SA4Ag Safety, Tolerability, and Immunogenicity Study in Japanese Adults

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, and immunogenicity of a single dose of Staphylococcus aureus 4 antigen vaccine in Japanese adults aged 20 to <86 years.

Official Title
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A Phase 1/2a Placebo-controlled, Randomized, Double-blind, Sponsor-unblinded Trial To Evaluate The Safety, Tolerability, And Immunogenicity Of Staphylococcus Aureus 4-antigen Vaccine (sa4ag) In Japanese Adults

Conditions
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Staphylococcal Infections

Intervention / Treatment
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* Biological: Staphylococcus aureus 4-antigen vaccine
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Japanese male and female adults aged 20 to <86 years, Determined as healthy by the investigator (Subjects with preexisting chronic medical conditions determined to be stable may be included), Must be available for the 12 month duration of the study, Subjects must agree to use an acceptable method of birth control for 3 months after study vaccination (if the subject or the subject's partner are/is capable of having children). Exclusion Criteria: Any contraindication to vaccination or vaccine components, including previous anaphylactic reaction to any vaccine or vaccine-related components, Unstable or serious chronic medical condition that would increase the subject's risk of participation, Immune system suppression or treatment with medications that suppress the immune system, Receipt of blood products or immunoglobulins within the past 12 months, Any infection proven or suspected to be caused by S.aureus within the past 6 months, A staff member at this site nor a relative of those site staff members, nor a sponsor's employee directly involved in the conduct of this research study, Living in a nursing home, long-term care facility or other institution or requiring any types of nursing care, A pregnant or a breast feeding woman.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 85 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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SA4Ag<br>Staphylococcus aureus 4-antigen vaccine | Biological: Staphylococcus aureus 4-antigen vaccine<br>* a single 0.5 mL dose of investigational product into the deltoid muscle in the upper arm<br>* Other names: SA4Ag;|
| Placebo Comparator: Placebo<br>a lyophile match to the vaccine, consisting of excipients of SA4Ag formulation minus the active ingredients | Biological: Placebo<br>* a single 0.5 mL dose of investigational product into the deltoid muscle in the upper arm<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With At Least 1 Local Reaction Within 14 Days of Vaccination | Local reactions were recorded using an electronic daily diary. Local reactions included redness, swelling and pain at injection site. Redness and swelling were defined as mild (2.5 to 5.0 centimeters [cm]), moderate (5.5 to 10.0 cm) and, severe (greater than or equal to [>=] 10.5 cm). Pain at injection site was defined as mild (did not interfere with activity), moderate (interfered with activity), and severe (prevented daily activity). In this outcome measure percentage of participants with any local reaction was reported. | Day 1 up to Day 14 | 
| Percentage of Participants With Local Reactions by Severity Within 14 Days of Vaccination | Local reactions were recorded using an electronic daily diary. Local reactions included redness, swelling and pain at injection site. Redness and swelling were graded as mild (2.5 to 5.0 cm), moderate (5.5 to 10.0 cm) and, severe (>=10.5 cm). Pain at injection site was graded as mild (did not interfere with activity), moderate (interfered with activity), and severe (prevented daily activity). | Day 1 up to Day 14 | 
| Percentage of Participants With At Least 1 Systemic Event Within 14 Days of Vaccination | Systemic reactions included fever, vomiting, diarrhea, headache, fatigue, muscle and joint pain (other than at the injection site) and recorded by using an e-diary. Fever was graded as 37.5 to 38.4 degree Celsius (C), 38.5 to 38.9 degree C, 39.0 to 40.0 degree C and greater than (>) 40.0 degree C. Vomiting was graded as mild (1-2 times in 24 hours), moderate (>2 times in 24 hours) and severe (required intravenous hydration). Diarrhea was graded as mild (2-3 loose stools in 24 hours), moderate (4-5 loose stools in 24 hours) and severe (>=6 loose stools in 24 hours). Headache, fatigue, muscle pain and joint pain were graded as mild (no interference with activity), moderate (some interference with activity) and severe (significant, prevented daily activity). In this outcome measure percentage of participants with any systemic event was reported. | Day 1 up to Day 14 | 
| Percentage of Participants With Systemic Events by Severity Within 14 Days of Vaccination | Systemic reactions included fever, vomiting, diarrhea, headache, fatigue, muscle and joint pain (other than at the injection site) and recorded by using an e-diary. Fever was graded as 37.5 to 38.4 degree C, 38.5 to 38.9 degree C, 39.0 to 40.0 degree C and >40.0 degree C. Vomiting was graded as mild (1-2 times in 24 hours), moderate (>2 times in 24 hours) and severe (required intravenous hydration). Diarrhea was graded as mild (2-3 loose stools in 24 hours), moderate (4-5 loose stools in 24 hours) and severe (>=6 loose stools in 24 hours). Headache, fatigue, muscle pain and joint pain were graded as mild (no interference with activity), moderate (some interference with activity) and severe (significant, prevented daily activity). | Day 1 up to Day 14 | 
| Percentage of Participants With Treatment-Emergent Adverse Events (AEs) Reported From Day 1 Up to Day 29 Visit | An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. AEs included both serious and non-serious AEs. Treatment-emergent AEs were events between the administration of investigational product and up to Day 29 that were absent before vaccination or that worsened relative to pre-administration state. | Day 1 up to Day 29 | 
| Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAE) Reported After Day 29 Visit Through Month 12 | An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly or deemed medically significant for any other reason. A treatment emergent AE was defined as an event that emerged during the study that was absent before administration of investigational product, or worsened relative to the pre-administration state. AEs reported during this time period included both SAEs and newly diagnosed chronic medical disorders (NDCMD). A NDCMD was defined as a disease or medical condition that was not identified prior to study start and was expected to be persistent or otherwise long-lasting in its effects. | After Day 29 up to Month 12 | 
| Percentage of Participants With Hematology Abnormalities at Day 5 | Hematology analysis included the following parameters: hemoglobin, white blood cells, neutrophils and platelets, and scaled as Grade 1= mild; Grade 2= moderate; Grade 3= severe; or Grade 4. Hematology abnormality was defined as at least 1 grade abnormal value. Percentage of participants with abnormal values in hematology parameters are reported in this outcome measure. | Day 5 | 
| Percentage of Participants With Hematology Abnormalities at Day 15 | Hematology analysis included the following parameters: hemoglobin, white blood cells, neutrophils and platelets, and scaled as Grade 1= mild; Grade 2= moderate; Grade 3= severe; or Grade 4. Hematology abnormality was defined as at least 1 grade abnormal value. Percentage of participants with abnormal values in hematology parameters are reported in this outcome measure. | Day 15 | 
| Percentage of Participants With Coagulation Abnormalities at Day 5 | Coagulation analysis included the following parameters: prothrombin time (PT), activated partial thromboplastin time (APTT), platelet aggregation (AGG) (with adenosine diphosphate [ADP], with arachidonic acid, and with collagen) and fibrinogen activity. PT and APTT were scaled as Grade 1= mild; Grade 2= moderate; Grade 3= severe; or Grade 4. Coagulation abnormality was defined as at least 1 grade abnormal value for PT and APTT, and deviation from local laboratory range for platelet aggregation assay and fibrinogen activity assay. Percentage of participants with abnormal values in coagulation parameters are reported in this outcome measure. | Day 5 | 
| Percentage of Participants With Coagulation Abnormalities at Day 15 | Coagulation analysis included the following parameters: PT, APTT, platelet AGG with ADP, platelet AGG with arachidonic acid, platelet AGG with collagen and fibrinogen activity. PT and APTT were scaled as Grade 1= mild; Grade 2= moderate; Grade 3= severe; or Grade 4. Coagulation abnormality was defined as at least 1 grade abnormal value for PT and APTT, and deviation from local laboratory range for platelet aggregation assay and fibrinogen activity assay. Percentage of participants with abnormal values in coagulation parameters are reported in this outcome measure. | Day 15 | 
| Percentage of Participants With Blood Chemistry Abnormalities at Day 5 | Blood chemistry laboratory analysis included the following parameters: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin, creatinine, creatine kinase and lactate dehydrogenase, and scaled as Grade 1= mild; Grade 2= moderate; Grade 3= severe; or Grade 4. Blood chemistry abnormality was defined as at least 1 grade abnormal value. Percentage of participants with abnormal values in blood chemistry laboratory parameters are reported in this outcome measure. | Day 5 | 
| Percentage of Participants With Blood Chemistry Abnormalities at Day 15 | Blood chemistry laboratory analysis included the following parameters: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin, creatinine, creatine kinase and lactate dehydrogenase, and scaled as Grade 1= mild; Grade 2= moderate; Grade 3= severe; or Grade 4. Blood chemistry abnormality was defined as at least 1 grade abnormal value. Percentage of participants with abnormal values in blood chemistry laboratory parameters are reported in this outcome measure. | Day 15 | 
| Percentage of Participants Achieving Predefined Antibody Response to Target Antigens at Day 29 | Percentage of participants achieving predefined antibody response to capsular polysaccharide serotype 5 (CP5), capsular polysaccharide serotype 8 (CP8), clumping factor A (ClfA) and manganese transporter C (MntC) at Day 29 were reported. The predefined thresholds for the target antigens were 1000 and 2000 based on opsonophagocytic activity (OPA) assay for CP5 and CP8, respectively; was 121 based on fibrinogen-binding inhibition (FBI) assay for ClfA and 512 based on competitive Luminex immunoassay (cLIA) for MntC. | Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Predefined Antibody Response to Target Antigens on Baseline, Day 11, 15 and Month 3 | Percentage of participants achieving predefined antibody response to CP5, CP8, ClfA and MntC at Baseline, Day 11, 15 and Month 3 were reported. The predefined thresholds for the target antigens were 1000 and 2000 based on OPA assay for CP5 and CP8, respectively; was 121 based on FBI assay for ClfA, 512 based on cLIA for MntC. | Baseline, Day 11, 15 and Month3 | 
| Antigen-specific Competitive Luminex Immunoassay (cLIA) Geometric Mean Titers (GMTs) | Geometric mean titer is commonly used to assess the immunogenicity of vaccine. Antibody GMTs as measured by cLIA for ClfA and MntC and corresponding 2-sided 95 percent (%) confidence intervals (CIs) were evaluated. CIs were computed by back transforming the CIs generated for means of the titers on the log scale based on the Student t distribution. | Baseline, Day 11, 15, 29 and Month 3 | 
| Antigen-specific Opsonophagocytic Activity (OPA) Geometric Mean Titers (GMTs) | Geometric mean titer is commonly used to assess the immunogenicity of vaccine. Antibody GMTs as measured by OPA for CP5 and CP8 and corresponding 2-sided 95 percent CIs were evaluated. CIs were computed by back transforming the CIs generated for means of the titers on the log scale based on the Student t distribution. | Baseline, Day 11, 15, 29 and Month 3 | 
| Antigen-specific Fibrinogen-binding Inhibition (FBI) Assay Geometric Mean Titers (GMTs) | Geometric mean titer is commonly used to assess the immunogenicity of vaccine. Antibody GMTs as measured by FBI for ClfA and corresponding 2-sided 95 percent CIs were evaluated. CIs were computed by back transforming the CIs generated for means of the titers on the log scale based on the Student t distribution. | Baseline, Day 11, 15, 29 and Month 3 | 
| Geometric Mean Fold Rise (GMFR) for Staphylococcus Aureus Antigen-specific cLIA Titers From Baseline to Day 11, 15, 29 and Month 3 | GMFRs of anti-Staphylococcus aureus cLIA for ClfA and MntC were computed. CIs which are reported below were computed by back transforming the CIs generated for the mean fold rise on the log scale based on the Student t distribution. GMFRs were computed as the fold rise in titer value at specified time point compared to baseline. | Baseline, Day 11, 15, 29 and Month 3 | 
| Geometric Mean Fold Rise (GMFR) for Staphylococcus Aureus Antigen-specific OPA Titers From Baseline to Day 11, 15, 29 and Month 3 | GMFRs of anti-Staphylococcus aureus OPA for CP5 and CP8 were computed. CIs which are reported below were computed by back transforming the CIs generated for the mean fold rise on the log scale based on the Student t distribution. GMFRs were computed as the fold rise in titer value at specified time point compared to baseline. | Baseline, Day 11, 15, 29 and Month 3 | 
| Geometric Mean Fold Rise (GMFR) for Staphylococcus Aureus Antigen-specific FBI Titers From Baseline to Day 11, 15, 29 and Month 3 | GMFR of anti-Staphylococcus aureus FBI for ClfA was computed. CIs which are reported below were computed by back transforming the CIs generated for the mean fold rise on the log scale based on the Student t distribution. GMFRs were computed as the fold rise in titer value at specified time point compared to baseline. | Baseline, Day 11, 15, 29 and Month 3 |