This U01 grant proposal will utilize a novel paradigm for the early assessment of vaccine efficacy and the selection of optimal vaccine formulation. We will conduct a Phase 2 clinical trial that enables the evaluation of an investigation hookworm vaccine by challenging human volunteers with a controlled human hookworm infection (CHHI) after vaccination. Hookworm is one of the most important parasitic infections, with over 500 million people infected worldwide, most with Necator americanus. The clinical hallmark of hookworm infection is iron deficiency anemia, resulting from intestinal blood loss directly caused by this parasite. Glutathione-S- Transferase-1 of N. americanus (Na-GST-1) is a component of the blood-feeding pathway of this intestinal helminth and was selected for clinical development based on its protective effect in animal studies. Recombinant Na-GST-1 formulated on Alhydrogel has been shown to be safe when administered to healthy adults in Phase 1 trials in the USA and in hookworm endemic areas of Brazil and Gabon. In the proposed Phase 2 study, healthy hookworm?nave adult volunteers will be vaccinated with Na-GST-1/Alhydrogel followed by challenging them with infective N. americanus larvae to determine the effect of vaccination on hookworm infection by parasitologic, hematologic, and immunologic parameters. Traditionally, proof-of-concept studies for investigational vaccines are conducted later in clinical development and usually in large field trials in pathogen endemic areas. These studies can take considerable time and involve large numbers of participants, depending on the incidence of the infection. The objective of this U01 proposal is to conduct a Phase 2 clinical trial in which proof-of-concept for this new vaccine for hookworm is tested early in clinical development and on a small number of volunteers. In addition, we will utilize state-of- the-art immunological technologies to comprehensively evaluate the humoral and cellular immune response to vaccination and how that translates into protection in the CHHI model. Hence, the proposed clinical trial will also serve to optimize the component combinations of the final vaccine formulation, especially the addition of novel Toll-Like Receptor immunostimulants such as GLA-AF and CpG. The results of this trial will permit critical decisions to be made on the further development of the Na-GST-1 hookworm vaccine and its final formulation, prior to conducting larger, more costly Phase 2 and 3 trials in hookworm endemic areas.
We will implement a Phase 2 clinical trial in healthy, hookworm-naive adults to evaluate proof-of-efficacy of different adjuvant formulations of the experimental hookworm vaccines, Na-GST-1/Alhydrogel. We will utilize an innovative controlled human infection model to challenge vaccinated volunteers with Necator americanus hookworm larvae to assess whether vaccination with these candidate antigen formulations has a significant impact on infection with this parasite. This will enable earlier decision-making on advancing candidate vaccines into later-stage clinical trials, particularly before large field efficacy studies in children, thereby saving time, expense, and exposure of human research subjects ? especially children ? to potential risk.
