Safety and Immunogenicity Study of Na-GST-1 With or Without CpG

Study Overview
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Brief Summary
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Na-GST-1 is a protein expressed during the adult stage of the hookworm life cycle that is thought to play a role in the parasite's degradation of host hemoglobin for use as an energy source. Vaccination with recombinant GST-1 has protected dogs and hamsters from infection in challenge studies. This study will evaluate the safety and immunogenicity of two formulations of Na-GST-1 in healthy adult volunteers when co-administered with the immunostimulant CpG 10104, a Toll-like Receptor-9 agonist.

Detailed Description
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This is a Phase 1 randomized double-blind dose-escalation clinical trial in healthy hookworm-naïve adults conducted at the George Washington Medical Faculty Associates, Washington, DC, and the George Washington University School of Medicine and Health Sciences, Department of Microbiology, Immunology and Tropical Medicine, Washington, DC. In total, 24 subjects will be progressively enrolled into 2 cohorts of 12 subjects each. In the first cohort 8 subjects will receive 30µg Na-GST-1/Alhydrogel co-administered with 500µg CpG 10104 and 4 subjects will receive 100µg Na-GST-1/Alhydrogel® only, in a randomized, double-blinded fashion. In the second cohort 8 subjects will receive 100µg Na-GST-1/Alhydrogel co-administered with 500µg CpG 10104 and 4 volunteers will receive 100µg Na-GST-1/Alhydrogel only, in a randomized, double-blinded fashion. Vaccinations will be administered intramuscularly in the deltoid muscle according to a 0, 2, 4-month schedule. Each subject will participate in the study for 68 weeks (16 months) and the total duration of the study is estimated at approximately 19 months.

Official Title
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Phase 1 Study of the Safety and Immunogenicity of Na-GST-1/Alhydrogel, With or Without a CpG ODN Adjuvant, in Healthy Adults

Conditions
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Hookworm Infection, Hookworm Disease

Intervention / Treatment
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* Biological: Na-GST-1/Alhydrogel®
* Biological: CpG 10104


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females between 18 and 50 years, inclusive. Good general health as determined by means of the screening procedure. Available for the duration of the trial (68 weeks). Willingness to participate in the study as evidenced by signing the informed consent document. Able to understand and comply with planned study procedures. Exclusion Criteria: Pregnancy as determined by a positive urine human choriogonadotropin (hCG) test (if female). Participant unwilling to use reliable contraception up until one month following the third immunization (if female and not surgically sterile, abstinent, at least 2 years post-menopausal, or determined otherwise by medical evaluation to be sterile). Currently lactating and breast-feeding (if female). Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic, rheumatologic, autoimmune, diabetes, or renal disease by history, physical examination, and/or laboratory studies. A history of essential hypertension that is well controlled by medication will not be considered exclusionary. Has a diagnosis of schizophrenia, bipolar disease or other major psychiatric condition that would make compliance with study visits/procedures difficult (e.g., subject with psychoses or history of suicide attempt or gesture in the 3 years before study entry, ongoing risk for suicide). Known or suspected immunodeficiency. Laboratory evidence of liver disease (alanine aminotransferase [ALT] greater than 1.25-times the upper reference limit). Laboratory evidence of renal disease (serum creatinine greater than 1.25-times the upper reference limit, or more than trace protein or blood on urine dipstick testing with the exception of greater than 1+ blood detected in females during menses). Laboratory evidence of hematologic disease (hemoglobin <11.1 g/dl [females] or <12.5 g/dl [males]; absolute leukocyte count <3400/mm3 or >10.8 x 103/mm3; or platelet count <140,000/mm3). Laboratory evidence of a coagulopathy (activated PTT or PT INR greater than 1.1-times the upper reference limit). Serum glucose greater than 1.2-times the upper reference limit. Other condition that in the opinion of the investigator would jeopardize the safety or rights of a volunteer participating in the trial or would render the subject unable to comply with the protocol. Planned participation in another investigational vaccine or drug trial within 30 days of starting this study or until Visit #17 (6 months after the third vaccination). Volunteer has had medical, occupational, or family problems as a result of alcohol or illicit drug use during the past 12 months. History of a severe allergic reaction or anaphylaxis. Severe asthma as defined by the need for daily use of inhalers, or emergency clinic visit or hospitalization within 6 months of the volunteer's expected first vaccination in the study. Positive test for hepatitis B surface antigen (HBsAg). Positive confirmatory test for HIV infection. Positive confirmatory test for hepatitis C virus (HCV) infection. Use of corticosteroids (excluding topical or nasal) or immunosuppressive drugs within 30 days of the volunteer's expected first vaccination in this study or planned use up to one month following the last vaccination. Receipt of a live vaccine within 4 weeks or a killed vaccine within 2 weeks prior to the volunteer's expected first vaccination in the study. Previous receipt of the Na-GST-1/Alhydrogel® hookworm vaccine. History of a surgical splenectomy. Receipt of blood products within the past 6 months. Pre-existing autoimmune or antibody-mediated diseases including but not limited to: systemic lupus erythematosis, rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome, autoimmune thrombocytopenia; or laboratory evidence of possible autoimmune disease determined by a positive anti-dsDNA titer, positive rheumatoid factor, proteinuria and/or a positive ANA. History of previous infection with hookworm or residence for more than 6 months in a community where hookworm is endemic.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 100 µg Na-GST-1/Alhydrogel<br>High Dose Na-GST-1/Alhydrogel® Only | Biological: Na-GST-1/Alhydrogel®<br>* The Na-GST-1 candidate vaccine contains the recombinant Na-GST-1 protein expressed by Pichia pastoris. Purified Na-GST-1 was subsequently adsorbed onto aluminum hydroxide gel (Alhydrogel®) and suspended in a solution containing 10% glucose and 10 mM imidazole. The final concentration of Na-GST-1 in the drug product is 0.1 mg/ml whereas that of Alhydrogel® is 0.8 mg/ml. Different doses of Na-GST-1 will be delivered by injecting different volumes of the 0.1 mg/ml Na-GST-1 preparation.<br>* Other names: Necator americanus glutathione S-transferase-1;|
| Experimental: 30 µg Na-GST-1/Alhydrogel + CpG 10104<br>Low Dose Na-GST-1/Alhydrogel® Plus 500 µg CpG 10104 | Biological: Na-GST-1/Alhydrogel®<br>* The Na-GST-1 candidate vaccine contains the recombinant Na-GST-1 protein expressed by Pichia pastoris. Purified Na-GST-1 was subsequently adsorbed onto aluminum hydroxide gel (Alhydrogel®) and suspended in a solution containing 10% glucose and 10 mM imidazole. The final concentration of Na-GST-1 in the drug product is 0.1 mg/ml whereas that of Alhydrogel® is 0.8 mg/ml. Different doses of Na-GST-1 will be delivered by injecting different volumes of the 0.1 mg/ml Na-GST-1 preparation.<br>* Other names: Necator americanus glutathione S-transferase-1;Biological: CpG 10104<br>* Unmethylated cytosine-guanine dinucleotides (CpGs) are found in bacterial DNA in the expected frequency predicted by random usage, whereas their occurrence is suppressed 4-fold in vertebrate DNA. In vertebrate DNA CpG motifs are also usually methylated. Bacterial CpG-DNA motifs are recognized by the human innate immune system via Toll-like Receptor-9 (TLR-9), a pathogen-associated molecular pattern (PAMP) receptor that is expressed, in particular, by antigen-presenting dendritic cells. Interactions between CpG-DNA and TLR9 rapidly activate antigen-presenting dendritic cells to upregulate co-stimulatory molecules and to produce Th1-polarizing cytokines such as interleukin-12 and interferon gamma. CpG 10104 is a short synthetic oligodeoxynucleotide of the following sequence: 5'-TCG TCG TTT CGT CGT TTT GTC GTT-3'.<br>* Other names: CpG ODN;|
| Experimental: 100 µg Na-GST-1/Alhydrogel + CpG 10104<br>High Dose Na-GST-1/Alhydrogel® Plus 500 µg CpG 10104 | Biological: Na-GST-1/Alhydrogel®<br>* The Na-GST-1 candidate vaccine contains the recombinant Na-GST-1 protein expressed by Pichia pastoris. Purified Na-GST-1 was subsequently adsorbed onto aluminum hydroxide gel (Alhydrogel®) and suspended in a solution containing 10% glucose and 10 mM imidazole. The final concentration of Na-GST-1 in the drug product is 0.1 mg/ml whereas that of Alhydrogel® is 0.8 mg/ml. Different doses of Na-GST-1 will be delivered by injecting different volumes of the 0.1 mg/ml Na-GST-1 preparation.<br>* Other names: Necator americanus glutathione S-transferase-1;Biological: CpG 10104<br>* Unmethylated cytosine-guanine dinucleotides (CpGs) are found in bacterial DNA in the expected frequency predicted by random usage, whereas their occurrence is suppressed 4-fold in vertebrate DNA. In vertebrate DNA CpG motifs are also usually methylated. Bacterial CpG-DNA motifs are recognized by the human innate immune system via Toll-like Receptor-9 (TLR-9), a pathogen-associated molecular pattern (PAMP) receptor that is expressed, in particular, by antigen-presenting dendritic cells. Interactions between CpG-DNA and TLR9 rapidly activate antigen-presenting dendritic cells to upregulate co-stimulatory molecules and to produce Th1-polarizing cytokines such as interleukin-12 and interferon gamma. CpG 10104 is a short synthetic oligodeoxynucleotide of the following sequence: 5'-TCG TCG TTT CGT CGT TTT GTC GTT-3'.<br>* Other names: CpG ODN;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vaccine-related Adverse Events | The frequency of immediate, systemic, and local injection site adverse events, graded by severity, for Na-GST-1/Alhydrogel administered alone or in combination with CpG 10104 | Up to study day 470 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IgG antibody response to Na-GST-1 | Dose and formulation of Na-GST-1 that generates the highest IgG antibody response at Day 126 (14 days after final vaccination), as determined by an indirect enzyme-linked immunosorbent assay (ELISA) | 14 days after final vaccination | 
| B cell response to Na-GST-1 | Dose and formulation of the Na-GST-1 vaccine that results in the highest production of Na-GST-1 specific B cells and subtypes (memory or plasma) | Up to study day 290 | 
| Exploratory cellular immune response to Na-GST-1 | Exploratory studies of the cellular immune responses to the Na-GST-1 antigen both before and after immunization. | Up to study day 290 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Human Hookworm, Necator americanus, Hookworm, Hookworm Disease, Iron-deficiency anemia, Soil-transmitted helminth infection, Neglected Tropical Disease, Na-GST-1, CpG