Safety and Immunogenicity of Co-Administered Hookworm Vaccine Candidates Na-GST-1 and Na-APR-1 in Gabonese Adults

Randomized, Controlled, Phase 1 Study to Assess Safety and Immunogenicity of Co-administered Hookworm Vaccine Candidates Na-GST-1 and Na-APR-1 Adjuvanted With Alhydrogel® and Gluco-pyranosylphospho-lipid A in Gabonese Adults

Na-GST-1 and Na-APR-1 are proteins expressed during the adult stage of the Necator americanus hookworm life cycle that are thought to play a role in the parasite's degradation of host hemoglobin for use as an energy source. Vaccination with recombinant GST-1 or APR-1 has protected dogs and hamsters from infection in challenge studies. This study will evaluate the safety and immunogenicity of co-administering Na-GST-1 and Na-APR-1 to healthy Gabonese adults living in an area of endemic hookworm infection.

Study Overview

• Status: Completed
• Conditions: Hookworm Infection; Hookworm Disease
• Intervention / Treatment: Biological: Na-APR-1 (M74)/Alhydrogel®; Biological: Na-GST-1/Alhydrogel®; Biological: Hepatitis B vaccine

Detailed Description

Double-blind, randomized, controlled dose-escalation Phase 1 clinical trial in hookworm exposed adults.

Study site: Centre de Recherches Médicales de Lambaréné Number of participants: 32 in 2 cohorts of 16

Doses of Na-GST-1 to be tested: 30 and 100 μg Doses of Na-APR-1 to be tested: 30 and 100 μg Dose of GLA-AF: 5 μg per antigen

Cohort 1: 30 μg of each of the two antigens (Na-GST-1/Alhydrogel® and Na-APR-1 (M74)/Alhydrogel®) or hepatitis B vaccine; Cohort 2: 100 μg of each of the two antigens (Na-GST- 1/Alhydrogel® and Na-APR-1 (M74) /Alhydrogel®) or hepatitis B vaccine.

Randomization: Cohort 1: 30 μg Na-GST-1 + 30 μg Na-APR-1 (M74) (n = 12) versus Hepatitis B Vaccine/placebo (n = 4) Cohort 2: 100 μg Na-GST-1 + 100 μg Na-APR-1 (M74) (n = 12) versus Hepatitis B Vaccine + placebo (n = 4)

The cohorts will be enrolled in a staggered fashion with safety data assessed prior to the Na-GST-1 and Na-APR-1 dose escalation from 30 to 100 µg.

Pre-treatment: Albendazole (400 mg) at least 2 weeks prior to first vaccination

Immunization schedule: Study days 0, 28 and 180 Route: Intramuscular in the deltoid muscle

Study duration: approximately 20 months; each participant will be followed for a total of 12 months.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 1

Contacts and Locations

Study Locations

• Gabon
  • Lambaréné, Gabon, BP: 118
    • Centre de Recherches Médicales de Lambaréné Albert Schweitzer Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Males or females between 18 and 50 years, inclusive, who are long-term residents of Gabon.
• Good general health as determined by means of the screening procedure.
• Assumed availability for the duration of the trial (12 months).
• Willingness to participate in the study as evidenced by signing the informed consent document.
• Negative for hookworm during screening, or if found to be infected with hookworm, has completed a course of three doses of albendazole.

Exclusion Criteria:

• Pregnancy as determined by a positive urine hCG (if female).
• Participant unwilling to use reliable contraception 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).
• Inability to correctly answer all questions on the informed consent comprehension questionnaire.
• 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 (absolute leukocyte count <3500/mm3; absolute leukocyte count >11.0 x 103/mm3; hemoglobin <10.000 g/dl [females] or <12.0 g/dl [males]; or, platelet count <140,000/mm3).
• 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 or for the duration of the 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 room/clinic visit or hospitalization within 6 months of the volunteer's planned first vaccination in the study.
• Positive for HCV
• Positive ELISA for HBsAg.
• Positive for HIV infection
• Use of corticosteroids (excluding topical or nasal) or immunosuppressive drugs within 30 days of starting this study or expect to use for the duration of the study.
• Receipt of a live vaccine within past 4 weeks or a killed vaccine within past 2 weeks prior to entry into the study.
• History of a surgical splenectomy.
• Receipt of blood products within the 6 months prior to entry into the study.
• Previous receipt of a primary series of any hepatitis B vaccine.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 30 µg Na-GST-1 + 30 µg Na-APR-1 (M74); 30 µg Na-GST-1/Alhydrogel plus 5 µg GLA-AF co-administered with 30 µg Na-APR-1 (M74)/Alhydrogel plus 5 µg GLA-AF	Biological: Na-APR-1 (M74)/Alhydrogel®; Biological: Na-GST-1/Alhydrogel®
Active Comparator: Hepatitis B vaccine; Hepatitis B vaccine co-administered with saline	Biological: Hepatitis B vaccine; Hepatitis B vaccine co-administered with saline
Experimental: 100 µg Na-GST-1 plus 100 µg Na-APR-1 (M74); 100 µg Na-GST-1/Alhydrogel plus 5 µg GLA-AF co-administered with 100 µg Na-APR-1 (M74)/Alhydrogel plus 5 µg GLA-AF	Biological: Na-APR-1 (M74)/Alhydrogel®; Biological: Na-GST-1/Alhydrogel®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vaccine-related Adverse Events	To estimate the frequency of vaccine-related adverse events, graded by severity, for each dose of co-administered Na-GST-1 and Na-APR-1 (M74). 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 1, 3, 7, 14, and 28 days following each vaccination.	Day 360

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
IgG response to Na-GST-1 and Na-APR-1 (M74)	To determine the doses of Na-GST-1 and Na-APR-1 (M74) that generate the highest IgG antibody responses at Day 194, as determined by indirect enzyme-linked immunosorbent assays (ELISA)	Day 194
Duration of antibody response to Na-GST-1 and Na-APR-1 (M74)	To assess and compare the duration of antibody responses to Na- GST-1 and Na-APR-1 (M74).	Day 14, 28, 42, 56, 180, 194, 208, 270, 360
Exploratory studies of memory B-cell responses	Exploratory studies of memory B-cell responses against the metabolomics changes before and after Na-GST-1 and NA-APR-1 (M74) vaccine antigens.	Days 14, 28, 42, 56, 180, 194, 208, 270, 360

Collaborators and Investigators

• Sponsor: Baylor College of Medicine
• Investigators: Principal Investigator: Ayola Adegnika, MD, Centre de Recherches Medicales de Lambarene

Publications and helpful links

General Publications

• Mouwenda YD, Betouke Ongwe ME, Sonnet F, Stam KA, Labuda LA, De Vries S, Grobusch MP, Zinsou FJ, Honkpehedji YJ, Dejon Agobe JC, Diemert DJ, van Leeuwen R, Bottazzi ME, Hotez PJ, Kremsner PG, Bethony JM, Jochems SP, Adegnika AA, Massinga Loembe M, Yazdanbakhsh M. Characterization of T cell responses to co-administered hookworm vaccine candidates Na-GST-1 and Na-APR-1 in healthy adults in Gabon. PLoS Negl Trop Dis. 2021 Oct 1;15(10):e0009732. doi: 10.1371/journal.pntd.0009732. eCollection 2021 Oct.
• Adegnika AA, de Vries SG, Zinsou FJ, Honkepehedji YJ, Dejon Agobe JC, Vodonou KG, Bikangui R, Bouyoukou Hounkpatin A, Bache EB, Massinga Loembe M, van Leeuwen R, Molemans M, Kremsner PG, Yazdanbakhsh M, Hotez PJ, Bottazzi ME, Li G, Bethony JM, Diemert DJ, Grobusch MP; HookVac Consortium. Safety and immunogenicity of co-administered hookworm vaccine candidates Na-GST-1 and Na-APR-1 in Gabonese adults: a randomised, controlled, double-blind, phase 1 dose-escalation trial. Lancet Infect Dis. 2021 Feb;21(2):275-285. doi: 10.1016/S1473-3099(20)30288-7. Epub 2020 Sep 11.

Study record dates

Study Major Dates

• Study Start: November 1, 2014
• Primary Completion (Actual): February 1, 2016
• Study Completion (Actual): June 1, 2016

Study Registration Dates

• First Submitted: April 28, 2014
• First Submitted That Met QC Criteria: April 29, 2014
• First Posted (Estimate): April 30, 2014

Study Record Updates

• Last Update Posted (Actual): May 31, 2017
• Last Update Submitted That Met QC Criteria: May 30, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: Hookworm; Necator americanus; Iron-deficiency anemia; Na-GST-1; 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: HV-001; 602843-2 (Other Grant/Funding Number: European Commission)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided