Dose-Finding Study of S.Pneumoniae Whole Cell Vaccine Adsorbed to Alum (PATH-wSP) in Healthy Kenyan Adults and Toddlers

NCT ID: NCT02097472

Last Updated: 2019-10-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 304 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-04-30
• Study Completion Date: 2015-12-31

Brief Summary

The purpose of this study is to assess the safety and tolerability of PATH-wSP, administered intramuscularly to healthy Kenyan adults and toddlers who have been primed with a pneumococcal conjugate vaccine (PCV).

Additionally, the study will explore whether a measurable immune response is elicited when PATH-wSP is administered to healthy Kenyan adults and toddlers who have been primed with PCV.

Detailed Description

S. pneumoniae whole cell vaccine (SPWCV) is a vaccine candidate made from whole, unencapsulated pneumococcal cells. S. pneumoniae whole cell antigen bulk was manufactured at Walter Reed Army Institute of Research from strain RM200 RX1E PdT ΔlytA and is inactivated with beta-propiolactone. Pneumolysin, a proven virulence factor, was genetically knocked out in SPWCV and replaced with pneumolysoid, a derivative carrying the toxin gene with 3 point mutations known to abolish both cytolytic activity and complement activation. When adsorbed to aluminum hydroxide (alum), SPWCV is utilized as the vaccine candidate Streptococcus pneumoniae whole cell vaccine with aluminum hydroxide adjuvant (PATH-wSP) for clinical investigation. PATH-wSP has been previously tested in adults in a Phase 1 trial in the US, in which doses of 100 to 600 μg were given to healthy young adults in a 3-vaccination series and showed a favorable safety, tolerability, and immunogenicity profile.

This study was a dose escalation and age de-escalation study, and sequential cohorts of subjects were identified to allow safety evaluations of dosing and ages to occur progressively during the study. The following PATH-wSP cohorts were defined for adult and toddler subjects:

• Adult Cohort 1: 600 μg PATH-wSP or saline
• Adult Cohort 2: 1000 μg PATH-wSP or saline
• Toddler Cohort 1: 300 μg PATH-wSP and/or active control vaccines
• Toddler Cohort 2: 600 μg PATH-wSP and/or active control vaccines.

Conditions

Pneumonia, Pneumococcal

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Adult Cohort 1, PATH-wSP, 600 mcg

A single injection of 600 mcg PATH-wSP in one arm, followed 4 weeks later by a single injection of 600 mcg PATH-wSP in the alternate arm.

Group Type: EXPERIMENTAL

PATH-wSP

Intervention Type: BIOLOGICAL

Streptococcus pneumoniae Whole Cell Vaccine adsorbed to Alum

Adult Cohort 1, Saline

A single injection of saline in one arm, followed 4 weeks later by a single injection of saline in the alternate arm.

Group Type: PLACEBO_COMPARATOR

Saline

Intervention Type: OTHER

0.9% Sodium Chloride Injection, USP

Adult Cohort 2, PATH-wSP, 1000 mcg

A single injection of 1000 mcg PATH-wSP in one arm, followed 4 weeks later by a single injection of 1000 mcg PATH-wSP in the alternate arm.

Group Type: EXPERIMENTAL

PATH-wSP

Intervention Type: BIOLOGICAL

Streptococcus pneumoniae Whole Cell Vaccine adsorbed to Alum

Adult Cohort 2, Saline

A single injection of saline in one arm, followed 4 weeks later by a single injection of saline in the alternate arm.

Group Type: PLACEBO_COMPARATOR

Saline

Intervention Type: OTHER

0.9% Sodium Chloride Injection, USP

Toddler Cohort 1 PATH-wSP 300 mcg+Active control

A single injection of PATH-wSP 300 mcg in the left thigh and a single injection of each of the two active comparator vaccines (Synflorix and Pentavac) in the right thigh. These 3 injections are followed by a single injection of PATH-wSP 300 mcg in the left thigh 8 weeks later.

Group Type: EXPERIMENTAL

PATH-wSP

Intervention Type: BIOLOGICAL

Streptococcus pneumoniae Whole Cell Vaccine adsorbed to Alum

Synflorix

Intervention Type: BIOLOGICAL

1 dose (0.5 mL) contains:

1 μg of each of the following pneumococcal polysaccharide serotypes:

1, 5, 6B, 7F, 9V, 14, and 23 F

And 3 μg of the following pneumococcal polysaccharide serotypes:

4, 18C and 19F.

The serotypes are conjugated to either:

protein D (derived from Non-Typeable Haemophilus influenzae) carrier protein, tetanus toxoid carrier protein or diphtheria toxoid carrier protein

Pentavac

Intervention Type: BIOLOGICAL

Each PFS contains 0.5 ml (single dose):

Diphtheria Toxoid 20 Lf to 30 Lf Tetanus Toxoid 2.5 Lf to 10 Lf B. Pertussis 4 IU HBsAg (rDNA) 10 mcg Purified capsular HIB Polysaccharide (PRP) Conjugated to Tetanus Toxoid (carrier protein) 10 mcg Adsorbed on Aluminium Phosphate, AL+++ 1.25 mg Preservative: Thiomersal 0.005 % Dose: O.5ml by intramuscular injection.

Toddler Cohort 1 PATH-wSP 300 mcg+Saline

A single injection of PATH-wSP 300 mcg in the left thigh and a single injection of saline in the right thigh along with a separate single injection of saline in the right thigh. These 3 injections are followed by a single injection of PATH-wSP 300 mcg in the left thigh 8 weeks later.

Group Type: EXPERIMENTAL

PATH-wSP

Intervention Type: BIOLOGICAL

Streptococcus pneumoniae Whole Cell Vaccine adsorbed to Alum

Saline

Intervention Type: OTHER

0.9% Sodium Chloride Injection, USP

Toddler Cohort 1: Active Control Only

A single injection of saline in the left thigh and a single injection of each of the two active comparator vaccines (Synflorix and Pentavac) in the right thigh. These 3 injections are followed by a single injection of saline in the left thigh 8 weeks later.

Group Type: ACTIVE_COMPARATOR

Synflorix

Intervention Type: BIOLOGICAL

1 dose (0.5 mL) contains:

1 μg of each of the following pneumococcal polysaccharide serotypes:

1, 5, 6B, 7F, 9V, 14, and 23 F

And 3 μg of the following pneumococcal polysaccharide serotypes:

4, 18C and 19F.

The serotypes are conjugated to either:

protein D (derived from Non-Typeable Haemophilus influenzae) carrier protein, tetanus toxoid carrier protein or diphtheria toxoid carrier protein

Pentavac

Intervention Type: BIOLOGICAL

Each PFS contains 0.5 ml (single dose):

Diphtheria Toxoid 20 Lf to 30 Lf Tetanus Toxoid 2.5 Lf to 10 Lf B. Pertussis 4 IU HBsAg (rDNA) 10 mcg Purified capsular HIB Polysaccharide (PRP) Conjugated to Tetanus Toxoid (carrier protein) 10 mcg Adsorbed on Aluminium Phosphate, AL+++ 1.25 mg Preservative: Thiomersal 0.005 % Dose: O.5ml by intramuscular injection.

Saline

Intervention Type: OTHER

0.9% Sodium Chloride Injection, USP

Toddler Cohort 2 PATH-wSP 600 mcg+Active control

A single injection of PATH-wSP 600 mcg in the left thigh and a single injection of each of the two active comparator vaccines (Synflorix and Pentavac) in the right thigh. These 3 injections are followed by a single injection of PATH-wSP 600 mcg in the left thigh 8 weeks later.

Group Type: EXPERIMENTAL

PATH-wSP

Intervention Type: BIOLOGICAL

Streptococcus pneumoniae Whole Cell Vaccine adsorbed to Alum

Synflorix

Intervention Type: BIOLOGICAL

1 dose (0.5 mL) contains:

1 μg of each of the following pneumococcal polysaccharide serotypes:

1, 5, 6B, 7F, 9V, 14, and 23 F

And 3 μg of the following pneumococcal polysaccharide serotypes:

4, 18C and 19F.

The serotypes are conjugated to either:

protein D (derived from Non-Typeable Haemophilus influenzae) carrier protein, tetanus toxoid carrier protein or diphtheria toxoid carrier protein

Pentavac

Intervention Type: BIOLOGICAL

Each PFS contains 0.5 ml (single dose):

Diphtheria Toxoid 20 Lf to 30 Lf Tetanus Toxoid 2.5 Lf to 10 Lf B. Pertussis 4 IU HBsAg (rDNA) 10 mcg Purified capsular HIB Polysaccharide (PRP) Conjugated to Tetanus Toxoid (carrier protein) 10 mcg Adsorbed on Aluminium Phosphate, AL+++ 1.25 mg Preservative: Thiomersal 0.005 % Dose: O.5ml by intramuscular injection.

Toddler Cohort 2 PATH-wSP 600 mcg+saline

A single injection of PATH-wSP 600 mcg in the left thigh and a single injection of saline in the right thigh along with a separate single injection of saline in the right thigh. These 3 injections are followed by a single injection of PATH-wSP 600 mcg in the left thigh 8 weeks later.

Group Type: EXPERIMENTAL

PATH-wSP

Intervention Type: BIOLOGICAL

Streptococcus pneumoniae Whole Cell Vaccine adsorbed to Alum

Saline

Intervention Type: OTHER

0.9% Sodium Chloride Injection, USP

Toddler Cohort 2: Active Control Only

A single injection of saline in the left thigh and a single injection of each of the two active comparator vaccines in the right thigh. These 3 injections are followed by a single injection of saline in the left thigh 8 weeks later.

Group Type: ACTIVE_COMPARATOR

Synflorix

Intervention Type: BIOLOGICAL

1 dose (0.5 mL) contains:

1 μg of each of the following pneumococcal polysaccharide serotypes:

1, 5, 6B, 7F, 9V, 14, and 23 F

And 3 μg of the following pneumococcal polysaccharide serotypes:

4, 18C and 19F.

The serotypes are conjugated to either:

protein D (derived from Non-Typeable Haemophilus influenzae) carrier protein, tetanus toxoid carrier protein or diphtheria toxoid carrier protein

Pentavac

Intervention Type: BIOLOGICAL

Each PFS contains 0.5 ml (single dose):

Diphtheria Toxoid 20 Lf to 30 Lf Tetanus Toxoid 2.5 Lf to 10 Lf B. Pertussis 4 IU HBsAg (rDNA) 10 mcg Purified capsular HIB Polysaccharide (PRP) Conjugated to Tetanus Toxoid (carrier protein) 10 mcg Adsorbed on Aluminium Phosphate, AL+++ 1.25 mg Preservative: Thiomersal 0.005 % Dose: O.5ml by intramuscular injection.

Saline

Intervention Type: OTHER

0.9% Sodium Chloride Injection, USP

Interventions

PATH-wSP

Streptococcus pneumoniae Whole Cell Vaccine adsorbed to Alum

Intervention Type: BIOLOGICAL

Synflorix

1 dose (0.5 mL) contains:

1 μg of each of the following pneumococcal polysaccharide serotypes:

1, 5, 6B, 7F, 9V, 14, and 23 F

And 3 μg of the following pneumococcal polysaccharide serotypes:

4, 18C and 19F.

The serotypes are conjugated to either:

protein D (derived from Non-Typeable Haemophilus influenzae) carrier protein, tetanus toxoid carrier protein or diphtheria toxoid carrier protein

Intervention Type: BIOLOGICAL

Pentavac

Each PFS contains 0.5 ml (single dose):

Diphtheria Toxoid 20 Lf to 30 Lf Tetanus Toxoid 2.5 Lf to 10 Lf B. Pertussis 4 IU HBsAg (rDNA) 10 mcg Purified capsular HIB Polysaccharide (PRP) Conjugated to Tetanus Toxoid (carrier protein) 10 mcg Adsorbed on Aluminium Phosphate, AL+++ 1.25 mg Preservative: Thiomersal 0.005 % Dose: O.5ml by intramuscular injection.

Intervention Type: BIOLOGICAL

Saline

0.9% Sodium Chloride Injection, USP

Intervention Type: OTHER

Other Intervention Names

10-valent Pneumococcal Conjugate Vaccine (PCV10); Diptheria Pertussis Tetanus Hep B Haemophilus b Conjugate

Eligibility Criteria

Inclusion Criteria

• Healthy young Kenyan adults between 18 to 45 years of age
• Willing to provide written informed consent, able to understand comply with study requirements/procedures.
• Adult female subjects surgically sterilized or with a negative serum pregnancy test on enrollment and prior to each vaccination. Adult females must be willing to avoid becoming pregnant over the duration of the study, and must agree to employ an effective form of birth control for the duration of the study.
• Subjects willing to avoid consumption of herbal medication (including herbal medication taken by a mother, which may transmit to a toddler through breast milk) that could have effects on liver function or bleeding indices during the course of the study.
• Healthy toddlers between 12 to 15 months of age who have completed their primary EPI vaccines.
• Toddler's parent willing to provide written informed consent for subject, able to understand and comply with study requirements and procedures.
• Not premature, had a birth weight of >2.5 kg, and a weight-to-height Z score of ≥ -2 at the time of enrollment.

Exclusion Criteria

• Use of any investigational or nonregistered drug within 90 days prior and during the course of study participation.
• History of administration of any vaccine within 30 days prior to administration of study vaccine or planned vaccination during the course of study.
• History of anaphylactic shock.
• Positive test for malaria (blood film) at time of screening and when retested at Visit 1.
• Immunosuppression or immunodeficiency, inclusive of human immunodeficiency virus, by medical history or by testing at screening.
• Chronic, clinically significant pulmonary, cardiovascular, hepatobiliary, gastrointestinal, renal, neurological, or hematological functional abnormality or major congenital defects or illness that requires medical therapy, as deemed by medical history or clinical assessment.
• Evidence of active hepatitis infection (B or C) by immunologic testing at screening.
• Any medical or social condition that in the opinion of the investigator will interfere with the study objectives or pose a risk to the study subject or may prevent the subject from completing the study follow-up.
• An employee (or first degree relative of employee) of the Sponsor, the Clinical Research Organization, or any investigator or site personnel.
• Any screening laboratory test result or vital sign measurement outside normal parameters and deemed by the clinician to be clinically significant, including a positive test for malaria.
• Acute illness (moderate or severe) and/or fever (tympanic temperature >38°C for adults and >37.5°C for toddlers), or any acute and limited illness requiring medical treatment, including the use of antibiotics and treatment for parasites.
• History of allergic disease or history of a serious reaction to any prior vaccination or known hypersensitivity to any component of the study vaccines.
• Disorders that require chronic administration of immune-modifying drugs within the past 6 months prior to the administration of the study vaccine.
• Administration of immunoglobulins and/or any blood products within the 6 months preceding enrollment in the study; or anticipation of such administration during the study period.
• Known disturbance of coagulation or other blood disorder in adult subject or in self/first degree relative of toddler subject; or receipt of anticoagulants in the past 3 weeks.
• History of meningitis or seizures or any neurological disorder or major psychiatric disorder (adult).
• Female subjects who are pregnant or breast-feeding.
• Suspicion or recent history of alcohol or substance abuse.
• Toddlers with evidence of congenital abnormality or developmental delay.
• Toddlers with evidence of fetal alcohol syndrome or history of alcohol abuse in mother during pregnancy.
• Toddlers exposed to HIV, born of an HIV infected mother, or who are HIV positive by either antibody or polymerase chain reaction testing.

• Minimum Eligible Age: 12 Months
• Maximum Eligible Age: 45 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

PATH

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Nekoye Otsyula, MD

Role: PRINCIPAL_INVESTIGATOR

Kenya Medical Research Institute/Walter Reed Project

Locations

Kenya Medical Research Institute/Walter Reed Project

Kisumu, Nyanza, Kenya

Countries

Kenya

Other Identifiers

VAC-010

Identifier Type: -

Identifier Source: org_study_id