86.7; 93.4] [91.5; 96.8] ≥0.01 72.4% 92.7% 96.0% 100% 95%CI [67.3; 77.2] [89.4; 95.3] [93.3; 97.9] [98.8; 100] Tetanus GMC 0.48 6.82 7.60 5.46 (ELISA, IU/ml) 95%CI [0.39;0.60] [5.92;7.87] [6.77;8.52] [5.01;5.96] ≥0.1 81.2% 98.5% 100% 100% 95%CI [76.6; 85.3] [96.5; 99.5] [98.9; 100] [98.8; 100] ≥0.01 92.4% 99.7% 100% 100% 95%CI [89.0; 95.0] [98.3; 100] [98.9; 100] [98.8; 100] Poliomyelitis (SN, 1/dil) Type 1 GMT 162.6 2 869.0 2 320.2 1 601.9 95%CI [133.6; 198.0] [2 432.9; 3 383.4] [2 010.9; 2 677.0] [1 425.4; 1 800.3] ≥8 93.3% 99.4% 100% 100% 95%CI [90.1; 95.8] [97.8; 99.9] [98.9; 100] [98.8; 100] Type 2 GMT 164.5 3 829.7 3 256.0 2 107.2 95%CI [137.6;196.8] [3 258.5;4 501.1] [2 818.2;3 761.7] [1 855.7;2 392.8] ≥8 95.5% 100% 100% 100% 95%CI [92.6; 97.4] [98.9; 100] [98.9; 100] [98.8; 100] Type 3 GMT 69.0 5 011.4 3 615.6 2 125.8 95%CI [56.9; 83.6] [4 177.4; 6 012.0] [3 100.5; 4216.4] [1 875.5; 2409.6] ≥8 89.1% 98.8% 99.7% 100% 95%CI [85.2; 92.2] [96.9; 99.7] [98.3; 100] [98.8; 100] Pertussis (ELISA, EU/ml) PT GMC 7.7 41.3 95%CI [6.8; 8.7] [36.7; 46.5] ≥5 - 96.3% - - 95%CI [93.6; 98.1] FHA GMC 28.5 186.7 95%CI [25.5; 31.8] [169.6; 205.6] ≥5 - 100% - - 95%CI [98.9; 100] PRN GMC 7.7 328.6 95%CI [6.7; 8.9] [273.0; 395.6] ≥5 - 99.4% - - 95%CI [97.8; 99.9] FIM GMC 6.1 149.6 95%CI [5.2; 7.1] [123.6; 181.0] ≥5 - 95.8% - - 95%CI [93.0; 97.7] GMC: Geometric mean antibody concentrations; GMT: Geometric mean antibody titres; CI: Confidence interval; SN: seroneutralisation; ELISA: Enzyme Linked Immunoassay; dil: dilution FAS: Full Analysis Set – includes all subjects who received a dose of the study vaccine and for whom a post-vaccination immunogenicity assessment was available. Immunogenicity in pregnant women Antibody responses to pertussis in pregnant women are generally similar to those in non-pregnant women. Vaccination during the second or third trimester is optimal for transplacental transfer of antibodies to the developing foetus. Immunogenicity against pertussis in infants (aged <3 months) born to women vaccinated during pregnancy Data from 2 published randomised controlled trials demonstrated that infants born to women vaccinated with ADACEL during pregnancy had higher pertussis antibody concentrations at birth and at two months of age (i.e., before the start of their primary vaccination) compared to infants born to women who were not vaccinated against pertussis during pregnancy. In the first study, 33 pregnant women received ADACEL and 15 received saline placebo at 30 to 32 weeks of gestation. The geometric mean concentration (GMC) of pertussis antibodies in EU/ml against PT, FHA, PRN and FIM antigens in infants of vaccinated women was 68.8, 234.2, 226.8 and 1,867.0 at birth and 20.6, 99.1, 75.7 and 510.4 at 2 months of age, respectively. In the control group of infants, the corresponding GMCs were 14.0, 25.1, 14.4 and 48.5 at birth and 5.3, 6.6, 5.2 and 12.0 at 2 months of age. The GMC ratios (ADACEL/control group) were 4.9, 9.3, 15.8 and 38.5 at birth and 3.9, 15.0, 14.6 and 42.5 at 2 months of age. In the second study, 134 pregnant women received ADACEL and 138 received a control tetanus and diphtheria vaccine at a mean gestational age of 34.5 weeks. The GMC (EU/ml) of pertussis antibodies against PT, FHA, PRN and FIM antigens in infants of vaccinated women was 54.2, 184.2, 294.1 and 939.6 at birth and 14.1, 51.0, 76.8 and 220.0 at 2 months of age, respectively. In the control group of infants, the corresponding GMCs were 9.5, 21.4, 11.2 and 31.5 at birth and 3.6, 6.1, 4.4 and 9.0 at 2 months of age. The GMC ratios (ADACEL/control group) were 5.7, 8.6, 26.3 and 29.8 at birth and 3.9, 8.4, 17.5 and 24.4 at 2 months of age. As demonstrated in observational effectiveness studies, higher antibody concentrations are expected to provide infants with passive immunity against pertussis during the first 2 to 3 months of life. Immunogenicity in infants and toddlers born to women vaccinated during pregnancy The immunogenicity of routine vaccination in infants of women vaccinated with ADACEL POLIO or ADACEL was assessed in several published studies. During the first year of life of these infants, their antibody responses to pertussis antigens and other antigens were evaluated. Maternal antibodies acquired from vaccination with ADACEL POLIO or ADACEL may be associated with blunting of the infant's immune response to active immunisation against pertussis. Based on data from current epidemiological studies, this blunting may not be clinically relevant. Data from several studies showed no clinically relevant blunting of the response to diphtheria, tetanus, Haemophilus influenzae type b, inactivated poliovirus and pneumococcal antigens in infants and toddlers as a result of vaccination with ADACEL POLIO or ADACEL during pregnancy. Efficacy against pertussis in infants born to women vaccinated during pregnancy Vaccine efficacy during the first 2-3 months of life in infants born to women vaccinated against pertussis during the third trimester of pregnancy was evaluated in three observational studies. Overall efficacy is > 90%. Table 6: Vaccine efficacy (VE) against pertussis in infants born to women vaccinated during pregnancy with Repevax (Adacel Polio**) or COVAXIS (Adacel**) in 3 retrospective studies. Study site Vaccine VE (95% CI) Vaccine efficacy estimation method Infant follow-up period UK Repevax 93% (81; 97) unmatched case-control 2 months US COVAXiS* 91.4% (19.5;99.1) cohort regression model 2 months UK Repevax 93% (89; 95) screening (case coverage) 3 months * Approximately 99% of women were vaccinated with ADACEL ** Product name in the Czech Republic