Safety and Immunogenicity of a Human Hookworm Candidate Vaccine With Different Doses of a Novel Adjuvant

Hookworm Infection Clinical Trial

Official title: Phase I Study of the Safety and Immunogenicity of Na-GST-1/Alhydrogel® With Different Doses of the Novel Immunostimulant GLA-AF in Healthy Adults

Status Completed

Clinical Trial Summary

This study is designed to evaluate the safety, reactogenicity, and immunogenicity of Na-GST-1 adsorbed to Alhydrogel® with or without two different dose concentrations of a novel adjuvant, GLA-AF (1 µg or 5 μg) among healthy adult volunteers.

Clinical Trial Description

Human hookworm infection is a soil-transmitted helminth infection caused by the nematode parasites Necator americanus and Ancylostoma duodenale. It is one of the most common chronic infections of humans, afflicting up to 740 million people in the developing nations of the tropics. The largest number of cases occurs in impoverished rural areas of sub-Saharan Africa, Southeast Asia, China, and the tropical regions of the Americas. Approximately 3.2 billion people are at risk for hookworm infection in these areas. N. americanus is the most common hookworm worldwide, whereas A. duodenale is more geographically restricted.

The primary approach to hookworm control worldwide has been the frequent and periodic mass administration of benzimidazole anthelminthics to school-aged children living in high-prevalence areas. In 2001, the World Health Assembly adopted Resolution 54.19 which urges member states to provide regular anthelminthic treatment to high-risk groups with the target of regular treatment of at least 75% of all at-risk school-aged children. However, the cure rates for a single dose of a benzimidazole varies with rates as low as 61% (400 mg) and 67% (800 mg) for albendazole and 19% (single dose) and 45% (repeated dose) for mebendazole being reported. These concerns have prompted interest in developing alternative tools for hookworm control. Vaccination to prevent the anemia associated with moderate and heavy intensity hookworm infection would alleviate the public health deficiencies of drug treatment alone.

The current strategy for development of Human Hookworm candidate vaccines is focused on antigens expressed during the adult stage of the hookworm life cycle which play a role in digesting the host hemoglobin, used by the worm as an energy source. These antigens are relatively hidden from the human immune system during natural infection, and hence have a low likelihood of inducing antigen-specific IgE in exposed/infected individuals, reducing the potential for allergic reaction upon vaccination.

The nutritional and metabolic requirements of the adult hookworm living in the human intestine are dependent upon degradation of host hemoglobin that has been ingested by the worm. N. americanus hookworms depend on host hemoglobin for survival. Following hemolysis, adult hookworms use an ordered cascade of hemoglobinases to cleave hemoglobin into smaller molecules. Following hemoglobin digestion, the freed heme generates toxic oxygen radicals that can be bound and detoxified by molecules such as glutathione S-transferase-1 (GST-1). GST-1 of N. americanus (Na-GST-1) is a critical enzyme that plays a role in parasite blood feeding; when used as a vaccine, the investigators hypothesize that the antigen will induce anti-enzyme neutralizing antibodies that will interfere with parasite blood-feeding and cause parasite death or reduce worm fecundity.

Following its selection as a candidate antigen Na-GST-1 has been successfully manufactured and tested in the laboratory and in animals with both Alhydrogel® (aluminum hydroxide suspension)and Alhydrogel® plus Gluco-Pyranosylphospho-Lipid A Aqueous Formulation (GLA-AF). Na-GST-1 has been shown to be pure, potent, and stable when administered as either of these two formulations.

Although GLA-AF has not yet been administered to humans, an oil-in-water emulsion of GLA (GLA-SE) has been used in combination with the Fluzone® trivalent killed influenza vaccine in a Phase 1 trial. In this study, doses up to 1 µg of GLA-SE were safe and well-tolerated and significantly enhanced influenza-specific antibody responses.

The phase 1 trial described here will enroll healthy adults who have not been infected with or exposed to hookworm who are living in the Washington DC area. A phase 1 trial of Na-GST-1/Alhydrogel (with or without GLA-AF) is planned to start in July 2011 in Brazil. In that study, both hookworm-naïve and hookworm-exposed healthy adults will be vaccinated with either Na-GST-1/Alhydrogel®, Na-GST-1/Alhydrogel® co-administered with 1 µg GLA-AF, or the Butang® hepatitis B vaccine. The objectives of that study will be to assess the safety and immunogenicity of the Na-GST-1 formulations in healthy Brazilian adults. The study described here will complement the study in Brazilian adults as it will provide additional information about different dose concentrations of GLA-AF as well as detailed data on the humoral immune response to the different formulations that will be tested.

In this study, 90 volunteers will be progressively enrolled into one of six dose cohorts. Dose cohorts will be enrolled and vaccinated in a consecutive fashion. The 15 volunteers in each cohort will be subsequently randomized in a 1:2 ratio to receive either the Na-GST-1/Alhydrogel® (n=5) or Na-GST-1/Alhydrogel®/GLA-AF (n=10). In the first, third and fifth cohorts, volunteers will be randomized to receive either Na-GST-1/Alhydrogel® (n=5) OR Na-GST-1/Alhydrogel® co-administered with 1 µg GLA-AF (n=10), while in the second, fourth, and sixth cohorts, volunteers will be randomized to receive either Na-GST-1/Alhydrogel® (n=5) or Na-GST-1/Alhydrogel® co-administered with 5 µg GLA-AF (n=10).

Each participant will receive 3 doses of the assigned study agent given in 56 day intervals (i.e. Day 0, Day 56 and Day 112). The trial is expected to last for approximately 18 months. Each participant will be followed for 16 months from the time of the first injection.

Safety parameters will be monitored throughout the study. The primary endpoint for the study will be measurement of antigen-specific antibody response. ;

Study Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Hookworm Disease
• Hookworm Infection
• Hookworm Infections

• NCT number: NCT01385189
• Study type: Interventional
• Source: Albert B. Sabin Vaccine Institute
• Status: Completed
• Phase: Phase 1
• Start date: May 2012
• Completion date: June 2015