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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
24
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.
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'.
George Washington University Medical Faculty Associates
Washington D.C., District of Columbia, United States
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
Time frame: Up to study day 470
IgG Antibody Response to Na-GST-1 on Study Day 126
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 a qualified indirect enzyme-linked immunosorbent assay (ELISA) and measured in Arbitrary Units (AU) that are interpolated from a standard reference curve formulated by serial dilutions of a serum pool derived from known high responders in previous clinical trials of this antigen. This ELISA has not been validated and does not report mass units since these have not yet been defined. Reporting ELISA values in AU is an accepted practice early in clinical development before full assay validation and quantification of mass units.
Time frame: 14 days after final vaccination
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.
Time frame: Up to study day 290
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