Clinical trial NCT02097472: Dose-Finding Study of S.Pneumoniae Whole Cell Vaccine Adsorbed to Alum (PATH-wSP) in Healthy Kenyan Adults and Toddlers
Official title: A Dose-Finding Study to Assess the Safety, Tolerability, and Immunogenicity of Inactivated Streptococcus Pneumoniae Whole Cell Vaccine Formulated With Alum (PATH-wSP) in Healthy Kenyan Young Adults and PCV-Primed Toddlers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Pneumonia, Pneumococcal
Lead sponsor: PATH
Sponsor class: OTHER
First posted: 2014-03-27
Enrollment: 304
Sex: ALL
Minimum age (years): 12
Maximum age (years): 45
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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.

Primary outcomes:
measure: Number/Percent of Adult Subjects Experiencing Fatigue/Malaise Following Vaccination
timeFrame: up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
measure: Number/Percent of Adult Subjects Experiencing Myalgia Following Vaccination
timeFrame: up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
measure: Number/Percent of Adult Subjects Experiencing Headache Following Vaccination
timeFrame: up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
measure: Number/Percent of Adult Subjects Experiencing Pain at Injection Site Following Vaccination
timeFrame: up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
measure: Number/Percent of Adult Subjects Experiencing Tenderness at Injection Site Following Vaccination
timeFrame: up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
measure: Number/Percent of Adult Subjects Experiencing Induration at Injection Site Following Vaccination
timeFrame: up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
measure: Number/Percent of Adult Subjects Experiencing Fever at Injection Site Following Vaccination
timeFrame: up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
measure: Number/Percent of Toddler Subjects Experiencing Fever Following Vaccination
timeFrame: up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
measure: Number/Percent of Toddler Subjects Experiencing Cutaneous Rash Following Vaccination
timeFrame: up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
measure: Number/Percent of Toddler Subjects Experiencing Irritability Following Vaccination
timeFrame: up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
measure: Number/Percent of Toddler Subjects Experiencing Drowsiness Following Vaccination
timeFrame: up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
measure: Number/Percent of Toddler Subjects Experiencing Loss of Appetite Following Vaccination
timeFrame: up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
measure: Number/Percent of Toddler Subjects Experiencing Pain/Tenderness at Injection Site Following Vaccination
timeFrame: up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
measure: Number/Percent of Toddler Subjects Experiencing Induration/Swelling at Injection Site Following Vaccination
timeFrame: up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
Secondary outcomes:
measure: Geometric Mean Concentrations (GMC) of IgG Antibodies Against Pneumolysoid (L460D) Pneumococcal Protein: ELISA Assay
timeFrame: 0 days, 28 days (Dose 1) and 56 days (Dose 2)
measure: Geometric Mean Concentrations (GMC) of IgG Antibodies Against PspA-Fam1 Pneumococcal Protein: ELISA Assay
timeFrame: 0 days, 28 days (Dose 1) and 56 days (Dose 2)
measure: Geometric Mean Concentrations (GMC) of IgG Antibodies Against L460D Pneumococcal Protein
timeFrame: 0 days, 28 days (Dose 1) and 56 days (Dose 2)
measure: Geometric Mean Concentrations (GMC) of IgG Antibodies Against PspA-Fam1 Pneumococcal Protein: Meso Scale Discovery (MSD) Assay
timeFrame: 0 days, 28 days (Dose 1) and 56 days (Dose 2)
measure: Geometric Mean Concentrations (GMC) of IgG Antibodies Against PhtD Pneumococcal Protein
timeFrame: 0 days, 28 days (Dose 1) and 56 days (Dose 2)
measure: Geometric Mean Concentrations (GMC) of IgG Antibodies Against BCH0785 Pneumococcal Protein
timeFrame: 0 days, 28 days (Dose 1) and 56 days (Dose 2)
measure: Geometric Mean Concentrations (GMC) of IgG Antibodies Against StkP Pneumococcal Protein
timeFrame: 0 days, 28 days (Dose 1) and 56 days (Dose 2)
measure: Geometric Mean Concentrations (GMC) of IgG Antibodies Against PcpA Pneumococcal Protein
timeFrame: 0 days, 28 days (Dose 1) and 56 days (Dose 2)
measure: Geometric Mean Concentrations (GMC) of IgG Antibodies Against SPWCA Pneumococcal Protein
timeFrame: 0 days, 28 days (Dose 1) and 56 days (Dose 2)
measure: Geometric Mean Concentrations (GMC) of IgG Antibodies Against PiuA Pneumococcal Protein
timeFrame: 0 days, 28 days (Dose 1) and 56 days (Dose 2)
measure: Geometric Mean Concentrations (GMC) of IgG Antibodies Against PiaA Pneumococcal Protein
timeFrame: 0 days, 28 days (Dose 1) and 56 days (Dose 2)
measure: Geometric Mean Fold Change of IgG Antibodies Against Pneumolysoid (L460D) Pneumococcal Protein: ELISA
timeFrame: 0 days, 28 days (Dose 1) and 56 days (Dose 2)
measure: Geometric Mean Fold Change of IgG Antibodies Against PspA-Fam1 Pneumococcal Protein: ELISA
timeFrame: 0 days, 28 days (Dose 1) and 56 days (Dose 2)
measure: Geometric Mean Fold Change of IgG Antibodies Against Pneumolysoid (L460D) Pneumococcal Protein: MSD
timeFrame: 0 days, 28 days (Dose 1) and 56 days (Dose 2)
measure: Geometric Mean Fold Change of IgG Antibodies Against PspA-Fam1 Pneumococcal Protein: MSD
timeFrame: 0 days, 28 days (Dose 1) and 56 days (Dose 2)
measure: Geometric Mean Fold Change of IgG Antibodies Against PhtD Pneumococcal Protein
timeFrame: 0 days, 28 days (Dose 1) and 56 days (Dose 2)
measure: Geometric Mean Fold Change of IgG Antibodies Against BCH0785 Pneumococcal Protein
timeFrame: 0 days, 28 days (Dose 1) and 56 days (Dose 2)
measure: Geometric Mean Fold Change of IgG Antibodies Against StkP Pneumococcal Protein
timeFrame: 0 days, 28 days (Dose 1) and 56 days (Dose 2)
measure: Geometric Mean Fold Change of IgG Antibodies Against PcpA Pneumococcal Protein
timeFrame: 0 days, 28 days (Dose 1) and 56 days (Dose 2)
measure: Geometric Mean Fold Change of IgG Antibodies Against SPWCA Pneumococcal Protein
timeFrame: 0 days, 28 days (Dose 1) and 56 days (Dose 2)
measure: Geometric Mean Fold Change of IgG Antibodies Against PiuA Pneumococcal Protein
timeFrame: 0 days, 28 days (Dose 1) and 56 days (Dose 2)
measure: Geometric Mean Fold Change of IgG Antibodies Against PiaA Pneumococcal Protein
timeFrame: 0 days, 28 days (Dose 1) and 56 days (Dose 2)
measure: Fold Change in IgG Response to Pneumolysoid (L460D) Pneumococcal Protein Among Toddler Cohort (ELISA)
timeFrame: 28 days (post-vaccination 1) and 56 days (post-vaccination 2)
measure: Fold Change in IgG Response to PspA-Fam1 (ELISA)
timeFrame: 28 days (post-vaccination 1) and 56 days (post-vaccination 2)
measure: Fold Change in IgG Response to L460D Pneumococcal Protein (MSD)
timeFrame: 28 days (post-vaccination 1) and 56 days (post-vaccination 2)
measure: Fold Change in IgG Response to PspA-Fam1 Pneumococcal Protein (MSD)
timeFrame: 28 days (post-vaccination 1) and 56 days (post-vaccination 2)
measure: Fold Change in IgG Response to PhtD Pneumococcal Protein
timeFrame: 28 days (post-vaccination 1) and 56 days (post-vaccination 2)
measure: Fold Change in IgG Response to BCH0785 Pneumococcal Protein
timeFrame: 28 days (post-vaccination 1) and 56 days (post-vaccination 2)
measure: Fold Change in IgG Response to StkP Pneumococcal Protein
timeFrame: 28 days (post-vaccination 1) and 56 days (post-vaccination 2)
measure: Fold Change in IgG Response to PcpA Pneumococcal Protein
timeFrame: 28 days (post-vaccination 1) and 56 days (post-vaccination 2)
measure: Fold Change in IgG Response to SPWCA Pneumococcal Protein
timeFrame: 28 days (post-vaccination 1) and 56 days (post-vaccination 2)
measure: Fold Change in IgG Response to PiuA Pneumococcal Protein
timeFrame: 28 days (post-vaccination 1) and 56 days (post-vaccination 2)
measure: Fold Change in IgG Response to PiaA Pneumococcal Protein
timeFrame: 28 days (post-vaccination 1) and 56 days (post-vaccination 2)
measure: Number/Percentage of Adult Subjects With Neutralizing Antibody Response to Pneumolysin
timeFrame: 0 days, 28 days (Dose 1) and 56 days (Dose 2)
measure: Number/Percentage of Toddler Subjects With Neutralizing Antibody Response to Pneumolysin
timeFrame: 0 days, 28 days (Dose 1) and 56 days (Dose 2)
Other outcomes:
measure: Geometric Mean Concentration (GMCs) of PNC-IgG Serotypes Among Toddler Subjects
timeFrame: 12 weeks (Cohort 1) and 4 weeks (Cohort 2) post-vaccination 1
measure: Geometric Mean Concentration (GMC) Ratio of Diptheria Booster Immune Response Among Toddler Subjects
timeFrame: 12 weeks post vaccination 1
measure: Geometric Mean Concentration (GMC) Ratio of Hepatitis B Booster Immune Response Among Toddler Subjects
timeFrame: 12 weeks post vaccination 1
measure: Geometric Mean Concentration (GMC) Ratio of Haemophilus Influenzae Type b (Hib) Booster Immune Response Among Toddler Subjects
timeFrame: 12 weeks post vaccination 1
measure: Geometric Mean Concentration (GMC) Ratio of Pertussis FHA and Pertussis Toxin Immune Response Among Toddler Subjects
timeFrame: 12 weeks post vaccination 1
measure: Geometric Mean Concentration (GMC) Ratio of Pertussis Fimbriae Immune Response Among Toddler Subjects
timeFrame: 12 weeks post vaccination 1
measure: Geometric Mean Concentration (GMC) Ratio of Tetanus Booster Immune Response Among Toddler Subjects
timeFrame: 12 weeks post vaccination 1
Locations:
city: Kisumu
country: Kenya
facility: Kenya Medical Research Institute/Walter Reed Project
state: Nyanza
Study officials:
affiliation: Kenya Medical Research Institute/Walter Reed Project
name: Nekoye Otsyula, MD
role: PRINCIPAL_INVESTIGATOR
References: