Review series

Helminth infections:
the great neglected tropical diseases
Peter J. Hotez,1 Paul J. Brindley,1 Jeffrey M. Bethony,1 Charles H. King,2
Edward J. Pearce,3 and Julie Jacobson4
1Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington, DC, USA.
2Center for Global Health and Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA. 3Department of Pathobiology,
University of Pennsylvania, Philadelphia, Pennsylvania, USA. 4Bill and Melinda Gates Foundation, Seattle, Washington, USA.

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

Introduction tion with intestinal helminths, ascariasis, trichuriasis, and hook-

Helminths (the word is derived from the Greek meaning “worms”; worm, followed by schistosomiasis and LF (Table 1). Practically 
ref. 1) have plagued humans since before the era of our earliest speaking, this means that the inhabitants of thousands of rural,
recorded history. The eggs of intestinal helminths can be found in impoverished villages throughout the tropics and subtropics are
the mummified feces of humans dating back thousands of years often chronically infected with several different species of parasitic
(2–4), and we can recognize many of the characteristic clinical worm; that is, they are polyparasitized (12, 13).
features of helminth infections from the ancient writings of Hip- For reasons not well understood, compared with any other age
pocrates, Egyptian medical papyri, and the Bible (2–4). These same group, school-aged children (including adolescents) and pre-
helminthiases markedly altered the course of modern twentieth school children tend to harbor the greatest numbers of intestinal
century world history (2, 4–7), especially in China during the Cold worms and schistosomes and as a result experience growth stunt-
War, when the schistosome was known as “the blood-fluke that ing and diminished physical fitness as well as impaired memory
saved Formosa” (7) because acute schistosomiasis sickened Mao’s and cognition (14). These adverse health consequences combine to
troops and aborted their amphibious assault of Taiwan (histori- impair childhood educational performance, reduce school atten-
cally known as Formosa) just long enough for American ships to dance (15), and account for the observation that hookworm (and
enter the Straits of Taiwan (5–7). presumably other diseases caused by parasitic worms) reduces 
There are two major phyla of helminths. The nematodes (also future wage-earning capacity (16). Hookworm and schistosomia-
known as roundworms) include the major intestinal worms (also sis are also important diseases during pregnancy, causing neo-
known as soil-transmitted helminths) and the filarial worms that natal prematurity, reduced neonatal birth weight, and increased
cause lymphatic filariasis (LF) and onchocerciasis, whereas the maternal morbidity and mortality (17). Among some adult pop-
platyhelminths (also known as flatworms) include the flukes (also ulations living in impoverished areas of developing countries,
known as trematodes), such as the schistosomes, and the tape- onchocerciasis is a leading cause of blindness and skin disease,
worms (also known as the cestodes), such as the pork tapeworm that while LF is a major cause of limb and genital deformities. LF and
causes cysticercosis (Table 1). In 1947, Norman Stoll published a onchocerciasis, together with hookworm and schistosomiasis,
landmark paper entitled “This wormy world,” in which he set out to are also major determinants of reduced worker productivity (4,
estimate the number of people infected with helminths worldwide 18, 19). Such chronic, disabling, and often disfiguring effects of
(8). Over the last 60 years, several estimates have confirmed Stoll’s helminths translate into enormous poverty-promoting effects
initial observation that hundreds of millions of people harbor and represent a major reason why poor people remain mired in a
parasitic worms (9–11). Today, it is estimated that approximately  downward cycle of destitution (19).
one-third of the almost three billion people that live on less than Adding to the global morbidity that results from human hel-
two US dollars per day in developing regions of sub-Saharan Africa, minth infections are the observations that they have both direct
Asia, and the Americas are infected with one or more helminth (12, and indirect effects on malaria and HIV/AIDS in developing coun-
13). The most common helminthiases are those caused by infec- tries. In sub-Saharan Africa and elsewhere, helminthiases are fre-
quently coendemic with malaria (12, 20–22) and HIV/AIDS (12,
Nonstandard abbreviations used: LF, lymphatic filariasis; MDA, mass drug admin- 23–26). Indeed, it is not uncommon for an individual to be coin-
istration.
fected with the malaria-causing parasite and one or more parasitic
Conflict of interest: P.J. Hotez is an inventor on two international patent applica-
worm (22), or HIV and one or more parasitic worm (25, 26). Such
tions for a hookworm vaccine. P.J. Hotez and J.M. Bethony received funding from the
Bill and Melinda Gates Foundation through the Sabin Vaccine Institute. The remain- coinfections have additive effects, such as severe anemia (21), and
ing authors have declared that no conflict of interest exists. synergistic effects, such as increased transmission of the malaria-
Citation for this article: J. Clin. Invest. 118:1311–1321 (2008). doi:10.1172/JCI34261. causing parasite, HIV, and/or increased susceptibility to infection

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Table 1
The major human helminthiases and their global prevalence and distribution

Disease Major etiologic agent Global prevalence Regions of highest prevalence

Soil-transmitted nematodes
Ascariasis Ascariasis lumbricoides (roundworm) 807 million Developing regions of Asia, Africa, and Latin America
Trichuriasis Trichuris trichiura (whipworm) 604 million Developing regions of Asia, Africa, and Latin America
Hookworm Necator americanus; Ancylostoma duodenale 576 million Developing regions of Asia, Africa, and Latin America
(especially areas of rural poverty)
Strongyloidiasis Strongyloides stercoralis (thread worm) 30–100 million Developing regions of Asia, Africa, and Latin America
(especially areas of rural poverty)
Filarial nematodes
LF Wuchereria bancrofti; Brugia malayi 120 million Developing regions of India, Southeast Asia,
and sub-Saharan Africa
Onchocerciasis (river blindness) Onchocerca volvulus 37 million Sub-Saharan Africa
Loiasis Loa loa 13 million Sub-Saharan Africa
Dracunculiasis (guinea worm) Dracunculus medinensis 0.01 million Sub-Saharan Africa
Platyhelminth flukes
Schistosomiasis Schistosoma haematobium; 207 million Sub-Saharan Africa
Schistosoma mansoni; Sub-Saharan Africa and Eastern Brazil
Schistosoma japonicum (blood flukes) China and Southeast Asia
Food-borne trematodiases Clonorchis sinensis (liver fluke); >40 million Developing regions of East Asia
Opisthorchis viverinni (liver fluke);
Paragonimus spp. (lung flukes);
Fasciolopsis buski (intestinal fluke);
Fasciola hepatica (intestinal fluke)
Platyhelminth tapeworms
Cysticercosis Taenia solium (pork tapeworm) 0.4 million Developing regions of Asia, Latin America,
(Latin America only) and sub-Saharan Africa

with these pathogens as well as cause an exacerbated progression helminths as well as influence the development of new therapeu-
of these two killer diseases (12, 20–26). tics for other human illnesses.
The high medical, educational, and economic burden of hel-
minth infections, together with their coendemicity with malaria Epidemiology of helminth infections
and AIDS, provides an important rationale for launching a global With the exception of Strongyloides stercoralis, helminths do not
assault on parasitic worms (13). However, the tools we currently replicate within the human host. This fundamental aspect of hel-
have for controlling worm infections are limited; of the 1,556 minth biology establishes a set of transmission dynamics quite
new chemical entities marketed between 1975 and 2004, only different than those for viruses, bacteria, fungi, and protozoa.
four drugs — albendazole, oxamniquine, praziquantel, and iver- For example, prevalence, which is the proportion of persons in a
mectin — were developed to treat helminthiases (4, 27). Together defined population at a given time point infected with the hel-
with diethylcarbamazine (developed in the first half of the twenti- minth (28), is seldom used as the only measure to assess the epide-
eth century) and mebendazole, these drugs represent almost our miological situation for that helminth infection, because morbid-
entire pharmacopeia for combating the most common infections ity is associated with the number of worms infecting the host (i.e.,
in the world. The dearth of available anthelminthic agents partly the worm burden) rather than the absence or presence of infec-
reflects the very modest commercial markets for drugs targeting tion. Prevalence is commonly combined with worm burden (also
human helminth infections and partly reflects how remarkably lit- referred to as the “intensity of infection”), which is commonly 
tle we know about the unique biochemical metabolism of parasitic measured by the number of eggs per gram (EPGs) of feces for
worms and the mechanisms by which worms evade human host intestinal helminths and schistosomes (29). Based on EPGs and
defenses, establish chronic infections, and cause adverse maternal their association with morbidity, individuals are classified into cat-
and child health (14). Indeed, the diseases caused by infection with egories of light, moderate, and heavy infection by the WHO (30).
helminths are considered neglected tropical diseases, and the study Furthermore, in the case of soil-transmitted helminths, the WHO
of these diseases receives less than 1% of global research dollars recommends use of both prevalence and intensity of infection to
(4). Despite this, as we discuss here, recent advances by molecu- classify communities into transmission categories — category I
lar and immunological helminthologists have indicated that hel- (high), category II (medium), and category III (low). These trans-
minths are a rich source of interesting molecules that could lead mission categories are assigned according to both the number of
to innovation for almost all aspects of biomedicine. We hope that heavily infected people in the community (greater or less than
such information might one day translate into the development 10%) and the prevalence of infection (greater or less than 50%).
of new drugs, diagnostics, and vaccines to combat infection with For example, a community with greater than 50% prevalence but

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less than 10% heavy infection would be considered a category II  (46). Briefly, if age-infection data are compared across host popu-
transmission community. The WHO uses this information in lations, the peak level of infection intensity (e.g., EPGs for intesti-
algorithms to determine the type of mass treatment a community nal helminths) is higher and occurs in younger individuals when
should receive. For filarial helminths, the transmission status in transmission is also higher, but the peak intensity of infection is
a community is determined by assessing the number of people lower and occurs in older individuals when transmission is lower
with blood-circulating microfilariae or microfilarial antigen; in (46). This shift in the peak level of infection intensity and the age
the case of onchocerciasis, it is determined by counting the num- at which this peak occurs is consistent with mathematical models
ber of microfilariae in a skin biopsy or even counting the number that assume a gradually acquired protective immunity, an interpre-
of palpable nodules (30). It important to note that the quantita- tation supported by experimental studies in animals (46).
tive assessment of worms provides no information on whether Household clustering. Evidence for household clustering of infected
the infection represents either a recent or long-term infection nor individuals exists for most diseases caused by infection with a hel-
does it indicate either the length or extent of exposure to infection minth, including ascariasis (47), trichuriasis (47), and strongyloi-
(i.e., an individual residing near a source of transmission for many diasis (48, 49). This clustering can persist through time, as shown
years may not necessarily have high egg count despite extensive by familial predisposition to heavy infection with Ascaris lumbricoi-
exposure). There are several key determinants underlying the epi- des and Trichuris trichiura in Mexico (50). Household aggregation of
demiology of helminth infections. lymphatic filarial infection (individuals with LF and/or microfila-
Environment. Climate and topography are crucial determinants raemia) has been described in India and Polynesia (51, 52). In one
of the distribution of helminth infections (31). Helminths trans- study of schistosomiasis, shared household accounted for 22% of
mitted by vectors are limited to landscapes in which host and vec- the variance in S. mansoni egg counts (53). There is also some evi-
tor come together in the same habitat, resulting highly focal dis- dence for a similarity in antibody isotype level among family mem-
tribution. For example, the distribution of schistosomiasis reflects bers for crude schistosome antigen extracts, reflecting the degree to
the biotic and abiotic features (i.e., climatic, physical, and chemical which this phenotype might be influenced by genetic factors (54).
factors) that affect the survival and development of the snail vector Genetics. For a number of species of parasitic worms, it has been
(32). In the case of onchocerciasis, the distribution and incidence established that the intensity of infection is a heritable phenotype
of the disease are limited by biogeographic variations favorable (55). The most advanced research program investigating the iden-
to exposure to the blackfly vectors (33, 34). Soil-transmitted hel- tity of host genes that influence helminth infection involves schis-
minths are highly affected by surface temperature (35), altitude, tosomiasis. The first genome scan for a helminth infection identi-
soil type, and rainfall (36, 37). fied linkage of intensity of infection with S. mansoni in a Brazilian
Heterogeneity. Heterogeneity in the worm burden among dif- population to the chromosomal region 5q31–q33 (56), and sub-
ferent individuals infected with the same helminth is a hallmark sequent confirmation of this link was established in a Senegalese
feature of helminth epidemiology (38). A consequence of such het- population (57). The 5q31–q33 region includes loci for numer-
erogeneity is the aggregated distribution of helminth infection in ous immune response genes, including those encoding the Th2
endemic communities, such that a small proportion of hosts are cytokines IL-3, IL-4, IL-5, IL-9, and IL-13, interferon regulatory
rapidly, frequently, and/or heavily infected (38, 39). For example, factor 1, colony-stimulating factor 2, colony-stimulating factor 1
70% of the worm burden occurs in 15% of the infected individuals receptor, and the IL-12/IL-23 p40 subunit (55). Genes controlling
at a given time point (40). The aggregated distribution of helminth IgE production, asthma, malaria parasitaemia, and inflammatory
infection has led some to hypothesize that certain “wormy” people bowel disease, among others, have also been mapped to this region
are “predisposed” to heavy infection from as yet undefined genetic, of chromosome 5, although the causative polymorphisms have
immunogenetic, ecological, behavioral, and social factors (41). Pre- not yet been identified.
disposition refers to studies in which intensity of infection prior Polyparasitism. Finally, an increasing number of studies of helminth
to anthelminthic treatment positively correlates with intensity of epidemiology have shown that it is common for individuals to be
reinfection 12–24 months after treatment (41). The bases of both infected with more than one species of helminth (21, 58–63). There
heterogeneity and predisposition to helminth infection have yet is also evidence suggesting synergism and antagonism in concur-
to be fully elucidated. However, among the major factors under rent intestinal nematode and schistosome infections (62–64) as well
consideration are age, household clustering, and genetics. as filarial nematode infection and soil-transmitted helminth infec-
Age dependency. Much epidemiologic research has focused on tions (65). A number of epidemiological studies have indicated that
heterogeneity in the intensity of helminth infection by age (42). individuals infected with multiple species of helminth often harbor
Changes with age in the average intensity of infection tend to be heavier infections than individuals infected with a single helminth
convex, rising in childhood and declining in adulthood. For Asca- species (58–61). An important consequence of simultaneous infec-
ris lumbricoides and Trichuris trichiura, the heaviest and most fre- tion with the parasites that cause hookworm, schistosomiasis, and
quent infections are in children aged 5–15 years, with a decline malaria is severe anemia (21, 66). It has also been speculated that hel-
in intensity and frequency in adulthood (43). Similarly, for all the minth infections may adversely influence host immune responses 
major schistosomes, the heaviest and most frequent infections are to the malaria-causing parasite and other pathogens (20).
in older children aged 10–15 years (44). In contrast, hookworm
frequently exhibits a steady rise in intensity of infection with age, Burden of helminthiases
peaking in adulthood (45). Similarly, the pathologic events that Most helminth infections, if left untreated, result in multi-year,
occur with filarial infections also predominate in adulthood. chronic inflammatory disorders that cause both concurrent and
Some of the strongest evidence for protective immunity to human delayed-onset pathology to the afflicted human host (67–69).
helminth infection has come from epidemiological observations In addition to the overt and dramatic effects of blindness and
of a “peak shift” in prevalence and intensity of infection with age elephantiasis in individuals with onchocerciasis and LF, respec-

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tively, it is now appreciated that chronic helminth infections are Helminth immunobiology
also linked to more insidious persistent health conditions such as The reduction in the intensity of some human helminth infections
anemia, growth stunting, protein-calorie undernutrition, fatigue, with age might be indicative of host immunity. Immune responses 
and poor cognitive development (68). These seemingly subtle and to helminths are intriguing not only from the perspectives of
often overlooked morbidities are very important because of the understanding protective immunity and immunopathology, but
high prevalence of helminthiases in the rural developing world, in also because a major branch of the mammalian immune system,
which any health impairment is substantially magnified in terms type 2 immunity, seems to have evolved specifically to deal with
of degradation of individual patient performance status (70). this class of pathogens. Type 2 immunity involves the rapid activa-
Initially, in childhood, it is the presence of helminth infection tion and engagement of cells of both the innate (eosinophils and
and the intensity of infection that determine the risk for disease basophils) and adaptive (CD4+ T cells that commit to the Th2 path-
formation. It is also true that for many of the tissue-invasive hel- way) immune systems (77). Cells of both the innate and adaptive
minths, such as the schistosomes and filariae, tissue damage can immune systems that are involved in type 2 immunity share the
continue into later adult life, with disease persisting and even ability to synthesize the core type 2 cytokine IL-4, which mediates
increasing long after the infection is cleared. As such, measures (both directly and indirectly) the reactions that historically have
of infection prevalence do not capture the prevalence of infection- been considered to be symptomatic of helminth infection such as
associated disease, particularly in adult life. Conditions such as IgE production, eosinophilia, and changes in the physiology of tar-
elephantiasis, which occurs in individuals with LF; visual impair- get organs (e.g., the intestine and lungs) that are associated with
ment, which occurs in individuals with onchocerciasis; peripor- goblet cell hyperplasia and smooth muscle contraction (78).
tal fibrosis and hypertension, which occur in individuals with Based on findings from studies of infections in humans and
intestinal schistosomiasis; biliary obstruction, cholangitis, and mouse models of helminth infections, we know that, depending
cholangiocarcinoma, which occur in individuals with food-borne on the infection in question, type 2 immune responses can prevent
trematodiasis; and urinary obstruction and bladder cancer, which the survival of infecting parasites during a homologous secondary
occur in individuals with urinary schistosomiasis, are potentially infection (79), expel adult parasites from the gut (78), allow host
the most life-threatening consequences of helminth infections. survival in a setting where the immune response cannot clear the
Although most likely to contribute to hospitalization and to cause parasites (80), and/or mediate pathological fibrotic responses (81).
mortality, these advanced outcomes are rare when compared to Fibrosis has its origins in the wound-healing responses that must
the disease burden of the average patient, which is characterized be required on an ongoing basis in animals chronically infected
by the subacute morbidities detailed earlier. with pathogens that cause large amounts of tissue damage, such
The temporal lag between initial high-intensity childhood as most helminths (82).
infection and the delayed onset of “classical” parasite-associated In key ways, our understanding of type 2 immunity has lagged
pathologic findings have led to a serious underappreciation of the behind that of type 1 immunity (which encompasses Th1 cells) and
day-to-day burden of helminthic diseases. In international health even of the more recently defined Th17 cells and Tregs. In each of
assessments based on the disability-adjusted life year (DALY) met- these cases, a set of cytokines made by cells of the innate immune
ric (71), DALY calculations are weighted to stress diseases preva- system, often in response to the ligation of TLRs by a component
lent among adults in the 20–40 age group, and therefore diseases of a pathogen, strongly promotes the development of defined
arising primarily in childhood carry far less weight (72). In the cur- CD4+ T cell lineages that in productive immune responses are
rent Global Burden of Disease (GBD) assessments by the WHO, appropriate to the particular situation. Thus, we know that IFN-γ
it is not clear whether prevalence of infection per se was used to and IL-12 can promote Th1 responses; TGF-β, IL-6, and IL-23 can
gauge the disease burden of helminths or the more appropriate promote Th17 cell development; and TGF-β alone plays a role in
duration of infection-associated pathology, which is often irrevers- driving Treg development (83, 84). Although we know that IL-4
ible. The DALY disability weights assigned to specific helminth and IL-13 are important for Th2 cell development, the production
infections were developed by nonpatient committees based on of these cytokines by innate immune cells seems to play little part
disease scenarios that did not reflect what we now appreciate as in promoting the initiation of Th2 responses, and it has been clear
the full spectrum of helminth infection–associated pathology (71). that other crucial, yet ill-defined, conditions are important in this
Although efforts are underway to revise the GBD assessments (73), process. Recent work in type 2 immunity, largely involving excel-
it is important that we do not underestimate the substantial dis- lent mouse models of human helminthiases and studies of allergy
ease burden of more than one billion individuals worldwide who and asthma, which share with helminth infections an association
are affected by helminth infections. with type 2 immune responses, has begun to shed light on some
A new focus for assessing the health burden related to helmin- of these issues. For example, it is now clear that in addition to IL-4, 
thic diseases has been the adoption of patient-based quality-of-life IL-13, IL-5, IL-9, and IL-10, Th2 cells can make IL-25 and IL-31,
(QoL) interview techniques for assessing disease burden across and that these two cytokines can have crucial roles in promoting
many international settings (74, 75). Although health-related QoL and/or regulating Th2 immune responses (85, 86). There have also
is in some sense a cultural construct, and subjective adaptation been substantial developments in understanding how the induc-
to physical impairments is likely to vary from region to region, tion of type 2 immune responses is influenced by other cells, spe-
certain universal features of disease impact can be identified. cifically through the recognition that thymic stromal lymphopoi-
Implementation of QoL assessment for most prevalent diseases, etin (TSLP), synthesized by epithelial cells, can condition dendritic
and the subsequent use of quality-adjusted life years (QALYs) for cells to promote Th2 cell development (87). Lastly, there has been
comparison of disease impacts (76), is likely to provide the most considerable progress in identifying genes that are expressed in
useful comparison of disease burdens across different societies response to stimulation by cytokines produced by Th2 cells and
and their economies. in defining the roles of the products of these genes as effectors of

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Th2 immunity as well as inducers and regulators of Th2 immune lowing the release recently of reasonably comprehensive descrip-
responses. Among these gene products are intelectins, arginases, tions of their transcriptomes (100, 101) and the proteome of 
resistin-like molecules (RELMs), and chitinases (88). Indeed, the S. japonicum (102). Schistosomes have sizeable genomes. The hap-
coordinated production of members of the latter three classes of loid genome of S. mansoi is estimated to be approximately 300 Mb,
molecules by macrophages exposed to IL-4 and/or IL-13 is a fea- arrayed on seven pairs of autosomes and one pair of sex chromo-
ture of the “alternative activation” pathway executed by these cells somes (103). For comparison, this genome size is about ten times
during helminth infections. This is an area of great current interest that of the genome of the malaria-causing parasite Plasmodium fal-
(89), especially since recent reports have highlighted the protective ciparum and one-tenth the size of the human genome. Schistosoma
effects of these cells during helminth infections (80, 90). haematobium and S. japonicum, the other major schistosome species
How more recently discovered components of type 2 immune that parasitize humans probably have a genome size similar to that
responses, such as IL-25 and IL-31, participate in host protective of S. mansoni, based on the similarity of their karyotypes (103). The
and immunopathologic processes is only just beginning to be S. mansoni genome is AT-rich (60%–70% AT in the euchromatin),
examined using helminth infections in the mouse (91–94), and replete with repetitive sequences. The approximately 13,000 pro-
little has been done as of yet to explore these pathways in humans tein-encoding genes include several, sometimes numerous, introns
infected with helminths. This is a target area for emphasis in ranging in size from small to very large. The complexity of the pro-
immunologic research on helminths in the near future, both in teome is expanded by the presence of single nucleotide polymor-
terms of increasing our understanding of the basic immunobiol- phisms, trans-splicing of a subset of the transcriptome, and alterna-
ogy of infections with these parasites, but also and more impor- tive splicing of some genes (reviewed in ref. 104).
tantly, as a means to improve attempts directed toward the ratio- The draft genome sequence of the filarial nematode parasite Brugia
nal development of vaccines and immunotherapeutics. malayi was reported recently (105). This was a landmark in human
Many helminthiases are chronic diseases, and it remains unclear parasitology as it represented the first genome sequence of a para-
how the Th2 immune response is regulated during the course of sitic helminth to be deciphered. B. malayi has a genome of 90 Mb,
these long-term infections, during which antigen loads remain with a compliment of 14,500–17,800 protein-encoding genes. As in
high and pathology is, at least in part, immune mediated (95). the free-living nematode Caenorhabditis elegans and many bacteria, a
There is great interest in the possibility that Tregs play a role in number of the B. malayi genes are organized into operons — units of
these processes, perhaps in combination with unusual immuno- transcription wherein several genes are regulated by the same pro-
regulatory helminth-derived products (96), and that such regula- moter, thereby enabling the cell or organism to facilitate global gene
tion underlies the reverse correlations between infection with a expression in response to stimuli and environmental conditions.
helminth and asthma, allergy, and certain autoimmune diseases The genome sequence of no parasitic nematode other than 
that have been reported in a growing number of studies (some- B. malayi has been completed. However, the draft genome sequence
thing that is known as the hygiene hypothesis) (97, 98). This for B. malayi offers a broad foundation for rational intervention
remains a key area for further exploration, not only in the hope for both filariae and parasitic nematodes at large. Comprehensive
that understanding the regulatory response will allow interven- analyses of the transcriptomes and genomes of a number of other
tion to enhance immune responses and decrease infection, but medically important parasites, including hookworms and Trichi-
also because of the potential therapeutic use of helminth regu- nella spiralis, are in progress (106, 107). Through both genomics
latory strategies for other disorders. Indeed, understanding how and more conventional biochemical methodologies, bioactive pro-
helminth infections regulate inflammation could promote new teins with remarkable therapeutic potential have been identified
approaches for the development of therapeutics for a wide variety and isolated from hookworms and other nematodes (reviewed in
of inflammatory conditions. ref. 108). These include a novel factor VIIa/tissue factor inhibitor
and a neutrophil inhibitory factor, which have undergone clinical
Helminth genomics, postgenomics, trials with beneficial and promising outcomes for human throm-
and gene manipulation botic disease (109–112). These successes serve to emphasize that
Deciphering the genetic code of helminth parasites will allow us genomic studies of the parasitic helminths are likely to lead to new
to understand the fundamental nature of these pathogens and the treatments for disease, including diseases not directly caused by
pathogenesis of the diseases that they cause. Genetic manipulation helminth pathogens.
of helminth genomes, including transgenesis approaches, offers Gene manipulation by RNA interference. Until recently, gene manip-
a means to determine the importance of specific helminth genes ulation approaches had not been seriously considered as tools to
in disease pathogenesis, including those that could be targeted by learn more about helminth-encoded proteins that might be inter-
novel therapeutic interventions. vention targets. This situation is now changing in response to the
Genomics. Helminth parasites have large complex genomes. In gen- availability of genome sequences and other advances. RNAi tech-
eral, for both nematodes and platyhelminths, genome size ranges  nology has revolutionized investigation of the role and importance
from approximately 50 to 500 Mb, with up to 20,000 protein- of genes in model organisms such as C. elegans. Methods developed
encoding genes. This genome size is comparable to that of insects. for RNAi in C. elegans are now being deployed in schistosomes
Several helminth parasites have become the focus of endeavors aim- and some parasitic nematodes. Skelly and coworkers established
ing to determine entire genome sequences. Information from these the feasibility of experimental RNAi in S. mansoni by describing
sequencing projects will facilitate determination of function and knockdown of the gut-associated cysteine protease cathepsin B
importance of genes or groups of genes in cellular and biochemical by soaking larval schistosomes in dsRNA that effects RNAi (113).
pathways and their role in the host-parasite relationship. Krautz-Peterson et al. extended these studies by comparing and
It is anticipated the complete genomes of Schistosoma mansoni and optimizing RNAi methodology (114). They reported that square-
Schistosoma japonicum will be reported within the next year (99), fol- wave electroporation was dramatically more efficient than either

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soaking the parasites in an equivalent dsRNA dose or soaking helminths that are known to mediate and modulate host immu-
them in an equivalent dsRNA dose in the presence of liposomes. nological responses to these parasites (131, 132). Moreover, tech-
They also demonstrated that small, interfering RNAs were as niques from developmental biology and other disciplines, such as
effective as longer dsRNAs. Other reports have confirmed the util- whole mount in situ hybridization (WISH) and gene microarrays,
ity of RNAi in schistosomes to address gene function and impor- have now been established as crucial tools for investigating the
tance (115–117). Indeed, RNAi has been used to demonstrate a function of helminth genes and proteins (133–135).
crucial role for S. mansoni inhibin/activin (SmInAct; a member
of the TGF-β receptor family) in embryogenesis; knockdown of Global control of helminthiases
SmInAct expression in eggs aborts their development (118). Given and clinical research imperatives
that eggs are responsible for the pathology of schistosomiasis, Beginning with the widespread use of the drug diethylcarbamazine
this protein is a potential therapeutic intervention target. As gene for the treatment of LF in China during the 1970s, the mass treat-
silencing by RNAi in schistosomes has been reported to deliver a ment of human populations with anthelminthic drugs, known as
specific effect, with no obvious or widespread nonspecific effects mass drug administration (MDA), has been a major approach to
on nontarget genes, gene manipulation by RNAi might have wide controlling human helminthiases in developing countries (13).
applicability and promote functional schistosome genomics. The During the late 1980s, the first public-private partnership was
latter are expected to improve our knowledge of the function of formed to provide MDA of ivermectin to African populations at
schistosome gene products and lead to new interventions for risk for onchocerciasis (13), and since then the mainstay of global
treatment and control. worm control has been MDA of anthelminthic drugs through the
In contrast to work with schistosomes, RNAi in parasitic nema- activities of public-private partnerships, using either drugs donated 
todes has had limited success or has been unsuccessful (119, 120). by multinational corporations or low-cost generic drugs (Table 2).
Given the importance of RNAi in revolutionizing our understand- An important stimulus for these partnerships has been a series of
ing of the biology of the C. elegans, this overall lack of success for resolutions adopted at the World Health Assembly — the major
parasitic nematodes has so far been a disappointment for the decision-making body for the WHO, which meets annually and
molecular helminthology community. The physiological basis for is attended by delegates from each member nation — calling for
the poor performance of RNAi in parasitic nematodes might relate MDA to control or eliminate one or more helminth infections of
to an absence of pivotal RNAi pathway components, as evidenced global importance. Since 2006, several partnerships committed
by the absence in B. malayi of the gene encoding the Sid-1 mem- to MDA have formed an alliance, which is known as the Global
brane channel that is involved in dsRNA uptake (105, 121). Network for Neglected Tropical Diseases and aims to increase effi-
Transgenesis. Gain-of-function approaches with reporter trans- ciencies and produce economies of scale by delivering a package of
genes, for example transgenes encoding either jellyfish GFP or drugs that simultaneously targets the six most common human
firefly luciferase, have also been investigated in parasitic worms. helminthiases (ascariasis, trichuriasis, hookworm, schistosomia-
Monitoring the expression of the reporter protein provides infor- sis, LF, and onchocerciasis) as well as trachoma (13). Because of its
mation on the progress of the transgenesis procedures. In para- low cost and cost savings, integrated helminth control has become
sitic nematodes, reporter gene activity driven by exogenous and highly attractive to both global policy makers and donors.
endogenous gene promoters has been demonstrated in B. malayi, In resource-poor settings with a substantial burden of helmin-
S. stercoralis, and Parastrongyloides trichosuri (122–124). In addition, thiases, it has become a common practice during MDA to treat
heritable transmission of plasmid-based transgenes has been individuals regardless of whether or not they are currently infect-
reported (123, 124). Similar findings have been described in schis- ed with the disease-causing parasitic worm. However, based on a
tosomes, and stage- and tissue-specific expression of schistosome mixed legacy of relying on drugs to control or eliminate a wide-
genes has been investigated using reporter transgenes driven by spread infectious disease, such as malaria, there are concerns that
the promoters of schistosome genes, including cathepsin L (125). emerging drug resistance or other factors could derail global efforts
Recently, Brindley and coworkers have described somatic trans- to implement MDA, integrated or otherwise (13). These concerns,
genesis of S. mansoni facilitated by either the piggyBac transposon together with a need to better understand a number of fundamen-
(126) or the murine leukemia retrovirus (127), including the first tal clinical and epidemiological aspects of human helminth infec-
demonstration of integration of reporter genes into the chromo- tions as well as their interactions with geographically overlapping
somes of a parasitic worm. coinfections (e.g., malaria and HIV/AIDS) have created an urgency
Proteomics, glycomics, and metabolomics. Proteomic analyses in par- for stepped up clinical research activities as they relate to large-
asitic helminths are not as advanced as genomic or transcriptomic scale helminth control. Such activities have focused around three
studies, but these aspects, along with glycomics and metabolomics, major areas: first, a reexamination of the health impact of human
have now begun to be addressed. For example, proteomic analysis helminthic infections, with particular interest in the effects of
of the tegument of adults, the excreted and secreted products of mono- and polyparasitism on childhood growth and develop-
adults, and the egg shells of S. japonicum and S. mansoni have yield- ment as well as their effects on pregnancy and birth outcomes (63,
ed several thousand proteins, many of which have been putatively 136–140); second, large-scale monitoring and evaluation of MDA
identified and many of which are much more closely related to and integrated control, along with operational research with goals
the orthologous host proteins than to orthologs of invertebrates to improve the access of populations to anthelminthic drugs and
(102, 128). Proteomic investigations have also revealed differences to monitor for possible drug resistance (141–145); and third, the
between the secretome of Trichinella spiralis and that of Trichinella development of new tools to control helminth infections, that is,
pseudospiralis (129) as well as the plasticity of the proteome of gut- drugs, diagnostics, and vaccines (19, 146).
dwelling nematodes in response to immunological pressure (130). For purposes of MDA and integrated control efforts, current
Glycomics will provide information about the glycan structures of synthesis of the available study data has culminated in a recently

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Table 2
Major global helminthic disease control initiatives

Disease(s) Public-private partnership Major drug or control tool Target date control
by WHA resolution
LF Global Alliance to Eliminate LF (GAELF) Diethylcarbamazine and albendazole; 2020
ivermectin and albendazole
Onchocerciasis African Programme for Onchocerciasis Control (APOC); Ivermectin 2010
Onchocerciasis Elimination Program of the Americas (OEPA)
Schistosomiasis Schistosomiasis Control Initiative (SCI); Praziquantel 2010
Partnership for Parasite Control (PPC)
Soil-transmitted Partnership for Parasite Control (PPC); Albendazole or mebendazole 2010
  helminth infections Schistosomiasis Control Initiative (SCI);
Human Hookworm Vaccine Initiative (HHVI)
Ascariasis, trichuriasis, Global Network for Neglected Tropical Ivermectin or diethylcarbamazine; praziquantel; 2015
  hookworm, schistosomiasis, LF, Diseases (GNNTDC) albendazole or mebendazole;
  onchocerciasis, and trachoma and azithromycin

issued set of WHO guidelines (147). Parallel studies are examining Wuchereria bancrofti and Onchocerca volvulus harbor bacterial endo-
the added benefits of micronutrient supplementation, particularly symbionts of the genus Wolbachia and depend on these endosym-
in combating the anemias associated with hookworm and schisto- bionts for normal metabolic and reproductive activities, there is
somiasis (148, 149). Other studies are specifically examining the excitement about the development and use of antibiotics to target
impact of infection among women who are pregnant and women adult filarial worms (168). This is of particular importance because
of child-bearing age, risk groups who are often excluded from MDA to date there is no effective drug that targets the adult stage of
because of fears of fetal toxicity (136, 150, 151), or they are examin- these parasitic worms.
ing the early developmental effects of helminthic infections among In parallel with drug discovery efforts are two anthelminthic
preschool children (152). Despite the evident success of MDA, limi- vaccine development efforts, each conducted by a dedicated prod-
tations have been observed in the effectiveness of treatment in some uct-development partnership. For hookworm, the high rate of
field settings, and concern has been raised about the potential for drug failure for single-dose mebendazole as well as rapid reinfec-
emergence of resistance to the mainstay drugs of MDA programs, tion and the possible emergence of drug-resistant parasites have
including the benzimidazole anthelminthic, used predominantly stimulated efforts by the Human Hookworm Vaccine Initiative
to combat soil-transmitted helminth infections, and ivermectin, to develop a bivalent vaccine comprised of recombinant hook-
which is used to combat filarial infections (146, 153–158). How- worm vaccine antigens that target the infective larval stages and
ever, with the exceptions of β-tubulin as a biomarker to determine adult blood-feeding stages (146, 169, 170). Currently, one larval
nematode resistance to the benzimidazoles mebendazole and antigen is being evaluated in a phase 1 clinical trial in a region of
albendazole (159) and possibly ABC transporters and β-tubulin Brazil that is endemic for hookworm and a second adult hook-
as biomarkers for determining resistance to ivermectin and other worm antigen is about to enter into clinical trials (170). Related
macrocyclic lactones (160), we lack robust biomarkers for detecting antigens are also being used to develop recombinant onchocer-
resistance to most anthelminthic drugs. ciasis vaccines (171). In addition, the Institut Pasteur is conduct-
Despite the remarkable successes of MDA programs, disease ing clinical trials in sub-Saharan Africa using a recombinant
elimination is often not obtained in highly endemic areas, and vaccine (encoding a glutathione S-transferase) to protect against
research on new drugs (and means for their successful imple- infection with S. haematobium (172). A surface protein encoding a
mentation) is clearly needed to maintain and expand effective novel tetraspanin is also awaiting early development as a vaccine
control. In the coming decade, the mining of newly completed to protect against infection with S. mansoni (173). Ultimately, it
helminth genomes should help to facilitate the discovery of new is anticipated that anthelminthic vaccines are likely to be used
anthelminthic drugs. In the meantime, recent animal and clinical alongside drugs in an integrated program linking vaccination
studies have documented the efficacy of artemether compounds with chemotherapy (146, 174).
for treating the early phases of schistosome infection (161) and a
new broad-spectrum agent known as tribendimidine for treating Concluding comments
soil-transmitted helminth infections (162). New classes of cyste- The recent developments in molecular and medical helminthology
ine protease inhibitors are being developed as anthelminthic and could relatively soon be translated into a new generation of anthel-
antiprotozoal drugs (163), and other studies have indicated the minthic therapeutics. Based on advances in schistosome genom-
efficacy of triclabendazole for infection with the difficult to treat ics, a family of promising schistosome vaccine antigens has already
liver fluke Fasciola hepatica (164, 165). Human and animal stud- been identified (173) and ultimately could be formulated into a
ies also suggest that tribendimidine will prove effective against schistosomiasis vaccine. Such a vaccine could be used together
food-borne flukes (166) and the drug moxidectin might become with a hookworm vaccine. At the same time, the recently revealed
an alternative to ivermectin for the treatment of filarial infections importance of Wolbachia endosymbionts is helping to launch new
(167). Finally, based on the observation that the filarial parasites drug discovery efforts for the treatment of LF and onchocerciasis

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review series

as well as treatment programs based on either existing or new anti- vaccines or new drugs are developed for human helminthiases,
biotics (168). The recent completion of the filarial genome might we must rely on a tiny pharmacopeia of existing drugs. Currently,
soon yield additional drug targets (105). Revelations within the integrated control of the six most common human helminthia-
last five years about the impact of helminthiases on the transmis- ses, which affect approximately one billion people in developing
sion of the pathogens that cause malaria and HIV/AIDS and on countries, depends on the availability and effectiveness of just four
the progression of these diseases (12), suggest that deworming and drugs — albendazole, mebendazole, praziquantel, and ivermectin.
other large-scale anthelminthic measures might promote impor- Adequate resources need to be set aside for the development of
tant “back-door” approaches for controlling them (12, 13). genetic resistance markers and for careful monitoring and evalu-
At the same time, our enthusiasm for seeing helminthological ation of large scale programs if we are to preserve these agents as
science translate into new interventions needs to be tempered public health control tools. Finally, in the absence adequate of new
because of some sobering elements. First, despite these new support for helminthology training, we risk losing a generation of
advances, overall, we are still at a relatively nascent stage of hel- whole-organism scientists who have the skills to study both the
minth translational research and development. The development parasites and the diseases they cause. Because of the enormous
of in vitro methodologies and high throughput technologies for benefits in human capital that would result from investing in
studying helminths has not, for the most part, kept up with the the study of fundamental and translational helminthology and
generation of parasitic helminth genomic and other bioinformatic because access to anthelminthic interventions has now been rec-
databases. Until there is greater investment of scientific horsepower  ognized as a fundamental human right (176), we believe that now,
and funds into fundamental helminthology research, we are still more than ever, the scientific and global public health communi-
a way off using the reverse genomic and vaccinology approaches ties should address the neglected status of the helminthiases and
that have benefited modern bacteriology. Second, because worm prioritize their study.
infections occur almost exclusively among the poorest people of
the world, there are no market incentives for mining bioinfor- Acknowledgments
matic databases for anthelminthic drug and vaccine discovery. The authors acknowledge with gratitude the editorial assistance of
Therefore, unless there is financial innovation for the poor or a Sophia Raff and Julie Ost. The authors are supported by grants from
paradigm shift by the multinationals in orphan drug development the Sabin Vaccine Institute and the Bill and Melinda Gates Foun-
for developing countries, we must either rely on the existing vet- dation (P.J. Hotez and J.M. Bethony), Geneva Global (P.J. Hotez),
erinary pipeline of new anthelminthics feeding into the human and National Institute of Allergy and Infectious Diseases, NIH (P.J.
pipeline or we need to expand the role of nonprofit product-devel- Hotez, P.J. Brindley, C.H. King, E.J. Pearce, and J.M. Bethony).
opment partnerships (4, 13, 146). Critical to the success of new
anthelminthic interventions is likely be North-South partnerships Address correspondence to: Peter J. Hotez, Department of Micro-
with so-called “innovative developing countries,” i.e., economically  biology, Immunology, and Tropical Medicine, George Washington
disadvantaged nations endemic for neglected tropical diseases University School of Medicine and Health Sciences, 2300 I Street
such as Brazil, China, and India, which have nonetheless achieved NW, Washington, DC 20037, USA. Phone: (202) 994-3532; Fax:
a high level of biotechnological sophistication (175). Third, until (202) 994-2913; E-mail: [email protected].
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