Bergquist 2010 Chapter 10 - Control of Important Helminthic Infections

CHAPTER
10
Control of Important Helminthic
Infections: Vaccine Development
as Part of the Solution
Robert Bergquist* and Sara Lustigman
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Contents
10.1. Introduction
10.2. Type of Vaccines
10.3. Vaccine Design
10.3.1. Correlate studies
10.3.2. Adjuvants
10.4. Progress in Vaccine Development
10.4.1. Cestode infections
10.4.2. Nematodes
10.4.3. Trematodes
10.5. Industrial Vaccine Production
10.6. Concluding Remarks
References
Abstract
Among the tools available for the control of helminth infections,

chemotherapy has come to totally dominate the field. In the
veterinary field, development of drug resistance has appeared but
this is not (yet) a problem in the control of human diseases.
Although there is no vaccine commercially available for any
human parasitic infection yet, recent progress in vaccine development is making this a future possibility for several diseases. The goal
of chemotherapy is to alleviate infection and morbidity in the
definitive host, or reduce transmission, while the effect of available
* Ingerod, Brastad, Sweden

{
Laboratory of Molecular Parasitology, Lindsley F. Kimball Research Institute, New York Blood Center,
New York, USA
Advances in Parasitology, Volume 73

ISSN 0065-308X, DOI: 10.1016/S0065-308X(10)73010-4
2010 Elsevier Ltd.

All rights reserved.
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Robert Bergquist and Sara Lustigman
vaccine candidates would mainly be to influence transmission

through targeting the intermediate or reservoir host, when the
infection is zoonotic. Apart from this general scheme, there are
also vaccine candidates targeting the parasites in the definitive
host, in particular the early developmental stages, which should
reduce the risk of drug failure. Since the biological targets in most
cases are different, vaccination would be synergistic with drug
therapy. This review covers diseases caused by helminthes in
both humans and animals and includes examples of diseases caused
by cestodes, nematodes and trematodes. The focus is on infections
for which vaccine development has been undertaken for a long
time, resulting in products that could realistically become
integrated into control strategies in the near future.
10.1. INTRODUCTION
Initially, based on the early success of anti-viral and anti-bacterial vaccines, it was believed that development of vaccines against parasites
would be likewise. The first vaccine candidates of this kind consisted of
attenuated or killed whole organisms, but the results were not entirely
successful and work therefore turned towards native parasite antigens
and recombinant subunit vaccines. At this point, it was already clear that
the way forward would be far from simple. Even after the first stumbling
block, large-scale antigen production, had been removed by the advent of
recombinant DNA technology in the 1980s, work on anti-parasite vaccines did not immediately take off. The situation has improved since then
but chemotherapy still completely dominates the control measures for
parasitic diseases of humans and animals alike. However, long-term drug
treatment represents a continuous expense and drug resistance is a permanent threat; in the veterinary field often a reality. The goal of vaccine
development in this area is not to produce a vaccine capable of inducing
sterilizing immunity but to create an adjunct to chemotherapy that would
reduce the likelihood of vaccinated individuals developing severe infections and thus reduce the burden of disease throughout the world. An
integrated approach, that is the follow-up of initial drug treatment with
vaccination to achieve long-term protection (Bergquist et al., 2008), has
much to offer but a repository of specific vaccines useful against the
variety of infectious agents that make up the neglected tropical diseases
(NTD) must first be established.
Commercially provided antiparasitic drugs with broad-spectrum
action have successfully been used to control parasitic diseases in livestock and other domestic animals. However, frequent emergence of drug
resistance in the target parasites has become a challenge. In addition,
Vaccine Development and Control of Helminthic Infections
299
issues regarding drug residues in the environment and food chain have
come to the forefront, boosting interest in alternative control methods and
renewed the appeal of vaccines.
Approaches based on molecular biology technology have resulted in
the elucidation of entire parasite genomes, as well as the identification of
individual genes (Abubucker et al., 2008; Berriman et al., 2009; Brindley
et al., 2009; Ghedin et al., 2007; Schistosoma japonicum Genome Sequencing
and Functional Analysis Consortium et al., 2009). Without doubt, further
understanding of the role of gene products in parasite biology will lead to
the identification of novel parasite vaccine target antigens. However, for
this aim to be fully realized, strong investment in basic research on the
complex interplay between parasite and host is necessary. Despite longterm work on vaccine development, notably in the fields of hookworm
infection, leishmaniasis, malaria, onchocerciasis and schistosomiasis, we
have yet to see an effective vaccine being implemented against a human
parasitic disease. On the other hand, for some of these infections, experiments using animal models have shown strong promise and there has
been clear progress on vaccines against veterinary helminthic infections
(Rickard et al., 1995). This may reflect fewer problems to be solved at the
biological level with regard to animal vaccine development, but the more
probable reasons are the much stricter regulatory demands governing
products for human use. The marketability of veterinary products is
another factor, as people who require parasite vaccines are generally not
in a position to pay for them.
With regard to veterinary vaccines, the immunological control of Fasciola
in sheep and cattle is within reach (Tendler and Simpson, 2008), and highly
effective recombinant vaccines have already been developed for the prevention of Taenia ovis in sheep, T. saginata in cattle, T. solium in pigs and
Echinococcus granulosus in livestock (Lightowlers, 2006a,b). While vaccines
against T. ovis and T. saginata are purely intended for assistance for
farming, vaccines against T. solium and E. granulosus vould primarily be
beneficial to humans. It should, in this connection, be mentioned that transmission-blocking Schistosoma japonicum vaccines, which also belong to
this category, are currently in field trials (Dadara et al., 2008; McManus
et al., 2009).
Parasites survive in the host by avoiding or confusing immune
responses against them, for example through stimulation of factors
down-regulating the cellular response or through non-specific activation
of B-cells. Parasite antigens are complex and difficult to characterise and
the host commonly responds with a range of various defence mechanisms. Western blotting (Burnette, 1981) is the traditional approach to
identifying potential antigens for vaccine development but few of the
antibodies identified by this technique are protective, as they are most
often raised against non-related intracellular proteins which are released
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when the parasite disintegrates. Protein polymorphism represents

another problem (Rosenzvit et al., 2006) that could make a the vaccine
ineffective against serotypes not included in the original design. Finally,
laboratory strains of parasites may become atypical, lose their natural
range of polymorphism or even develop new polymorphisms not
seen in nature by being maintained through long-term laboratory
propagation.
10.2. TYPE OF VACCINES

Vaccine production involves a spectrum of designs that can be based on
anything between attenuated organisms and complex compounds produced by molecular biology. Although the simplest approaches do not
generally result in useful products, it does not follow that the most
complicated approaches are necessarily superior. To facilitate orientation,
a brief guide to the different vaccine types is presented:
1. Vaccines consisting of whole parasites killed in various ways (heating,
irradiation, etc.) that conserve their structures.
2. Attenuated organismslive parasites treated so they cannot persist or
cause injury when injected.
3. Recombinant vaccineswell-characterised gene products (antigens)
that can be produced in large quantities, consistently and cheaply.
4. Peptide vaccinesshort synthetic protein sequences including the
desired immuno-dominant epitopes.
5. Recombinant-vector vaccinesattenuated virus or bacteria whose
genome has been supplied with extraneous DNA encoding parasite
antigenic determinants to be replicated and expressed by the vector.
6. DNA vaccinesplasmids containing the immune-dominant sequence
(s) capable of producing the desired parasite antigen intracellularly
(in host cells) in an approach similar to that of recombinant-vector
vaccines.
Synthetic peptide vaccines are excellent from the point of view that
they do not carry any danger of contamination with other proteins.
In addition, epitopes from different proteins can be incorporated into a
single construct. However, peptides are not immunogenic and are therefore utterly dependent on adjuvants. Although in theory this very fact
permits the option to select predominantly cell-mediated immunity or
antibody production (Al-Sherbiny et al., 2003), we do not yet have access
to the adjuvants needed to achieve this modulation precisely. However,
once the field has advanced further and products have been cleared for
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use in humans, it might well be possible to accomplish, for example cellmediated immunity by processing intracellular antigens and presenting
them together with Class 1 MHC proteins on the cell surface (Lafuente
and Reche, 2009), a pathway usually activated by bacteria and intracellular viruses. Conversely, blocking this pathway would result in exclusive
stimulation of antibody production.
The recombinant-vector approach is based on the introduction of
DNA, encoding parasite determinants, into the genome of an attenuated
virus or bacterium which expresses the desired gene product after being
introduced into the subject to be protected. The Vaccinia virus is a popular
vehicle for this approach as the virus can be engineered to express many
different recombinant genes but the result depends on the site of insertion
of the coding sequence in the viral genome (Coupar et al., 2000). The
recombinant Vaccinia approach has been much used for many kinds of
agents, including tumour antigens, and has also been relied on for malaria
vaccines (Prieur et al., 2004). Recombinant-vector vaccines induce both
cellular and antibody responses but as immunity to the vector itself may
also develop, it is advisable not to vaccinate recipients with the same
vector more than once.
DNA vaccines, usually consisting of circular plasmids encoding
the target antigen, can also generate both cell-mediated and antibody
responses. These vaccines are reliable and inexpensive as the technique
avoids the danger of contamination with foreign proteins and produces a
long-lived response. However, success depends not only on the identification of the key protective antigen(s), but also on enhancing antigen presentation, for example by targeting dendritic cells (Grossmann et al., 2009).
10.3. VACCINE DESIGN

Originally, new antigens were discovered through simple disintegration
and purification of tissues or cell organelles from the parasite in question
but when expression libraries became available for screening and when
individual proteins could be linked to their encoding DNA, many new
antigens could be identified. The sequencing of the parasite genome and
the generation of large transcriptome databases have greatly facilitated
finding new information (Brindley et al., 2009; Hu et al., 2003). A clear
understanding of the transcriptional components of a parasite enables the
discovery and identification of molecules essential for successful
parasitehost interactions (Almeida et al., 2009). Working in the field of
schistosomiasis, Fitzpatrick et al. (2009) have suggested a promising
bioinformatics-based approach, employing both statistical and network
analyses of transcriptomic data to find new vaccine targets. Further
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assistance in antigen discovery comes from the possibility of probing

preparations by Western blotting (Burnette, 1981) against protective sera
to identify the most antigenic components. The proteins in question can
be chromatographically analysed and the preferred band(s) identified,
extracted and subjected to liquid chromatography followed by mass
spectrometry for identification. The subsets of proteins, selected on the
basis of their involvement in the hostparasite relationship and parasite
biology, can then be produced in large amounts by means of recombinant
DNA techniques for the routinely required efficacy-testing in animal
models.
10.3.1. Correlate studies

Once a panel of protective antigens has been established, the next step is
to find out how animals and humans in endemic areas react immunologically to natural infection. The investigation of individual immune
responses to specific antigens, focusing interest on the underlying
mechanisms in resistance at the molecular level, is one of the key
approaches to vaccine design. Well-researched antigen panels have been
set up for various parasites with the aim of identifying antibody and
cytokine correlates of apparent resistance and apparent susceptibility.
The approach was pioneered for S. mansoni antigens (Acosta et al., 2002;
Al-Sherbiny et al., 2003; Ribeiro de Jesus et al., 2000). In a comprehensive
study of this subject, carried out by the Egyptian Reference Diagnostic
Center (ERDC) in Cairo, immune responses against a panel of 10 priority
S. mansoni vaccine candidate molecules were determined in cohorts of
humans living in areas where they were exposed to infection daily, and
the results compared with the corresponding data emanating from parasitological diagnosis (Al-Sherbiny et al., 2003). Responses significantly
correlating either with resistance or with susceptibility to re-infection
were demonstrated and it was also possible to group the protective
responses to some of the antigens as belonging either to the Th1 or to
the Th2 sphere. This type of study is instructive not only for identifying
the few antigens that directly and exclusively correlate with resistance,
but also by indicating which of them can be modulated to produce the
sought-after immune response. In a similar approach from the field of
filariasis, Vedi et al. (2008) have identified a 2.0 kb cDNA clone coding for
Brugia malayi heavy chain myosin which exhibited strong immunoreactivity with bancroftian sera from endemic putatively immune human
subjects. Similarly, sera from individuals immune against Onchocerca
volvolus have been used successfully to clone vaccine candidates subsequently shown to be protective against O. volvulus infective third-stage
larvae in a mouse model (Lustigman et al., 2003).
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10.3.2. Adjuvants
Efforts made so far to create practically useful vaccines against parasitic
infections have made it clear that the challenge is formidable and might
not even be possible without well-defined adjuvants. Design and
development of adjuvants have until recently been empirical, but molecular-based approaches are now enhancing the field based on the knowledge that they may essentially act via receptors of the innate immune
system (Hauguel and Hackett, 2008; Kwissa et al., 2007). There are,
however, vaccines that are capable of inducing robust T- and B-cell
immunity without any extra stimulatory additives. Emerging evidence
suggests that such vaccines induce innate immune activation via a
range of stimuli, including ligands specific for toll-like receptors
(Kwissa et al., 2007).
Adjuvants improve immune stimulation by antigens which are only
weakly immunogenic but they also frequently induce side effects, sometimes significant toxicity. Pro-inflammatory pathways induced by innate
immune receptors trigger many of these toxic effects and it has been
shown that at least some of them are distinct from those involved in the
stimulation of protective adaptive immune responses (Hauguel and
Hackett, 2008). If indeed toxicity can be separated from efficacy, the
road is open for progress towards the use of vaccine adjuvants that are
both safe and effective.
Focussing on the specific mode of action of adjuvants, attempts are
underway to develop compounds capable of manipulating the vaccine
response to nudge it in specific directions. Immunogenicity is a complicated affair relying on antigenic access to particular pathways promoting
the secretion of cytokines from antigen-presenting and other cells to
stimulate dendritic cells and macrophage phagocytic activity as well as
to enhance the T-cell response. This can now be achieved artificially by
using immune-modulators, that is chemical agents such as lipopeptides,
lipopolysaccharide (LPS), saponins, muramyl dipeptides and oligodeoxynucleotides, research into whose modes of action may provide
clues as to how vaccines should be formulated (Jiang and Koganty,
2003) to steer the immune response in the desired direction, be it a cellmediated response or an antibody response. Indeed, adjuvants which can
facilitate vaccine delivery by the activation of specific, adaptive immune
responses are already in advanced clinical trials (Pichichero, 2008).
Monophosphoryl lipid A (MPL) is a good example of the new generation of adjuvants in which the toxic side effects of LPS have been dissected
from the immune-modulating ones (Steeghs et al., 2004). For example, the
MPL adjuvant developed by Corixa (Hamilton, MT, USA) induces a
strong Th1 response mediated by IL-1, tumour necrosis factor (TNF)-a,
interferon (INF)-g and IL-12 (Persing et al., 2002), yet its side effects are no
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worse than those produced by potassium aluminium sulphate (alum), the

only widely used adjuvant in human vaccines today. However, since
alum probably acts more as a depot than anything else (Lindblad, 2004),
the need for specific adjuvants is growing. Already, an adjuvant from
GlaxoSmithKline (London, UK) based on MPL and Quil (ASO4) has been
licensed for use in human vaccines in more than 100 countries
(Pichichero, 2008).
10.4. PROGRESS IN VACCINE DEVELOPMENT

Overall, the development of vaccines against parasitic diseases in humans
has not been taken seriously by donor agencies. The main reason for this
is the easy access to cheap, effective drugs which, apart from malaria
chemotherapy, have not been prone to produce resistance in their target
parasites. In the veterinary field, there is a stronger need for vaccines as
drug resistance is commonplace. This is probably due to the particularly
high drug pressure realized when herds and flocks are exposed to regular
recurrent blanket treatments. Also humans are subjected to repeated
chemotherapy against various helminth infections but the risk for drug
resistance is relatively low as the treatment cycles promoted by control
programmes rely on lower doses spaced by relatively long intermissions.
Still, development of resistance against drugs used for control of human
infections can definitely not be ruled out, but it may take longer than the
20 years commonly mentioned by veterinarians. Notably, the emergence
of resistant strains of the O. volvulus parasite is suggested by reports of
onchocerciasis patients failing to respond to ivermectin treatment
(Churcher et al., 2009). In addition, an increased frequency of a resistant
allele has been identified in Wuchereria bancrofti microfilariae in patients in
areas subjected to mass drug administration (MDA) with benzimidazole
(Schwab et al., 2005). Both drugs are used for MDA of onchocerciasis
and/or lymphatic filariasis (LF).
A typical characteristic of parasitic diseases is that the life cycles of the
infectious agents require that their life forms oscillate between different
hosts which often involve vertebrates both as intermediate and as definitive host. Although the intermediate host can also be a gastropod or an
insect (as in schistosomiasis and malaria, respectively), vertebrate hosts
other than humans can also play the role of disease reservoir. For example, in contrast to other schistosome species, S. japonicum infects a broad
range of animals which are sometimes more important for the transmission of the disease than humans (Gray et al., 2007; Wang et al., 2005).
Against this background, one might think that vaccination of key vertebrate species involved in the propagation of diseases eventually implicating humans should be part of control activities, yet it is not. In the absence
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of any human vaccine against parasites, veterinary vaccines should be tried

for the control of human endemic diseases. It is a positive sign that this is
subject to research (Dadara et al., 2008; Gray et al., 2007; Guo et al., 2006;
Lightowlers, 2004). The current situation with respect to vaccine development is reviewed below with respect to major zoonotic helminthiases such
as cysticercosis, echinococcosis and schistosomiasis japonica as well as for
human helminth hookworm infection, LF and onchocerciasis.
10.4.1. Cestode infections

T. solium (see life cycle in the back of volume 72), the cestode whose larval
encystation gives rise to neurocysticercosis in humans, belongs to a zoonotic
disease complex that is endemic in a large number of countries where pigs
are kept under unhygienic conditions and without adequate sanitary disposal of human faeces. Since the pig is the obligate intermediate host for
T. solium, and effective drugs are available, it should be possible to curb the
transmission of this major parasitic disease that frequently affects human
health and economy in the developing countries. Since a veterinary vaccine
has also been developed against this disease (Lightowlers, 2004), it is almost
surprising that neurocysticercosis has not already been eliminated. The
explanation for this lack of progress is that the pig readily establishes new
tapeworm infections in humans, leading to renewed transmission after each
round of treatment. A detailed review of the disease and its present situation is given by Willingham et al. (2010).
A well-designed vaccine strategy should have a good chance to prevent
infection in the pig and thus interrupt the parasite life cycle. Indeed,
vaccine research has been moving well ahead during the last decade as
the work to decipher this parasite genetically has provided novel antigens.
For example, Almeida et al. (2009) generated more than 1500 high-quality
Expressed Sequence Tags (ESTs) from 20 cDNA T. solium mini-libraries.
Identification of protective antigens and their production by recombinant
DNA technology has been researched by Lightowlers (2003 and 2004). Ten
years ago, Johnson et al. (1989) published the cloning of a recombinant
T. ovis antigen which stimulated high levels of protective immunity in
sheep. Relatively rapidly, this was followed by the development of effective vaccines not only against T. ovis in sheep but also against T. saginata in
cattle, T. solium in pigs and E. granulosus in livestock, indicating that
reliable, high-level protection against a complex metazoan parasite can
be achieved using defined recombinant antigens (Lightowlers, 2006a,b;
Lightowlers et al., 2003).
Several approaches based on recombinant antigens have been made
towards development of vaccines against T. solium. For example, two
highly immunogenic oncosphere antigens, TSOL18 and TSOL45, have
been shown to induce near-complete protection against experimental
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challenge infection in four separate vaccine trials in pigs (Kyngdon et al.,

2006; Lightowlers, 2004) and another oncospheral stage-specific 45W
protein has shown similar results (Luo et al., 2009). In addition, a review
on vaccines against cysticercosis by Sciutto et al. (2008) highlights work on
S3Pvac, the only synthetic peptide vaccine that has been tested and
proved effective in the field against naturally acquired disease. Thus,
from the technical point of view, we have access to vaccines with the
capability to break the parasite life cycle in the pig intermediate host.
If correctly deployed and monitored, any of these vaccines would without
doubt rapidly lead to the eradication of human cysticercosis.
E. granulosus (for life cycle see back of volume 72 and McManus, 2010)
is another cestode stimulating strong immune responses which open
possibilities for the development of vaccines directed against this infection, both in the intermediate and in the definitive host. An effective
strategy would be to stop the development of adult gravid tapeworms in
dogs with a vaccine, so preventing the oncosphere from producing hydatid cysts in animals, for example sheep. This is a straightforward strategy
which relies on the fact that echinococcosis induces cell-mediated cellular
responses as well as significant antibody production in their human and
intermediate hosts. However, for the approach to be successful, a thorough understanding of the immune mechanisms involved is required.
The many recent reviews of immunity mechanisms at work in echinococcosis are evidence of the large body of knowledge amassed so far, for
example Amri et al. (2009), Gottstein and Hemphill (2008), Lightowlers
(2006a), Lightowlers and Heath (2004), Torgerson (2009) and Zhang et al.
(2008). Clearly, a very high coverage of flocks would need to be achieved
for vaccination alone to be effective, but a combination of vaccination of
the sheep and drug treatment of surrounding dogs could achieve a good
level of transmission control, even with a less-than-perfect vaccine as
pointed out by Torgerson (2006).
EG95, the recombinant E. granulosus vaccine based on an oncosphere
protein containing a glycosylphosphatydilinositol (GPI) anchor and a
fibronectin domain, is strongly immunogenic and induces effective protection against challenge infection (Gauci et al., 2005). However, its immunological coverage may not be as broad as desired, since the E. granulosus
genome also contains several other EG95-related genes which may affect
the efficacy of this vaccine (Chow et al., 2008). Further sequencing has
uncovered a large amount of variability in this organism (Haag et al.,
2009) confirming this suspicion. Nevertheless, as the sheep-dog strain of
the parasite is responsible for most cases of human disease, EG95 remains
promising.
Although it would be of huge benefit in reducing the effective period
required to stop transmission of E. granulosus, no effective vaccine exists
against canine echinococcosis. Apart from that, however, a long list of
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deliverables needs to be consulted to efficiently approach this goal, for

example improved diagnostics, characterization of infection dynamics
and determination of the longevity of protection induced, to mention
just a few. In addition, further down the road, mathematical models will
need to be developed to facilitate impact evaluation. Even incorporation
of only a few of these measures should increase the efficiency of control
and reduce the time required to achieve prevention of disease transmission. Above all, the scarcity of vaccine candidates for immune protection
against adult tapeworms reflects the lack of immune correlates and the
ambiguity of natural immunity in dogs (Craig et al., 2007; Zhang and
McManus, 2008).
Before leaving the topic of vaccines against echinococcosis, E. multilocularis (see life cycle on page tbc) should briefly be mentioned. Unlike
E. granulosus, this species produces multiple, small cysts that spread
throughout the body in many mammals, including rodents and humans.
Although this infection is mainly distributed in the northern hemisphere
and is much less common than that caused by E. granulosus, it is referred
to here since there are prospects that a vaccine can be developed against it.
A tetraspanin candidate (E24) has been cloned from a full-length cDNA
library emanating from the E. multilocularis metacestode. Antibodies
against this antigen specifically recognize a 25 kDa cyst antigen from
the germinal layer of the E. multilocularis metacestode, highlighting its
potential both for diagnostics and vaccine development (Dang et al.,
2009a,b)
10.4.2. Nematodes
The Phylum Nematoda (roundworms) includes tens of thousands of often
very diverse species, a large number of which are parasitic. Nematodes
causing disease in humans include filarids, hookworms, pinworms and
whipworms, as well as individual species such as Ascaris lumbricoides and
Trichinella spiralis. While drug treatment is an adequate approach for most
of these, it is realized that the long-term control of some of them, that is
human hookworm infection (due to Ancylostoma duodenale or Necator
americanus), LF (due to W. bancrofti or B. malayi,) and river blindness
(caused by O. volvulus) will not be possible with drugs alone. While
regular, annual or semi-annual chemotherapy is an important part of
any public health interventions, high rates of re-infection and the spectre
of diminished efficacy of drugs used often and repeatedly, conspire to
chip away at the sustainability of this approach. Indeed, macrofilarial
drug cure, such as treatment with the adulticide melarsomine, can even
reduce natural (or induced) protective immunity as shown by a longitudinal study in a bovine model (Tchakoute et al., 2006). However, currently
the treatment is with ivermectin, which has potent efficacy against the
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microfilariae only. Duerr et al. (2008), on the other hand, have suggested
that the resistance against filarial parasites includes a time-dependent
component caused by an early immune response with short-term memory. While vaccine studies are moving forward, clinical studies to investigate this conjecture are warranted.
Hookworm (see life cycles on back of volume 72) is a leading cause of
maternal and child morbidity in the developing countries of the tropics and
subtropics. Together, the two species of hookworms that infect humans,
N. americanus and A. duodenale, infect more than 500 million people worldwide (Hotez and Kamath, 2009; Hotez et al., 2008). The former species is
common in the Americas, sub-Saharan Africa and Southeast Asia, with
A. duodenale mainly found in the Middle East, North Africa and India.
The excretory/secretory (ES) component, a mixture of proteins, carbohydrates and lipids emanating from the parasite, represents the host
parasite interface and is probably involved in modulation of the host
immune responses to promote the survival of the parasite. The dog
hookworm A. caninum is the common model for the study of hookworm
infection and information from its genome coupled with functional genomics and proteomics is accelerating the move towards human hookworm
control. This work has resulted in the identification of a suite of ES
proteins which are important for the parasitic lifestyle and which provide
insights into the biology of hookworm infection. For example, Abubucker
et al. (2008) generated 104,000 genome survey sequences (GSSs) and
assembled them into 57.6 Mb of unique sequence, while Mulvenna et al.
(2009) identified 105 different proteins and characterised much of the ES
proteome.
Vaccine research targets both the larval and adult stages of the worm
but vaccine candidates based on the larval forms are in the lead. The
currently most promising vaccine candidate is the N. americanus ASP-2
(Na-ASP-2) antigen, first shown in secretions from A. duodenale but later
also isolated from N. americanus (Diemert et al., 2008). A well-controlled
study has shown this candidate to be safe in animals and capable of
inducing protective responses, consisting of both specific IgG antibodies
and cellular immune responses. (Bethony et al., 2008). A Phase I safety
trial has been completed in the United States, while corresponding Phase I
trials in endemic areas are underway (Bethony et al., 2008).
With regard to potential adult worm antigens, vaccine-oriented
research has focused on how the worm feeds, specifically investigating
how to interfere with the action of the enzymes involved in the breaking
down of haemoglobin. Indeed, several of the proteins involved in the
proteolytic cascade utilized by the adult worm to degrade haemoglobulin
from host erythrocytes, and thus essential for its nutrition and survival,
have been shown to induce protective immune responses. Among these,
cysteine protease-haemoglobinase (CP-2) (Loukas et al., 2004), aspartic
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protease-haemoglobinase (APR-1) (Loukas et al., 2005) and glutathione

S-transferase (GST) (Zhan et al., 2005) have been selected as possible
targets as they are essential for the digestive pathway. In fact, work
already carried out has shown that vaccination with the two former
antigens has been shown to reduce blood loss and faecal egg counts in
dogs (Loukas et al., 2004, 2005). Although an attack against the larval
stages by the Na-ASP-2 antigen, combined with interference of the adult
worms digestive pathway, is theoretically attractive, we are not yet there.
Nevertheless, great strides have been made and a partially effective
vaccine should soon be within reach.
LF, also known as elephantiasis, directly affects more than 120 million
people with about 10 times more at risk in the 80 countries where the
infection is now endemic (WHO fact sheet No. 102 on lymphatic filariasis,
2010). One-third of those infected live in India, one-third in Africa and
most of the remainder in Southeast Asia. The overall prevalence of LF is
increasing due to the rapid, unplanned growth of cities producing
expanded breeding sites for the mosquitoes that transmit the disease.
The causative filarial worms W. bancrofti and B. malayi (see life cycle on
back of volume 72) lodge in the lymphatic system of humans, the definitive host of these parasites. Despite the hostile environment surrounding
them, these nematodes can survive up to 6 years, which they accomplish
by adopting various immunomodulatory strategies. During its lifespan,
each worm produces millions of microfilariae that eventually reach and
circulate in the blood, assuring transmission to the mosquito vector.
Application of drugs targeting the first-stage-larvae (L1) can block transmission but there are also drawbacks such as inadequate drug coverage,
reappearance of infection through migration of infected people into controlled areas and partial success leading to reduced compliance. This has
led to a call for complementary approaches that include both improved
chemotherapy and vaccine development. Mouse and gerbil models of
Brugia infection have provided information on the immune response
elicited by the different stages of these nematodes. Studies by Lawrence
and Devaney (2001) reinforce the concept that the different developmental stages each have their own mechanism of modulating responses leading to the down-regulation of potentially host beneficial immune
responses. In an approach similar to that used by Almeida et al. (2009)
for identifying potential vaccine antigens from T. solium, Nagaraj et al.
(2008) have carried out a large-scale analysis of excreted or secreted
proteins inferred from EST data. Although this inventory of known and
novel excreted or secreted proteins covers an enormous range of nematodes, it can be used as a source of new vaccine candidates against filarial
worms infecting humans.
A large-scale, proteomic analysis to identify the ES products of the L3,
L3 to L4 moulting, adult male, adult female and microfilarial stages of the
310
filarial parasite B. malayi has recently been published (Bennuru et al.,

2009). This analysis provides extended insight into the hostparasite
interaction, while the reported abundance of a number of previously
characterised immunomodulatory proteins in the ES of microfilariae
increases the chances of identifying novel vaccine candidates.
Various vaccine candidates have already been put forward. For example, Veerapathran et al. (2009), focusing on the key role of GST for the
survival of the parasite in the host, achieved 61% protection against
B. malayi challenge infection in subsequent vaccination studies in the
jird model. This work built on the effect of human and mice anti-GST
antibodies in an antibody-dependent cellular cytotoxicity (ADCC) assay
(Veerapathran et al., 2009). In another development, Vedi et al. (2008)
showed the potential of B. malayi recombinant myosin as a vaccine in a
rodent model. The authors reported a 76% reduction in microfilarial
burden and a 5458% lower adult worm establishment that was conferred
through the induction of both humoral and cellular immunities (Vedi
et al., 2008). There are also other antigens worth mentioning, for example
ALT-2 (Ramachandran et al., 2004), a microfilarial soluble 38 kDa protease
isolated from B. malayi (Krithika et al., 2005) and a zinc-containing
175 kDa collagenase (Pokharel et al., 2006) that have shown significant
protection against B. malayi in animal models. Any of these antigens
have the potential to be developed into a useful vaccine but there is still
a long way before a vaccine against LF will reach the stage of clinical
trials.
Contrary to LF, in which the adult worms cause the pathology, the
microfilariae constitute the culprit in onchocerciasis, a disease caused by
the filarial worm O. volvulus. The infection is transmitted by the Simulium
blackfly vector and is almost exclusively found in Africa. However,
isolated foci also exist in Yemen and six countries in central and South
America (WHO, 2009a). Onchocerciasis affects an estimated 40 million
people, causing visual impairment in half a million; the disease also
causes depigmentation and a severe, unrelenting itching. For years, control activities were based on insecticides sprayed by aircraft over the
blackfly breading sites but with the donation of Mectizan (ivermectin),
by the U.S. Company Merck & Co. in 1987 (Colatrella, 2008), control
operations changed towards chemotherapy. Regrettably, resistance to
this drug appeared in the veterinary field early on (Coles et al., 2005;
Egerton et al., 1988; Xu et al., 1998). The risk for a parallel situation vis-a`vis O. volvulus is therefore a worry and it seems already to be emerging
(Boussinesq, 2008; Lustigman and McCarter, 2007; Osei-Atweneboana
et al., 2007). Above all, this development is a prompt for immediate and
increased activities in the vaccine field.
Like so many other parasitic diseases, there is a lack of good animal
models as O. volvulus can develop fully only in humans. In a recent review
311
(Allen et al., 2008), however, Litomosoides sigmodontis in mice and

O. ochengi in cattle are placed in the context of how these models can
better our ability to control the human disease. The case for vaccine
development with regard to O. volvulus has recently been reviewed by
Lustigman and Abraham (2009) and several other authors have also
stressed the need for a vaccine (Boussinesq, 2008; Cook et al., 2001).
Importantly, protective immunity against O. volvulus larvae has now
been definitively demonstrated in humans, cattle and mice, thereby proving the conceptual underpinnings that a vaccine can be produced against
this infection (Lustigman and Abraham, 2009). As noted by Nutman
(2002), an additional modality, complementing chemotherapy and vector
control, is conditional to eliminate onchocerciasis. This makes it all the
more important to develop a vaccine before resistance has spread widely
rendering an integrated approach impossible. Vaccine studies supported
by the Edna McConnell Clark Foundation USA resulted in the identification of 15 protective antigens out of 44 screened that induced significant
but partial protection, using the diffusion chamber model in mice
(Lustigman et al., 2002). Additional numbers of antigens with protective
properties have been reported in the last decade, for example Ov-FBA-1
(McCarthy et al., 2002), Ov-ASP-1 (MacDonald et al., 2004), Ov-ALT-1
(Wu et al., 2004), Ov-GAPDH (Erttmann et al., 2005), Ov-AST-1 (Borchert
et al., 2007) and paramyosin (Erttmann and Buttner, 2009). However,
as with vaccines against LF, much more work is needed before a vaccine
can be put to use. Recent reports using the cow model and O. ochengi
have clearly proved the possibility of developing vaccines against
O. volvulus as well (Achukwi et al., 2007; Makepeace et al., 2009;
Tchakoute et al., 2006).
10.4.3. Trematodes
Several species of flatworm threaten human health. Some exist only in
Southeast Asia, that is Clonorchis sinensis, Paragonimus spp. and
Opisthorchis spp. (Keiser and Utzinger, 2005), while others are globally
distributed, for example Fasciola and Schistosoma. The diseases caused by
Clonorchis, Paragonimus, Opisthorchis and also Fasciola may be grouped
together as foodborne treamatodiases due to the way they are transmitted. Apart from F. hepatica (McManus and Dalton, 2006; Vilar et al., 2003),
the few antigens reported for this group mainly regard diagnostic use but
reports on protective antigens have started to appear (Zhou et al., 2008).
Interestingly, in this connection, the schistosomiasis Sm14-FABP vaccine
candidate (Tendler and Simpson, 2008; Vilar et al., 2003) cross-reacts with
Fasciola antigens (see below).
With close to 800 million people in 74 countries at risk, and directly
affecting more than 200 million (Steinmann et al., 2006; WHO, 2009b),
312
schistosomiasis is the second-most, socio-economically devastating parasitic disease after malaria. Five species cause human schistosomiasis but
only two exist in Southeast Asia (for life cycle see back of volume 72).
S. japonicum is the only species in the Peoples Republic of China
(P.R. China) and the Philippines, while small pockets of S. mekongi infection
constitute serious, local problems in Cambodia and Lao Peoples Democratic Republic (Attwood et al., 2008). In contrast to all other schistosomiasis
species, S. japonicum is a zoonotic infection affecting a wide range of animals,
including wild and domestic ungulates as well as rodents, which all act as
reservoirs. The only available drug is praziquantel, which is also one of the
few not fully subsidized drugs. With an estimated 423 million tablets
needed globally every year (The Carter Center Schistosomiasis Control
Program, Atlanta, USA, 2010), the total expenditure needed for control is
staggering even though the average cost per dose is less than 20 cents.
Although modern schistosomiasis control has clearly shown that chemotherapy alone is capable of reducing morbidity in the human host
(WHO, 2002a,b), rapid re-infection is a reminder that the impact of drug
treatment on transmission is marginal. The case for schistosomiasis
vaccine development is based on the understanding that vaccination,
even if not 100% effective, would contribute to long-term reduction of
egg-excretion from the host. An effective vaccine would also contribute to
a positive trade-off regarding the aggressive inflammatory response that
has been observed following interrupted chemotherapy in children living
in high-transmission areas (Olveda et al., 1996; Reimert et al., 2008). The
underlying reason for this rebound morbidity is unclear but is probably
due to interruption of the Th1 response reducing the modulation that
normally takes place during the course of natural infection.
The arguments supporting the utility of a vaccine against schistosomiasis,
based on more than 50 years of laboratory and field research, are strong.
For example, it has long been known that humans living in schistosomeendemic areas develop some degree of protection naturally (Butterworth
et al., 1985) and the injection of mice with irradiated schistosome cercariae
consistently induce 6085% protection (Dean, 1983). Vaccine development
was originally focused on S. mansoni but a panel of well-characterised
S. japonicum antigens have now also shown protective efficacy in animals
justifying support for further consideration (McManus and Loukas, 2008).
Due to its wide spectrum of final hosts, a transmission-blocking veterinary
vaccine is the priority in areas in which S. japonicum is endemic. The possibility that this approach could pay off is supported by studies in P.R. China
showing that the animalsnailhuman transmission cycle is more prominent
than the humansnailhuman cycle in sustaining the infection in the field
(Gray et al., 2007). An additional advantage in S. japonicum experimentation
is that the access to full-size animal models escapes the limitations of the
mouse model (Johansen et al., 2000; Zhu et al., 2006).
313
More than a hundred schistosome antigens have been identified and

characterised but few have shown sufficient promise to be selected for
further development. Despite the fact that Sh28-GST, a S. haematobium
GST molecule, is the current lead candidate, the great majority of Schistosoma candidate vaccine antigens, reviewed by Bergquist and Colley
(1998), derive from S. mansoni. The most well-researched are Sm28-GST
and Sh28-GST (Capron, 1998; Capron et al., 2005), paramyosin (Pearce
et al., 1988), triose phosphate isomerase (Sm28-TPI) (Harn et al., 1992),
Sm37-GADPH (Goudot-Crozel et al., 1989), Sm14-FABP (Tendler and
Simpson, 2008; Vilar et al., 2003) and Sm-p80 calpain (Ahmad et al.,
2009; Siddiqui et al., 2005). There are also multiple antigenic peptide
(MAP) constructs made from various integrated membrane antigens
such as Sm10, Sm23, Sm28-TPI and Sm28-GST (Argiro et al., 2000; Ferru
et al., 1997; Ribeiro de Jesus et al., 2000). The average protection of these
antigens, which have been tested either as native, full-length antigens,
recombinant antigens, MAP constructs or as DNA vaccines, is around
50% (in some cases higher) in the various animal models used.
The vaccine candidates mentioned above have been developed during
the last two decades. Meanwhile, technology has become progressively
more sophisticated resulting in an unprecedented expansion of parasite
sequence databases. This accumulation of molecular data allows rational
vaccine discovery such as the two novel S. mansoni vaccine candidates
detected at the parasite surface by proteomics which was recently
reported by DeMarco and Verjovski-Almeida (2009).
Although fund raising for vaccine development has become an
increasingly uphill exercise, nationally available funds have been
invested in Brazil and France, supporting the road toward clinical trials
for Sm14-FASB and Sh28-GST, respectively. Industrial scale-up was first
achieved for Sh28-GST, now in clinical trials under the name of Bilhvax
(Capron et al., 2005). This vaccine candidate has successfully passed
Phase I/II clinical trials and been shown to be safe, producing Th2
cytokines (IL-5 and IL-13) followed by high titres of neutralizing antibodies after three injections. Chemotherapy followed by immunization was
felt to be the most appropriate modality and the best time to give the
vaccine seems to be about three months after treatment, when patients
have switched to the Th2 type of response which takes time to occur and
is generally not seen until after drug treatment. Therefore, the Phase II
trials of Bilhvax were based on this model, including both primary clinical
and secondary parasitological endpoints in measuring efficacy.
Industrial scale-up has also been achieved for Sm14-FABP (Tendler
and Simpson, 2008). Interestingly, thanks to a shared antigen between
Fasciola and Schistosoma, both natural infection and experimental animal
research show cross-protection (Vilar et al., 2003). The former parasite
causes great losses in sheep and cattle breeding and can also infect
314
humans. Commercial interest in a vaccine for veterinary applications has

contributed to move this vaccine candidate into advanced veterinary field
trials which made it possible to piggyback the adoption of the same
molecule for developing a human vaccine against schistosomiasis
(Tendler and Simpson, 2008). A collaborative initiative in Brazil for the
scale-up of Sm14-FABP according to Good Manufacturing Practice (GMP)
was established between the government-funded research centre
Oswaldo Cruz Foundation (FIOCRUZ) and Butantan, a producer of vaccines for the Brazilian Ministry of Health. The previously used laboratoryscale expression system was substituted for systems based on vectors
appropriate for GMP production. Studies of the gene structure of Sm14
were undertaken and provided the basis for functional and structural
analysis to access the preparation of a more stable form of the antigen
based on site-directed mutagenesis. Stability and functionality (fatty acid
binding) quality control assays were designed and developed. The new
construct provided a highly purified protein in large yields with preserved protective activity for both parasites opening the way to Phase I
safety trials (Ramos et al., 2003, 2009).
As S. japonicum is a zoonotic infection, the possibility of creating a
transmission-blocking vaccine for livestock offers a shortcut in the development of vaccines for P.R. China and the Philippines. This and the recent
publication of the S. japonicum genome (Schistosoma japonicum Genome
Sequencing and Functional Analysis Consortium et al., 2009) have no
doubt contributed to the increase in activities focused on this species in
the last few years (Dadara et al., 2008; McManus and Dalton, 2006;
McManus and Loukas 2008; Zhu et al., 2004, 2006). Based on the notion
that reduced schistosome infection in water buffaloes would also reduce
disease transmission to humans, randomised double blind trials in water
buffaloes using DNA vaccines encoding well-researched S. japonicum
antigens (Sj28-TPI, Sj23) have taken place in P.R. China (Dadara et al.,
2008). The results were all close to 50% protection which exceeds the
hypothetical level predicted by mathematical modelling to be needed to
achieve a significant reduction of schistosome transmission.
10.5. INDUSTRIAL VACCINE PRODUCTION

It has been a long road in the development of vaccines against parasitic
diseases, and as scientific hurdles are overcome and we are reaching the
industrial level, the identification of partners and financial support grows
in importance. This undertaking is as critical as dealing with the science,
but the problems may be unfamiliar as they are played out in the real
world of commerce and politics. The commercial-scale production of
GMP-grade material, required at the clinical-trials level, is not only
315
more expensive than the previous developmental steps but can also be
more difficult. Indeed, the transfer from the research laboratory to industry amounts to a real bottleneck, capable of making or breaking a vaccine
candidate. In fact, two of the most promising schistosomiasis vaccine
candidates had to be shelved for this reason (Bergquist and Colley,
1998). In one case, sustained industrial production was not possible even
after large amounts had been made in the laboratory and commercialgrade production had originally achieved production at the gram-level
by the commercial partner. Another predicament, stressed by Lightowlers
(2006a), is that the uncertain market potential of the product generally
dashes the hope to attract the interest of bio-pharmaceutical companies
in the industrialized countries. However, there are real possibilities in
the developing, endemic countries as they have a vested interest in
producing vaccines for their own needs. For example, the vaccine production facility at the Research Institute of Tropical Medicine (RITM) in the
Philippines, which was established using a modular, turnkey approach for
the production of certified GMP-grade biological materials according to
Standard Operating Procedures (SOP). At present, RITM is producing
BCG to cover national needs. However, with this facility in place, adding
a few more modules would not be an insurmountable barrier. Thus, multipurpose industrial plants can be established in endemic countries, not
only for use as vaccine research/development laboratories but also for
batch scale-up for clinical trials and, eventually, for full-scale vaccine
production.
Vaccine development requires long-term commitment as well as sustained, high-level funding (Todd and Colley, 2002) and, as shown in
Fig. 10.1, the process is one of increasing risks. Once promising antigens
have been identified and tested in pilot studies, the researchers must learn
to master laboratory large-scale production and focus on implementation
of the vaccine in the field. At this point, the workload multiplies as
activities become more multifaceted requiring a different infrastructure,
and when this has been put in place, the demanding phase of applied field
studies begins. Like the move from the bench to the field, the change from
experimental approaches to industrial GMP-grade production of antigen
material is one of increasing complexity. In fact, there are steps involved
in the process (ringed in the figure) which are critical to the developmental chain: for example without convincing, independent protection studies the project must revert back to the bench and, if large amounts of
standard material cannot be produced in a sustainable manner, the developmental chain breaks and no further work is possible even with vaccine
candidates shown to be protective and overall strongly experimentally
supported. Finally, after safety and immunogenicity have been shown
(Phase I), there is still no guarantee that the vaccine will prove effective in
the field (Phase II/III). However, when all is said and done, the fact that
316
Vaccine development:
discovery to implementation
Antigens and
host responses
Identification
Antigen
production
Laboratory-scale
Clinical trials
Main objective
Study area
Subjects
Number
Time
Endpoints
Phase I
Protection studies
Selection
Field studies
Industrial-scale
Phase III
Phase IV
Safety
Nonendemic
Healthy adults
> 20
About 3 months
Immunogenicity
Endemic
Infected/noninf.
>100
About 3 years
Phase II
Efficacy
Endemic
Infected/healthy
>1000
Up to 5 years
General impact
Endemic
Infected/healthy
Many thousands
> 5 years
Adverse effects
Immune responses
Protection
Long-term effects
Expenditure
FIGURE 10.1 Many steps are involved in the process of vaccine development, most of
them more technically demanding (symbolized by larger script) than the previous one.
The three encircled stages in this process are critical, that is convincing protection in
animal models, ability to scale-up antigen production and showing impact in the field
(evidence of human protection).
we are entering this phase is testimony to a series of successes in the

laboratory and field which augur well for the future.
Clinical-trials are time consuming and constitute the most labourintensive part of the whole process. A Phase I trial can be carried out
with limited staff and funding but the steps to follow require multifaceted
activities. Already at the Phase II level, the need for staff multiplies and
resource consumption increases logarithmically, as this step entails vaccination and follow-up testing of large numbers of people in an endemic
area. The even longer observation periods needed to follow the immunological responses in the subjects participating in trials to show proof of
efficacy (Phase III) may well hamper securing the funds needed. The final
level (Phase IV) represents the follow-up of an already licensed product
for hidden side effects, an activity that requires even larger population
data and goes on for a long time indeed. After that, regulatory authorities,
involving many administrative levels, will have their say and the hurdles
to be overcome at this stage often require considerable additional input.
The consequence is that the time from discovery to ready product takes
decades rather than years.
The situation regarding vaccines for the veterinary market are somewhat less constrained than that of vaccines aimed to be used in humans.
317
This may explain the rapid progress of vaccines against E. granulosus,

T. solium and F. hepatica. Rather than intended for prevention of infections
in livestock per se, some vaccines against zoonotic parasites, notably that
against T. solium, have been developed to assist with the control of
transmission of the human disease. Although animals rather than
humans are the recipients of these vaccines, the main aim is not protection
of livestock but the control of human disease resulting from ingestion of
infected meat. However, as these diseases occur primarily in the developing world, vaccines against them are of little commercial interest. For
example, the T. ovis vaccine was registered by the New Zealand Animal
Remedies Board in February 1994 (Rickard et al., 1995). In spite of the high
efficacy of this vaccine, which has the capability to wipe out neurocysticercosis if properly applied, the product has yet to be generally applied in
the endemic areas on a large scale.
Table 10.1 summarizes the current situation in a way that illuminates
differences and similarities between vaccine-related activities in the various fields covered. An obvious difference is that progress has been particularly strong in the field of schistosomiasis vaccines. This does not
reflect that this is an easier parasite to work with but is rather a reflection
of the relatively large amounts of financial support available for this
parasite in the 1980s and 1990s. At this time, the UNICEF/UNDP/
World Bank/WHO Special Programme for Research and Training in
Tropical Diseases (TDR), the United States National Institutes of Health
(NIH) and the Edna McConnell Clark Foundation (EMCF) (USA) ran large
well-funded research programmes; first on schistosomiasis and later on
onchocerciasis. In addition, the United States Agency for International
Development (USAID) and the Government of Egypt supported a 10year general Schistosomiasis Research Project (SRP) continued by SVDP,
a specific Schistosomiasis Vaccine Development Project (Bergquist and
Colley, 1998).
10.6. CONCLUDING REMARKS

Vector control and drug administration have reduced infection and disease rates for many parasitic diseases significantly. However, as we are
currently learning from the field of onchocerciasis, ivermectins selective
activity on microfilariae, the need for 1015 years of annual treatments,
logistical obstacles and the emergence of drug-resistant strains demand
alternative strategies. This is also the case for schistosomiasis, in which
large-scale drug distribution is proving a stopgap solution which must be
followed up by the development of an integrated control process.
Helminthic diseases of both humans and animals tend to occur together
geographically but have historically been targeted by disease-specific
TABLE 10.1
Overview of candidates for some helminth vaccines
Parasite
Antigen discovery Industrial scale-up
T. solium*
E. granulosus
E. multilocularis
Hookworm
W. bancrofti
B. malayi
O. volvulus
S. mansoni
S. haematobium
S. japonicum
S. mekongi
Food-borne infection
>10
>20
<10
>10
>10
>10
>10
>100***
>10***
<100***
?
<5
* Vaccine for pigs intended to benefit the human host by breaking the transmission cycle.
** Two vaccine candidates upscaled.
*** Corresponding antigens exist in the various species; only a few are species-specific.
Phase I trial
Phase II trial
Phase III trial
Registration
1**
3
1
319
treatment programs which are now being integrated into a strategy of

preventive chemotherapy. Although these programmes have made considerable progress reducing prevalence and intensity of disease, this
approach runs the risk not only of having to be continued indefinitely
but also of inducing drug resistance without the long-term protection a
vaccine can offer as a complementary intervention.
A particularly interesting observation is that transmission-blocking
vaccines developed for intermediate or reservoir hosts have largely been
successful, for example the pioneering T. solium vaccine initiative against
human cysticercosis is being emulated by a vaccine against S. japonicum
targeting the water buffalo reservoir. The fact that these veterinary vaccines also contribute to creation of healthier animal herds is worth
highlighting.
The successful vaccines against taeniases show that it is indeed possible to create a sterilizing vaccine against a multicellular parasite. Regretfully though, it seems that, despite the availability of excellent vaccines,
they will not be widely applied without a commercial incentive. This can
only be remedied by convincing international donor agencies and private
foundations to support large-scale vaccination projects and/or by public
health provision of vaccines through local production in the endemic
countries themselves.
The current accumulation of molecular data and expansion of parasite
sequence databases is providing a fresh start by permitting a more rational approach to vaccine discovery. A range of new vaccines can be
expected during the next few years provided international donor organizations and private foundations can agree on a joint, major NTD vaccine
initiative. The task ahead is to assure product delivery by convincing
potential donors that vaccine production in the developing world is a
realistic goal worth supporting.
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CHAPTER

Among the tools available for the control of helminth infections,

* Ingerod, Brastad, Sweden

Advances in Parasitology, Volume 73

2010 Elsevier Ltd.

Robert Bergquist and Sara Lustigman

vaccine candidates would mainly be to influence transmission

Vaccine Development and Control of Helminthic Infections

Robert Bergquist and Sara Lustigman

when the parasite disintegrates. Protein polymorphism represents

10.2. TYPE OF VACCINES

Vaccine Development and Control of Helminthic Infections

10.3. VACCINE DESIGN

Robert Bergquist and Sara Lustigman

assistance in antigen discovery comes from the possibility of probing

10.3.1. Correlate studies

Vaccine Development and Control of Helminthic Infections

Robert Bergquist and Sara Lustigman

worse than those produced by potassium aluminium sulphate (alum), the

10.4. PROGRESS IN VACCINE DEVELOPMENT

Vaccine Development and Control of Helminthic Infections

of any human vaccine against parasites, veterinary vaccines should be tried

10.4.1. Cestode infections

Robert Bergquist and Sara Lustigman

challenge infection in four separate vaccine trials in pigs (Kyngdon et al.,

Vaccine Development and Control of Helminthic Infections

deliverables needs to be consulted to efficiently approach this goal, for

Robert Bergquist and Sara Lustigman

Vaccine Development and Control of Helminthic Infections

protease-haemoglobinase (APR-1) (Loukas et al., 2005) and glutathione

Robert Bergquist and Sara Lustigman

filarial parasite B. malayi has recently been published (Bennuru et al.,

Vaccine Development and Control of Helminthic Infections

(Allen et al., 2008), however, Litomosoides sigmodontis in mice and

Robert Bergquist and Sara Lustigman

Vaccine Development and Control of Helminthic Infections

More than a hundred schistosome antigens have been identified and

Robert Bergquist and Sara Lustigman

humans. Commercial interest in a vaccine for veterinary applications has

10.5. INDUSTRIAL VACCINE PRODUCTION

Vaccine Development and Control of Helminthic Infections

Robert Bergquist and Sara Lustigman

we are entering this phase is testimony to a series of successes in the

Vaccine Development and Control of Helminthic Infections

This may explain the rapid progress of vaccines against E. granulosus,

10.6. CONCLUDING REMARKS

Overview of candidates for some helminth vaccines

Antigen discovery Industrial scale-up

Phase III trial

Vaccine Development and Control of Helminthic Infections

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