Experimental Infection of Hookworm-naïve Adults With Dermally-applied Infectious Necator Americanus Hookworm Larvae

An Experimental Infection Study of Dermally-applied Infectious Necator Americanus Hookworm Larvae in Hookworm-naïve Adults

An experimental hookworm infection model is being developed to provide early proof-of-concept that a hookworm vaccine targeting the blood-feeding pathway of adult hookworms is feasible and efficacious. The proposed model consists of vaccinating healthy, hookworm-naïve adults with a candidate hookworm vaccine, followed by challenging them with the investigational product, Necator americanus Larval Inoculum to assess the effect of vaccination on infection. The first proposed study will be a feasibility study that will consist of administering different doses of the Necator americanus Larval Inoculum to healthy adult volunteers to determine the optimal dose (i.e., number of infectious larvae) that is safe, well-tolerated and results in consistent infection.

Study Overview

• Status: Recruiting
• Conditions: Hookworm Infection
• Intervention / Treatment: Biological: Necator americanus Hookworm Larvae

Detailed Description

Open-label, dose-escalation clinical study in healthy, hookworm-naïve adults:

• Study site: George Washington Medical Faculty Associates, Washington, DC
• Number of participants: up to 30 in 3 cohorts of 10 volunteers each

In Cohort 1, ten (10) volunteers will receive an inoculum of 25 infectious Necator americanus larvae. In Cohort 2, ten (10) volunteers will receive an inoculum of 50 infectious Necator americanus larvae. In the optional Cohort 3, ten (10) volunteers will receive an inoculum of 75 infectious Necator americanus larvae.

The cohorts will be enrolled in a staggered fashion with safety data assessed prior to larval dose escalation. Cohort 2 will be inoculated no earlier than 8 weeks after the last volunteer is inoculated in Cohort 1. The optional Cohort 3 will be inoculated no sooner than 8 weeks after the last volunteer is inoculated in Cohort 2. Cohort 3 will be enrolled only if the tolerability of the experimental infection of Cohort 2 is acceptable and does not result in significant adverse events.

Within each cohort, after Study Day 70, but before Study Day 77, up to 5 volunteers will undergo capsule endoscopy in order to visualize and count adult N. americanus hookworms residing in the intestine. Informed consent for capsule endoscopy will be obtained separately from the primary study, and agreement or refusal will not impact on a subject's eligibility to enroll or continue participation in the primary study.

Three months after larval administration, or at the time of study withdrawal, all participants will receive a 3-dose treatment of albendazole (400 mg per dose) for clearance of experimental infection.

• Larval inoculum schedule: Study Day 0 (single application)
• Route: applied to intact skin on the volar aspect of forearm
• Doses of N. americanus Larval Inoculum to be tested: 25, 50 and 75 infectious larvae (high dose optional)
• Study duration: 6 months per study participant; total duration of the study estimated at approximately 13 months
• Anthelmintic treatment: 3 months post larval inoculum, or at study withdrawal, 3-dose treatment with 400 mg albendazole

• Study Type: Interventional
• Enrollment (Estimated): 28
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Study Coordinator; Phone Number: (202) 994-1599; Email: gwvru@gwu.edu

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • Recruiting
      • George Washington University Medical Faculty Associates
      • Sub-Investigator: Aimee Desrosiers, PA
      • Sub-Investigator: Elissa Malkin, DO, MPH
      • Sub-Investigator: Caroline Thoreson, PA
      • Contact: Study Coordinator; Phone Number: 202-994-1599; Email: gwvru@gwu.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Males or females between 18 and 45 years, inclusive.
• Good general health as determined by means of the screening procedure.
• Available for the duration of the trial (6 months).
• 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 while participating in the study (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 <3.6 or >10.7 x 103/mm3; absolute neutrophil count [ANC] <1.7 x 103/mm3; absolute lymphocyte count <0.7 x 103/mm3; or platelet count <140 x 103/mm3).
• History of iron deficiency anemia.
• History of hypoalbuminemia.
• 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.
• 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 Day 0 of 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 Day 0 of this study or planned use during the study.
• Receipt of a live vaccine within 4 weeks or a killed vaccine within 2 weeks prior to the volunteer's expected Day 0 of the study.
• Receipt of blood products within the past 6 months.
• Known allergy to amphotericin B or gentamicin.
• 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: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 25 Necator americanus Hookworm Larvae	Biological: Necator americanus Hookworm Larvae; Infectious larvae of the human hookworm Necator americanus; Other Names: Na-L3
Experimental: 50 Necator americanus Hookworm Larvae	Biological: Necator americanus Hookworm Larvae; Infectious larvae of the human hookworm Necator americanus; Other Names: Na-L3
Experimental: 75 Necator americanus Hookworm Larvae	Biological: Necator americanus Hookworm Larvae; Infectious larvae of the human hookworm Necator americanus; Other Names: Na-L3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Study product-related adverse events	Frequency of study product-related adverse events, graded by severity, for different doses of N. americanus Larval Inoculum.	Up to 6 months after dosing

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fecal egg counts	To determine the dose of N. americanus Larval Inoculum that generates the highest fecal egg counts, measured by fecal microscopy.	Up to Study Day 101
Number of adult hookworms in feces post-treatment	To compare the N. americanus Larval Inoculum dose received with the number of adult worms present in the gut, as determined by capsule endoscopy.	Study Days 87-101

Collaborators and Investigators

• Sponsor: Baylor College of Medicine
• Investigators: Principal Investigator: David J Diemert, MD, George Washington University

Publications and helpful links

General Publications

• Diemert D, Campbell D, Brelsford J, Leasure C, Li G, Peng J, Zumer M, Younes N, Bottazzi ME, Mejia R, Pritchard DI, Hawdon JM, Bethony JM. Controlled Human Hookworm Infection: Accelerating Human Hookworm Vaccine Development. Open Forum Infect Dis. 2018 Apr 19;5(5):ofy083. doi: 10.1093/ofid/ofy083. eCollection 2018 May.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2015
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): February 1, 2025

Study Registration Dates

• First Submitted: September 9, 2013
• First Submitted That Met QC Criteria: September 9, 2013
• First Posted (Estimated): September 12, 2013

Study Record Updates

• Last Update Posted (Actual): October 12, 2023
• Last Update Submitted That Met QC Criteria: October 10, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Necator americanus; Hookworm Infection; Experimental challenge infection
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Parasitic Diseases; Secernentea Infections; Nematode Infections; Helminthiasis; Strongylida Infections; Infections; Communicable Diseases; Hookworm Infections; Ancylostomiasis
• Other Study ID Numbers: SVI-CH-01