Hookworm Disease, Hookworm Infection
Conditions
Keywords
Human Hookworm, Necator americanus, Hookworm, Hookworm Disease, Iron-deficiency anemia, Soil-transmitted helminth infection, Neglected Tropical Disease, Na-APR-1
Brief summary
Hookworms digest hemoglobin from erythrocytes for use as an energy source via a proteolytic cascade that begins with the aspartic protease, APR-1. Vaccination with recombinant APR-1 has protected animals from infection in challenge studies. This study will evaluate the safety and immunogenicity of two formulations of Na-APR-1 (M74) in healthy adult volunteers when co-administered with different concentrations of the immunostimulant GLA-AF.
Detailed description
Open-label, dose-escalation phase 1 clinical trial in healthy, hookworm-naïve adults: * Study site: George Washington Medical Faculty Associates, Washington, DC * Number of participants: 40 in 2 cohorts of 20. In Cohort 1 five (5) volunteers will receive 30 µg Na-APR-1 (M74) /Alhydrogel®, five (5) will receive 30 µg Na-APR-1 (M74)/Alhydrogel® plus 2.5 µg GLA-AF, and ten (10) will receive 30 µg Na-APR-1 (M74) /Alhydrogel® plus 5 µg GLA-AF. In Cohort 2 five (5) volunteers will receive 100 µg Na-APR-1 (M74)/Alhydrogel®, five (5) will receive 100 µg Na-APR-1 (M74) /Alhydrogel® plus 2.5 µg GLA-AF, and ten (10) will receive 100 µg Na-APR-1 (M74)/Alhydrogel® plus 5 µg GLA-AF. The cohorts will be enrolled in a staggered fashion with safety data assessed prior to the Na-APR-1 dose escalation from 30 to 100 µg. In addition, within each cohort, vaccinations will be staggered such that formulations containing 0, 2.5, and 5 µg GLA-AF will be tested sequentially: for example, those receiving Na-APR-1 (M74)/Alhydrogel® in combination with 2.5 µg GLA-AF will be vaccinated no sooner than 3 days after the last volunteer is vaccinated with the formulation containing no GLA-AF, whereas those vaccinated with Na-APR-1 (M74)/Alhydrogel® plus 5 µg GLA-AF will be vaccinated no sooner than 7 days after the last one receives the 2.5 µg GLA-AF formulation. * Immunization schedule: Study days 0, 56 and 112. * Route: IM in the deltoid muscle. * Doses of Na-APR-1 (M74) to be tested: 30 and 100 µg. * Doses of Alhydrogel®: 240 and 800 µg for the 30 and 100 µg doses of Na-APR-1 (M74), respectively. * Doses of GLA-AF to be tested: 2.5 µg and 5 µg. * Study duration: 44 weeks (10 months) per study participant; total duration of the study estimated at approximately 13 months.
Interventions
BIOLOGICALNa-APR-1 (M74)/Alhydrogel®
The Na-APR-1 (M74) candidate vaccine contains the recombinant Na-APR-1 (M74) protein expressed by Nicotiana plants. Purified Na-APR-1 (M74) was subsequently adsorbed onto aluminum hydroxide gel (Alhydrogel®) and suspended in a solution containing 10 mM imidazole, 150 mM sodium chloride and 0.3% Empigen BB, with pH 7.4 ± 0.1. The final concentration of Na-APR-1 (M74) in the drug product is 0.1 mg/ml, whereas that of Alhydrogel® is 0.8 mg/ml. Different doses of Na-APR-1 (M74) will be delivered by injecting different volumes of the 0.1 mg/ml Na-APR-1 (M74) preparation.
BIOLOGICALGluco-Pyranosylphospho-Lipid A Aqueous Formulation
GLA-AF contains a synthetic monophosphoryl lipid A (MPL) molecule that has Toll-Like Receptor-4 agonist activity. MPL is itself derived from the lipopolysaccharide (LPS) of Salmonella minnesota, a natural TLR4 agonist that is pyrogenic and can induce toxic shock. LPS, and more specifically, its lipid A component, has long been known for its strong adjuvant effects; however, its high toxicity has precluded its use in a vaccine formulation.
Sponsors
George Washington University
Baylor College of Medicine
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
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 (44 weeks). * Willingness to participate in the study as evidenced by signing the informed consent document.
Exclusion criteria
* Pregnancy as determined by a positive urine human choriogonadotropin (hCG) (if female). * Participant unwilling to use reliable contraception methods 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). * 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 (hemoglobin \<11.5 g/dl \[females\] or \<12.5 g/dl \[males\]; absolute leukocyte count \<3600/mm3 or \>10.7 x 103/mm3; absolute neutrophil count \[ANC\] \<1700/ mm3; absolute lymphocyte count \<700/mm3; or platelet count \<140,000/mm3). * Laboratory evidence of a coagulopathy (PTT or PT INR greater than 1.1-times the upper reference limit). * Serum glucose (random) 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. * Participation in another investigational vaccine or drug trial within 30 days of starting this 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 clinic visit or hospitalization within 6 months of the volunteer's expected first vaccination in the study. * Positive ELISA 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. * 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. * History of a surgical splenectomy. * Receipt of blood products within the past 6 months. * History of previous infection with hookworm or residence for more than 6 months in a hookworm-endemic area.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Vaccine-related Adverse Events | Day 290 | 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 3, 7, 14, and 28 days following each vaccination. In addition, study participants will be asked to complete symptom diaries for the 7 days after each vaccination. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| IgG antibody response to Na-APR-1 | 14 days after final vaccination | Dose and formulation of Na-APR-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). |
| B cell response to Na-APR-1 | Study Days 14, 70, 126, 140 and 290 | Dose and formulation of the Na-APR-1 (M74) vaccine that results in the highest production of Na-APR-1 (M74) specific B cells and subtypes (memory or plasma). |
| Exploratory cellular immune response to Na-APR-1 | Study Days 14, 70, 126, 140 and 290 | Exploratory studies of the cellular immune responses to the Na APR-1 (M74) antigen both before and after immunization. |
Countries
United States
Outcome results
None listed