Safety and immunogenicity of the Na-GST-1 hookworm vaccine in Brazilian and American adults

Abstract

Necator americanus Glutathione-S-Transferase-1 ( Na-GST-1) plays a role in the digestion of host hemoglobin by adult N. americanus hookworms. Vaccination of laboratory animals with recombinant Na-GST-1 is associated with significant protection from challenge infection. Recombinant Na-GST-1 was expressed in Pichia pastoris and adsorbed to aluminum hydroxide adjuvant (Alhydrogel) according to current Good Manufacturing Practice. Two Phase 1 trials were conducted in 142 healthy adult volunteers in the United States and Brazil, first in hookworm-naïve individuals and then in residents of a N. americanus endemic area in Brazil. Volunteers received one of three doses of recombinant Na-GST-1 (10, 30, or 100 μg) adjuvanted with Alhydrogel, adjuvanted with Alhydrogel and co-administered with an aqueous formulation of Glucopyranosyl Lipid A (GLA-AF), or the hepatitis B vaccine. Vaccinations were administered via intramuscular injection on days 0, 56, and 112. Na-GST-1/Alhydrogel was well tolerated in both hookworm-naïve and hookworm-exposed adults, with the most common adverse events being mild to moderate injection site pain and tenderness, and mild headache and nausea; no vaccine-related severe or serious adverse events were observed. Antigen-specific IgG antibodies were induced in a dose-dependent fashion, with increasing levels observed after each vaccination in both trials. The addition of GLA-AF to Na-GST-1/Alhydrogel did not result in significant increases in specific IgG responses. In both the US and Brazil studies, the predominant IgG subclass induced against Na-GST-1 was IgG1, with lesser amounts of IgG3. Vaccination of both hookworm-naïve and hookworm-exposed adults with recombinant Na-GST-1 was safe, well tolerated, and resulted in significant antigen-specific IgG responses. Based on these results, this vaccine will be advanced into clinical trials in children and eventual efficacy studies.

Trial registration

ClinicalTrials.gov ( NCT01261130 for the Brazil trial and NCT01385189 for the US trial)

Author summary

Hookworm infection caused by Necator americanus is a major neglected tropical disease with significant associated morbidity. New tools, such as vaccines, are needed due to the inadequacy of current control strategies. Glutathione-S-Transferase-1 of N. americanus ( Na-GST-1) is one of the lead hookworm vaccine candidates; antibodies induced by this vaccine are postulated to interfere with the digestion of host hemoglobin by adult N. americanus hookworms, thereby impairing their development and survival. We conducted two Phase 1 trials of recombinant Na-GST-1 adjuvanted with Alhydrogel in 142 healthy adults living in the United States and Brazil. Each participant received three vaccinations every 2 months by intramuscular injection of the vaccine administered with or without an aqueous solution of the Toll-like receptor-4 agonist, Glucopyranosyl Lipid A (GLA-AF). Na-GST-1/Alhydrogel was well tolerated in both hookworm-exposed and hookworm-naïve adults; no vaccine-related severe or serious adverse events were observed. Antigen-specific IgG antibodies were induced in a dose-dependent fashion with increasing levels observed after each vaccination. The addition of GLA-AF to the vaccine did not result in significantly higher antibody responses. Based on these results, the vaccine will be advanced into clinical trials in children and eventual efficacy studies.