Safety and Immunogenicity of Co-Administered Hookworm Vaccine Candidates Na-GST-1 and Na-APR-1 in Gabonese Adults

Study Overview
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Brief Summary
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Na-GST-1 and Na-APR-1 are proteins expressed during the adult stage of the Necator americanus hookworm life cycle that are thought to play a role in the parasite's degradation of host hemoglobin for use as an energy source. Vaccination with recombinant GST-1 or APR-1 has protected dogs and hamsters from infection in challenge studies. This study will evaluate the safety and immunogenicity of co-administering Na-GST-1 and Na-APR-1 to healthy Gabonese adults living in an area of endemic hookworm infection.

Detailed Description
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Double-blind, randomized, controlled dose-escalation Phase 1 clinical trial in hookworm exposed adults. Study site: Centre de Recherches Médicales de Lambaréné Number of participants: 32 in 2 cohorts of 16 Doses of Na-GST-1 to be tested: 30 and 100 μg Doses of Na-APR-1 to be tested: 30 and 100 μg Dose of GLA-AF: 5 μg per antigen Cohort 1: 30 μg of each of the two antigens (Na-GST-1/Alhydrogel® and Na-APR-1 (M74)/Alhydrogel®) or hepatitis B vaccine; Cohort 2: 100 μg of each of the two antigens (Na-GST- 1/Alhydrogel® and Na-APR-1 (M74) /Alhydrogel®) or hepatitis B vaccine. Randomization: Cohort 1: 30 μg Na-GST-1 + 30 μg Na-APR-1 (M74) (n = 12) versus Hepatitis B Vaccine/placebo (n = 4) Cohort 2: 100 μg Na-GST-1 + 100 μg Na-APR-1 (M74) (n = 12) versus Hepatitis B Vaccine + placebo (n = 4) The cohorts will be enrolled in a staggered fashion with safety data assessed prior to the Na-GST-1 and Na-APR-1 dose escalation from 30 to 100 µg. Pre-treatment: Albendazole (400 mg) at least 2 weeks prior to first vaccination Immunization schedule: Study days 0, 28 and 180 Route: Intramuscular in the deltoid muscle Study duration: approximately 20 months; each participant will be followed for a total of 12 months.

Official Title
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Randomized, Controlled, Phase 1 Study to Assess Safety and Immunogenicity of Co-administered Hookworm Vaccine Candidates Na-GST-1 and Na-APR-1 Adjuvanted With Alhydrogel® and Gluco-pyranosylphospho-lipid A in Gabonese Adults

Conditions
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Hookworm Infection, Hookworm Disease

Intervention / Treatment
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* Biological: Na-APR-1 (M74)/Alhydrogel®
* Biological: Na-GST-1/Alhydrogel®
* Biological: Hepatitis B vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females between 18 and 50 years, inclusive, who are long-term residents of Gabon. Good general health as determined by means of the screening procedure. Assumed availability for the duration of the trial (12 months). Willingness to participate in the study as evidenced by signing the informed consent document. Negative for hookworm during screening, or if found to be infected with hookworm, has completed a course of three doses of albendazole. Exclusion Criteria: Pregnancy as determined by a positive urine hCG (if female). Participant unwilling to use reliable contraception up until one month following the third immunization (if female and not surgically sterile, abstinent or at least 2 years post-menopausal). Currently lactating and breast-feeding (if female). Inability to correctly answer all questions on the informed consent comprehension questionnaire. Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic, rheumatologic, autoimmune, diabetes, or renal disease by history, physical examination, and/or laboratory studies. 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). Laboratory evidence of hematologic disease (absolute leukocyte count <3500/mm3; absolute leukocyte count >11.0 x 103/mm3; hemoglobin <10.000 g/dl [females] or <12.0 g/dl [males]; or, platelet count <140,000/mm3). 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. Participation in another investigational vaccine or drug trial within 30 days of starting this study or for the duration of the study. 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 room/clinic visit or hospitalization within 6 months of the volunteer's planned first vaccination in the study. Positive for HCV Positive ELISA for HBsAg. Positive for HIV infection Use of corticosteroids (excluding topical or nasal) or immunosuppressive drugs within 30 days of starting this study or expect to use for the duration of the study. Receipt of a live vaccine within past 4 weeks or a killed vaccine within past 2 weeks prior to entry into the study. History of a surgical splenectomy. Receipt of blood products within the 6 months prior to entry into the study. Previous receipt of a primary series of any hepatitis B vaccine.

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 30 µg Na-GST-1 + 30 µg Na-APR-1 (M74)<br>30 µg Na-GST-1/Alhydrogel plus 5 µg GLA-AF co-administered with 30 µg Na-APR-1 (M74)/Alhydrogel plus 5 µg GLA-AF | Biological: Na-APR-1 (M74)/Alhydrogel®<br> <br> Biological: Na-GST-1/Alhydrogel®<br> <br> |
| Active Comparator: Hepatitis B vaccine<br>Hepatitis B vaccine co-administered with saline | Biological: Hepatitis B vaccine<br>* Hepatitis B vaccine co-administered with saline<br>|
| Experimental: 100 µg Na-GST-1 plus 100 µg Na-APR-1 (M74)<br>100 µg Na-GST-1/Alhydrogel plus 5 µg GLA-AF co-administered with 100 µg Na-APR-1 (M74)/Alhydrogel plus 5 µg GLA-AF | Biological: Na-APR-1 (M74)/Alhydrogel®<br> <br> Biological: Na-GST-1/Alhydrogel®<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vaccine-related Adverse Events | To estimate the frequency of vaccine-related adverse events, graded by severity, for each dose of co-administered Na-GST-1 and Na-APR-1 (M74). The frequency of immediate, systemic, and local injection site adverse events will be summarized. Adverse events will be assessed by study team members at 1 hour post-vaccination as well as 1, 3, 7, 14, and 28 days following each vaccination. | Day 360 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IgG response to Na-GST-1 and Na-APR-1 (M74) | To determine the doses of Na-GST-1 and Na-APR-1 (M74) that generate the highest IgG antibody responses at Day 194, as determined by indirect enzyme-linked immunosorbent assays (ELISA) | Day 194 | 
| Duration of antibody response to Na-GST-1 and Na-APR-1 (M74) | To assess and compare the duration of antibody responses to Na- GST-1 and Na-APR-1 (M74). | Day 14, 28, 42, 56, 180, 194, 208, 270, 360 | 
| Exploratory studies of memory B-cell responses | Exploratory studies of memory B-cell responses against the metabolomics changes before and after Na-GST-1 and NA-APR-1 (M74) vaccine antigens. | Days 14, 28, 42, 56, 180, 194, 208, 270, 360 | 

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