Phase I Clinical Trial of Diphtheria-Tetanus-acellular Pertussis Component Combined Vaccine

Diphtheria, Pertussis, Tetanus

This study is a randomized, blinded, active-controlled phase I clinical trial to evaluate the safety and preliminary immunogenicity of the Diphtheria-Tetanus-acellular Pertussis Component Combined Vaccine (DTacP) in subjects (aged 2 months to 6 years). Primary safety endpoints are the occurrence of solicited adverse events within 30 minutes after each dose, the occurrence of solicited adverse events within 7 days after each dose, the occurrence of unsolicited adverse events within 30 days after each dose, and the occurrence of adverse events 30 days after immunization. The secondary safety endpoint is the occurrence of serious adverse events (SAEs) within 12 months after immunization. Secondary immunogenicity endpoints are the geometric mean concentration (GMC), geometric mean fold increase (GMFI), seropositive rates, seroconversion rates, or 4-fold increase rates of anti-DT, anti-TT, anti-PT, anti-FHA, and anti-PRN antibodies 30 days after immunization. The exploratory endpoints are the GMC, GMFI, seropositive rates, seroconversion rates, or 4-fold increase rates of anti-DT, anti-PT, and anti-FHA neutralizing antibodies 30 days after immunization in all groups, the GMC and seropositive rates of anti-DT, anti-TT, anti-PT, anti-FHA, and anti-PRN antibodies 12 months after primary immunization in the infant group, the seropositive rates and geometric mean tie (GMT) of anti- type I, type II, type III poliovirus neutralizing antibodies 30 days after immunization in all groups, the seropositive rates and geometric mean tie (GMT) of anti- type I, type II, type III poliovirus neutralizing antibodies 12 months after primary immunization in the infant group.

This is a randomized, blinded, active-controlled phase I clinical trial to evaluate the safety and preliminary immunogenicity in 460 subjects (aged 2 months to 6 years). Then 40 children (aged 6 years), 60 toddlers (aged 18-24 months), and 360 infants (180 subjects aged 3 months and 180 subjects aged 2 months) are eligible for enrollment after assessing thorough medical history and physical examination according to the principle of age escalating from children to infants. \[First Stage\] 40 Children (aged 6 years) in the first stage of the study will be randomly assigned to the vaccine cohort and DT cohort in a ratio of 1:1, that is, 20 subjects in such group will be injected with the DTacP vaccine while 20 subjects with the DT vaccine. All children will receive the injection in the deltoid muscle of the upper arm on Day 0. The safety evaluation will be conducted by the Data and Safety Monitoring Board (DSMB) through assessing the preliminary safety data between Day 0 and Day 7 after administration. If results given by DSMB meet the criterion (no more than 25% of participants experienced Grade 3 or above adverse events and/or laboratory abnormalities), the study will continue to the second stage. \[Second Stage\] 60 Toddlers (aged 18-24 months) in the second stage of the study will be randomly assigned to the vaccine cohort, DTaP cohort, and Pentaxim cohort in a ratio of 1:1:1, that is, 20 subjects in such group will be injected with the DTacP vaccine, 20 subjects will be injected with the DTaP vaccine, and the 20 subjects will be injected with DTaP-IPV-Hib (Pentaxim). All toddlers will receive the injection in the deltoid muscle of the upper arm on Day 0. The safety evaluation will be conducted by the Data and Safety Monitoring Board (DSMB) through assessing the preliminary safety data between Day 0 and Day 7 after administration. If results given by DSMB meet the criterion (no more than 25% of participants experienced Grade 3 or above adverse events and/or laboratory abnormalities), the study will continue to the third stage. \[Third Stage\] (1) 180 Children (aged 3 months) in the third stage of the study will be randomly assigned to the vaccine cohort, DTaP cohort, and Pentaxim cohort in a ratio of 1:1:1, that is, 60 subjects in such group will be injected with the DTacP vaccine, 60 subjects will be injected with the DTaP vaccine, and 60 subjects will be injected with DTaP-IPV-Hib (Pentaxim). The vaccine cohort will be randomly assigned to two sub-cohorts in a ratio of 1:1 according to different injection sites, that is, 30 subjects will receive three injections in the anterolateral midthigh while 30 subjects in the deltoid muscle of the upper arm on an M3-M4-M5 immunization schedule. The DTaP cohort will receive three injections in the deltoid muscle of the upper arm on an M3-M4-M5 immunization schedule. The Pentaxim cohort will receive three injections in the anterolateral midthigh on an M3-M4-M5 immunization schedule. (2) 180 Children (aged 2 months) in the third stage of the study will be randomly assigned to the vaccine cohort, and Pentaxim cohort in a ratio of 2:1, that is, 120 subjects in such group will be injected with the DTacP vaccine, and 60 subjects will be injected with DTaP-IPV-Hib (Pentaxim). The vaccine cohort will be randomly assigned to four sub-cohorts in a ratio of 1:1:1:1 according to different injection sites and immunization schedules, that is, 30 subjects will receive three injections in the anterolateral midthigh on an M2-M3-M4 immunization schedule, 30 subjects will receive three injections in the anterolateral midthigh on an M2-M4-M6 immunization schedule, 30 subjects will receive three injections in the deltoid muscle of the upper arm on an M2-M3-M4 immunization schedule, 30 subjects will receive three injections in the deltoid muscle of the upper arm on an M2-M4-M6 immunization schedule. The Pentaxim cohort will receive three injections in the anterolateral midthigh on an M2-M3-M4 immunization schedule. The duration of children and toddlers for intervention is 1 day. Thus, the duration of each subject in these two groups will be approximately 12 months. The duration of infants for intervention is 2 or 4 months, and as infants will be followed up to 18 months old, thus, each subject in such group will be approximately 15 or 16 months. For safety assessment, the observation and evaluation of adverse events from Day 0 to Day 30 after each dose will be conducted by diary/contact cards and investigators' phone calls. Besides, the observation and evaluation of serious adverse events up to 12 months after vaccination will be conducted by active reports by subjects' legal guardians, or investigators' phone calls as well as face-to-face visits. Meanwhile, subjects will be observed at the site for at least 30 minutes after each dose. For laboratory examination, blood biochemistry, blood routine, and urine routine tests will be performed on Day 0 before vaccination as well as Day 4 after administration in Children and Toddlers groups. If one of these two groups meets the criteria assessed by DSMB that over 20% of subjects in each group experience grade 3 or above laboratory abnormalities related to investigational vaccines on Day 4, then blood biochemistry, blood routine, and urine routine tests will be performed in the Infant Group on Day 0 before first dose, Day 4 after first dose and Day 4 after third dose. For immunogenicity assessment, antibodies against anti-DT, anti-TT, anti-PT, anti-FHA, and anti-PRN, as well as neutralizing antibodies against anti-DT, anti-PT, anti-FHA, and anti-type I, type II, and type III poliovirus will be assessed in all subjects before vaccination and 30 days after vaccination. Moreover, antibodies against anti-DT, anti-TT, anti-PT, anti-FHA, and anti-PRN, as well as neutralizing antibodies against anti-type I, type II, and type III poliovirus will be assessed in infants around 12 months after primary vaccination (aged 18 months).

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