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

Phase 1

Completed

Conditions: Pneumonia, Pneumococcal

Interventions: Biological: PATH-wSP
Other: Saline
Biological: Synflorix
Biological: Pentavac

Registration Number: NCT02097472

Lead Sponsor: PATH

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 304

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Adult Cohort 1, PATH-wSP, 600 mcg	PATH-wSP	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.
Adult Cohort 1, Saline	Saline	A single injection of saline in one arm, followed 4 weeks later by a single injection of saline in the alternate arm.
Adult Cohort 2, PATH-wSP, 1000 mcg	PATH-wSP	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.
Adult Cohort 2, Saline	Saline	A single injection of saline in one arm, followed 4 weeks later by a single injection of saline in the alternate arm.
Toddler Cohort 1 PATH-wSP 300 mcg+Active control	Pentavac	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.
Toddler Cohort 1 PATH-wSP 300 mcg+Saline	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.
Toddler Cohort 2 PATH-wSP 600 mcg+Active control	PATH-wSP	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.
Toddler Cohort 1 PATH-wSP 300 mcg+Active control	PATH-wSP	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.
Toddler Cohort 1 PATH-wSP 300 mcg+Active control	Synflorix	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.
Toddler Cohort 2 PATH-wSP 600 mcg+Active control	Pentavac	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.
Toddler Cohort 1: Active Control Only	Synflorix	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.
Toddler Cohort 1: Active Control Only	Pentavac	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.
Toddler Cohort 2 PATH-wSP 600 mcg+Active control	Synflorix	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.
Toddler Cohort 1: Active Control Only	Saline	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.
Toddler Cohort 2 PATH-wSP 600 mcg+saline	PATH-wSP	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.
Toddler Cohort 1 PATH-wSP 300 mcg+Saline	PATH-wSP	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.
Toddler Cohort 2: Active Control Only	Saline	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.
Toddler Cohort 2 PATH-wSP 600 mcg+saline	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.
Toddler Cohort 2: Active Control Only	Pentavac	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.
Toddler Cohort 2: Active Control Only	Synflorix	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.

Primary Outcome Measures

Name	Time	Method
Number/Percent of Adult Subjects Experiencing Tenderness at Injection Site Following Vaccination	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)	Solicited reactions were assessed for severity during the 60 minutes post vaccination time period, daily for the first week by Field Staff and then at the clinic visit 1 week post vaccination.
Number/Percent of Adult Subjects Experiencing Headache Following Vaccination	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)	Solicited reactions were assessed for severity during the 60 minutes post vaccination time period, daily for the first week by Field Staff and then at the clinic visit 1 week post vaccination. Grade 2 includes repeated use of non-narcotic pain reliever for more than 24 hours.
Number/Percent of Toddler Subjects Experiencing Fever Following Vaccination	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)	Solicited reactions were assessed for severity during the 60 minutes post vaccination time period, daily for the first week by Field Staff and then at the clinic visit 1 week post vaccination.
Number/Percent of Adult Subjects Experiencing Fatigue/Malaise Following Vaccination	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)	Solicited reactions were assessed for severity during the 60 minutes post vaccination time period, daily for the first week by Field Staff and then at the clinic visit 1 week post vaccination.
Number/Percent of Adult Subjects Experiencing Induration at Injection Site Following Vaccination	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)	Solicited reactions were assessed for severity during the 60 minutes post vaccination time period, daily for the first week by Field Staff and then at the clinic visit 1 week post vaccination. Grade 1: does not interfere with activity Grade 2: interferes with activity
Number/Percent of Toddler Subjects Experiencing Drowsiness Following Vaccination	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)	Solicited reactions were assessed for severity during the 60 minutes post vaccination time period, daily for the first week by Field Staff and then at the clinic visit 1 week post vaccination. Severity was defined in the protocol as grade 0-4 (none, mild, moderate, and severe).
Number/Percent of Toddler Subjects Experiencing Loss of Appetite Following Vaccination	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)	Solicited reactions were assessed for severity during the 60 minutes post vaccination time period, daily for the first week by Field Staff and then at the clinic visit 1 week post vaccination. Severity was defined in the protocol as grade 0-4 (none, mild, moderate, and severe).
Number/Percent of Toddler Subjects Experiencing Pain/Tenderness at Injection Site Following Vaccination	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)	Solicited reactions were assessed for severity during the 60 minutes post vaccination time period, daily for the first week by Field Staff and then at the clinic visit 1 week post vaccination.
Number/Percent of Toddler Subjects Experiencing Induration/Swelling at Injection Site Following Vaccination	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)	Solicited reactions were assessed for severity during the 60 minutes post vaccination time period, daily for the first week by Field Staff and then at the clinic visit 1 week post vaccination. Severity was defined in the protocol as grade 0-4 (none, mild, moderate, and severe).
Number/Percent of Adult Subjects Experiencing Myalgia Following Vaccination	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)	Solicited reactions were assessed for severity during the 60 minutes post vaccination time period, daily for the first week by Field Staff and then at the clinic visit 1 week post vaccination.
Number/Percent of Adult Subjects Experiencing Pain at Injection Site Following Vaccination	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)	Solicited reactions were assessed for severity during the 60 minutes post vaccination time period, daily for the first week by Field Staff and then at the clinic visit 1 week post vaccination. Grade 2 includes use of non-narcotic pain reliever for more than 24 hours.
Number/Percent of Adult Subjects Experiencing Fever at Injection Site Following Vaccination	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)	Solicited reactions were assessed for severity during the 60 minutes post vaccination time period, daily for the first week by Field Staff and then at the clinic visit 1 week post vaccination.
Number/Percent of Toddler Subjects Experiencing Irritability Following Vaccination	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)	Solicited reactions were assessed for severity during the 60 minutes post vaccination time period, daily for the first week by Field Staff and then at the clinic visit 1 week post vaccination. Severity was defined in the protocol as grade 0-4 (none, mild, moderate, and severe).
Number/Percent of Toddler Subjects Experiencing Cutaneous Rash Following Vaccination	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)	Solicited reactions were assessed for severity during the 60 minutes post vaccination time period, daily for the first week by Field Staff and then at the clinic visit 1 week post vaccination. Grade 2: includes diffuse macular/maculopapular/morbilliform rash

Secondary Outcome Measures

Name	Time	Method
Geometric Mean Concentrations (GMC) of IgG Antibodies Against PhtD Pneumococcal Protein	0 days, 28 days (Dose 1) and 56 days (Dose 2)	Measured using Meso Scale Discovery (MSD) Assay
Geometric Mean Fold Change of IgG Antibodies Against PhtD Pneumococcal Protein	0 days, 28 days (Dose 1) and 56 days (Dose 2)	Measured using MSD
Geometric Mean Concentrations (GMC) of IgG Antibodies Against PspA-Fam1 Pneumococcal Protein: ELISA Assay	0 days, 28 days (Dose 1) and 56 days (Dose 2)	Measured with enzyme-linked immunosorbent assay (ELISA).
Geometric Mean Concentrations (GMC) of IgG Antibodies Against StkP Pneumococcal Protein	0 days, 28 days (Dose 1) and 56 days (Dose 2)	Measured using Meso Scale Discovery (MSD) Assay
Geometric Mean Fold Change of IgG Antibodies Against Pneumolysoid (L460D) Pneumococcal Protein: MSD	0 days, 28 days (Dose 1) and 56 days (Dose 2)	Measured using MSD
Geometric Mean Fold Change of IgG Antibodies Against PiuA Pneumococcal Protein	0 days, 28 days (Dose 1) and 56 days (Dose 2)	Measured using MSD
Geometric Mean Fold Change of IgG Antibodies Against PiaA Pneumococcal Protein	0 days, 28 days (Dose 1) and 56 days (Dose 2)	Measured using MSD
Fold Change in IgG Response to Pneumolysoid (L460D) Pneumococcal Protein Among Toddler Cohort (ELISA)	28 days (post-vaccination 1) and 56 days (post-vaccination 2)	Measured using ELISA
Geometric Mean Concentrations (GMC) of IgG Antibodies Against SPWCA Pneumococcal Protein	0 days, 28 days (Dose 1) and 56 days (Dose 2)	MSD Assay
Geometric Mean Concentrations (GMC) of IgG Antibodies Against PiaA Pneumococcal Protein	0 days, 28 days (Dose 1) and 56 days (Dose 2)	MSD Assay
Geometric Mean Fold Change of IgG Antibodies Against PspA-Fam1 Pneumococcal Protein: MSD	0 days, 28 days (Dose 1) and 56 days (Dose 2)	Measured using ELISA
Geometric Mean Concentrations (GMC) of IgG Antibodies Against L460D Pneumococcal Protein	0 days, 28 days (Dose 1) and 56 days (Dose 2)	Measured using meso scale discovery (MSD).
Geometric Mean Concentrations (GMC) of IgG Antibodies Against PspA-Fam1 Pneumococcal Protein: Meso Scale Discovery (MSD) Assay	0 days, 28 days (Dose 1) and 56 days (Dose 2)
Geometric Mean Concentrations (GMC) of IgG Antibodies Against PcpA Pneumococcal Protein	0 days, 28 days (Dose 1) and 56 days (Dose 2)	Measured using Meso Scale Discovery (MSD) Assay
Geometric Mean Concentrations (GMC) of IgG Antibodies Against PiuA Pneumococcal Protein	0 days, 28 days (Dose 1) and 56 days (Dose 2)	MSD Assay
Geometric Mean Fold Change of IgG Antibodies Against PspA-Fam1 Pneumococcal Protein: ELISA	0 days, 28 days (Dose 1) and 56 days (Dose 2)	Measured using ELISA
Geometric Mean Fold Change of IgG Antibodies Against BCH0785 Pneumococcal Protein	0 days, 28 days (Dose 1) and 56 days (Dose 2)	Measured using MSD
Geometric Mean Fold Change of IgG Antibodies Against StkP Pneumococcal Protein	0 days, 28 days (Dose 1) and 56 days (Dose 2)	Measured using MSD
Geometric Mean Concentrations (GMC) of IgG Antibodies Against Pneumolysoid (L460D) Pneumococcal Protein: ELISA Assay	0 days, 28 days (Dose 1) and 56 days (Dose 2)	Measured with enzyme-linked immunosorbent assay (ELISA).
Geometric Mean Concentrations (GMC) of IgG Antibodies Against BCH0785 Pneumococcal Protein	0 days, 28 days (Dose 1) and 56 days (Dose 2)	Measured using Meso Scale Discovery (MSD) Assay
Geometric Mean Fold Change of IgG Antibodies Against Pneumolysoid (L460D) Pneumococcal Protein: ELISA	0 days, 28 days (Dose 1) and 56 days (Dose 2)	Measured using ELISA
Geometric Mean Fold Change of IgG Antibodies Against PcpA Pneumococcal Protein	0 days, 28 days (Dose 1) and 56 days (Dose 2)	Measured using MSD
Fold Change in IgG Response to PspA-Fam1 (ELISA)	28 days (post-vaccination 1) and 56 days (post-vaccination 2)	Measured using ELISA
Fold Change in IgG Response to BCH0785 Pneumococcal Protein	28 days (post-vaccination 1) and 56 days (post-vaccination 2)	Measured using MSD
Geometric Mean Fold Change of IgG Antibodies Against SPWCA Pneumococcal Protein	0 days, 28 days (Dose 1) and 56 days (Dose 2)	Measured using MSD
Fold Change in IgG Response to StkP Pneumococcal Protein	28 days (post-vaccination 1) and 56 days (post-vaccination 2)	Measured using MSD
Fold Change in IgG Response to PcpA Pneumococcal Protein	28 days (post-vaccination 1) and 56 days (post-vaccination 2)	Measured using MSD
Fold Change in IgG Response to SPWCA Pneumococcal Protein	28 days (post-vaccination 1) and 56 days (post-vaccination 2)	Measured using MSD
Number/Percentage of Adult Subjects With Neutralizing Antibody Response to Pneumolysin	0 days, 28 days (Dose 1) and 56 days (Dose 2)	Functional antibody responses to Ply (pneumolysin) were assessed using a toxin neutralization assay based on the ability of antibodies to neutralize wild-type Ply-induced lysis of rabbit red blood cells. Briefly, serial 2-fold dilutions (starting at 1/5 dilution) of human serum samples were added together with wild-type Ply in 96-well plates. Rabbit red blood cells were then added and following incubation supernatants removed and transferred to new 96-well plates and absorbance measured at 540 nm using a spectrophotometer plate reader. The mean A450 nm blank value was subtracted by 10% to obtain the Plate Specific Cut Point for each plate. Each sample was categorized as negative (\<1/20) or positive (with titer between 1/20 and 1/320).
Fold Change in IgG Response to L460D Pneumococcal Protein (MSD)	28 days (post-vaccination 1) and 56 days (post-vaccination 2)	Measured using MSD
Fold Change in IgG Response to PiuA Pneumococcal Protein	28 days (post-vaccination 1) and 56 days (post-vaccination 2)	Measured using MSD
Number/Percentage of Toddler Subjects With Neutralizing Antibody Response to Pneumolysin	0 days, 28 days (Dose 1) and 56 days (Dose 2)	Functional antibody responses to Ply (pneumolysin) were assessed using a toxin neutralization assay based on the ability of antibodies to neutralize wild-type Ply-induced lysis of rabbit red blood cells. Briefly, serial 2-fold dilutions (starting at 1/5 dilution) of human serum samples were added together with wild-type Ply in 96-well plates. Rabbit red blood cells were then added and following incubation supernatants removed and transferred to new 96-well plates and absorbance measured at 540 nm using a spectrophotometer plate reader. The mean A450 nm blank value was subtracted by 10% to obtain the Plate Specific Cut Point for each plate. Each sample was categorized as negative (\<1/20) or positive (with titer between 1/20 and 1/320).
Fold Change in IgG Response to PspA-Fam1 Pneumococcal Protein (MSD)	28 days (post-vaccination 1) and 56 days (post-vaccination 2)	Measured using MSD
Fold Change in IgG Response to PhtD Pneumococcal Protein	28 days (post-vaccination 1) and 56 days (post-vaccination 2)	Measured using MSD
Fold Change in IgG Response to PiaA Pneumococcal Protein	28 days (post-vaccination 1) and 56 days (post-vaccination 2)	Measured using MSD