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

Pneumonia, Pneumococcal Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02097472
• Other study ID #: VAC-010
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: April 2014
• Est. completion date: December 2015

Study information

• Verified date: October 2019
• Source: PATH
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 304
• Est. completion date: December 2015
• Est. primary completion date: December 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 12 Months to 45 Years

Eligibility

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.

Related Conditions & MeSH terms

• Pneumonia
• Pneumonia, Pneumococcal

Intervention

Biological:
• PATH-wSP
Streptococcus pneumoniae Whole Cell Vaccine adsorbed to Alum
• 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
• 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.

Other:
• Saline
0.9% Sodium Chloride Injection, USP

Locations

Country	Name	City	State
Kenya	Kenya Medical Research Institute/Walter Reed Project	Kisumu	Nyanza

Sponsors (1)

Lead Sponsor	Collaborator
PATH

Country where clinical trial is conducted

Kenya, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Geometric Mean Concentration (GMCs) of PNC-IgG Serotypes Among Toddler Subjects	GMCs of these IgG proteins were measured to assess potential interference of PATH-wSP with 10-valent pneumococcal conjugate vaccine (Synflorix). GMCs of Cohort 1 were measured at a different time point than those in Cohort 2, so results are presented separately.	12 weeks (Cohort 1) and 4 weeks (Cohort 2) post-vaccination 1
Other	Geometric Mean Concentration (GMC) Ratio of Diptheria Booster Immune Response Among Toddler Subjects	GMCs of these proteins were measured to assess potential interference of PATH-wSP with Pentavac booster dose.	12 weeks post vaccination 1
Other	Geometric Mean Concentration (GMC) Ratio of Hepatitis B Booster Immune Response Among Toddler Subjects	GMCs of these proteins were measured to assess potential interference of PATH-wSP with Pentavac booster dose.	12 weeks post vaccination 1
Other	Geometric Mean Concentration (GMC) Ratio of Haemophilus Influenzae Type b (Hib) Booster Immune Response Among Toddler Subjects	GMCs of these proteins were measured to assess potential interference of PATH-wSP with Pentavac booster dose.	12 weeks post vaccination 1
Other	Geometric Mean Concentration (GMC) Ratio of Pertussis FHA and Pertussis Toxin Immune Response Among Toddler Subjects	GMCs of these proteins were measured to assess potential interference of PATH-wSP with Pentavac booster dose.	12 weeks post vaccination 1
Other	Geometric Mean Concentration (GMC) Ratio of Pertussis Fimbriae Immune Response Among Toddler Subjects	GMCs of these proteins were measured to assess potential interference of PATH-wSP with Pentavac booster dose.	12 weeks post vaccination 1
Other	Geometric Mean Concentration (GMC) Ratio of Tetanus Booster Immune Response Among Toddler Subjects	GMCs of these proteins were measured to assess potential interference of PATH-wSP with Pentavac booster dose.	12 weeks post vaccination 1
Primary	Number/Percent of Adult Subjects Experiencing Fatigue/Malaise Following Vaccination	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.	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
Primary	Number/Percent of Adult Subjects Experiencing Myalgia Following Vaccination	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.	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
Primary	Number/Percent of Adult Subjects Experiencing Headache Following Vaccination	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.	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
Primary	Number/Percent of Adult Subjects Experiencing Pain at Injection Site Following Vaccination	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.	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
Primary	Number/Percent of Adult Subjects Experiencing Tenderness at Injection Site Following Vaccination	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.	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
Primary	Number/Percent of Adult Subjects Experiencing Induration at Injection Site Following Vaccination	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	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
Primary	Number/Percent of Adult Subjects Experiencing Fever at Injection Site Following Vaccination	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.	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
Primary	Number/Percent of Toddler Subjects Experiencing Fever Following Vaccination	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.	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
Primary	Number/Percent of Toddler Subjects Experiencing Cutaneous Rash Following Vaccination	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	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
Primary	Number/Percent of Toddler Subjects Experiencing Irritability Following Vaccination	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).	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
Primary	Number/Percent of Toddler Subjects Experiencing Drowsiness Following Vaccination	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).	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
Primary	Number/Percent of Toddler Subjects Experiencing Loss of Appetite Following Vaccination	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).	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
Primary	Number/Percent of Toddler Subjects Experiencing Pain/Tenderness at Injection Site Following Vaccination	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.	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
Primary	Number/Percent of Toddler Subjects Experiencing Induration/Swelling at Injection Site Following Vaccination	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).	up to 1 week following first vaccination (Day 7) or second vaccination (Day 35)
Secondary	Geometric Mean Concentrations (GMC) of IgG Antibodies Against Pneumolysoid (L460D) Pneumococcal Protein: ELISA Assay	Measured with enzyme-linked immunosorbent assay (ELISA).	0 days, 28 days (Dose 1) and 56 days (Dose 2)
Secondary	Geometric Mean Concentrations (GMC) of IgG Antibodies Against PspA-Fam1 Pneumococcal Protein: ELISA Assay	Measured with enzyme-linked immunosorbent assay (ELISA).	0 days, 28 days (Dose 1) and 56 days (Dose 2)
Secondary	Geometric Mean Concentrations (GMC) of IgG Antibodies Against L460D Pneumococcal Protein	Measured using meso scale discovery (MSD).	0 days, 28 days (Dose 1) and 56 days (Dose 2)
Secondary	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)
Secondary	Geometric Mean Concentrations (GMC) of IgG Antibodies Against PhtD Pneumococcal Protein	Measured using Meso Scale Discovery (MSD) Assay	0 days, 28 days (Dose 1) and 56 days (Dose 2)
Secondary	Geometric Mean Concentrations (GMC) of IgG Antibodies Against BCH0785 Pneumococcal Protein	Measured using Meso Scale Discovery (MSD) Assay	0 days, 28 days (Dose 1) and 56 days (Dose 2)
Secondary	Geometric Mean Concentrations (GMC) of IgG Antibodies Against StkP Pneumococcal Protein	Measured using Meso Scale Discovery (MSD) Assay	0 days, 28 days (Dose 1) and 56 days (Dose 2)
Secondary	Geometric Mean Concentrations (GMC) of IgG Antibodies Against PcpA Pneumococcal Protein	Measured using Meso Scale Discovery (MSD) Assay	0 days, 28 days (Dose 1) and 56 days (Dose 2)
Secondary	Geometric Mean Concentrations (GMC) of IgG Antibodies Against SPWCA Pneumococcal Protein	MSD Assay	0 days, 28 days (Dose 1) and 56 days (Dose 2)
Secondary	Geometric Mean Concentrations (GMC) of IgG Antibodies Against PiuA Pneumococcal Protein	MSD Assay	0 days, 28 days (Dose 1) and 56 days (Dose 2)
Secondary	Geometric Mean Concentrations (GMC) of IgG Antibodies Against PiaA Pneumococcal Protein	MSD Assay	0 days, 28 days (Dose 1) and 56 days (Dose 2)
Secondary	Geometric Mean Fold Change of IgG Antibodies Against Pneumolysoid (L460D) Pneumococcal Protein: ELISA	Measured using ELISA	0 days, 28 days (Dose 1) and 56 days (Dose 2)
Secondary	Geometric Mean Fold Change of IgG Antibodies Against PspA-Fam1 Pneumococcal Protein: ELISA	Measured using ELISA	0 days, 28 days (Dose 1) and 56 days (Dose 2)
Secondary	Geometric Mean Fold Change of IgG Antibodies Against Pneumolysoid (L460D) Pneumococcal Protein: MSD	Measured using MSD	0 days, 28 days (Dose 1) and 56 days (Dose 2)
Secondary	Geometric Mean Fold Change of IgG Antibodies Against PspA-Fam1 Pneumococcal Protein: MSD	Measured using ELISA	0 days, 28 days (Dose 1) and 56 days (Dose 2)
Secondary	Geometric Mean Fold Change of IgG Antibodies Against PhtD Pneumococcal Protein	Measured using MSD	0 days, 28 days (Dose 1) and 56 days (Dose 2)
Secondary	Geometric Mean Fold Change of IgG Antibodies Against BCH0785 Pneumococcal Protein	Measured using MSD	0 days, 28 days (Dose 1) and 56 days (Dose 2)
Secondary	Geometric Mean Fold Change of IgG Antibodies Against StkP Pneumococcal Protein	Measured using MSD	0 days, 28 days (Dose 1) and 56 days (Dose 2)
Secondary	Geometric Mean Fold Change of IgG Antibodies Against PcpA Pneumococcal Protein	Measured using MSD	0 days, 28 days (Dose 1) and 56 days (Dose 2)
Secondary	Geometric Mean Fold Change of IgG Antibodies Against SPWCA Pneumococcal Protein	Measured using MSD	0 days, 28 days (Dose 1) and 56 days (Dose 2)
Secondary	Geometric Mean Fold Change of IgG Antibodies Against PiuA Pneumococcal Protein	Measured using MSD	0 days, 28 days (Dose 1) and 56 days (Dose 2)
Secondary	Geometric Mean Fold Change of IgG Antibodies Against PiaA Pneumococcal Protein	Measured using MSD	0 days, 28 days (Dose 1) and 56 days (Dose 2)
Secondary	Fold Change in IgG Response to Pneumolysoid (L460D) Pneumococcal Protein Among Toddler Cohort (ELISA)	Measured using ELISA	28 days (post-vaccination 1) and 56 days (post-vaccination 2)
Secondary	Fold Change in IgG Response to PspA-Fam1 (ELISA)	Measured using ELISA	28 days (post-vaccination 1) and 56 days (post-vaccination 2)
Secondary	Fold Change in IgG Response to L460D Pneumococcal Protein (MSD)	Measured using MSD	28 days (post-vaccination 1) and 56 days (post-vaccination 2)
Secondary	Fold Change in IgG Response to PspA-Fam1 Pneumococcal Protein (MSD)	Measured using MSD	28 days (post-vaccination 1) and 56 days (post-vaccination 2)
Secondary	Fold Change in IgG Response to PhtD Pneumococcal Protein	Measured using MSD	28 days (post-vaccination 1) and 56 days (post-vaccination 2)
Secondary	Fold Change in IgG Response to BCH0785 Pneumococcal Protein	Measured using MSD	28 days (post-vaccination 1) and 56 days (post-vaccination 2)
Secondary	Fold Change in IgG Response to StkP Pneumococcal Protein	Measured using MSD	28 days (post-vaccination 1) and 56 days (post-vaccination 2)
Secondary	Fold Change in IgG Response to PcpA Pneumococcal Protein	Measured using MSD	28 days (post-vaccination 1) and 56 days (post-vaccination 2)
Secondary	Fold Change in IgG Response to SPWCA Pneumococcal Protein	Measured using MSD	28 days (post-vaccination 1) and 56 days (post-vaccination 2)
Secondary	Fold Change in IgG Response to PiuA Pneumococcal Protein	Measured using MSD	28 days (post-vaccination 1) and 56 days (post-vaccination 2)
Secondary	Fold Change in IgG Response to PiaA Pneumococcal Protein	Measured using MSD	28 days (post-vaccination 1) and 56 days (post-vaccination 2)
Secondary	Number/Percentage of Adult Subjects With Neutralizing Antibody Response to Pneumolysin	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).	0 days, 28 days (Dose 1) and 56 days (Dose 2)
Secondary	Number/Percentage of Toddler Subjects With Neutralizing Antibody Response to Pneumolysin	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).	0 days, 28 days (Dose 1) and 56 days (Dose 2)