Human hookworms are parasitic nematodes infecting about 700 million individuals, largely in tropical regions of the world [1]. In endemic areas, most infected people carry a mixed worm burden, including Ascaris lumbricoides (roundworms), Trichuris trichuria (whipworms), and Ancylostoma duodenale and/or Necator americanus (both hookworms). Of these soil-transmitted helminths, hookworms are the most pathogenic because of their propensity to feed on blood, resulting in anaemia, particularly in those with low iron reserves such as children and women of reproductive age

Bethony

de Silva

Eileen Devaney

Hotez

Jarrett

Knox

Loukas

Miller

Summers

Williamson

English

PubMed

Devaney Eileen

Public Library of Science (PLOS)

The End of the Line for Hookworm? An Update on Vaccine Development

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The end of the line for hookworm? An update on vaccine development.

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Devaney, E.

Enlighten: Publications

 
 
 
 
 
 
 
Devaney, E. (2005) The end of the line for hookworm? An update on 
vaccine development. PLoS Medicine, 2 (10). e327. ISSN 1549-1277 
 
 
 
 
 
 
http://eprints.gla.ac.uk/27513/ 
 
 
 
 
Deposited on: 5 January 2012 
 
 
Enlighten – Research publications by members of the University of Glasgow 
http://eprints.gla.ac.uk 
PLoS Medicine  |  www.plosmedicine.org 0948
Perspectives
Open access, freely available online
October 2005  |  Volume 2  |  Issue 10  |  e327
Human hookworms are parasitic nematodes infecting about 700 million individuals, 
largely in tropical regions of the 
world [1]. In endemic areas, most 
infected people carry a mixed worm 
burden, including Ascaris lumbricoides 
(roundworms), Trichuris trichuria 
(whipworms), and Ancylostoma 
duodenale and/or Necator americanus 
(both hookworms). Of these soil-
transmitted helminths, hookworms are 
the most pathogenic because of their 
propensity to feed on blood, resulting 
in anaemia, particularly in those with 
low iron reserves such as children and 
women of reproductive age. 
The Pathogenesis of Hookworm 
Infection
Hookworms’ blood-feeding 
(hematophagous) habits cause 
pathology in humans and animals. 
The worms attach to the wall of the 
small intestine using their mouthparts 
and feed on blood from ruptured 
capillaries. Each female worm is 
estimated to ingest a minimal 0.1 ml 
of blood per day. However, actual 
blood loss can be signifi cantly greater; 
the worms change their feeding sites 
several times a day, and the secretion of 
anti-coagulants means that the vacated 
sites continue to bleed, contributing 
greatly to blood loss.
Hookworms do not kill, but they can 
cause subclinical disease, most notably 
anaemia and impaired physical and 
cognitive development in children. 
As hookworm infection is associated 
with low socioeconomic status, it adds 
signifi cantly to the burden of disease in 
such areas [1].
Natural Infection Elicits Poor 
Immunity 
Hookworms have a simple life cycle in 
which the third-stage larvae (L3) infect 
humans, generally by skin penetration, 
although some species are also infective 
via oral ingestion. The parasites enter 
the bloodstream and migrate to the 
lungs; from there, they are coughed 
and swallowed to the small intestine 
(Figure 1). The adult parasites mature 
in the intestine, and following mating, 
the female worm produces many 
thousands of eggs that pass out in the 
faeces and develop on the ground to 
infective L3.
Hookworms can be treated 
using anthelmintic drugs such as 
albendazole, but treated people soon 
become reinfected. Additionally, recent 
epidemiological studies from China 
and Brazil show the highest worm 
burden and the highest prevalence of 
infection in the elderly [2], contrasting 
with the intensity/prevalence curves for 
other soil-transmitted helminths, which 
typically peak in mid-to-late childhood. 
These data suggest that under natural 
conditions of exposure, little immunity 
is evoked. Given this immuno-
epidemiological picture, developing a 
vaccine is a signifi cant challenge. 
The Search for a Vaccine
Recent studies suggest that the 
hematophagous lifestyle of hookworms 
may prove their downfall. Hookworms 
are armed with an array of molecules 
that are essential for blood feeding and 
digestion; these include anticoagulants 
and a variety of proteases that digest 
haemoglobin (Hb) and other serum 
proteins. In a new article in PLoS 
Medicine, Loukas et al. [3] now 
describe a vaccination schedule 
using one such protease—an aspartic 
haemoglobinase—from the hookworm 
Ancylostoma caninum (Ac-APR-1). In 
their study, the schedule protected 
against blood loss in an animal model 
of hookworm infection.
As with other parasitic nematodes, 
hookworms are complex multicellular 
organisms that have evolved an array 
of mechanisms for suppressing or 
avoiding host immune responses. The 
only commercially available vaccine 
against a parasitic nematode is Huskvac 
(an oral lungworm vaccine for calves), 
a preparation of radiation-attenuated 
L3 of Dictyocaulus viviparus, which 
protects against parasitic bronchitis 
[4]. In the 1960s, a similar approach 
was adopted to controlling hookworm 
infection in dogs using irradiated L3 
of A. caninum [5]. While this vaccine 
was effi cacious, it was a commercial 
failure. However, these older vaccines 
established the principle that protective 
immunity can be elicited. The 
challenge now is to identify protective 
antigens and present them to the 
immune system in an appropriate 
manner. 
Proteases as Potential Vaccine 
Candidates 
Hookworms express a range of 
proteases, including cysteine, aspartic, 
and metallo-proteases, several of which 
have been characterised in detail. 
These enzymes are localised to the 
brush border of the worm intestine and 
have been shown to function in a multi-
enzyme cascade to digest Hb and other 
serum proteins [6]. Some of these 
molecules show an exquisite specifi city; 
for example, Na-APR-2, an aspartic 
protease from N. americanus, cleaves Hb 
from the permissive host (human) with 
The Perspectives section is for experts to discuss the 
clinical practice or public health implications of a 
published article that is freely available online.
The End of the Line for Hookworm? 
An Update on Vaccine Development
Eileen Devaney
Citation: Devaney E (2005) The end of the line for 
hookworm? An update on vaccine development. 
PLoS Med 2(10): e327.
Copyright: © 2005 Eileen Devaney. This is an open-
access article distributed under the terms of the 
Creative Commons Attribution License, which permits 
unrestricted use, distribution, and reproduction in any 
medium, provided the original work is properly cited.
Abbreviations: Hb, haemoglobin; L3, third-stage larvae
Eileen Devaney is Professor of Parasite 
Immunobiology, Parasitology Group, Institute 
of Comparative Medicine, Faculty of Veterinary 
Medicine, University of Glasgow, Glasgow, United 
Kingdom. E-mail: e.devaney@vet.gla.ac.uk
Competing Interests: The author is on the Board 
of Directors of the Moredun Research Institute 
(http://www.moredun.org.uk), a grant-aided public 
body. A group at the institute is working on vaccine 
development against nematodes of livestock.
DOI: 10.1371/journal.pmed.0020327
PLoS Medicine  |  www.plosmedicine.org 0949
twice the effi ciency of Hb from a non-
permissive host (dog) [7]. 
These gut-associated molecules of the 
parasite have been the focus of recent 
interest as potential vaccine candidates. 
The rationale behind this approach 
is that the induction of antibodies to 
molecules that function in parasite 
feeding will neutralise their activity 
and effectively “starve” the worm. A 
similar approach has previously been 
trialled against nematode parasites of 
livestock such as Haemonchus contortus 
[8], and some important lessons 
have been learned. One of these is 
the requirement for expression of 
recombinant molecules in a eukaryotic 
system [9]. In general, bacterial-
expressed antigens do not stimulate 
protection, presumably because they 
are improperly folded and/or modifi ed 
and catalytically inactive. 
Under the auspices of the Human 
Hookworm Vaccine Initiative and the 
Sabin Vaccine Institute (http:⁄⁄www.
sabin.org/hookworm.htm), which 
supported Loukas and colleagues’ 
study [3], the drive to develop 
a hookworm vaccine has gained 
signifi cant momentum. A number of 
candidate antigens have been tested in 
the A. caninum dog model with varying 
degrees of success. Ideally, vaccination 
would protect against infection with 
L3. The same team of researchers have 
previously identifi ed one such secreted 
molecule of the L3 of N. americanus, Na-
ASP-2 (for abundant secreted protein-
2), and have shown it to partially 
protect dogs against infection [10]. 
Phase 1 safety trials are now underway 
with this antigen. 
Other candidate molecules are the 
cysteine and aspartic haemoglobinases 
from the adult worm. In another study 
by Loukas and colleagues, vaccination 
with a catalytically active cathepsin-
B-like protease from A. caninum (Ac-
CP-2) produced in the yeast Pischia 
pastoris resulted in worms that were 
stunted and produced fewer eggs 
but did not produce a reduction in 
number of worms or protect against 
anaemia [11]. The current study 
from the same group tested an active 
aspartic haemoglobinase (Ac-APR-
1) in the same model [3]. A modest 
reduction in worm burden was 
observed in immunised animals, but a 
highly signifi cant reduction in worm 
fecundity was observed (up to 85% 
reduction in mean egg output between 
vaccinated and adjuvant-only controls), 
emphasising the nutritional demand 
of the parasite for egg laying and 
presumably refl ecting an accumulation 
of neutralising antibodies. Most 
importantly, four of fi ve vaccinated 
animals showed a reduction in Hb 
loss. Thus Ac-APR-1 could represent 
a pathology-limiting component of 
a future multivalent vaccine [3]. In 
addition, by restricting worm fecundity 
it would, in essence, also act as a 
“transmission blocking” vaccine.
The Challenges Ahead
Despite these achievements, signifi cant 
challenges remain, such as the 
selection of appropriate adjuvants 
for use in humans, the production 
of the vaccine at low cost and high 
yield, its distribution in the tropics, 
and the possible requirement to de-
worm individuals prior to vaccination. 
However, the Human Hookworm 
Vaccine Initiative is progressing 
on many of these fronts and is an 
excellent example of what can be 
achieved with proper funding and 
good collaborations. It has the 
potential to become a 21st-century 
paradigm for a control programme 
aimed at a neglected tropical disease 
and should also provide renewed 
impetus to control programmes aimed 
at vaccine development against other 
hematophagous helminths of humans 
and domestic animals. 
Finally, it is somewhat ironic to 
note that as attempts are made to 
eradicate worm infection in tropical 
regions of the world, worms are being 
used in the developed countries to 
regulate pathogenic proinfl ammatory 
immune responses. For example, 
patients with ulcerative colitis have 
shown an encouraging amelioration of 
pathology following infection with the 
pig whipworm Trichuris suis [12]. These 
studies demonstrate the capacity of 
helminth parasites to induce regulatory 
DOI: 10.1371/journal.pmed.0020327.g001
Figure 1. Life Cycle of the Human Hookworm N. americanus
(Illustration: Sapna Khandwala, reproduced from [13]) 
October 2005  |  Volume 2  |  Issue 10  |  e327
PLoS Medicine  |  www.plosmedicine.org 0950
immune networks in their hosts, 
and they emphasise the scale of the 
challenge facing the development of 
vaccines against worms. 
References
1. de Silva NR, Brooker S, Hotez PJ, Montresor 
A, Engels D, et al. (2003) Soil-transmitted 
helminth infections: Updating the global 
picture. Trends Parasitol 19: 547–551.
2. Bethony J, Chen J, Lin S, Xiao S, Zhan B, et 
al. (2002) Emerging patterns of hookworm 
infection: Infl uence of aging on the intensity 
of Necator infection in Hainan province, 
People’s Republic of China. Clin Infect Dis 35: 
1336–1344.
3. Loukas A, Bethony JM, Mendez S, Fujiwara 
RT, Goud GN, et al. (2005) Vaccination with 
recombinant aspartic hamoglobinase reduces 
parasite load and blood loss after hookworm 
infection. PLoS Med 2: e295. DOI: 10.1371/
journal.pmed.0020295
4. Jarrett WFH, Jennings FW, McIntyre WIM, 
Mulligan W, Sharp NCC (1961) A pasture trial 
using two immunising doeses of a parasitic 
bronchitis vaccine. Am J Vet Res 22: 492–494.
5. Miller TA (1978) Industrial development and 
fi eld use of the canine hookworm vaccine. Adv 
Parasitol 16: 333–332.
6. Williamson AL, Lecchi P, Turk BE, Choe Y, 
Hotez PJ, et al. (2004) A multi-enzyme cascade 
of hemoglobin proteolysis in the intestine of 
blood-feeding hookworms. J Biol Chem 279: 
35950–35957.
7. Williamson AL, Brindley PJ, Abbenante G, 
Prociv P, Berry C, et al. (2002) Cleavage of 
hemoglobin by hookworm cathepsin D aspartic 
proteases and its potential contribution to host 
specifi city. FASEB J 16: 1458–1460. 
8. Knox DP, Smith WD (2001) Vaccination 
against gastro-intestinal nematode parasites of 
ruminants using gut-expressed antigens. Vet 
Parasitol 100: 21–32.
9. Hotez PJ, Zhan B, Bethony JM, Loukas A, 
Williamson A, et al. (2003) Progress in the 
development of a recombinant vaccine for 
human hookworm disease: The Human 
Hookworm Vaccine Initiative. Int J Parasitol 33: 
1245–1258.
10. Bethony J, Loukas A, Smout M, Brooker S, 
Mendez S, et al. (2005) Antibodies against a 
secreted protein from hookworm larvae reduce 
the intensity of hookworm infection in humans 
and vaccinated laboratory animals. FASEB J. E-
pub ahead of print.
11. Loukas A, Bethony JM, Williamson AL, Goud 
GN, Mendez S, et al. (2004) Vaccination of 
dogs with a recombinant cysteine protease 
from the intestine of canine hookworms 
diminishes the fecundity and growth of worms. 
J Infect Dis 189: 1952–1961.
12. Summers RW, Elliott DE, Urban JF Jr, 
Thompson RA, Weinstock JV (2005) Trichuris 
suis therapy for active ulcerative colitis: A 
randomized controlled trial. Gastroenterology 
128: 825–832. 
13. Hotez PJ, Bethony J, Bottazzi ME, Brooker S, 
Buss P (2005) Hookworm: “The great infection 
of mankind.” PLoS Med 2: e67. DOI: 10.1371/
journal.pmed.0020067
October 2005  |  Volume 2  |  Issue 10  |  e327


The end of the line for hookworm? An update on vaccine development

Enlighten

       Devaney, E. (2005) The end of the line for hookworm? An update on vaccine development. PLoS Medicine, 2 (10). e327. ISSN 1549-1277       http://eprints.gla.ac.uk/27513/     Deposited on: 5 January 2012   Enlighten – Research publications by members of the University of Glasgow http://eprints.gla.ac.uk PLoS Medicine  |  www.plosmedicine.org 0948PerspectivesOpen access, freely available onlineOctober 2005  |  Volume 2  |  Issue 10  |  e327Human hookworms are parasitic nematodes infecting about 700 million individuals, largely in tropical regions of the world [1]. In endemic areas, most infected people carry a mixed worm burden, including Ascaris lumbricoides (roundworms), Trichuris trichuria (whipworms), and Ancylostoma duodenale and/or Necator americanus (both hookworms). Of these soil-transmitted helminths, hookworms are the most pathogenic because of their propensity to feed on blood, resulting in anaemia, particularly in those with low iron reserves such as children and women of reproductive age. The Pathogenesis of Hookworm InfectionHookworms’ blood-feeding (hematophagous) habits cause pathology in humans and animals. The worms attach to the wall of the small intestine using their mouthparts and feed on blood from ruptured capillaries. Each female worm is estimated to ingest a minimal 0.1 ml of blood per day. However, actual blood loss can be signiﬁ cantly greater; the worms change their feeding sites several times a day, and the secretion of anti-coagulants means that the vacated sites continue to bleed, contributing greatly to blood loss.Hookworms do not kill, but they can cause subclinical disease, most notably anaemia and impaired physical and cognitive development in children. As hookworm infection is associated with low socioeconomic status, it adds signiﬁ cantly to the burden of disease in such areas [1].Natural Infection Elicits Poor Immunity Hookworms have a simple life cycle in which the third-stage larvae (L3) infect humans, generally by skin penetration, although some species are also infective via oral ingestion. The parasites enter the bloodstream and migrate to the lungs; from there, they are coughed and swallowed to the small intestine (Figure 1). The adult parasites mature in the intestine, and following mating, the female worm produces many thousands of eggs that pass out in the faeces and develop on the ground to infective L3.Hookworms can be treated using anthelmintic drugs such as albendazole, but treated people soon become reinfected. Additionally, recent epidemiological studies from China and Brazil show the highest worm burden and the highest prevalence of infection in the elderly [2], contrasting with the intensity/prevalence curves for other soil-transmitted helminths, which typically peak in mid-to-late childhood. These data suggest that under natural conditions of exposure, little immunity is evoked. Given this immuno-epidemiological picture, developing a vaccine is a signiﬁ cant challenge. The Search for a VaccineRecent studies suggest that the hematophagous lifestyle of hookworms may prove their downfall. Hookworms are armed with an array of molecules that are essential for blood feeding and digestion; these include anticoagulants and a variety of proteases that digest haemoglobin (Hb) and other serum proteins. In a new article in PLoS Medicine, Loukas et al. [3] now describe a vaccination schedule using one such protease—an aspartic haemoglobinase—from the hookworm Ancylostoma caninum (Ac-APR-1). In their study, the schedule protected against blood loss in an animal model of hookworm infection.As with other parasitic nematodes, hookworms are complex multicellular organisms that have evolved an array of mechanisms for suppressing or avoiding host immune responses. The only commercially available vaccine against a parasitic nematode is Huskvac (an oral lungworm vaccine for calves), a preparation of radiation-attenuated L3 of Dictyocaulus viviparus, which protects against parasitic bronchitis [4]. In the 1960s, a similar approach was adopted to controlling hookworm infection in dogs using irradiated L3 of A. caninum [5]. While this vaccine was efﬁ cacious, it was a commercial failure. However, these older vaccines established the principle that protective immunity can be elicited. The challenge now is to identify protective antigens and present them to the immune system in an appropriate manner. Proteases as Potential Vaccine Candidates Hookworms express a range of proteases, including cysteine, aspartic, and metallo-proteases, several of which have been characterised in detail. These enzymes are localised to the brush border of the worm intestine and have been shown to function in a multi-enzyme cascade to digest Hb and other serum proteins [6]. Some of these molecules show an exquisite speciﬁ city; for example, Na-APR-2, an aspartic protease from N. americanus, cleaves Hb from the permissive host (human) with The Perspectives section is for experts to discuss the clinical practice or public health implications of a published article that is freely available online.The End of the Line for Hookworm? An Update on Vaccine DevelopmentEileen DevaneyCitation: Devaney E (2005) The end of the line for hookworm? An update on vaccine development. PLoS Med 2(10): e327.Copyright: © 2005 Eileen Devaney. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Abbreviations: Hb, haemoglobin; L3, third-stage larvaeEileen Devaney is Professor of Parasite Immunobiology, Parasitology Group, Institute of Comparative Medicine, Faculty of Veterinary Medicine, University of Glasgow, Glasgow, United Kingdom. E-mail: e.devaney@vet.gla.ac.ukCompeting Interests: The author is on the Board of Directors of the Moredun Research Institute (http://www.moredun.org.uk), a grant-aided public body. A group at the institute is working on vaccine development against nematodes of livestock.DOI: 10.1371/journal.pmed.0020327PLoS Medicine  |  www.plosmedicine.org 0949twice the efﬁ ciency of Hb from a non-permissive host (dog) [7]. These gut-associated molecules of the parasite have been the focus of recent interest as potential vaccine candidates. The rationale behind this approach is that the induction of antibodies to molecules that function in parasite feeding will neutralise their activity and effectively “starve” the worm. A similar approach has previously been trialled against nematode parasites of livestock such as Haemonchus contortus [8], and some important lessons have been learned. One of these is the requirement for expression of recombinant molecules in a eukaryotic system [9]. In general, bacterial-expressed antigens do not stimulate protection, presumably because they are improperly folded and/or modiﬁ ed and catalytically inactive. Under the auspices of the Human Hookworm Vaccine Initiative and the Sabin Vaccine Institute (http:⁄⁄www.sabin.org/hookworm.htm), which supported Loukas and colleagues’ study [3], the drive to develop a hookworm vaccine has gained signiﬁ cant momentum. A number of candidate antigens have been tested in the A. caninum dog model with varying degrees of success. Ideally, vaccination would protect against infection with L3. The same team of researchers have previously identiﬁ ed one such secreted molecule of the L3 of N. americanus, Na-ASP-2 (for abundant secreted protein-2), and have shown it to partially protect dogs against infection [10]. Phase 1 safety trials are now underway with this antigen. Other candidate molecules are the cysteine and aspartic haemoglobinases from the adult worm. In another study by Loukas and colleagues, vaccination with a catalytically active cathepsin-B-like protease from A. caninum (Ac-CP-2) produced in the yeast Pischia pastoris resulted in worms that were stunted and produced fewer eggs but did not produce a reduction in number of worms or protect against anaemia [11]. The current study from the same group tested an active aspartic haemoglobinase (Ac-APR-1) in the same model [3]. A modest reduction in worm burden was observed in immunised animals, but a highly signiﬁ cant reduction in worm fecundity was observed (up to 85% reduction in mean egg output between vaccinated and adjuvant-only controls), emphasising the nutritional demand of the parasite for egg laying and presumably reﬂ ecting an accumulation of neutralising antibodies. Most importantly, four of ﬁ ve vaccinated animals showed a reduction in Hb loss. Thus Ac-APR-1 could represent a pathology-limiting component of a future multivalent vaccine [3]. In addition, by restricting worm fecundity it would, in essence, also act as a “transmission blocking” vaccine.The Challenges AheadDespite these achievements, signiﬁ cant challenges remain, such as the selection of appropriate adjuvants for use in humans, the production of the vaccine at low cost and high yield, its distribution in the tropics, and the possible requirement to de-worm individuals prior to vaccination. However, the Human Hookworm Vaccine Initiative is progressing on many of these fronts and is an excellent example of what can be achieved with proper funding and good collaborations. It has the potential to become a 21st-century paradigm for a control programme aimed at a neglected tropical disease and should also provide renewed impetus to control programmes aimed at vaccine development against other hematophagous helminths of humans and domestic animals. Finally, it is somewhat ironic to note that as attempts are made to eradicate worm infection in tropical regions of the world, worms are being used in the developed countries to regulate pathogenic proinﬂ ammatory immune responses. For example, patients with ulcerative colitis have shown an encouraging amelioration of pathology following infection with the pig whipworm Trichuris suis [12]. These studies demonstrate the capacity of helminth parasites to induce regulatory DOI: 10.1371/journal.pmed.0020327.g001Figure 1. Life Cycle of the Human Hookworm N. americanus(Illustration: Sapna Khandwala, reproduced from [13]) October 2005  |  Volume 2  |  Issue 10  |  e327PLoS Medicine  |  www.plosmedicine.org 0950immune networks in their hosts, and they emphasise the scale of the challenge facing the development of vaccines against worms. References1. de Silva NR, Brooker S, Hotez PJ, Montresor A, Engels D, et al. (2003) Soil-transmitted helminth infections: Updating the global picture. Trends Parasitol 19: 547–551.2. Bethony J, Chen J, Lin S, Xiao S, Zhan B, et al. (2002) Emerging patterns of hookworm infection: Inﬂ uence of aging on the intensity of Necator infection in Hainan province, People’s Republic of China. Clin Infect Dis 35: 1336–1344.3. Loukas A, Bethony JM, Mendez S, Fujiwara RT, Goud GN, et al. (2005) Vaccination with recombinant aspartic hamoglobinase reduces parasite load and blood loss after hookworm infection. PLoS Med 2: e295. DOI: 10.1371/journal.pmed.00202954. Jarrett WFH, Jennings FW, McIntyre WIM, Mulligan W, Sharp NCC (1961) A pasture trial using two immunising doeses of a parasitic bronchitis vaccine. Am J Vet Res 22: 492–494.5. Miller TA (1978) Industrial development and ﬁ eld use of the canine hookworm vaccine. Adv Parasitol 16: 333–332.6. Williamson AL, Lecchi P, Turk BE, Choe Y, Hotez PJ, et al. (2004) A multi-enzyme cascade of hemoglobin proteolysis in the intestine of blood-feeding hookworms. J Biol Chem 279: 35950–35957.7. Williamson AL, Brindley PJ, Abbenante G, Prociv P, Berry C, et al. (2002) Cleavage of hemoglobin by hookworm cathepsin D aspartic proteases and its potential contribution to host speciﬁ city. FASEB J 16: 1458–1460. 8. Knox DP, Smith WD (2001) Vaccination against gastro-intestinal nematode parasites of ruminants using gut-expressed antigens. Vet Parasitol 100: 21–32.9. Hotez PJ, Zhan B, Bethony JM, Loukas A, Williamson A, et al. (2003) Progress in the development of a recombinant vaccine for human hookworm disease: The Human Hookworm Vaccine Initiative. Int J Parasitol 33: 1245–1258.10. Bethony J, Loukas A, Smout M, Brooker S, Mendez S, et al. (2005) Antibodies against a secreted protein from hookworm larvae reduce the intensity of hookworm infection in humans and vaccinated laboratory animals. FASEB J. E-pub ahead of print.11. Loukas A, Bethony JM, Williamson AL, Goud GN, Mendez S, et al. (2004) Vaccination of dogs with a recombinant cysteine protease from the intestine of canine hookworms diminishes the fecundity and growth of worms. J Infect Dis 189: 1952–1961.12. Summers RW, Elliott DE, Urban JF Jr, Thompson RA, Weinstock JV (2005) Trichuris suis therapy for active ulcerative colitis: A randomized controlled trial. Gastroenterology 128: 825–832. 13. Hotez PJ, Bethony J, Bottazzi ME, Brooker S, Buss P (2005) Hookworm: “The great infection of mankind.” PLoS Med 2: e67. DOI: 10.1371/journal.pmed.0020067October 2005  |  Volume 2  |  Issue 10  |  e327

A multi-enzyme cascade of hemoglobin proteolysis in the intestine of blood-feeding hookworms.

A pasture trial using two immunising doeses of a parasitic bronchitis vaccine.

Antibodies against a secreted protein from hookworm larvae reduce the intensity of hookworm infection in humans and vaccinated laboratory animals. FASEB J. Epub ahead of print.

Cleavage of hemoglobin by hookworm cathepsin D aspartic proteases and its potential contribution to host speciﬁ city.

Emerging patterns of hookworm infection: Inﬂ uence of aging on the intensity of Necator infection in Hainan province, People’s Republic of China.

Hookworm: “The great infection of mankind.”

Industrial development and ﬁ eld use of the canine hookworm vaccine.

Progress in the development of a recombinant vaccine for human hookworm disease: The Human Hookworm Vaccine Initiative.

Soil-transmitted helminth infections: Updating the global picture.

Trichuris suis therapy for active ulcerative colitis: A randomized controlled trial.

Vaccination against gastro-intestinal nematode parasites of ruminants using gut-expressed antigens.

Vaccination of dogs with a recombinant cysteine protease from the intestine of canine hookworms diminishes the fecundity and growth of worms.

Vaccination with recombinant aspartic hamoglobinase reduces parasite load and blood loss after hookworm infection.

http://eprints.gla.ac.uk/27513/1/journal.pmed.0020327.pdf

The end of the line for hookworm? An update on vaccine development

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