Abstract
BackgroundHuman hookworms (Necator americanus, Ancylostoma duodenale, and Ancylostoma ceylanicum) are intestinal blood-feeding parasites that infect ~500 million people worldwide and are among the leading causes of iron-deficiency anemia in the developing world. Drugs are useful against hookworm infections, but hookworms rapidly reinfect people, and the parasites can develop drug resistance. Therefore, having a hookworm vaccine would be of tremendous benefit.Methodology/Principal findingsWe investigated the vaccine efficacy in outbred Syrian hamsters of three A. ceylanicum hookworm antigen candidates from two classes of proteins previously identified as promising vaccine candidates. These include two intestinally-enriched, putatively secreted cathepsin B cysteine proteases (AceyCP1, AceyCPL) and one small Kunitz-type protease inhibitor (AceySKPI3). Recombinant proteins were produced in Pichia pastoris, and adsorbed to Alhydrogel. Recombinant AceyCPL (rAceyCPL)/Alhydrogel and rAceySKPI3/Alhydrogel induced high serum immunoglobulin G (IgG) titers in 8/8 vaccinates, but were not protective. rAceyCP1/Alhydrogel induced intermediate serum IgG titers in ~60% of vaccinates in two different trials. rAceyCP1 serum IgG responders had highly significantly decreased hookworm burdens, fecal egg counts and clinical pathology compared to Alhydrogel controls and nonresponders. Protection was highly correlated with rAceyCP1 serum IgG titer. Antisera from rAceyCP1 serum IgG responders, but not nonresponders or rAceyCPL/Alhydrogel vaccinates, significantly reduced adult A. ceylanicum motility in vitro. Furthermore, rAceyCP1 serum IgG responders had canonical Th2-specific recall responses (IL4, IL5, IL13) in splenocytes stimulated ex vivo.Conclusions/SignificanceThese findings indicate that rAceyCP1 is a promising vaccine candidate and validates a genomic/transcriptomic approach to human hookworm vaccine discovery.
Highlights
Human hookworms (Necator americanus, Ancylostoma duodenale, and Ancylostoma ceylanicum) are soil-transmitted nematodes (STNs) that infect the small intestine and feed on blood [1]
We identified a cysteine protease in the intestine of the human hookworm Ancylostoma ceylanicum that is among the most strongly expressed genes during blood feeding and that may help digest blood and be essential for hookworm survival
These antigen-specific antibodies made hookworms less mobile in culture. This cysteine protease is a promising candidate for further investigation as a human hookworm vaccine antigen
Summary
Human hookworms (Necator americanus, Ancylostoma duodenale, and Ancylostoma ceylanicum) are soil-transmitted nematodes (STNs) that infect the small intestine and feed on blood [1]. Among human STNs, hookworms carry the highest disease burden [2]. Infection by hookworms causes significant growth stunting, cognitive deficiencies, malnutrition, iron-deficiency anemia and hypoproteinemia; in adults infection results in adverse birth outcomes (e.g., low birthweight babies) and reduced productivity [3,4,5]. Hookworm disease is estimated to cause 4.1 million disability adjusted life years (DALYs) and US$139 billion in indirect economic losses each year [9]. Human hookworms (Necator americanus, Ancylostoma duodenale, and Ancylostoma ceylanicum) are intestinal blood-feeding parasites that infect ~500 million people worldwide and are among the leading causes of iron-deficiency anemia in the developing world. Having a hookworm vaccine would be of tremendous benefit.
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