Safety and Immunogenicity of the Na-APR-1 Hookworm Vaccine in Healthy Adults
Study Details
Study Description
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.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 1 |
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: 30 µg Na-APR-1 (M74)/Alhydrogel®
|
Biological: Na-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.
Other Names:
|
Experimental: 30 µg Na-APR-1 (M74)/Alhydrogel® plus 2.5 µg GLA-AF
|
Biological: Na-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.
Other Names:
Biological: Gluco-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.
Other Names:
|
Experimental: 30 µg Na-APR-1 (M74)/Alhydrogel® plus 5.0 µg GLA-AF
|
Biological: Na-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.
Other Names:
Biological: Gluco-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.
Other Names:
|
Experimental: 100 µg Na-APR-1 (M74)/Alhydrogel®
|
Biological: Na-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.
Other Names:
|
Experimental: 100 µg Na-APR-1 (M74)/Alhydrogel® plus 2.5 µg GLA-AF
|
Biological: Na-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.
Other Names:
Biological: Gluco-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.
Other Names:
|
Experimental: 100 µg Na-APR-1 (M74)/Alhydrogel® plus 5.0 µg GLA-AF
|
Biological: Na-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.
Other Names:
Biological: Gluco-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.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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.
Eligibility Criteria
Criteria
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.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | George Washington University Medical Faculty Associates | Washington | District of Columbia | United States | 20036 |
Sponsors and Collaborators
- Baylor College of Medicine
- George Washington University
Investigators
- Principal Investigator: David J Diemert, MD, George Washington University
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- SVI-12-01