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Background Hookworms cause substantial morbidity in children and women of reproductive age. The control strategy of mass drug administration is suboptimal, hence the need for a vaccine. Necator americanus aspartic protease-1 (Na-APR-1) and N americanus glutathione S-transferase-1 (Na-GST-1) are involved in the digestion and detoxification of haemoglobin in the hookworm digestive tract. In animal models, vaccination against these antigens resulted in protection from challenge infection. Both vaccine candidates were shown to be safe and well tolerated when administered separately to healthy adults. We assessed the safety and immunogenicity of co-administered Na-GST-1 and Na-APR-1 (M74) vaccines in healthy Gabonese adults.Methods This randomised, controlled, double-blind, phase 1, dose-escalation trial was done at the Centre de Recherches Medicales de Lambarene, in a region of Gabon where N americanus and other helminths are prevalent. Healthy adults aged 18-50 years and living in Lambarene or the surrounding areas were recruited to the study. Participants were enrolled consecutively into two dose cohorts (30 mu g or 100 mu g of the experimental vaccines) and randomly assigned in blocks (block size four) to receive three doses of either co-administered Na-GST-1 plus Na-APR-1 (M74; 30 mu g or 100 mu g of each), adjuvanted with Alhydrogel (aluminium hydroxide gel suspension) together with an aqueous formulation of glucopyranosyl lipid A, or hepatitis B vaccine plus saline (control group). Vaccines were administered intramuscularly on days 0, 28, and 180. The primary endpoint was safety, with immunogenicity a secondary endpoint. The intention-to-treat population was used for safety analyses, whereas for immunogenicity analyses, the per-protocol population was used (participants who received all scheduled vaccinations). Control vaccine recipients for both dose cohorts were combined for the analyses. The trial is registered with ClinicalTrials.gov, NCT02126462.Findings Between Oct 27, 2014, and Jan 31, 2015, 56 individuals were screened for eligibility, of whom 32 were enrolled and randomly assigned to one of the three study groups (12 each in the 30 mu g and 100 mu g experimental vaccine groups and eight in the control group). Both study vaccines were well tolerated in both dose groups. The most common adverse events were mild-to-moderate injection-site pain, headache, myalgia, and nausea. No severe or serious adverse events related to the vaccines were recorded. 52 unsolicited vaccine-related adverse events occurred during the study, but there was no difference in frequency between vaccine groups. IgG antibodies were induced to each of the vaccine antigens, with mean IgG levels increasing after each vaccination. Vaccination with 100 mu g of each vaccine antigen consistently induced IgG seroconversion (IgG levels above the reactivity threshold). Peak IgG responses were observed 2 weeks after the third vaccine dose for both antigens, with all participants who received the 100 mu g doses seroconverting at that timepoint. IgG levels steadily declined until the final study visit 6 months after the third vaccination, although they remained significantly higher than baseline in the 100 mu g dose group.Interpretation Vaccination with recombinant Na-GST-1 and Na-APR-1 (M74) in healthy adults living in N americanusendemic areas of Gabon was safe and induced IgG to each antigen. To our knowledge, this study is the first to report results of Na-APR-1 (M74) co-administered with Alhydrogel in participants from an N americanus-endemic area. Further clinical development of these vaccines should involve efficacy studies. Funding European Union Seventh Framework Programme. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

Background Hookworm disease is one of the most prevalent of the neglected tropical diseases. To date, the control of hookworm infection has been limited to mass-administration of anthelminthic drugs. Despite this, the global hookworm prevalence does not decrease, thus there is a need for a vaccine. We evaluated the Na-GST-1 and Na-APR-1 hookworm vaccine candidates simultaneously in a hookworm endemic Gabonese population. Methods Eligible healthy Gabonese adults aged 18–50 years were enrolled in a randomised, double blind, controlled phase I trial. The first cohort received 30 µg Na-GST-1 co-administered with 30 µg Na-APR-1. The second cohort received 100 µg Na-GST-1 and 100 µg Na-APR-1. All doses were administered after mixing with 5 µg of an aqueous formulation of glucopyranosyl Lipid A (GLA-AF), a Toll-like Receptor-4 agonist. Hepatitis B vaccination (HBV) was administered as a comparator. Study subjects were vaccinated on days 0, 28 and 180 by intramuscular injection. IgG antibody levels were measured by qualified ELISA. This study evaluated the safety, reactogenicity, and immunogenicity of Na- GST-1/Alhydrogel® co-administered with Na-APR-1/Alhydrogel®. Results Thirty-two study participants were enrolled. No serious adverse events or significant changes in haematological, renal or liver function parameters were observed. Mild-to-moderate injection-site pain, headache and fever were common adverse events. Elevated Na-GST-1 and Na-APR-1 IgG antibody levels were detected on day 194. Significant differences in mean antibody levels were observed between dose groups for Na-APR-1 [30 µg: 18 (50–86.9) vs 100 µg: 197 (131– 264); p vs 100 µg: 402.54 (283.65–521); p=0.5]. Conclusions Co-administration of the hookworm vaccine candidates (Na-GST-1 and Na-APR-1) was safe and well tolerated. In order to achieve optimal antibody levels, a series of three high doses needs to be administered. Additional investigations are necessary to consider this combination as a potential bivalent vaccine candidate.