Safety and Immunogenicity of a 10 Valent Pneumococcal Conjugate Vaccine (SIILPCV10) in Healthy Adults, Toddlers, Infants

Study Overview
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Brief Summary
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Phase 1/2, Prospective, Single Center, Randomized, ActiveControlled, Double-Blind, Age De-escalation Study to assess the safety and tolerability of SIILPCV10 administered as a single-dose regimen to healthy Gambian pneumococcal conjugate vaccine (PCV)-naïve young adults and PCV-primed toddlers through 4 weeks post vaccination. Each adult and toddler subject will undergo a total of 4 clinic visits. Each infant subject will undergo a total of 9 scheduled visits. Blood will be collected from all subjects during the screening visit for safety and potential immunological assessments, and 28 days after completion of the vaccination schedule for immunological assessments. For adults, the vaccine was given intramuscularly into the mid-deltoid muscle of nondominant arm using a 24-gauge needle. For toddlers and infants, the vaccine will be given IM into the anterolateral aspect of the left thigh. Blood will be collected from adults and toddlers for safety labs at the Day 7 post-vaccination visit.

Detailed Description
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This was a prospective, single-center, randomized, active-controlled, double-blind, age de escalation study in healthy Gambian PCV-naïve adults (18-40 years old), PCV primed toddlers (12-15 months old) and PCV-naïve infants (6-8 weeks old). In the adult cohort, at least 34 eligible PCV-naïve adults (18-40 years old) were planned to be randomized into the study to receive a single dose of either SIILPCV10 or Pneumovax 23 in a 1:1 ratio on Day 0 (V1), with stratification by sex (although no fixed proportion of males and females was required in the cohort as a whole). In the toddler cohort, at least 112 eligible PCV-primed toddlers (12-15 months old) were planned to be randomized into the study to receive a single dose of either SIILPCV10 or Prevenar 13 in a 1:1 ratio on Day 0 (V1). Each adult and toddler subject underwent a total of 4 clinic visits, including at least 1 screening visit (V0) no more than 14 days prior to Day 0, a vaccination visit on Day 0 (V1), and follow-up clinic visits at 7 (+3) and 28 (+14) days after vaccination (V2 and V3, respectively). A total of 3 blood samples were obtained for laboratory safety and immunogenicity assessments. In the infant cohort, at least 200 eligible PCV-naïve infants (6 to 8 weeks old) were randomized into the study to receive 3 doses of either SIILPCV10 or Prevenar 13 in a 1:1 ratio along with standard Expanded Program on Immunisation (EPI) vaccinations (pentavalent diphtheria, tetanus, whole-cell pertussis, hepatitis B, and Haemophilus influenzae type b combined vaccine [DTwP-HepB-Hib], oral poliovirus vaccine [OPV], rotavirus vaccine [RV], and inactivated poliovirus vaccine [IPV]). Each infant subject underwent a total of 9 scheduled visits for the primary series: at least 1 screening visit (V0); 3 primary vaccination visits at 28 (+14)-day intervals (V1, 3, 5); follow-up clinic visits at 7 (+3) days after each primary vaccination (V2, 4, 6); and 2 follow-up visits 28 and 84 days after the last primary vaccination (V7 and V8, respectively). Windows for follow-up and subsequent vaccination visits were calculated based on the actual calendar date of the prior vaccination, rather than relative to the day of randomization. Vaccinations included the blinded PCV study vaccine (SIILPCV10 or Prevenar 13) and the unblinded EPI vaccines (DTwP-HepB-Hib, OPV, RV, and IPV). A total of 2 blood samples were obtained for the primary series (V0 and V7), with the first sample used for safety laboratory eligibility assessment, and if randomized, for baseline immunogenicity testing. Immunogenicity testing was also done on the second sample. During the supplemental booster phase, infant subjects underwent 2 additional visits: a fourth (booster) vaccination visit (V9) at ≥ 9 months of age, and a follow-up visit 28 days after the booster dose (V10). The EPI vaccines scheduled for 9 months of age in The Gambia were not given as part of the study. However, study personnel contacted parents of infant subjects to remind them of the need to attend this EPI vaccination visit at the due date to allow for effective scheduling of the subsequent booster. The vaccine (SIILPCV10 or Prevenar 13) was given at least 4 weeks after the routine EPI vaccines given at 9 months of age in The Gambia (measles and rubella, yellow fever, and OPV). Infants who received SIILPCV10 at V9 were offered a booster dose of Prevenar 13 at least 56 days following the SIILPCV10 boost. Immunogenicity testing was performed on 2 additional blood samples collected during the booster phase (V9 and V10). In the adult and toddler cohorts, on the day of vaccination, a malaria rapid test was performed using a finger prick to rule out parasitemia and a urine pregnancy test was performed (in adult women who were not surgically sterile) to rule out pregnancy before final eligibility was confirmed and randomization occurred. In the infant cohort, on each day of vaccination, a malaria rapid test was performed using a finger prick to rule out parasitemia before vaccination occurred. Any infant showing signs of acute illness or abnormal vital signs on the day of vaccination were not vaccinated until recovery was documented by the study team. After all vaccinations, subjects were monitored for solicited reactogenicity. All adult and toddler subjects were monitored for AEs at each clinic visit until V3, and ongoing AEs at study exit were followed until last subject last visit (LSLV). Infant subjects were monitored for AEs at each clinic visit until V8. For infants who participated in the booster phase of the study, AEs were recorded at V10, and any conditions present at V9 were considered baseline. SAS software was used to analyze data.

Official Title
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A Phase 1/2, Prospective,Randomized, Active-Controlled, Double-Blind, Age De-escalation Study to Evaluate the Safety, Tolerability, Immunogenicity of Serum Institute of India's PCV10 in Healthy Adults, Toddlers, and Infants

Conditions
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Pneumococcal Disease

Intervention / Treatment
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* Biological: SIILPCV10
* Biological: Pneumovax 23
* Biological: Prevenar 13


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: • Healthy adults (18-40 yrs), toddlers (12-15 mo), full term infants (6-8 wks) and ≥ 3.5 kg Able to provide informed consent (for themselves or child) Willing to comply with study requirements and procedures. Toddlers have completed their Gambian infant EPI schedule Infants who have received the birth doses of BCG, HepB and OPV but who have not received any additional vaccines. Infants and toddlers with a weight-to-height Z score of ≥ -2. Subjects resident in the study area with no plans to travel outside the study area during the period of study participation. Exclusion Criteria: Use of any investigational medicinal product within 90 days prior to randomization and throughout the study. Ingestion of herbal or other traditional local medication within 14 days of randomization. Adults and infants who have previously been vaccinated against S. pneumoniae. History of S. pneumoniae infection confirmed by culture from a normally sterile site. History of allergic disease or history of a serious reaction to any prior vaccination or known hypersensitivity to any component of the study vaccines. History of anaphylactic shock. Screening laboratory test or vital signs outside the normal range. HIV-positive or HbsAg- positive based on testing during screening. Acute illness (moderate or severe) and/or fever (axillary temperature of ≥ 38.0°C for adults or ≥ 37.5°C for toddlers and infants). Use of antibiotics within 5 days of randomization (excluding treatment for malaria). A positive test for malaria at time of screening, which remains positive post treatment when retested at time of randomization (Day 0). Administration of any non-study vaccine within 30 days prior to administration of study vaccine or planned vaccination during the course of study participation. Chronic administration of immunosuppressant or other immune modifying drugs prior to the administration of the study. The use of topical and inhaled glucocorticoids will be permitted. Administration of immunoglobulins and/or any blood products within the 6 months prior to administration of the study vaccine or during the study period. History of known disturbance of coagulation or blood disorder that could cause anemia or excess bleeding. Employee of, or direct descendant of any person employed by the Sponsor, the CRO, the PI, study site personnel, or site. Adults only Recent history or signs of alcohol or substance abuse. History of major psychiatric disorder. Female adult subjects who are pregnant or breast-feeding. Infants/Toddlers only Family history of suspected primary immunodeficiency in first-degree relative. Had a sibling die suddenly and without apparent other cause or preceding illness in the first year of life. Evidence of a clinically significant congenital abnormality as judged by the PI. Evidence of fetal alcohol syndrome or maternal history of alcohol abuse during pregnancy. History of meningitis, seizures or any neurological disorder. Evidence of exposure to an HIV-positive individual through maternal fetal transmission, breast milk, or other bloodborne mechanisms

Ages Eligible for Study
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Minimum Age: 4 Weeks
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Adult SIILPCV10<br>Single dose of SIILPCV10 on day 0 | Biological: SIILPCV10<br>* 10-valent Pneumococcal Conjugate Vaccine (SIILPCV10) at a dosage of 2 µg for each serotype polysaccharide, except 4 µg for 6B serotype, conjugated to a carrier protein (CRM197), with adjuvant (aluminum phosphate [alum]) and preservative (thiomersal).<br>|
| Active Comparator: Adult Pneumovax 23<br>Single dose of Pneumovax 23 on day 0 | Biological: Pneumovax 23<br>* 23-valent Pneumococcal Polysaccharide Vaccine (Pneumovax 23; MSD Pharmaceuticals) for the adult cohort.<br>* Other names: 23-valent Pneumococcal Polysaccharide Vaccine;|
| Experimental: Toddler SIILPCV10<br>Single dose of SIILPCV10 on day 0 | Biological: SIILPCV10<br>* 10-valent Pneumococcal Conjugate Vaccine (SIILPCV10) at a dosage of 2 µg for each serotype polysaccharide, except 4 µg for 6B serotype, conjugated to a carrier protein (CRM197), with adjuvant (aluminum phosphate [alum]) and preservative (thiomersal).<br>|
| Active Comparator: Toddler Prevenar 13<br>Single dose of Prevenar 13 on day 0 | Biological: Prevenar 13<br>* 13-valent Pneumococcal Conjugate Vaccine (Prevenar 13; Pfizer-Wyeth) for the toddler and infant cohorts<br>* Other names: 13-valent Pneumococcal Conjugate Vaccine;|
| Experimental: Infants SIIL PCV10<br>A three-dose series of SIILPCV10 on day 0, day 28, and day 56 | Biological: SIILPCV10<br>* 10-valent Pneumococcal Conjugate Vaccine (SIILPCV10) at a dosage of 2 µg for each serotype polysaccharide, except 4 µg for 6B serotype, conjugated to a carrier protein (CRM197), with adjuvant (aluminum phosphate [alum]) and preservative (thiomersal).<br>|
| Active Comparator: Infants Prevenar 13<br>A three-dose series of Prevenar 13 on day 0, day 28, and day 56 | Biological: Prevenar 13<br>* 13-valent Pneumococcal Conjugate Vaccine (Prevenar 13; Pfizer-Wyeth) for the toddler and infant cohorts<br>* Other names: 13-valent Pneumococcal Conjugate Vaccine;|
| Experimental: Infant Booster Dose SIILPCV 10<br>One dose of SIILPCV 10 at 9 months of age | Biological: SIILPCV10<br>* 10-valent Pneumococcal Conjugate Vaccine (SIILPCV10) at a dosage of 2 µg for each serotype polysaccharide, except 4 µg for 6B serotype, conjugated to a carrier protein (CRM197), with adjuvant (aluminum phosphate [alum]) and preservative (thiomersal).<br>|
| Active Comparator: Infant Booster Dose Prevenar 13<br>One dose of SIILPCV 10 at 9 months of age | Biological: Prevenar 13<br>* 13-valent Pneumococcal Conjugate Vaccine (Prevenar 13; Pfizer-Wyeth) for the toddler and infant cohorts<br>* Other names: 13-valent Pneumococcal Conjugate Vaccine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adult and Toddler Subjects Experiencing Local and Systemic Reactogenicity, by Severity | Local and systemic reactogenicity of the study vaccine was evaluated for severity by toxicity grading scale (0 [none], 1 [mild], 2 [moderate], 3 [severe], 4 [potentially life threatening]) and relatedness to the vaccination. Injection site events were by definition considered related to study vaccine. Reactogenicity was monitored at the following times: At 60 (± 15) minutes following primary vaccination Daily by field workers during Days 1 to 6 post vaccination In the clinic on Day 7 (+3) following each vaccination (Visit 2 for adults and toddlers). | 7 days | 
| Infant Subjects Experiencing Local and Systemic Reactogenicity, by Severity: Vaccination 1 | Local and systemic reactogenicity of the study vaccine was evaluated for severity by toxicity grading scale (0 [none], 1 [mild], 2 [moderate], 3 [severe], 4 [potentially life threatening]) and relatedness to the vaccination. Injection site events were by definition considered related to study vaccine. Reactogenicity was monitored at the following times: At 60 (± 15) minutes following primary vaccination Daily by field workers during Days 1 to 6 post vaccination In the clinic on 7 days (+3) following each vaccination (Visit 2, 4, and 6 for infants). | 7 days | 
| Infant Subjects Experiencing Local and Systemic Reactogenicity, by Severity: Vaccination 2 | Local and systemic reactogenicity of the study vaccine was evaluated for severity by toxicity grading scale (0 [none], 1 [mild], 2 [moderate], 3 [severe], 4 [potentially life threatening]) and relatedness to the vaccination. Injection site events were by definition considered related to study vaccine. Reactogenicity was monitored at the following times: At 60 (± 15) minutes following primary vaccination Daily by field workers during Days 1 to 6 post vaccination In the clinic on 7 days (+3) following each vaccination (Visit 2, 4, and 6 for infants). | 7 days | 
| Infant Subjects Experiencing Local and Systemic Reactogenicity, by Severity: Vaccination 3 | Local and systemic reactogenicity of the study vaccine was evaluated for severity by toxicity grading scale (0 [none], 1 [mild], 2 [moderate], 3 [severe], 4 [potentially life threatening]) and relatedness to the vaccination. Injection site events were by definition considered related to study vaccine. Reactogenicity was monitored at the following times: At 60 (± 15) minutes following primary vaccination Daily by field workers during Days 1 to 6 post vaccination In the clinic on 7 days (+3) following each vaccination (Visit 2, 4, and 6 for infants). | 7 days | 
| Occurrence, Severity and Relatedness of All Adverse Events in Adults and Toddlers | Reported here are only adverse events occurring in 5% or more of subjects; unless specifically stated, AEs were regarded as unrelated. | 28 days | 
| Occurrence, Severity and Relatedness of All Adverse Events in Infants | Reported here are adverse events that occurred in 5% or more of the infant cohort. Booster dose safety results are reported separately. Unless stated, AEs are regarded as unrelated. | 12 weeks post last vaccination | 
| Occurrence, Severity and Relatedness of Clinically Significant Hematological and Biochemistry Lab Values in Adults and Toddlers | Blood samples were collected for safety hematology and clinical chemistry evaluations, organ function tests, and, for adults, coagulation panel evaluation. Laboratory assessments were only performed at baseline for infants. Testing for HIV was undertaken only following pre-test counseling of the subject/subject's parent as to the implications of the test result. Post test counseling was also undertaken, and on the basis of a positive result the subject and subject's parents would have been referred on for HIV care according to normal local practice in The Gambia. | 7 days after vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Concentration of Immunoglobulin G (IgG) for Adults | Serum samples were collected 28 days after the vaccination in adults to determine the ELISA IgG concentration for all 10 serotypes contained in SIILPCV10. | 4 weeks after vaccination | 
| Geometric Mean Concentration of Immunoglobulin G (IgG) 4 Weeks After Vaccination for Toddlers | Serum samples were collected 28 days after vaccination for toddlers to determine the ELISA IgG concentration for all 10 serotypes contained in SIILPCV10. | 4 weeks after vaccination | 
| Geometric Mean Concentration of Immunoglobulin G (IgG) 4 Weeks After Vaccination for Infants | Serum samples were collected 28 days after the third vaccination for infants to determine the ELISA IgG concentration for all 10 serotypes contained in SIILPCV10. | 4 weeks after the third dose | 
| Geometric Mean Fold Rise (GMFR) of Immunoglobulin G (IgG) in Toddlers, by Serotype | Serum samples were collected before the first vaccination and 28 days after the last vaccination for adults and toddlers and 28 days after the completion of the primary series for infants to determine the ELISA IgG concentration for all 10 serotypes contained in SIILPCV10. Blood samples were also collected for immunogenicity testing before and 28 days after the booster dose for infants. Baseline serum samples for infants and adults were not assayed. The IgG concentration was also determined for each component of the co administered pentavalent vaccine (DTwP-HepB-Hib) in sera from the infant cohort. If there were limitations to blood volumes, appropriate subsets and priorities for immune testing were established with the immunology laboratories to ensure measurements were unbiased and representative of the entire cohort. | 4 weeks after vaccination (28 days) | 
| Number and Percentage of Immunoglobulin G (IgG) Seroresponders Among Infants, by Serotype | Seroresponse was defined as ≥ 0.35 µg/mL. In infants, serum samples were collected 28 days after receipt of three doses of the vaccine to determine the ELISA IgG concentration for all 10 serotypes contained in SIILPCV10. | 4 weeks after third dose | 
| Functional Antibody (OPA) Geometric Mean Titers | The functional activity of the IgG response to the 10 serotypes contained in SIILPCV10 was determined in randomly selected subsets of the infant and toddler cohorts and all adult subjects in the same serum samples collected 28 days after the last vaccinations. This activity was determined using the 4-fold multiplexed OPA developed at the University of Alabama at Birmingham. | 4 weeks after last vaccination | 
| Number and Percentage of Functional (OPA) Infant Seroresponders, by Serotype | The functional activity of the immune response to the 10 serotypes contained in SIILPCV10 was determined in randomly selected subsets of the infant cohort in the same serum samples collected 28 days after the completion of the primary series. This activity was determined using the 4-fold multiplexed OPA developed at the University of Alabama at Birmingham. | 84 days | 
| Number and Percentage of Immunoglobulin G (IgG) Seroresponders Against Pentavalent Vaccine Components | Serum samples were collected 28 days after the third vaccination for infants to determine the ELISA IgG concentration for each component of the co administered pentavalent vaccine (DTwP-HepB-Hib) . Seroresponse was defined as equal to or greater concentrations for: Diptheria toxoid: 0.1 IU/mL Hepatitis B: 10 milli-International unit (mIU) /mL Hib: 0.15 mcg/mL Tetanus toxoid: 0.1 IU/mL | 84 days |