This study evaluates the efficacy, safety and immunogenicity of different formulations of the Na-GST-1 hookworm vaccine using a controlled human hookworm infection model in healthy, hookworm-naive adults.
Double blind, randomized, controlled, Phase 2 clinical trial in hookworm-unexposed adults living in the metropolitan area of Washington, DC. Subjects will receive three doses of the assigned vaccine formulation, or saline placebo, delivered intramuscularly on approximately Days 0, 56, and 112. Subjects will be challenged with 50 infectious N. americanus larvae 4 weeks after 3rd vaccination. Fecal samples will be collected weekly starting 4 weeks post-challenge. Albendazole will be administered 20 weeks post-challenge to cure infections. Subjects will be followed until 10 months after their final vaccination. Safety of vaccination will be measured from the time of each study vaccination (Day 0) through 14 days after each study vaccination by the occurrence of solicited injection site and systemic reactogenicity events. Safety of CHHI will be measure from the time of larval application (Day 140) through the first day of treatment with albendazole (Day 280). Unsolicited non-serious adverse events (AEs) will be collected until approximately 1 month following each study vaccination and from study Day 140 (day of CHHI) through Day 280. New-onset chronic medical conditions and Serious Adverse Events (SAEs) will be collected from the time of the first study vaccination through approximately 10 months after the third study vaccination (final visit). Clinical laboratory evaluations for safety will be performed on venous blood collected approximately 14 days after each vaccination and CHHI. Immunogenicity testing will include IgG antibody responses to Na-GST-1, by a qualified indirect enzyme-linked immunosorbent assay (ELISA), on serum obtained prior to each study vaccination and CHHI, and at time points after each vaccination and after CHHI (see Appendix A); the affinity of vaccine-induced antibodies against Na-GST-1 using Surface Plasmon Resonance; the functional activity of vaccine-induced antibodies via in vitro enzyme neutralization assay; antigen-specific memory B cell responses; and, the innate immune responses to each of the TLR receptor immunostimulants. Parasitological testing will include microscopic fecal egg detection by a qualified saline flotation technique, fecal egg counts by the McMaster method, fecal PCR for hookworm DNA, and peripheral eosinophil counts. Recruitment and enrollment into the study will occur on an ongoing basis, with each group being recruited and vaccinated in sequence. 48 subjects will be enrolled into 4 groups of 12. Subjects will be enrolled sequentially and upon enrollment will be randomized to one of the following IP assignments in a double-blind fashion: * Group 1 IP allocation (n=12 subjects): 12 subjects will receive 100µg Na-GST-1/Alhydrogel® delivered by IM injection in the deltoid muscle. * Group 2 IP allocation (n=12): 12 subjects will receive Na-GST-1/Alhydrogel® plus 500µg CpG 10104 delivered by IM injection in the deltoid muscle. * Group 3 IP allocation (n=12): 12 subjects will receive Na-GST-1/Alhydrogel® plus 5µg GLA-AF delivered by IM injection in the deltoid muscle. * Group 4 IP allocation (n=12): 12 subjects will receive sterile saline delivered by IM injection in the deltoid muscle.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
39
Recombinant Necator americanus Glutathione-S Transferase adjuvanted with Alhydrogel
Recombinant Necator americanus Glutathione-S Transferase adjuvanted with Alhydrogel and co-administered with CPG 10104, a synthetic oligodeoxynucleotide
Recombinant Necator americanus Glutathione-S Transferase adjuvanted with Alhydrogel and co-administered with an aqueous formulation of Glucopyranosyl-Lipid A (GLA-AF)
George Washington University
Washington D.C., District of Columbia, United States
Detectable Hookworm Infection
Proportion of subjects with detectable hookworm eggs, at any time point, in fecal samples, as determined by microscopy using the qualified saline flotation technique
Time frame: On Study Days 175, 182, 189, 203, 217, 231, 245, 259, 273, and 280.
Incidence of Serious Adverse Events
Frequency of study vaccine-related Serious Adverse Events from the time of the first study vaccination through approximately 10 months after the last study vaccination.
Time frame: Beginning on Day 0 when the first dose is received and ending on Day 380 (final study visit).
Incidence of Solicited Injection Site and Systemic Reactogenicity
Frequency of solicited injection site and systemic reactogenicity, graded by severity, on the day of each study vaccination through 14 days after each study vaccination.
Time frame: Dose 1: Days 0, 3, 7, 14; Dose 2: Days 56, 59, 63, 70; Dose 3: Days 112, 115, 119, 126
Incidence of Solicited Adverse Events
Frequency of solicited adverse events, graded by severity, on the day of CHHI through study Day 280
Time frame: Day of CHHI, Day 140, and study days: 143, 147, 154, 175, 182, 189, 196, 203, 210, 217, 224, 231, 238, 245, 252, 259, 266, 273, 280. Day 280 is the day of anti-worm treatment.
Incidence of Clinical Safety Laboratory Abnormalities
Frequency of clinical safety laboratory adverse events.
Time frame: Study days: 0, 14, 56, 70, 112, 126, 140, 154, 175, 189, 203, 217, 231, 259, 280.
Incidence of Unsolicited Adverse Events
Frequency of unsolicited adverse events, graded by severity, from the time of each study vaccination through approximately 1 month after each study vaccination; and from the time of CHHI through treatment with albendazole (Day 280)
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Physiological sterile saline solution
Treatment with 3 daily oral doses of 400 mg albendazole at end of study.
50 infectious Necator americanus larvae applied via dermal application (challenge infection).
Time frame: From Dose 1 on Day 0 until anti-worm treatment on Day 280.
Incidence of New-onset Chronic Medical Conditions
Frequency of new-onset chronic medical conditions through approximately 10 months after the third study vaccination.
Time frame: Entire duration of the study. Beginning Day 0, day of first dose, until Day 380, final study visit.
Incidence of Adverse Events of Special Interest
Frequency of Adverse Events of Special Interest through approximately 10 months after the third study vaccination.
Time frame: Entire duration of the study. Beginning Day 0, day of first dose, until Day 380, final study visit.
Fecal Egg Counts
Fecal egg counts as determined by microscopy using the McMaster method, weekly from Weeks 5 through 20 post-CHHI
Time frame: Week 5 and Week 20 post-CHHI. Study days: 175, 182, 189, 203, 217, 231, 245, 259, 273, and 280.
Anti-Na-GST-1 IgG Antibody Response
Anti-Na-GST-1 IgG antibody response as measured in Arbitrary Units per milliliter (AU/mL) of serum, determined by a qualified indirect enzyme-linked immunosorbent assay (ELISA) at approximately 14 days after each vaccination, and approximately 1, 2, 4, 6, 7, 8 and 10 months after the third dose. Levels of IgG antibodies against Na-GST-1 were converted to AUs by homologous interpolation of Optical Density readings at 492nm (OD492) from a standard calibration curve derived from serial dilutions of a human standard reference serum pool collected from high IgG responders (OD492 ≥ 1.000).
Time frame: Study days: 14, 70, 126, 140, 175, 189, 231, 280, 320, and 380