20-valent Pneumococcal Conjugate Vaccine Safety and Immunogenicity Study of a 4-Dose Series in Healthy Infants

An AE was any untoward medical occurrence in a participants, temporally associated with the use of study treatment, whether or not considered related to the study treatment. 95% CI was based on the Clopper and Pearson method. AEs reported in this outcome measure excluded local reactions and systemic events.

Time frame: From Dose 1 to 1 Month after Dose 3

Population: Safety population included all the participants who received at least 1 dose of the IP with safety follow up after any dose. Here, 'Number of Participants Analyzed' = number of participants who received Dose 1.

An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. 95% CI was based on the Clopper and Pearson method. AEs reported in this outcome measure excluded local reactions and systemic events.

Time frame: From Dose 4 to 1 month after Dose 4

Population: Safety population included all the participants who received at least 1 dose of the IP with safety follow up after any dose. Here, 'Number of Participants Analyzed' = number of participants who received Dose 4 and had safety follow up after Dose 4.

Local reactions were recorded using an electronic diary. Local reactions included redness, swelling and pain at the injection site. Redness and swelling were graded as mild (0.5 to 2.0 cm), moderate (\>2.0 to 7.0 cm) and severe (\>7.0 cm). Pain at injection site was graded as mild (hurt if gently touched example, whimpered, winced, protested, or withdrew), moderate (hurt if gently touched, with crying), and severe (caused limitation of limb movement).

Time frame: Within 7 days after Dose 1

Population: Safety population included all the participants who received at least 1 dose of the investigational product (IP) with safety follow up after any dose. 'Number of Participants Analyzed' = number of participants with any electronic diary (e-diary) data reported after Dose 1.

Local reactions were recorded using an electronic diary. Local reactions included redness, swelling and pain at the injection site. Redness and swelling were graded as mild (0.5 to 2.0 cm), moderate (\>2.0 to 7.0 cm) and severe (\>7.0 cm). Pain at injection site was graded as mild (hurt if gently touched example, whimpered, winced, protested, or withdrew), moderate (hurt if gently touched, with crying), and severe (caused limitation of limb movement).

Time frame: Within 7 days after Dose 3

Population: Safety population included all the participants who received at least 1 dose of the investigational product (IP) with safety follow up after any dose. 'Number of Participants Analyzed' = number of participants with any electronic diary (e-diary) data reported after Dose 3.

Local reactions were recorded using an electronic diary. Local reactions included redness, swelling and pain at the injection site. Redness and swelling were graded as mild (0.5 to 2.0 cm), moderate (\>2.0 to 7.0 cm) and severe (\>7.0 cm). Pain at injection site was graded as mild (hurt if gently touched example, whimpered, winced, protested, or withdrew), moderate (hurt if gently touched, with crying), and severe (caused limitation of limb movement). 95 percent (%) confidence interval (CI) was based on Clopper and Pearson method.

Time frame: Within 7 days after Dose 4

Population: Safety population included all the participants who received at least 1 dose of the investigational product (IP) with safety follow up after any dose. Here, 'Number of Participants Analyzed' = number of participants with any electronic diary (e-diary) data reported after Dose 4.

Local reactions were recorded using an electronic diary. Local reactions included redness, swelling and pain at the injection site. Redness and swelling were graded as mild (0.5 to 2.0 cm), moderate (\>2.0 to 7.0 cm) and severe (\>7.0 cm). Pain at injection site was graded as mild (hurt if gently touched example, whimpered, winced, protested, or withdrew), moderate (hurt if gently touched, with crying), and severe (caused limitation of limb movement).

Time frame: Within 7 Days After Dose 2

Population: Safety population included all the participants who received at least 1 dose of the investigational product (IP) with safety follow up after any dose. 'Number of Participants Analyzed' = number of participants with any electronic diary (e-diary) data reported after Dose 2.

An NDCMC was defined as a significant disease or medical condition, not previously identified, that was expected to be persistent or was otherwise long-lasting in its effects. 95% CI was based on the Clopper and Pearson method.

Time frame: From Dose 1 to 6 months following Dose 4

Population: Safety population included all the participants who received at least 1 dose of the IP with safety follow up after any dose. Here, 'Number of Participants Analyzed' = number of participants who received Dose 1.

Pre-specified levels of serotypes were as follows: for serotype 1, 3, 4, 6A, 7F, 9V, 14, 18C, 19F, 23F, 8, 10A, 11A, 12F, 15B, 22F, 33F: \>=0.35 microgram per mL (mcg/mL), for serotype 5: \>=0.23 mcg/mL, for serotype 6B: \>=0.10 mcg/mL and for serotype 19A: \>=0.12 mcg/mL. 95% CI was based on the Clopper and Pearson method.

Time frame: 1 month after Dose 3

Population: Dose 3 evaluable immunogenicity population: eligible participants aged 42-98 days on Dose 1, received the first 3 doses randomized, had at least 1 valid immunogenicity result 27 to 56 days post Dose 3, and had no major protocol deviations. Number of Participants Analyzed= participants in Dose 3 evaluable immunogenicity population, Number Analyzed = number of participants with valid IgG concentrations for the specified serotype reported at 1 month after Dose 3.

Concentration of antibody to diphtheria toxoid (predefined level ≥0.1 IU/mL), tetanus toxoid (predefined level ≥0.1 IU/mL), IgG antibodies to pertussis antigens (pertussis toxin, filamentous hemagglutinin and pertactin, each with the predefined level as the 5th percentile observed in the 13vPnC group), hepatitis B antibody (in milli-international units per mL \[mIU/mL\]) (predefined level ≥10 mIU/mL), neutralizing antibody (NA) titers to poliovirus types 1, 2, and 3 (predefined level NA titer ≥1:8), Haemophilus influenzae type b (Hib) (≥0.15 μg/mL) were determined on subsets of sera collected at the immunogenicity time point 1 month after Dose 3. The antibody levels were measured by a validated multiplex Luminex immunoassay. The concomitant immune responses were measured on random subsets.

Time frame: 1 month after Dose 3

Population: Dose 3 evaluable population: eligible participants aged 42-98 days on Dose 1, received the first 3 doses randomized, had at least 1 valid immunogenicity result 27 to 56 days post Dose 3, had no major protocol deviations. Number of Participants Analyzed=participants in Dose 3 evaluable immunogenicity population, Number Analyzed = number of participants with valid assay results for the specified antigen at 1 month after Dose 3.

A SAE was any untoward medical occurrence that, at any dose: resulted in death; required inpatient hospitalisation or prolongation of existing hospitalisation; was life-threatening; resulted in persistent or significant disability/ incapacity; congenital anomaly/birth defect and other important medical events. 95% CI was based on the Clopper and Pearson method.

Time frame: From Dose 1 to 6 months following Dose 4

Population: Safety population included all the participants who received at least 1 dose of the IP with safety follow up after any dose. Here, 'Number of Participants Analyzed' = number of participants who received Dose 1.

Systemic events included fever, decreased appetite, drowsiness/increased sleep and irritability, recorded by parents/legal guardians of participant's using an e-diary. Fever was defined as temperature greater than or equal to (\>=) 38.0 degrees Celsius (C) and categorized as \>=38.0 to 38.4 degrees C, \>38.4 to 38.9 degrees C, \>38.9 to 40.0 degrees C and \>40.0 degrees C. Decreased appetite was graded as mild (decreased interest in eating), moderate (decreased oral intake) and severe (refusal to feed). Drowsiness was graded as mild (increased or prolonged sleeping bouts), moderate (slightly subdued, interfered with daily activity) and severe (disabling, not interested in usual daily activity). Irritability was graded as mild (easily consolable), moderate (required increased attention) and severe (inconsolable, crying could not be comforted). 95% CI was based on Clopper and Pearson method.

Time frame: Within 7 days after Dose 1

Population: Safety population included all the participants who received at least 1 dose of the IP with safety follow up after any dose. 'Number of Participants Analyzed' = number of participants with any e-diary data reported after Dose 1.

Systemic events included fever, decreased appetite, drowsiness/increased sleep and irritability, recorded by parents/legal guardians of participant's using an e-diary. Fever was defined as temperature \>= 38.0 degrees C and categorized as \>=38.0 to 38.4 degrees C, \>38.4 to 38.9 degrees C, \>38.9 to 40.0 degrees C and \>40.0 degrees C. Decreased appetite was graded as mild (decreased interest in eating), moderate (decreased oral intake) and severe (refusal to feed). Drowsiness was graded as mild (increased or prolonged sleeping bouts), moderate (slightly subdued, interfered with daily activity) and severe (disabling, not interested in usual daily activity). Irritability was graded as mild (easily consolable), moderate (required increased attention) and severe (inconsolable, crying could not be comforted). 95% CI was based on Clopper and Pearson method.

Time frame: Within 7 days after Dose 2

Population: Safety population included all the participants who received at least 1 dose of the IP with safety follow up after any dose. 'Number of Participants Analyzed' = number of participants with any e-diary data reported after Dose 2.

Systemic events included fever, decreased appetite, drowsiness/increased sleep and irritability, recorded by parents/legal guardians of participant's using an e-diary. Fever was defined as temperature \>= 38.0 degrees C and categorized as \>=38.0 to 38.4 degrees C, \>38.4 to 38.9 degrees C, \>38.9 to 40.0 degrees C and \>40.0 degrees C. Decreased appetite was graded as mild (decreased interest in eating), moderate (decreased oral intake) and severe (refusal to feed). Drowsiness was graded as mild (increased or prolonged sleeping bouts), moderate (slightly subdued, interfered with daily activity) and severe (disabling, not interested in usual daily activity). Irritability was graded as mild (easily consolable), moderate (required increased attention) and severe (inconsolable, crying could not be comforted). 95% CI was based on Clopper and Pearson method.

Time frame: Within 7 days after Dose 3

Population: Safety population included all the participants who received at least 1 dose of the IP with safety follow up after any dose. 'Number of Participants Analyzed' = number of participants with any e-diary data reported after Dose 3.

Systemic events included fever, decreased appetite, drowsiness/increased sleep and irritability, recorded by parents/legal guardians of participant's using an e-diary. Fever was defined as temperature \>= 38.0 degrees C and categorized as \>=38.0 to 38.4 degrees C, \>38.4 to 38.9 degrees C, \>38.9 to 40.0 degrees C and \>40.0 degrees C. Decreased appetite was graded as mild (decreased interest in eating), moderate (decreased oral intake) and severe (refusal to feed). Drowsiness was graded as mild (increased or prolonged sleeping bouts), moderate (slightly subdued, interfered with daily activity) and severe (disabling, not interested in usual daily activity). Irritability was graded as mild (easily consolable), moderate (required increased attention) and severe (inconsolable, crying could not be comforted). 95% CI was based on Clopper and Pearson method.

Time frame: Within 7 days after Dose 4

Population: Safety population included all the participants who received at least 1 dose of the IP with safety follow up after any dose. 'Number of Participants Analyzed' = number of participants with any e-diary data reported after Dose 4.

Concentrations of anticapsular IgG for the 20 pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F, 8, 10A, 11A, 12F, 15B, 22F, and 33F) were determined in all participants at 1 month after Dose 4 using the Luminex assay. Results were expressed as IgG concentrations. GMCs and 2-sided CIs were calculated by exponentiating the mean logarithm of the concentrations and the corresponding CIs based on the Student's t distribution. Assay result below LLOQ was set to 0.5\*LLOQ. Geometric mean ratios (GMRs) were reported in statistical analysis section and were calculated by exponentiating mean difference of logarithm of concentration and corresponding 2-sided 95% CIs (based on Student's t distribution).

Time frame: From Dose 1 to 6 months following Dose 4

Population: Dose 4 evaluable immunogenicity population: aged 42-98 days on Dose 1, received the first 4 doses randomized, had at least 1 valid immunogenicity result 27 to 56 days after Dose 4, had no major protocol deviations. Number of Participants Analyzed= participants in Dose 4 evaluable immunogenicity population, Number Analyzed = number of participants with valid IgG concentrations for the specified serotype reported at 1 month after Dose 4.

Antibody concentrations to concomitant vaccine antigen (measles) were determined on sera collected 1 month after Dose 4 from a randomly selected subset of participants with sufficient sera volumes. GMs and 2-sided CIs were calculated by exponentiating the mean logarithm of the concentrations and the corresponding CIs based on the Student's t distribution and were reported from Dose 4 evaluable immunogenicity participants.

Time frame: 1 month after Dose 4

Population: Dose 4 evaluable immunogenicity population: eligible participants aged 42-98 days on Dose 1, received all 4 doses, have at least 1 valid immunogenicity result within 27 to 56 days after Dose 4, and had no other major protocol deviations as determined by the clinician. Number of Participants Analyzed=number of participants in Dose 4 evaluable immunogenicity population with valid antibody concentrations for the specified antigen reported at 1 month after Dose 4.

Antibody concentrations to concomitant vaccine antigen (mumps) were determined on sera collected 1 month after Dose 4 from a randomly selected subset of participants with sufficient sera volumes. GMs and 2-sided CIs were calculated by exponentiating the mean logarithm of the concentrations and the corresponding CIs based on the Student's t distribution and were reported from Dose 4 evaluable immunogenicity participants.

Time frame: 1 month after Dose 4

Population: Dose 4 evaluable immunogenicity population: eligible participants aged 42-98 days on Dose 1, received all 4 doses, have at least 1 valid immunogenicity result within 27 to 56 days after Dose 4, and had no other major protocol deviations as determined by the clinician. Number of Participants Analyzed=number of participants in Dose 4 evaluable immunogenicity population with valid antibody concentrations for the specified antigen reported at 1 month after Dose 4.

Antibody concentrations to concomitant vaccine antigen (rubella) were determined on sera collected 1 month after Dose 4 from a randomly selected subset of participants with sufficient sera volumes. GMs and 2-sided CIs were calculated by exponentiating the mean logarithm of the concentrations and the corresponding CIs based on the Student's t distribution and were reported from Dose 4 evaluable immunogenicity participants.

Time frame: 1 month after Dose 4

Population: Dose 4 evaluable immunogenicity population: eligible participants aged 42-98 days on Dose 1, received all 4 doses, had at least 1 valid immunogenicity result within 27 to 56 days after Dose 4, and had no other major protocol deviations as determined by the clinician. Number of Participants Analyzed= number of participants in Dose 4 evaluable immunogenicity population with valid antibody concentrations for the specified antigen reported at 1 month after Dose 4

Antibody concentrations to concomitant vaccine antigen (varicella) were determined on sera collected 1 month after Dose 4 from a randomly selected subset of participants with sufficient sera volumes. GMs and 2-sided CIs were calculated by exponentiating the mean logarithm of the concentrations and the corresponding CIs based on the Student's t distribution and were reported from Dose 4 evaluable immunogenicity participants.

Time frame: 1 month after Dose 4

Population: Dose 4 evaluable immunogenicity population: eligible participants aged 42-98 days on Dose 1, received all 4 doses, had at least 1 valid immunogenicity result within 27 to 56 days after Dose 4, and had no other major protocol deviations as determined by the clinician. Number of Participants Analyzed= number of participants in Dose 4 evaluable immunogenicity population with valid antibody concentrations for the specified antigen reported at 1 month after Dose 4.

Antibody concentration to the Hib vaccine antigens were determined on sera collected from a randomly selected subset of participants with sufficient sera volumes. Percentage of participants with alternative prespecified Hib antibody (≥1.0 μg/mL) were reported from Dose 3 evaluable immunogenicity participants.

Time frame: 1 month after Dose 3

Population: Dose 3 evaluable population: eligible participants aged 42-98 days on Dose 1, received the first 3 doses, had at least 1 valid immunogenicity result within 27 to 56 days post Dose 3, and had no other major protocol deviations. Number of Participant Analyzed = Dose 3 evaluable immunogenicity population with valid Hib antibody level. Number Analyzed = number of participants with valid Hib antibody level.

Pre-specified levels of serotypes were as follows: for serotype 1, 3, 4, 6A, 7F, 9V, 14, 18C, 19F, 23F, 8, 10A, 11A, 12F, 15B, 22F, 33F: \>=0.35 microgram per mL (mcg/mL), for serotype 5: \>=0.23 mcg/mL, for serotype 6B: \>=0.10 mcg/mL and for serotype 19A: \>=0.12 mcg/mL. 95% CI was based on the Clopper and Pearson method.

Time frame: 1 month after Dose 4

Population: Dose 4 evaluable immunogenicity population: eligible participants aged 42-98 days on Dose 1, received all 4 doses as randomized, had at least 1 valid immunogenicity result within 27 to 56 days after Dose 4, and had no other major protocol deviations. Number of Participants Analyzed=participants in Dose 4 evaluable immunogenicity population, Number Analyzed = number of participants with valid IgG concentrations for the specified serotype reported at 1 month after Dose 4.

GMFR of pneumococcal 20vPnC serotypes included: 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F and 33F. The GMFR from 1 month after Dose 3 to before Dose 4 were reported from Dose 3 evaluable immunogenicity participant.

Time frame: 1 month after Dose 3 to before Dose 4

Population: Dose 3 evaluable immunogenicity population: eligible participants aged 42-98 days on Dose 1, received the first 3 doses as randomized, had at least 1 valid immunogenicity result 27 to 56 days after Dose 3, and had no major protocol deviations. Number of Participants Analyzed= participants in Dose 3 evaluable immunogenicity population; Number Analyzed= number of participants with valid IgG concentrations at both timepoints for the specified serotype.

Pneumococcal IgG antibody against each of the 20 pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F, 8, 10A, 11A, 12F, 15B, 22F and 33F) was measured using direct binding Luminex assay. Results were expressed as IgG concentrations. GMCs and 2-sided CIs were calculated by exponentiating the mean logarithm of the concentrations and the corresponding CIs based on the Student's t distribution. Assay result below LLOQ were set to 0.5\*LLOQ.GMRs were reported in statistical analysis section and were calculated by exponentiating mean difference of logarithm of concentration and corresponding 2-sided 95% CI (based on Student's t distribution). Assay result below LLOQ were set to 0.5\*LLOQ.GMRs were reported in statistical analysis section and were calculated by exponentiating mean difference of logarithm of concentration and corresponding 2-sided 95% CI (based on Student's t distribution).

Time frame: 1 month after Dose 3

Population: Dose 3 evaluable immunogenicity population: eligible participants aged 42-98 days on Dose 1, received the first 3 doses randomized, had at least 1 valid immunogenicity result 27 to 56 days post Dose 3, and had no major protocol deviations. Number of Participants Analyzed= participants in Dose 3 evaluable immunogenicity population, Number Analyzed = number of participants with valid IgG concentrations for the specified serotype reported at 1 month after Dose 3.

GMFR of pneumococcal 20vPnC serotypes included: 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F and 33F. The GMFR from 1 month after Dose 3 to 1 month after Dose 4 were reported from participants in both Dose 3 and Dose 4 evaluable immunogenicity populations.

Time frame: from 1 month after Dose 3 to 1 month after Dose 4

Population: Dose 3 and Dose 4 evaluable population: participants aged 42-98 days on Dose 1, received the first 3 doses and 4 doses, had at least 1 valid immunogenicity result 27 to 56 days post Dose 3 or Dose 4. Number of Participants Analyzed= maximum number of participants in both Dose 3 and Dose 4 evaluable immuno populations that had a valid IgG concentration at both timepoints. Number Analyzed= number of participants with valid IgG concentrations at both timepoints for the specified serotype.

GMFR of pneumococcal 20vPnC serotypes included: 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15B, 18C, 19A, 19F, 22F, 23F and 33F. The GMFR from 1 month before Dose 4 to 1 month after Dose 4 were reported from Dose 4 evaluable immunogenicity participants.

Time frame: From 1 month before to 1 month after Dose 4

Population: Dose 4 evaluable immunogenicity population: eligible participants aged 42-98 days on Dose 1, received all 4 doses as randomized, had at least 1 valid immunogenicity result 27 to 56 days after Dose 4, and had no major protocol deviations. Number of Participants Analyzed= participants in Dose 4 evaluable immunogenicity population; Number Analyzed= number of participants with valid IgG concentrations at both timepoints for the specified serotype.

OPA titers for the 20 pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F, 8, 10A, 11A, 12F, 15B, 22F, and 33F) were determined in randomized subsets of participants at 1 month after Dose 4. Results were expressed as OPA titers. GMTs and 2-sided CIs were calculated by exponentiating the mean logarithm of the concentrations and the corresponding CIs based on the Student's t distribution. OPA titers were determined in randomized subsets of participants at 1 month after Dose 4.

Time frame: 1 month after Dose 4

Population: Dose 4 evaluable immunogenicity population: aged 42-98 days on Dose 1, received the first 4 doses randomized, had at least 1 valid immunogenicity result 27 to 56 days after Dose 4, had no major protocol deviations. Number of Participants Analyzed = Dose 4 evaluable immunogenicity populations. Number Analyzed = number of participants with valid OPA titers for the specified serotype reported at 1 month after Dose 4.

OPA titers for the 20 pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F, 8, 10A, 11A, 12F, 15B, 22F, and 33F) were determined in randomized subsets of participants at 1 month after Dose 3. Results were expressed as OPA titers. GMTs and 2-sided CIs were calculated by exponentiating the mean logarithm of the concentrations and the corresponding CIs based on the Student's t distribution. OPA titers were determined in randomized subsets of participants at 1 month after Dose 3.

Time frame: 1 month after Dose 3

Population: Dose 3 evaluable immunogenicity population: aged 42-98 days on Dose 1, received the first 3 doses randomized, had at least 1 valid immunogenicity result 27 to 56 days after Dose 3, had no protocol deviations. Number of Participants Analyzed = Dose 3 evaluable immunogenicity populations. Number Analyzed = number of participants with valid OPA titers for the specified serotype reported at 1 month after Dose 3.