Safety and Immunogenicity of a Human Hookworm Candidate Vaccine With Different Doses of a Novel Adjuvant
Condition: Hookworm Infection; Hookworm Disease
MeSH terms: Hookworm Infections; Ancylostomiasis
Study type: Interventional
Phase: Phase 1

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.
    

Detailed 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.
    

Intervention name(s): 10 μg Na-GST-1/Alhydrogel; 30 μg Na-GST-1/Alhydrogel; 100 μg Na-GST-1/Alhydrogel; 10 μg Na-GST-1/Alhydrogel/GLA-AF (1 μg); 30 μg Na-GST-1/Alhydrogel/GLA-AF (1 μg); 30 μg Na-GST-1/Alhydrogel/GLA-AF (5 μg); 100 μg Na-GST-1/Alhydrogel/GLA-AF (5 μg)
Intervention type(s): Biological; Biological; Biological; Biological; Biological; Biological; Biological
Intervention description(s): 3 doses 10 μg Na-GST-1/Alhydrogel administered at 56 day intervals; 3 doses 30 μg Na-GST-1/Alhydrogel administered at 56 day intervals; 3 doses 100 μg Na-GST-1/Alhydrogel administered at 56 day intervals; 3 doses 10 μg Na-GST-1/Alhydrogel/GLA-AF (1 μg) administered at 56 day intervals; 3 doses of 30 μg Na-GST-1/Alhydrogel/GLA-AF (1 μg) administered at 56 day intervals; 3 doses 30 μg Na-GST-1/Alhydrogel/GLA-AF (5 μg) administered at 56 day intervals; 3 doses 100 μg Na-GST-1/Alhydrogel/GLA-AF (5 μg) administered at 56 day intervals
Intervention MeSH terms: Aluminum Hydroxide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Human Hookworm Vaccine Initiative; HHVI; Human Hookworm; Hookworm; Hookworm Disease; N. americanus; Soil-transmitted helminth infection; Intestinal blood loss; Iron deficiency anemia