Study of a Pneumococcal Conjugate Vaccine When Administered Concomitantly With Routine Pediatric Vaccines in Healthy Toddlers and Infants

For toddlers, the duration of each participant's participation in the study will be approximately 6 months for subjects enrolled in Groups 1, 2, 3, and 4.

For infants, the duration of each participant's participation in the study will be approximately 16 to 19 months for subjects enrolled in Groups 5, 6, 7, and 8.

• Pneumococcal Conjugate Vaccine formulation 1 (Biological), also known as SP0202-IIb: Pharmaceutical form:liquid Route of administration: intramuscular
• Pneumococcal Conjugate Vaccine formulation 2 (Biological), also known as SP0202-VI: Pharmaceutical form:liquid Route of administration: intramuscular
• Pneumococcal Conjugate Vaccine formulation 3 (Biological), also known as SP0202-VII: Pharmaceutical form:liquid Route of administration: intramuscular
• Varicella Virus Vaccine Live (Biological), also known as Varicella vaccine, VARIVAX®: Pharmaceutical form:liquid Route of administration: subcutaneous
• Measles, Mumps, and Rubella Virus Vaccine Live (Biological), also known as MMR vaccine, M-M-R ®II: Pharmaceutical form:liquid Route of administration: subcutaneous
• Pneumococcal 13-valent Conjugate Vaccine [Diphtheria CRM197 Protein] (Biological), also known as Prevnar 13®: Pharmaceutical form:liquid Route of administration: intramuscular
• Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus and Haemophilus b Conjugate (Tetanus Toxoid Conjugate) (Biological), also known as DTaP-IPV// Hib vaccine, Pentacel®: Pharmaceutical form:liquid Route of administration: intramuscular
• Rotavirus Vaccine, Live, Oral, Pentavalent (Biological), also known as Rotavirus vaccine, RotaTeq: Pharmaceutical form:liquid Route of administration: oral
• Hepatitis B Vaccine* [Recombinant] *as applicable (Biological), also known as Hepatitis B vaccine, ENGERIX-B®: Pharmaceutical form:liquid Route of administration: intramuscular

Primary outcomes

• Number of Participants With Immediate Adverse Events (AEs) [Up to 30 minutes after each vaccination]: An AE was any untoward medical occurrence in a participant or in a clinical investigation participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. Immediate events were recorded to capture medically relevant unsolicited systemic AEs (including those related to the product administered) that occurred within the first 30 minutes after vaccination. An unsolicited AE was an observed AE that did not fulfill the conditions prelisted in the case report book (CRB) in terms of diagnosis and/or onset window post-vaccination and included both serious adverse events (SAEs) and non-serious unsolicited AEs.
• Number of Participants With Solicited Injection Site Reactions [Up to 7 days after each vaccination]: A solicited reaction was an "expected" adverse reaction (sign or symptom) observed and reported under the conditions (nature and onset) prelisted in the protocol and CRB and were considered to be related to the product administered. An injection site reaction was an adverse reaction at and around the injection site which were commonly inflammatory reactions. Solicited injection site reactions included tenderness, erythema and swelling around the injection site and were planned to be collected and reported for SP0202/Prevnar 13 for both toddlers and infants.
• Number of Participants With Solicited Systemic Reactions [Up to 7 days after each vaccination]: A solicited reaction was an "expected" adverse reaction (sign or symptom) observed and reported under the conditions (nature and onset) pre-listed in the protocol and CRB and considered as related to the product administered. Solicited systemic reactions included fever, vomiting, abnormal crying, drowsiness, appetite loss, and irritability. Reported AEs for each arm were presented as pre-specified in protocol.
• Number of Participants With Unsolicited AEs [Up to 30 days after each vaccination]: An AE was any untoward medical occurrence in a clinical investigation participant administered a medicinal product, and which did not necessarily have a causal relationship with this treatment. An unsolicited AE was an observed AE that did not fulfill the conditions prelisted in the CRB in terms of diagnosis and/or onset window post-vaccination. Unsolicited AEs included both SAEs and non-serious unsolicited AEs. Reported AEs for each arm were presented as pre-specified in protocol.
• Number of Participants With SAEs and Adverse Event of Special Interest (AESIs) [From first dose vaccine administration (Day 1) until 6 months after the last dose administration, 490 days]: An SAE was any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was an important medical event. An AESI (serious or non-serious) was defined as one of scientific and medical concern specific to the Sponsor's product or program, for which ongoing monitoring and rapid communication by the Investigator to the Sponsor was appropriate. The following AE were captured as AESI throughout the study: Anaphylaxis defined as per the Brighton collaboration case definition, convulsions including febrile convulsions, hypotonic-hyporesponsive episode and apnea. Reported AEs for each arm were presented as pre-specified in protocol.
• For Toddlers: Serotype Specific Immunoglobulin G (IgG) Geometric Mean Concentrations (GMCs) for Each Pneumococcal Serotype at 30 Days Post-Dose [Day 30]: The GMCs for serotype specific pneumococcal IgG antibodies were measured using pneumococcal capsular polysaccharide-electro-chemiluminescent assay (PnPS-ECL), a multiplexed serological assay which allows for the simultaneous quantification of human IgG against pneumococcal polysaccharide antigens.
• For Infants: Percentage of Participants With Serotype Specific IgG Concentration >=0.35 mcg/mL 30 Days Post-Dose 3 [Day 150]: Percentage of infants with serotype specific IgG concentration >=0.35 mcg/mL for each pneumococcal serotype included in the SP0202 formulations were measured using ECL, a multiplexed serological assay which allows for the simultaneous quantification of human IgG against pneumococcal polysaccharide antigens.
• For Infants: Serotype Specific IgG GMCs for Each Pneumococcal Serotype at 30 Days Post-Dose 3 [Day 150]: The GMCs for serotype-specific pneumococcal IgG antibodies were measured using PnPS-ECL, a multiplexed serological assay which allows for the simultaneous quantification of human IgG against pneumococcal polysaccharide antigens.
• For Infants: Serotype Specific IgG GMCs for Each Pneumococcal Serotype at 30 Days Post-Dose 4 [Day 330]: The GMCs for serotype specific pneumococcal IgG antibodies were measured using PnPS-ECL, a multiplexed serological assay which allows for the simultaneous quantification of human IgG against pneumococcal polysaccharide antigens.

Secondary outcomes

• For Toddlers: Serotype Specific OPA Geometric Mean Titers (GMTs) for Each Pneumococcal Serotype 30 Days Post-Dose [Day 30]: The GMs for serotype specific OPA titers were measured using multiplex opsonophagocytic assay (MOPA) which is used to evaluate the opsonophagocytic index (50% killing) of pneumococcal anti-capsular polysaccharide antibodies in human serum samples following vaccination.
• For Infants: Serotype Specific OPA GMTs for Each Pneumococcal Serotype 30 Days Post-Dose 3 [Day 150]: The GMs for serotype specific OPA titers were measured using MOPA which is used to evaluate the opsonophagocytic index (50% killing) of pneumococcal anti-capsular polysaccharide antibodies in human serum samples following vaccination.
• For Infants: Serotype Specific OPA GMTs for Each Pneumococcal Serotype 30 Days Post-Dose 4 [Day 330]: The GMs for serotype specific OPA titers were measured using MOPA which is used to evaluate the opsonophagocytic index (50% killing) of pneumococcal anti-capsular polysaccharide antibodies in human serum samples following vaccination.
• For Infants: GMC of Anti-Rotavirus Serum Immunoglobulin A (IgA) Antibodies 30 Days Post-Dose 3 [Day 150]: Anti-rotavirus IgA antibodies in human serum were measured by enzyme linked immunosorbent assay (ELISA). A reference standard assayed on each plate was used to calculate the amount of specific anti-rotavirus IgA antibody in the units assigned by the reference standard.
• For Infants: Percentage of Participants With Antibody Responses to Diphtheria, Tetanus and Polyribosylribitol Phosphate Antigens 30 Days Post-Dose 3 [Day 150]: Percentage of participants with toxoid concentration >=0.10 mcg/mL for diphtheria and tetanus and >=0.15 mcg/mL for PRP are presented. Anti-diphtheria and anti-tetanus concentrations were measured using electro-chemiluminescence assay (ECL) and anti-PRP concentrations were measured using a Farr-type radioimmunoassay.
• For Infants: Percentage of Participants With Antibody Responses to Poliovirus 1, 2 and 3 30 Days Post-Dose 3 [Day 150]: Anti-poliovirus types 1, 2, and 3 were measured by neutralization assay. Response was defined as a titer >=8.
• For Infants: GMCs of Antibodies to Pertussis Antigens 30 Days Post-Dose 3 [Day 150]: Serum samples were collected for analysis by ECL to determine the GMC of antibodies to the following Pertussis antigens: Pertussis toxoid/toxin, Filamentous hemagglutinin, Pertactin and Fimbriae types 2 and 3.
• For Infants: Percentage of Participants With Antibody Responses to Hepatitis-B Antigens 30 Days Post-Dose 3 [Day 150]: Anti-Hepatitis B antibodies were measured by the commercially available VITROS ECi/ECiQ immunodiagnostic system using chemiluminescence detection technology. The VITROS ECi immunodiagnostic system uses an antibody mediated antigen sandwich formation to detect the presence of anti-hepatitis B surface antigen total immunoglobulin in human serum. The threshold presented is >=10 milli international units (mIU).
• For Infants: Percentage of Participants With Antibody Responses to M-MRII and Varivax Antigens 30 Days Post-Dose 4 [Day 330]: Anti-measles antibodies were determined by bulk measles IgG enzyme immunoassay (EIA); anti-mumps antibodies by ELISA, anti-rubella antibodies by bulk rubella IgG EIA and anti-varicella antibodies were determined by glycoprotein ELISA to detect total IgG antibody to respective virus before and after vaccination with a virus-containing vaccine. Percentage of participants with anti-measles antibody concentrations >=255 mIU/mL, anti-mumps antibody concentrations: >=10 antibody units/mL, anti-rubella antibody concentrations >=10 IU/mL and anti-varicella concentrations >=5 units/mL is reported in this outcome measure.

Sex: All, ages: 42 Days to 15 Months, accepts healthy volunteers

Inclusion criteria :

Toddlers and infants:

* Participant and parent/guardian are able to attend all scheduled visits and to comply with all study procedures
* Born at full term of pregnancy (≥ 37 weeks) and/or with a birth weight ≥ 5.5 lbs or 2.5 kg

Specifically for toddlers:

* Aged 12 to 15 months on the day of the first study visit
* Participant has received 3 doses of Prevnar 13 and 3 doses of diphteria, tetanus, acellular pertussis, poliovirus and Haemophilus influenzae type b antigens in infancy

Specifically for infants:

\- Aged 42 to 89 days on the day of the first study visit

Exclusion criteria:

Toddlers and infants

* Participation at the time of study enrollment (or in the 4 weeks preceding the first study vaccination) or planned participation during the present study period in another clinical study investigating a vaccine, drug, medical device, or medical procedure
* Family history of congenital or hereditary immunodeficiency, until the immune competence of the potential vaccine recipient is demonstrated
* Blood dyscrasias, leukemia, lymphoma of any type, or other malignant neoplasms affecting the bone marrow or lymphatic systems
* Active tuberculosis
* History of S. pneumoniae infection or disease, confirmed either serologically or microbiologically
* History of any neurologic disorder, including any seizures and progressive neurologic disorders
* History of Guillain-Barré syndrome
* Known systemic hypersensitivity to any of the vaccine components or to latex, or history of a life-threatening reaction to the vaccines used in the study or to a vaccine containing any of the same substances
* Verbal report of thrombocytopenia contraindicating intramuscular vaccination in the Investigator's opinion
* Bleeding disorder, or receipt of anticoagulants in the 3 weeks preceding inclusion, contraindicating intramuscular vaccination in the Investigator's opinion
* Receipt of oral or injectable antibiotic therapy within 72 hours prior to the first blood draw
* Chronic illness (including, but not limited to, cardiac disorders, congenital heart disease, chronic lung disease, renal disorders, auto-immune disorders, diabetes, psychomotor diseases, and know congenital or genetic diseases) that, in the opinion of the Investigator, is at a stage where it might interfere with study conduct or completion
* Any condition which, in the opinion of the Investigator, might interfere with the evaluation of the study objectives
* In an emergency setting, or hospitalized involuntarily
* Moderate or severe acute illness/infection (according to Investigator judgment) on the day of vaccination or febrile illness (temperature ≥ 38.0 C / ≥ 100.4 F). A prospective participant should not be included in the study until the condition has resolved or until 3 days after the febrile event has resolved
* Identified as a natural or adopted child of the Investigator or employee with direct involvement in the proposed study Specifically for toddlers
* Receipt of any vaccine in the 4 weeks preceding the study vaccination or planned receipt of any vaccine from enrollment through the last blood sampling Visit (Visit 2), except for influenza vaccination, which may be received at least 2 weeks before or 2 weeks after any study vaccination. This exception includes monovalent pandemic influenza vaccines and multivalent influenza vaccines
* Receipt of immune globulins, blood or blood-derived products in the past 3 months
* Known or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy, within the preceding 6 months; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks within the past 3 months)
* History of diphtheria, tetanus, pertussis, poliomyelitis, and/or H. influenzae type b infection or disease Specifically for infants
* Receipt of any vaccine in the 4 weeks preceding the study vaccination or planned receipt of any vaccine from enrollment through the last blood sampling Visit (Visit 6), except for influenza vaccination or COVID-19 vaccination, which may be received at least 2 weeks before or 2 weeks after any study vaccination. This exception includes monovalent pandemic influenza vaccines and multivalent influenza vaccines, and COVID-19 vaccines as applicable per local recommendations
* Receipt of immune globulins, blood or blood-derived products since birth.
* Known or suspected congenital or acquired immunodeficiency; or receipt of immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy; or long-term systemic corticosteroid therapy (prednisone or equivalent for more than 2 consecutive weeks) since birth
* Previous vaccination against S. pneumoniae
* Previous vaccination against the following antigens: diphteria, tetanus, pertussis, H. influenzae type b, poliovirus, rotavirus, measles, mumps, rubella, and varicella
* Receipt of more than 1 previous dose of hepatitis B vaccine
* History of diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B, measles, mumps, rubella, varicella, H. influenzae type b, and/or rotavirus infection or disease
* History of intussusception

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Participant flow

Outcome results

• Number of Participants With Immediate Adverse Events (AEs) (Primary), Count of participants, Participants: Stage I: Group 1 SP0202-IIb 0; Stage I: Group 2 SP0202-VI 0; Stage I: Group 3 SP0202-VII 0; Stage I: Group 4 Prevnar 13 0; Stage II: Group 5 SP0202-IIb 0; Stage II: Group 6 SP0202-VI 0; Stage II: Group 7 SP0202-VII 0; Stage II: Group 8 Prevnar 13 0
• Number of Participants With Solicited Injection Site Reactions (Primary), Count of participants, Participants: Stage I: Group 1 SP0202-IIb 21; Stage I: Group 2 SP0202-VI 18; Stage I: Group 3 SP0202-VII 21; Stage I: Group 4 Prevnar 13 13; Stage II: Group 5 SP0202-IIb 119; Stage II: Group 6 SP0202-VI 128; Stage II: Group 7 SP0202-VII 126; Stage II: Group 8 Prevnar 13 124
• Number of Participants With Solicited Systemic Reactions (Primary), Count of participants, Participants: Stage I: Group 1 SP0202-IIb 25; Stage I: Group 2 SP0202-VI 23; Stage I: Group 3 SP0202-VII 27; Stage I: Group 4 Prevnar 13 24; Stage II: Group 5 SP0202-IIb 139; Stage II: Group 6 SP0202-VI 143; Stage II: Group 7 SP0202-VII 137; Stage II: Group 8 Prevnar 13 138
• Number of Participants With Unsolicited AEs (Primary), Count of participants, Participants: Stage I: Group 1 SP0202-IIb 7; Stage I: Group 2 SP0202-VI 3; Stage I: Group 3 SP0202-VII 4; Stage I: Group 4 Prevnar 13 6; Stage II: Group 5 SP0202-IIb 122; Stage II: Group 6 SP0202-VI 116; Stage II: Group 7 SP0202-VII 118; Stage II: Group 8 Prevnar 13 117
• Number of Participants With SAEs and Adverse Event of Special Interest (AESIs) (Primary), Count of participants, Participants: Stage I: Group 1 SP0202-IIb 0; Stage I: Group 2 SP0202-VI 1; Stage I: Group 3 SP0202-VII 0; Stage I: Group 4 Prevnar 13 0; Stage II: Group 5 SP0202-IIb 3; Stage II: Group 6 SP0202-VI 9; Stage II: Group 7 SP0202-VII 8; Stage II: Group 8 Prevnar 13 9
• For Toddlers: Serotype Specific Immunoglobulin G (IgG) Geometric Mean Concentrations (GMCs) for Each Pneumococcal Serotype at 30 Days Post-Dose (Primary), Geometric mean, microgram/millilitre (mcg/mL): Stage I: Group 1 SP0202-IIb 2.46 (1.59 to 3.82); Stage I: Group 2 SP0202-VI 2.12 (1.40 to 3.21); Stage I: Group 3 SP0202-VII 3.29 (2.55 to 4.24); Stage I: Group 4 Prevnar 13 3.80 (2.76 to 5.24)
• For Infants: Percentage of Participants With Serotype Specific IgG Concentration >=0.35 mcg/mL 30 Days Post-Dose 3 (Primary), Number, percentage of participants: Stage II: Group 5 SP0202-IIb 97.7 (93.5 to 99.5); Stage II: Group 6 SP0202-VI 96.7 (91.8 to 99.1); Stage II: Group 7 SP0202-VII 95.2 (89.8 to 98.2); Stage II: Group 8 Prevnar 13 97.0 (92.4 to 99.2)
• For Infants: Serotype Specific IgG GMCs for Each Pneumococcal Serotype at 30 Days Post-Dose 3 (Primary), Geometric mean, mcg/mL: Stage II: Group 5 SP0202-IIb 1.91 (1.66 to 2.19); Stage II: Group 6 SP0202-VI 2.21 (1.88 to 2.61); Stage II: Group 7 SP0202-VII 1.97 (1.66 to 2.34); Stage II: Group 8 Prevnar 13 2.81 (2.39 to 3.30)
• For Infants: Serotype Specific IgG GMCs for Each Pneumococcal Serotype at 30 Days Post-Dose 4 (Primary), Geometric mean, mcg/mL: Stage II: Group 5 SP0202-IIb 3.16 (2.68 to 3.73); Stage II: Group 6 SP0202-VI 3.59 (3.02 to 4.26); Stage II: Group 7 SP0202-VII 3.44 (2.87 to 4.12); Stage II: Group 8 Prevnar 13 3.89 (3.35 to 4.50)
• For Toddlers: Serotype Specific OPA Geometric Mean Titers (GMTs) for Each Pneumococcal Serotype 30 Days Post-Dose (Secondary), Geometric mean, 1/dilution (1/dil): Stage I: Group 1 SP0202-IIb 138 (62.1 to 306); Stage I: Group 2 SP0202-VI 94.2 (49.9 to 178); Stage I: Group 3 SP0202-VII 177 (92.3 to 339); Stage I: Group 4 Prevnar 13 247 (140 to 434)
• For Infants: Serotype Specific OPA GMTs for Each Pneumococcal Serotype 30 Days Post-Dose 3 (Secondary), Geometric mean, 1/dil: Stage II: Group 5 SP0202-IIb 73.6 (53.4 to 101); Stage II: Group 6 SP0202-VI 81.7 (59.1 to 113); Stage II: Group 7 SP0202-VII 66.4 (46.7 to 94.5); Stage II: Group 8 Prevnar 13 114 (86.4 to 151)
• For Infants: Serotype Specific OPA GMTs for Each Pneumococcal Serotype 30 Days Post-Dose 4 (Secondary), Geometric mean, 1/dil: Stage II: Group 5 SP0202-IIb 407 (295 to 561); Stage II: Group 6 SP0202-VI 355 (255 to 495); Stage II: Group 7 SP0202-VII 320 (211 to 486); Stage II: Group 8 Prevnar 13 318 (251 to 403)
• For Infants: GMC of Anti-Rotavirus Serum Immunoglobulin A (IgA) Antibodies 30 Days Post-Dose 3 (Secondary), Geometric mean, Units (U)/mL: Stage II: Group 5 SP0202-IIb 407 (303 to 545); Stage II: Group 6 SP0202-VI 390 (283 to 537); Stage II: Group 7 SP0202-VII 494 (369 to 661); Stage II: Group 8 Prevnar 13 393 (277 to 560)
• For Infants: Percentage of Participants With Antibody Responses to Diphtheria, Tetanus and Polyribosylribitol Phosphate Antigens 30 Days Post-Dose 3 (Secondary), Number, percentage of participants: Stage II: Group 5 SP0202-IIb 94.6 (89.2 to 97.8); Stage II: Group 6 SP0202-VI 97.5 (92.7 to 99.5); Stage II: Group 7 SP0202-VII 95.9 (90.8 to 98.7); Stage II: Group 8 Prevnar 13 96.9 (92.3 to 99.2)
• For Infants: Percentage of Participants With Antibody Responses to Poliovirus 1, 2 and 3 30 Days Post-Dose 3 (Secondary), Number, percentage of participants: Stage II: Group 5 SP0202-IIb 99.2 (95.6 to 100); Stage II: Group 6 SP0202-VI 100 (96.7 to 100); Stage II: Group 7 SP0202-VII 97.4 (92.5 to 99.5); Stage II: Group 8 Prevnar 13 100 (97.1 to 100)
• For Infants: GMCs of Antibodies to Pertussis Antigens 30 Days Post-Dose 3 (Secondary), Geometric mean, ELISA units (EU)/mL: Stage II: Group 5 SP0202-IIb 67.9 (60.1 to 76.6); Stage II: Group 6 SP0202-VI 77.2 (67.4 to 88.5); Stage II: Group 7 SP0202-VII 66.3 (57.4 to 76.6); Stage II: Group 8 Prevnar 13 68.3 (59.7 to 78.2)
• For Infants: Percentage of Participants With Antibody Responses to Hepatitis-B Antigens 30 Days Post-Dose 3 (Secondary), Number, percentage of participants: Stage II: Group 5 SP0202-IIb 98.3 (94.2 to 99.8); Stage II: Group 6 SP0202-VI 99.1 (94.9 to 100); Stage II: Group 7 SP0202-VII 98.1 (93.5 to 99.8); Stage II: Group 8 Prevnar 13 99.2 (95.6 to 100)
• For Infants: Percentage of Participants With Antibody Responses to M-MRII and Varivax Antigens 30 Days Post-Dose 4 (Secondary), Number, percentage of participants: Stage II: Group 5 SP0202-IIb 97.5 (92.7 to 99.5); Stage II: Group 6 SP0202-VI 97.1 (91.8 to 99.4); Stage II: Group 7 SP0202-VII 96.9 (91.3 to 99.4); Stage II: Group 8 Prevnar 13 98.4 (94.3 to 99.8)

Adverse events

Time frame: AEs data was collected from first dose vaccine administration (Day 1) until 6 months after the last dose administration, 490 days. All-cause mortality was collected up to end of the study (Stage I: 6 months and Stage II: 19 months)

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2022-04-04)
• Statistical Analysis Plan (PDF, 2022-05-05)

• Clinical Sciences & Operations, Study director, Sanofi Pasteur, a Sanofi Company