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Old herborn university monograph 24 article 5Old Herborn University Seminar Monograph 24: Development of strategies to overcome barriers to effective mucosal immunization of infants in developing countries. Editors: Peter J. Heidt, Richard I. Walker, and Volker Rusch. Old Herborn University Foundation, Herborn-Dill, Germany: 51-60 (2010).
GEOHELMINTH INFECTIONS MAY HAVE DELETERIOUS EFFECTS
ON IMMUNITY TO ORAL VACCINES
PHILIP J. COOPER Liverpool School of Tropical Medicine, Liverpool, United Kingdom, and Colegio de Ciencias de la Salud, Universidad San Francisco de Quito, There is compelling evidence that immune responses to mucosal vac- cines are impaired in non-affluent populations living in the Tropics and enteric co-infections such as geohelminths may contribute to this effect. Geohelminths have been associated with impaired immune re- sponses to the live attenuated oral cholera vaccine CVD 103-HgR and treatment for geohelminths prior to vaccination partially reversed the impaired immune responses. Other factors such as host nutrition and the presence of environmental enteropathy with which geohelminth infections are associated are likely to contribute also to this tropical barrier to mucosal immunization. There is a need for research on the mechanisms by which geohelminths may suppress immunity to mu- cosal vaccines and such research could contribute to the development of more effective mucosal vaccines. The geohelminth (also known as intes- larly among pre-school and school-age tinal or soil-transmitted helminth in- children in whom infections are associ- fections) parasites, Ascaris lumbricoi- ated with adverse effects on nutrition, des, Trichuris trichiura, hookworm, growth, and cognition (Bethony et al., and Stronglyoides stercoralis, are 2006). The level of morbidity caused common infectious diseases of child- by geohelminth infections is strongly hood in tropical regions, particularly associated with parasite burden (Ander- among populations living in poverty son and May, 1985) that is greatest with poor access to sanitation and clean among children. water. In endemic areas, geohelminth Geohelminth infections induce an infections are chronic infections and immune responses in humans charac- individuals generally become infected terized by elevated IgE and eosino- during the second year of life and re- philia and the production of Th2 cyto- main infected into adulthood through kines by peripheral blood leukocytes repeated infectious exposures. An es- (PBLs) when stimulated with parasite timated 2 billion humans are infected antigen in vitro (Cooper et al., 2000a; with geohelminths worldwide (Savioli Cooper et al., 2008). Chronic infections et al., 2005). Infections are considered are associated with a tightly regulated to cause significant morbidity particu- inflammatory response in which anti- parasite allergic reactions appear to be 2001; Elias et al., 2001). Because many suppressed (Maizels and Yazdan- mucosal vaccines are poorly immuno- bakhsh, 2003; Cooper, 2009a). Such a genic among poor populations living in response reflects a stated of balanced the Tropics, an observation that has parasitism allowing the parasite to sur- been referred to as a mucosal barrier to vive but protecting the host from po- tentially damaging immunopathology.
(Czerkinsky and Holmgren, 2009), There is evidence that the regula- there is growing awareness of how en- tion of host immunity by chronic geo- teric parasites such as geohelminths helminth infections may affect re- may contribute to such an effect sponses not just to parasite antigens but through their effects on the intestinal also other exogenous antigens such as the antigenic constituents of vaccines (Czerkinsky and Holmgren, 2009; Coo- (Malhotra et al., 1999; Cooper et al., per, 2009b). STUDIES OF EFFECTS OF GEOHELMINTH INFECTIONS ON MUCOSAL IMMUNITY IN CHILDREN Geohelminth parasites have intimate faeces and saliva) and peripheral blood contact with the mucosal immune sys- for sampling of B and T cells that traf- tem being separated from the intestinal fic between mucosal sites after mucosal tissues by a single layer of epithelium.
vaccination (Lewis et al., 1991; Although there are extensive data Castello-Branco et al., 1994; Wasser- available from experimental animals of man et al., 1994). Developments such the mucosal immune response to intes- as wireless endoscopy will allow the tinal helminth infections, such data easier sampling of intestinal mucosa in from human populations are limited. future studies although such technology This is because of difficulties in ac- is rarely available to researchers cessing mucosal tissues in humans al- working in populations where geo- though useful data can be obtained by helminth infections are present. collection of mucosal secretions (e.g. CHANGES IN THE INTESTINAL MUCOSA ASSOCIATED WITH GEOHELMINTH INFECTIONS The expulsion of intestinal helminth called epithelial escalator (Artis and parasites in animal models has been Grencis, 2008). Such alterations make associated with marked changes in the the intestinal lumen a hostile environ- intestinal mucosa characterized by vil- ment and reduce the surface area for lous atrophy, crypt hypertrophy, and parasite attachment. Both parasite ex- increases in mucous-secreting goblet pulsion and intestinal enteropathy are cells (Finkelman et al., 1997; Anthony considered to be Th2-dependent proc- et al., 2007). The intestinal epithelium esses (Garside et al., 2000; Anthony et proliferates so that parasites that live partly or completely in the epithelium There are limited data from humans (e.g. Trichinella spiralis and Trichuris on the histological changes in the in- spp.) are shed into the gut - the so- testine associated with geohelminth infections. Geohelminth parasites that Chronic infections may be associated dwell in the small intestine, A. lumbri- with minimal inflammatory response in coides, hookworm, and S. stercoralis, the mucosa and mild histologic altera- have been associated with enteropathy tions (e.g. partial villus atrophy) re- although generally the mucosa appears flecting active immune regulation by histologically normal (Arean and host and or parasite. Chronic infections Crandall, 1971; Burman et al., 1970; in a few individuals may be associated O'Brien, 1975; Garcia et al., 1977) in with severe inflammation (e.g. TDS) individuals living in endemic areas. A but most children are likely to be as- minority with chronic infections show ymptomatic. Chronic infections down- changes of partial villous atrophy, crypt regulate inflammatory responses in the hyperplasia and increased inflamma- intestinal mucosa to avoid the long- tory infiltrate in the lamina propria term consequences of an inflamed in- (Burman et al., 1970). Humans infected testinal mucosa on host nutrition. Dur- experimentally with hookworm larvae ing initial infections, benefit to the host develop eosinophilic enteritis (Croese may be obtained by mounting strong et al., 2006), although this inflamma- inflammatory responses to expel para- tion tends to largely resolve after re- sites. The findings of partial villus at- peated infections (Croese and Speare, rophy and crypt hypertrophy in the 2006). T. trichiura that inhabits the small intestine (Keusch et al., 1972; large intestine has been more exten- Gracey, 1979; Fagundes-Neto et al., sively studied because of the ease of 1984; Haghighi and Wolf, 1997; Veitch sampling particularly of the rectal mu- et al., 2001) and a non-specific in- cosa. Such infections may occasionally flammatory infiltrate in the small and cause a dysentery-like syndrome large intestine (Mathan and Mathan, (Trichuris dysentery syndrome [TDS]) 1985) has been referred to as tropical (Cooper et al., 1991) associated with an or environmental enteropathy/colono- increase in inflammatory cells in the pathy. Tropical enteropathy is a com- lamina propria (MacDonald et al., mon histologic finding in apparently 1991), and an increase in numbers and healthy individuals living in the Trop- state of activation of mucosal mast ics (Humphrey, 2009) and may reflect a cells (Cooper et al., 1991; MacDonald T-cell mediated inflammatory process et al., 1994). The histological picture (Veitch et al., 2001) to intestinal micro- observed is likely to be determined by biota and pathogens such as geo- chronicity of infection, intensity of in- fections, and host genetic factors. EFFECTS OF GEOHELMINTHS ON MUCOSAL VACCINATION Current mucosal vaccines are designed may become available for widespread to stimulate immune cells in the intes- use during the next decade.
tinal tract to induce both mucosal and Several oral vaccines have been systemic immunity. The most widely shown to be less immunogenic in used are trivalent oral poliovirus (OPV) populations in non-affluent compared and oral rotavirus vaccines, both of to affluent regions including trivalent which are live attenuated vaccines. oral poliovirus vaccine, rotavirus vac- There are several new oral vaccines cines (Rotashield, Rotarix, and RIT under development, some of which 4237 bovine vaccines), oral cholera Table 1: Barriers to effective vaccination with oral vaccines in non-affluent populations living in
the Tropics. Other factors include high cost and logistic considerations such as cold-chain and vaccine distribution and delivery systems. o Nutritional deficiencies • Vitamin A • Zinc o Tropical/environmental enteropathy o Chronic diarrhoea • Enteric bacterial infections • Intestinal protozoa (e.g. Giardia intestinalis) • Intestinal helminths Ascaris lumbricoides Hookworm Strongyloides stercoralis Trichuris trichiura o Previous exposures to natural infections (e.g. intestinal sIgA) o Maternal antibodies in breast milk vaccine (CVD-103HgR), and Shigella intestine, was associated with impaired flexneri 2a SC602 vaccine (Czerkinsky IFN-γ production to OVA following and Holmgren, 2009). Effective vac- vaccination with a novel OVA-ex- cine immunity with such vaccines in pressing Salmonella vaccine (Urban et non-affluent populations has required an increase in the dose or number of However, geohelminth infections doses administered to achieve adequate alone are unlikely to explain impaired vaccine immunity (Patriarca et al., immunity to oral vaccines. A study 1991, Perez-Schael et al., 1997).
investigating the impact of A. lumbri- Geohelminth infections may have coides infection on responses to oral deleterious effects on immunity to oral BCG Moreau, failed to demonstrate vaccines. Children infected with geo- post-vaccination increases in the fre- helminths had reduced vibriocidal anti- tuberculin-stimulated body levels (Cooper et al., 2000b) and PBMCs expressing IFN-γ among chil- IL-2 responses to cholera toxin B– dren with either active infections or subunit (Cooper et al., 2001) following those who had received either short or vaccination with a single dose of live long courses of anthelmintics before attenuated oral cholera vaccine (CVD vaccination (Cooper et al., unpublished 103-HgR), and these deficits were re- data). The same vaccine showed strong versed partially by anthelmintic treat- boosting of post-vaccination IFN-γ re- ment before vaccination. Similarly, sponses in healthy UK adults (Cos- Heligmosoisdes polygyrus a natural and grove et al., 2006). These data indicate chronic infection of the mouse small the presence of a mucosal barrier to oral vaccination among children living to children of pre-school or school age.
in the rural Tropics that is present in However, there is evidence that mater- the absence of geohelminth infections.
nal infections with geohelminths may Factors that may contribute to poor modify the infant immune response vaccine immune responses in popula- (Malhotra et al., 1999; Pit et al., 2000; tions living in non-affluent regions are Elliott et al., 2005; Guadalupe et al., listed in Table 1. 2009) and such effects have been asso- An important issue for evaluating ciated with impaired immunity to par- the potential effects of enteric infec- enteral vaccines given during the first 6 tions such as geohelminths on immune months of life such as BCG (Malhotra responses to oral vaccines is the age of et al., 1999), Haemophilus influenzae acquisition of infection. Geohelminth type B (Labeaud et al., 2009), and teta- infections, in most endemic settings, nus toxoid (Cooper et al., unpublished are acquired towards the end of the first data). The extent to which effects of year of life, and are unlikely to affect maternal geohelminth infections could immune responses to vaccines given contribute to impaired mucosal im- during the first 6 months of life (e.g.
mune responses in infants is not known oral poliovirus and rotavirus vaccines).
but is being investigated in birth co- Geohelminth infections may have sig- horts being conducted in populations nificant effects on oral vaccines given endemic for these parasites. MECHANISMS OF MODULATION OF MUCOSAL IMMUNE RESPONSES The limited inflammatory response (Turner et al., 2008; Figueiredo et al., observed in the intestinal mucosal in 2010) and TGF-β (Turner et al., 2008). the presence of chronic geohelminth CTLA-4 is more highly expressed infections is likely to reflect potent during chronic helminth infections immune regulation. The mechanisms (Steel and Nutman, 2003). Co-culture by which such infections modulate mu- of peripheral blood leukocytes (PBLs) cosal immunity are not well under- with hookworm antigen impaired PBL stood. Findings from experimental proliferation and cytokine production murine models show that intestinal (Geiger et al., 2007) while dendritic helminth infections suppress dendritic cells show lower expression of CD86, cell-responses to TLR ligands (Balic et CD1a, HLA-ABC, and HLA-DR and al., 2004; Segura et al., 2007) and the have a reduced capacity to promote cell production of IL-12 (Balic et al., 2004; proliferation (Fujiwara et al., 2009). Cervi et al., 2004), and induce the de- Similarly, the co-culture of PBLs with velopment of alternatively activated parasite antigen has been shown to in- macrophages (Kreider et al., 2007) and creased the expression of regulatory IL-10-producing immune cells. Several (e.g. CTLA-4, TGF-β, PD-1, and studies have pointed to a central role ICOS) and anergy-associated markers for IL-10 in suppressing systemic in- (e.g. cbl, Itch, and Nedd4), an effect flammation associated with human that can be reversed at least partially by helminth infections (Fallon and Man- neutralization of CTLA-4 and TGF-β gan, 2007). Peripheral blood leuko- (Babu et al., 2006).
cytes from infected individuals produce The modulation of intestinal mu- elevated levels spontaneously of IL-10 cosal immune responses by geo- helminths may not only have adverse effects were associated with an in- effects on immune responses to oral creased risk of severe illness. The po- vaccines, but may increase susceptibil- tent regulatory effects of geohelminths ity to infection with pathogenic bacte- on mucosal inflammation have been ria (Mansfield et al., 2003; Chen et al., used therapeutically to treat inflamma- 2005). A study of severe cholera infec- tory bowel diseases (Summers et al., tion provided evidence that patients 2005a,b; Croese et al., 2006) - although with concurrent intestinal helminth the efficacy of such treatment remains infections including A. lumbricoides controversial it may be useful in spe- had attenuated IgA responses to CTB cific sub-groups of patients (Reddy and in faeces and serum (Harris et al., Fried, 2009; Cooper, 2009b). 2009), although it is unclear if such Chronic geohelminth infections have fants from non-affluent populations potent regulatory effects on intestinal will require detailed evaluation in geo- immune responses and may contribute helminth-endemic to the impaired immunogenicity of oral widespread distribution. An under- vaccines observed in non-affluent standing of the mechanisms by which populations. The mechanisms by which geohelminths and other enteric infec- geohelminth infections may suppress tions may suppress mucosal vaccine mucosal immune responses to vaccines responses could lead to the develop- are poorly understood. Under some ment of new interventions designed to circumstances, treatment with an- enhance the effectiveness of mucosal thelmintic drugs before vaccination immunization in non-affluent popula- may improve such responses. The effi- cacy of new mucosal vaccines in in- ACKNOWLEDGEMENTS Philip J. Cooper is supported by Wellcome Trust grants no. 088862/Z/09/Z Anderson, R.M. and May, R.M: Helminth in- Diseases (Marcial-Rojas, R.A., Ed.). Wil- fections of humans: Mathematical models, liams & Wilkins, New York, 769-807 population dynamics, and control. Adv. Parasitol. 2, 1-101 (1985). Artis, D. and Grencis, R.K.: The intestinal epi- Anthony, R.M., Rutitzky, L.I., Urban, J.F. 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