Safety and Immunogenicity of the Na-APR-1 Hookworm Vaccine in Healthy Adults

Phase 1 Study of the Safety and Immunogenicity of Na-APR-1 (M74)/Alhydrogel® in Healthy Adults

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.

Study Overview

• Status: Completed
• Conditions: Hookworm Infection; Hookworm Disease
• Intervention / Treatment: Biological: Na-APR-1 (M74)/Alhydrogel®; Biological: Gluco-Pyranosylphospho-Lipid A Aqueous Formulation

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 Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20036
      • George Washington University Medical Faculty Associates

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

6

Arms and Interventions

Participant Group / 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: Na-APR-1; Necator americanus Aspartic Protease-1
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: Na-APR-1; Necator americanus Aspartic Protease-1; 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: GLA-AF
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: Na-APR-1; Necator americanus Aspartic Protease-1; 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: GLA-AF
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: Na-APR-1; Necator americanus Aspartic Protease-1
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: Na-APR-1; Necator americanus Aspartic Protease-1; 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: GLA-AF
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: Na-APR-1; Necator americanus Aspartic Protease-1; 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: GLA-AF

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vaccine-related Adverse Events	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.	Day 290

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
IgG antibody response to Na-APR-1	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).	14 days after final vaccination
B cell response to Na-APR-1	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).	Study Days 14, 70, 126, 140 and 290
Exploratory cellular immune response to Na-APR-1	Exploratory studies of the cellular immune responses to the Na APR-1 (M74) antigen both before and after immunization.	Study Days 14, 70, 126, 140 and 290

Collaborators and Investigators

• Sponsor: Baylor College of Medicine
• Collaborators: George Washington University

Study record dates

Study Major Dates

• Study Start: September 1, 2013
• Primary Completion (ACTUAL): June 1, 2015
• Study Completion (ACTUAL): September 1, 2015

Study Registration Dates

• First Submitted: October 25, 2012
• First Submitted That Met QC Criteria: October 29, 2012
• First Posted (ESTIMATE): October 31, 2012

Study Record Updates

• Last Update Posted (ACTUAL): July 31, 2019
• Last Update Submitted That Met QC Criteria: July 29, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Hookworm; Necator americanus; Iron-deficiency anemia; Na-APR-1; Human Hookworm; Hookworm Disease; Soil-transmitted helminth infection; Neglected Tropical Disease
• Additional Relevant MeSH Terms: Infections; Parasitic Diseases; Secernentea Infections; Nematode Infections; Helminthiasis; Strongylida Infections; Hookworm Infections; Ancylostomiasis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Immunologic Factors; Gastrointestinal Agents; Adjuvants, Immunologic; Antacids; Aluminum Hydroxide
• Other Study ID Numbers: SVI-12-01

Plan for Individual participant data (IPD)

Study Data/Documents

1. Clinical Study Report