Hookworm vaccines: past, present, and future

Loukas, Alex; Bethony, Jeffrey M.; Brooker, Simon; Hotez, Peter J.

doi:10.1016/s1473-3099(06)70630-2

Cited by 126 publications

(109 citation statements)

References 70 publications

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“…Recently, recombinant Na-GST-3 has been found to induce the synthesis of prostaglandin, an important mediator of inflammation, indicating its potential role in immunomodulation (P. M. Brophy, unpublished data). An important vaccine strategy for the Human Hookworm Vaccine Initiative (HHVI), an international product development partnership with a mission to produce and test recombinant vaccines, relies on targeting adult parasite blood feeding (22,38). Because of the putative role of Na-GSTs in heme detoxification, the ability of these molecules to function as potential drug or vaccine targets was studied.…”

Section: Discussionmentioning

confidence: 99%

Molecular Cloning, Biochemical Characterization, and Partial Protective Immunity of the Heme-Binding GlutathioneS-Transferases from the Human HookwormNecator americanus

et al. 2010

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Hookworm glutathione S-transferases (GSTs) are critical for parasite blood feeding and survival and represent potential targets for vaccination. Three cDNAs, each encoding a full-length GST protein from the human hookworm Necator americanus (and designated Na-GST-1, Na-GST-2, and Na-GST-3, respectively) were isolated from cDNA based on their sequence similarity to Ac-GST-1, a GST from the dog hookworm Ancylostoma caninum. The open reading frames of the three N. americanus GSTs each contain 206 amino acids with 51% to 69% sequence identity between each other and Ac-GST-1. Sequence alignment with GSTs from other organisms shows that the three Na-GSTs belong to a nematode-specific nu-class GST family. All three Na-GSTs, when expressed in Pichia pastoris, exhibited low lipid peroxidase and glutathione-conjugating enzymatic activities but high heme-binding capacities, and they may be involved in the detoxification and/or transport of heme. In two separate vaccine trials, recombinant Na-GST-1 formulated with Alhydrogel elicited 32 and 39% reductions in adult hookworm burdens (P < 0.05) following N. americanus larval challenge relative to the results for a group immunized with Alhydrogel alone. In contrast, no protection was observed in vaccine trials with Na-GST-2 or Na-GST-3. On the basis of these and other preclinical data, Na-GST-1 is under possible consideration for further vaccine development.

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Section: Discussionmentioning

confidence: 99%

Molecular Cloning, Biochemical Characterization, and Partial Protective Immunity of the Heme-Binding GlutathioneS-Transferases from the Human HookwormNecator americanus

et al. 2010

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“…For hookworm, the high rate of drug failure for single-dose mebendazole as well as rapid reinfection and the possible emergence of drug-resistant parasites have stimulated efforts by the Human Hookworm Vaccine Initiative to develop a bivalent vaccine comprised of recombinant hookworm vaccine antigens that target the infective larval stages and adult blood-feeding stages (146,169,170). Currently, one larval antigen is being evaluated in a phase 1 clinical trial in a region of Brazil that is endemic for hookworm and a second adult hookworm antigen is about to enter into clinical trials (170).…”

Section: Global Control Of Helminthiases and Clinical Research Imperamentioning

confidence: 99%

Helminth infections: the great neglected tropical diseases

et al. 2008

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Helminths are parasitic worms. They are the most common infectious agents of humans in developing countries and produce a global burden of disease that exceeds better-known conditions, including malaria and tuberculosis. As we discuss here, new insights into fundamental helminth biology are accumulating through newly completed genome projects and the nascent application of transgenesis and RNA interference technologies. At the same time, our understanding of the dynamics of the transmission of helminths and the mechanisms of the Th2-type immune responses that are induced by infection with these parasitic worms has increased markedly. Ultimately, these advances in molecular and medical helminth biology should one day translate into a new and robust pipeline of drugs, diagnostics, and vaccines for targeting parasitic worms that infect humans.

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“…This approach yielded a snapshot of the intestome of these hookworms and identified a suite of molecules with proven or potential roles in digestion of the blood meal, including aspartic (Loukas et al, 2005;Williamson et al, 2002) and cysteine proteases , putative hemolysins (Don et al, 2004), and peptide transporters (Hotez et al, 2010). Proteins involved in the digestion of the blood meal are a major target for vaccine development within the Human Hookworm Vaccine Initiative (Hotez et al, 2010;Loukas et al, 2006;Pearson et al, 2010), and we are currently focusing on candidate molecules that have been identified using a range of ''omics'' approaches.…”

Section: Hookwormsmentioning

confidence: 99%

“…Targeting the hookworm gut for vaccine development has shown to be a worthwhile pursuit (Hotez et al, 2010;Loukas et al, 2006). Other blood-feeding parasites, including the barber's pole worm of livestock (Haemonchus contortus) and the cattle tick (Rhipicephalus microplus), are effectively killed by vaccine-induced antibodies against native proteins and protein complexes derived from the guts of these parasites (Smith et al, 1994).…”

Section: Hookworm Intestomementioning

confidence: 99%

Vaccinomics for the Major Blood Feeding Helminths of Humans

Loukas

Gaze

Mulvenna

et al. 2011

OMICS: A Journal of Integrative Biology

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Approximately one billion people are infected with hookworms and/or blood flukes (schistosomes) in developing countries. These two parasites are responsible for more disability adjusted life years lost than most other neglected tropical diseases (NTDs), and together, are second only to malaria. Although anthelmintic drugs are effective and widely available, they do not protect against reinfection, resistant parasites are likely to emerge, and mass drug administration programs are unsustainable. Therefore, there is a pressing need for the development of vaccines against these parasites. In recent years, there have been major advances in our understanding of hookworms and schistosomes at the molecular level through the use of ''omics'' technologies. The secretomes of these parasites have been characterized using transcriptomics, genomics, proteomics, and newly developed gene manipulation and silencing techniques, and the proteins of interest are now the target of novel antigen discovery approaches, notably immunomics. This research has resulted in the discovery, development, and early stage clinical trials of subunit vaccines against hookworms and schistosomes.

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Hookworm vaccines: past, present, and future

Cited by 126 publications

References 70 publications

Molecular Cloning, Biochemical Characterization, and Partial Protective Immunity of the Heme-Binding GlutathioneS-Transferases from the Human HookwormNecator americanus

Molecular Cloning, Biochemical Characterization, and Partial Protective Immunity of the Heme-Binding GlutathioneS-Transferases from the Human HookwormNecator americanus

Helminth infections: the great neglected tropical diseases

Vaccinomics for the Major Blood Feeding Helminths of Humans

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