Antibody response to Schistosoma haematobium and other helminth species in malaria-exposed populations from Burkina Faso

Journal Pre-proof

Antibody response to Schistosoma haematobium and other helminth species in malaria-exposed populations from Burkina Faso Valentina D. Mangano , Claretta Bianchi , Mireille Ouedraogo , Youssouf Kabore , Patrick Corran , Nilupa Silva , Sodiomon B. Sirima , Issa Nebie , Fabrizio Bruschi , David Modiano PII: DOI: Reference:

S0001-706X(19)30358-4 https://doi.org/10.1016/j.actatropica.2020.105381 ACTROP 105381

To appear in:

Acta Tropica

Received date: Revised date: Accepted date:

25 March 2019 25 January 2020 29 January 2020

Please cite this article as: Valentina D. Mangano , Claretta Bianchi , Mireille Ouedraogo , Youssouf Kabore , Patrick Corran , Nilupa Silva , Sodiomon B. Sirima , Issa Nebie , Fabrizio Bruschi , David Modiano , Antibody response to Schistosoma haematobium and other helminth species in malaria-exposed populations from Burkina Faso, Acta Tropica (2020), doi: https://doi.org/10.1016/j.actatropica.2020.105381

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier B.V.

TITLE PAGE

Title Antibody response to Schistosoma haematobium and other helminth species in malariaexposed populations from Burkina Faso

Running title IgG responses to helminths

Authors Valentina D. Mangano Patrick Corran

5-6,

David Modiano

1

1-2@,

Claretta Bianchi

2-3,

Mireille Ouedraogo 4, Youssouf Kabore 4,

Nilupa Silva 5, Sodiomon B. Sirima 4, Issa Nebie 4, Fabrizio Bruschi 2,

Affiliations 1. Department of Public Health and Infectious Diseases, Sapienza University of Rome, Italy 2. Department of Translational Research, N.T.M.S., University of Pisa, Italy 3. Life Science Research Centre, Faculty of Science, University of Ostrava, Czech Republic 4. Centre National de Recherche et Formation sur le Paludisme, Burkina Faso 5. National Institute for Biological Standards and Controls, United Kingdom

6. London School of Hygiene and Tropical Medicine, United Kingdom @ corresponding author: Valentina D. Mangano, Department of Translational Research, University of Pisa, via Roma 55, 56124 Pisa, Italy; [email protected]

Acknowledgments We thank all participants and communities who made this study possible. We are grateful to: the staff of physicians, nurses, and laboratory technicians as well as the data management staff at Centre National of Research and Formation sur le Paludisme for their skilled work; Federica Verra, previously at Sapienza University of Rome, Italy, for support with the epidemiological survey; Zeno Bisoffi at Centre for Tropical Diseases in Negrar, Italy, for contributing sera samples of patients infected with Schistosoma

haematobium.

Funding information Field work and malaria ELISA assays were funded by the Malaria Genomic Epidemiology Network (MalariaGEN) through Consortial Project 2 grant to DM at Sapienza University of Rome. MalariaGEN is supported by the Wellcome Trust (077383/Z/05/Z) and by the Foundation for the National Institutes of Health (566) as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative. Helminth ELISA assays and VDM were funded by Evimalar (European Community's Seventh Framework Programme Network of

Excellence) Research Fellowship to VDM at Sapienza University of Rome (242095). MO was funded by Fondazione Arpa Visiting Fellowship to University of Pisa.

Declaration of interest None.

Author contributions VDM, FB, DM conceived and designed the study. VDM, CB, MO, PC, NS performed ELISA experiments. YK, VDM conducted the epidemiological survey. BSS, IN coordinated the epidemiological survey. VDM analysed the data and wrote the manuscript. All authors approved the final manuscript.

ORCID Valentina D. Mangano orcid.org/0000-0002-2021-6162

Abstract Infection with helminths in sub-Saharan Africa could modulate the immune response towards Plasmodium falciparum as well as susceptibility to malaria infection and disease. The aim of this study is to assess the antibody responses to helminths species in in malaria-exposed populations from Burkina Faso. Plasma samples were collected in rural villages of Burkina Faso inhabited by Fulani, Mossi and Rimaibe communities, and IgG against parasitic helminths were measured by ELISA.

The prevalence of IgG against antigens of Strongyloides stercoralis, Wuchereria bancrofti and Schistosoma haematobium (Soluble Egg Antigen, SEA) was 5%, 16% and 63% respectively, in line with estimates of infection prevalence in the region for the three parasites. Anti-SEA IgG prevalence was highest at 10-20 years of age, higher in males than females, and did not show differences between ethnic groups. However, the Fulani showed lower levels of anti-SEA IgG suggesting that lighter S. haematobium infections may occur in the ethnic group known for a marked lower susceptibility to P. falciparum. The present data support the use of serological methods for integrated surveillance of neglected tropical diseases such as soil-transmitted helminths, lymphatic filariasis and bilharzia. Furthermore, as helminth infections might promote downregulation of immune responses against intracellular pathogens, the observation of lower anti-SEA IgG levels in the

malaria resistant Fulani population

warrants further

investigation

into the

immunological cross-talk between S. haematobium and P. falciparum in this geographical region.

Keywords Malaria, soil-transmitted helminths, schistosomiasis, lymphatic filariasis, immunity, subSaharan Africa, Fulani

MAIN TEXT

Introduction Parasitic infections impose a heavy burden on sub-Saharan African populations in terms of high rates of premature mortality, morbidity and disability. Although the highest impact is due to Plasmodium falciparum malaria (1), diseases caused by helminths - such as those associated with infection with intestinal nematodes (2), lymphatic filariasis (3) and schistosomiasis (4) - are common but often neglected (5). The geographical overlap of these parasitic diseases and their high prevalence makes co-infections frequent. Several studies indicate that co-infection with helminths might modulate the immune response towards Plasmodium parasites as well as susceptibility to malaria parasite infection and/or disease, although the mechanisms are not fully understood as yet (6). The specific objectives of the present study are to assess the seroprevalence and levels of immunoglobulins directed against selected parasitic helminths in populations from Burkina Faso, a country with intense seasonal malaria transmission, and to investigate any association with age, sex, ethnicity and infection with P. falciparum. To this end, species with different transmission routes were selected for

investigation: soil

(Strongyloides stercoralis), vector (Wuchereria bancrofti) and water contact (Schistosoma

haematobium) transmission. The choice of parasites was also based on the availability of

serological assays for indirect diagnosis, and of estimates of infection prevalence in the study area. The results of the present study will inform the future investigation of the impact of helminth infections on different immune responses and susceptibility to malaria shown by ethnic groups from Burkina Faso. Fulani have been shown to mount stronger immune responses to P. falciparum antigens and to be less susceptible to malaria parasite infection and mild disease than neighboring Mossi and Rimaibe exposed to comparable transmission levels (7).

Materials and Methods

Ethics Statement The study received approval from the ethical committees of the Ministry of Health of Burkina Faso and the University of Oxford. Study subjects or their guardians gave written informed consent for participation.

Study Area and Populations The study was carried out in two rural villages of Burkina Faso, Barkoundouba Peulh and Barkoundouba Mossi, located northeast of Ouagadougou in the Plateau Central region and inhabited by Fulani, Mossi and Rimaibe (Non-Fulani) communities. Malaria transmission is hyperendemic and seasonal, with a rainy season from June to October. The entomological inoculation rates, estimated at about 100–200 infective bites per

person per year, are similar across villages (7). P. falciparum accounts for >90% of malaria infections (8).

Epidemiological survey A cross-sectional survey was carried out in August 2007 (from 16/08/2007 to 29/08/2007), at the beginning of the high malaria transmission season including 1078 individuals. A team of physicians examined participants for clinical signs and measured axillary body temperature. Subjects exhibiting fever (temperature ≥37.5°C) were treated presumptively with artemether-lumefantrine (Coartem). Blood slides for malaria diagnosis were prepared from finger pricks, stained with Giemsa according to standard procedures and read independently by 2 skilled microscopists (8). A 2ml venous blood sample per participant was collected in ethylenediaminetetraacetic acid tubes and transported within 3 hours to the laboratory at Centre National de Recherche et Formation sur le Paludisme, Ouagadougou, where plasma was separated by centrifugation (3 minutes at 2,000 rpm), transferred in two aliquots into sterile screw-cap 1.5ml tubes and stored at -80°C until immunological assays were performed.

Enzyme Linked ImmunoSorbant Assays (ELISA) IgG against S. stercolaris were measured using the commercial ELISA kit by Bordier Affinity (cat. n° 9450) based on S. ratti somatic larval antigens (9), following manufacturer’ instructions. IgG against lymphatic filariae were measured using the

commercial ELISA kit by Bordier Affinity (cat. n° 9400) based on Acanthocheilonema viteae somatic antigens (10), following manufacturer’ instructions. In both cases a sample was defined positive when the ratio bewteen the absorbance of the sample and the absorbance

of

the

cutoff

serum

provided

with

the

kit

was

higher

than

1

(ODsample/ODcutoff>1), according to manufacturer’ indications. IgG against S. haematobium Soluble Egg Antigen (SEA) were measured using a in house ELISA protocol (Supplementary Information) adapted from Mutapi and colleagues (11). The cutoff used for positivity was the mean absorbance plus 3 standard deviations of 30 negative control samples (cutoff=mean ODneg + 3 SDneg). Total IgE and specific IgG against P. falciparum antigens CSP, MSP1, MSP2 and AMA1 were measured using in house ELISA protocols as previously described (12). ELISA assays were performed on 288 individuals selected by random sampling from the whole-sample set. The selected subjects showed comparable distribution of key variables such as age, sex, ethnicity and infection with P. falciparum with respect to the whole sample-set of which was therefore deemed representative (data not shown). The characteristics of the study subjects stratified by ethnicity are shown in Table 1. Table 1. Characteristics of study subjects.

Characteristics of study subjects

Age-group (years)

<1 1-4 5-9 10-14 15-19 20-39

N 1 7 20 22 18 20

Fulani % 1.0% 7.3% 20.8% 22.9% 18.8% 20.8%

Non-Fulani N % 5 34 34 37 20 40

2.6% 17.7% 17.7% 19.3% 10.4% 20.8%

Total N 6 41 54 59 38 60

% 2.1% 14.2% 18.8% 20.5% 13.2% 20.8%

Sex P. falciparum infection Total

40-60 Females Males Negative Positive

8 49 47 70 26 96

8.3% 51.0% 49.0% 72.9% 27.1% 100.0%

22 92 100 75 117 192

11.4% 47.9% 52.1% 39.1% 60.4% 100.0%

30 141 147 145 143

10.4% 49.0% 51.0% 50.7% 49.3%

288

100%

The table shows the number (N) and percentage (%) of study subjects according to agegroup, sex, ethnicity and infection with P. falciparum.

Statistical methods Statistical analysis was performed using STATAv10. Logistic regression was performed to assess association between age group (<1, 1-4, 5-9, 10-14, 15-19, 20-39, 40-60 years old), sex (females vs males), ethnicity (Fulani vs Non-Fulani), infection with P. falciparum (infected vs non-infected), and the seropositivity for a specific IgG (yes/no). The frequency of seropositive individuals was shown by bar graphs. Linear regression was performed to assess association between the above epidemiological factors and the level of a specific IgG (nOD) among seropositive individuals. The distribution of IgG levels was shown by box-whiskers plots. Multivariate analysis was conducted including in the regression model the factors that showed a significant association with the outcome in univariate analysis, and the association results (OR, 95% CI, p-value) presented in the text are adjusted where appropriate. Linear relationship of IgG against parasitic helminths with IgG against P. falciparum as well as with total IgE was assessed using Spearman correlation and was shown by scatterplots including a best fit curve with its 95% confidence interval.

Results and discussion

Prevalence of IgG against parasitic helminth antigens The prevalence of anti-Strongyloides IgG was 5% (15/288). The prevalence of S.

stercoralis infection in the study area has not been previously reported. However, the Global Atlas of Helminth Infections (GAHI, 13) reports an estimated prevalence in the 19.9% range for soil-transmitted helminth infections as a whole in the Plateau Central region (14). The prevalence of IgG against lymphatic filariae was 16% (46/288). A national control programme to eliminate lymphatic filariasis, caused by W. bancrofti, was launched in Burkina Faso in 2001 and five rounds of Mass Drug Administration with ivermectin and albendazole were completed with 79% coverage by 2009 (15). In the region, GAHI reports an estimated prevalence of lymphatic filariasis in the 1-49.9 % range pre-control intervention (16) and in the 0.1-10% range post-intervention (17). Prevalence of anti-SEA IgG was 63% (182/288). The prevalence of S. haematobium infection reported in the region was 79% in 1987 (18). Treatment of school aged children with praziquantel started in 2004, and GAHI reports an estimated current prevalence of urinary schistosomiasis in the 1-49% range in the region (19) (20). These observations indicate that measures of seroprevalence of IgG against the parasitic helminths under study lie within the infection prevalence ranges as obtained by direct diagnosis.

Because of the low prevalence of anti-S. strongyloides and anti-W. bancrofti IgG and the limited sample size, we did not conduct further analyses on these data, which we restricted to anti-SEA IgG.

Variation of anti-SEA IgG prevalence and levels with host factors Anti-SEA IgG prevalence was zero in infants, showed an increase during childhood to reach its peak in teens, and a decrease from 20 years old onwards (OR=1.61, 95% CI=1.35-1.92, P<0.001; Figure 1; Table S1). Prevalence of S. haematobium infection has been reported to show a similar age distribution (21) (22). Indeed, the burden of infection increases during childhood with repeated exposure to infectious cercariae, and the prevalence is highest in young adolescents while decreases in adulthood (reviewed in 4).

Figure 1. Prevalence of anti-SEA IgG according to age-group.

100

anti-SEA IgG seropositivity

90 80 70 60 50 40 30 20 10 0 <1

1-4

5-9

10-14

15-19

20-39

40-60

age-group (years) The figure shows the frequency (%) of anti-SEA IgG seropositive individuals according to age-group (<1, n=6; 1-4, n=41; 5-9, n=54; 10-14, n=59; 15-19, n=38; 20-39, n=59; 40-60, n=31). Bars indicate the standard error of the frequency.

Anti-SEA IgG prevalence was significantly lower in females than males (55.1% vs 71.6% respectively, OR=0.34, 95% CI=0.20-0.59, P<0.001; Table S1). Previous studies reported lower frequency of S. haematobium infection in females than males (23) (24). This difference could be accounted for by different duties and/or behaviours of females and males that affect chances to get in contact with contaminated water. These observations provide further indirect evidence that the seroprevalence of anti-SEA IgG is a good marker of S. haematobium infection prevalence, as the two estimates are comparable and vary similarly with key host factors such as age and sex, confirming previous reports (11,25,26). Differences in prevalence were not observed between ethnic groups (Fulani=65.6%, NonFulani=62.0%, OR=1.19, 95% CI= 0.71-1.98, P=0.511; TableS1), nor between P.

falciparum infected and non-infected subjects (Pfpositive=57.7%, Pfnegative=68.5%, OR=0.88, 95% CI= 0.52-1.51, P=0.641; TableS1). However, the Fulani showed lower levels of antiSEA IgG (OR=0.70, 95% CI=0.61-0.79, P<0.001, Figure 2). It has been previously shown that anti-SEA antibody levels positively correlate with S. haematobium infection intensity (26). This observation could therefore suggest that lighter S. haematobium infections may occur in the ethnic group known for a marked lower susceptibility to P. falciparum (7). The results of univariate and multivariate regression analysis to investigate the association of host factors with anti-SEA IgG positivity and levels are shown in Table 2 and Table 3 respectively.

Table 2. Results of univariate and multivariate regression analysis of association between host factors and anti-SEA IgG positivity.

Host factor OR Age-group 1.51 Sex 0.48 Ethnicity 1.19 P.falciparum infection 0.62

anti-SEA IgG positivity (yes/no) Univariate Multivariate 95% LCL 95% UCL P-value OR 95% LCL 95% UCL P-value 1.29 1.78 0.000 1.61 1.35 1.92 0.000 0.29 0.78 0.003 0.34 0.20 0.59 0.000 0.71 1.98 0.511 0.38 1.00 0.050 0.88 0.51 1.51 0.641

The table shows the results of univariate and multivariate logistic regression analysis performed to investigate the association of age group (<1, 1-4, 5-9, 10-14, 15-19, 2039, 40-60 years old), sex (females vs males), ethnicity (Fulani vs Non-Fulani), infection with P. falciparum (infected vs non-infected) with the positivity of anti-SEA IgG (yes/no). OR: Odds Ratio; 95% LCL: 95% Lower Confidence Limit of the OR, 95% UCL: 95% Upper Confidence Limit of the OR. Ethnicity was not included in the multivariate analysis since univariate analysis did not show a significant association of this factor with the outcome.

Table 3. Results of univariate and multivariate regression analysis of association between host factors and anti-SEA IgG levels.

Host factor Age-group Sex

anti-SEA IgG levels (nOD) Univariate Multivariate OR 95% LCL 95% UCL P-value OR 95% LCL 95% UCL P-value

0.92 0.75 0.69 Ethnicity P.falciparum infection 1.30

0.87 0.66 0.60 1.13

0.96 0.86 0.79 1.48

0.001 0.000 0.000 0.000

0.75 0.94 0.70 1.09

0.66 0.90 0.61 0.96

0.84 0.99 0.79 1.25

0.000 0.013 0.000 0.189

The table shows the results of univariate and multivariate linear regression analysis performed to investigate the association of age group (<1, 1-4, 5-9, 10-14, 15-19, 2039, 40-60 years old), sex (females vs males), ethnicity (Fulani vs Non-Fulani), infection with P. falciparum (infected vs non-infected) with the levels of anti-SEA IgG (normalized OD). OR: Odds Ratio; 95% LCL: 95% Lower Confidence Limit of the OR, 95% UCL: 95% Upper Confidence Limit of the OR. Figure 2. Levels of anti-SEA IgG in Fulani and Non-Fulani populations.

The figure shows a boxplot of the distribution of anti-SEA IgG levels (nOD) among Fulani (n=63) and Non-Fulani (n=118) seropositive subjects. The horizontal black line indicates the 50% percentile, the grey box indicates the 25%-75% percentiles, the lower whisk indicates the 5% and the upper whisk the 95% percentiles respectively, dots indicate individual data that lie out of the distribution (outliers).

Correlation of anti-SEA IgG with total IgE and with anti-P. falciparum IgG IgE levels were higher in anti-SEA IgG seropositive subjects (Fulani: OR=1.15, 95% CI=1.02-1.30, P=0.024; Non-Fulani: OR=1.12; 95% CI=1.03-1.24; P=0.019; Figure 3A). This observation is in line with the knowledge that helminths infections are associated with increased levels of total IgE (27,28). Furthermore, a positive correlation was observed between levels of anti-SEA IgG and total IgE (Fulani: rho=0.25, P=0.012; Non-Fulani: rho=0.28, P=0.001; Figure 3B). A positive correlation between the burden of infection and total IgE levels has been previously reported for both intestinal nematodes and schistosomes (29–31). These observations taken together provide further, although indirect, evidence that antiSEA IgG prevalence and levels might be good markers for S. haematobium infection prevalence and intensity, respectively. Figure 3. Total IgE levels in anti-SEA IgG seropositive and seronegative individuals, and correlation with anti-SEA IgG levels.

The figure in panel A) shows boxplots of the distribution of total IgE levels (nOD) in antiSEA IgG seropositive and seronegative subjects, both in Fulani and Non-Fulani populations. The horizontal black line indicates the 50% percentile, the grey box indicates the 25%-75% percentiles, the lower whisk indicates the 5% and the upper whisk the 95% percentiles respectively, dots indicate individual data that lie out of the distribution (outliers). In panel B) the figure shows scatter plots describing the linear correlation between the level of anti-SEA IgG (nOD, y axis) and the level of total IgE (nOD, x axis), both in Fulani and Non-Fulani populations. The points indicate individual data, the line indicates the best linear curve fitted to the data, the grey area indicates the 95% confidence interval of the fitted linear curve.

Weak or no correlation was observed between anti-S. haematobium (SEA) and anti-P.

falciparum (CSP, MSP1, MSP2, AMA1) IgG levels (Supplementary Information TableS2 and FigureS1).

Conclusions The conclusions that can be drawn by the data herein presented are limited by the relatively small sample size of the study, the cross-sectional design and, importantly, by the fact that infection with helminths was not assessed by direct methods and it was therefore not possible to discriminate between past and active infection. The present preliminary findings provide indirect evidence that the seroprevalence of anti-helminth specific IgG is a good proxy measure for the prevalence of helminth infection in a given study area and population. ELISA or other serological methods may therefore be suitable for population screening and evaluation of control programmes against different neglected tropical diseases such as soil-transmitted helminthiasis, lymphatic filariasis and schistosomiasis, for the achievement of integrated surveillance requiring the sampling of only one biological specimen (32,33). The present data show >50% prevalence of IgG specific for S. haematobium SEA in the study area. We did not observe differences in anti-SEA IgG prevalence or levels according to P. falciparum infection. Lower levels of anti-SEA IgG were observed among the malaria resistant Fulani population, although it remains to be confirmed whether lower anti-SEA IgG levels are indicative of lower intensity of S. haematobium infection in this ethnic

group. Differences in infection intensities between ethnic groups could be the result of exposure differences, driven by either social or geographical factors, and/or of genetic differences. Regarding the latter, it is noteworthy that the 5q31 region of the human genome - containing a cluster of loci encoding key mediators of Th2 (IL4, IL5, IL13) and Th1 (CSF2, IRF1) responses - has been reported to affect susceptibility to both schistosomiasis and malaria infections (34). A recent systematic review and meta-analysis suggested that infection with S.

haematobium may be associated with increased prevalence of P. falciparum infection (35). Future work based on larger cohort studies should therefore investigate the impact of infection with S. haematobium on immunity to P. falciparum in the study area and populations. Moreover, it has been previously shown that helminths Escretory Secretory (ES) molecules can induce production of immunoregulatory cytokines and downregulation of immune responses against intracellular pathogens such as Plasmodium (reviewed in 6). As Fulani have been previously reported to show lower plasma levels of TGF-β and lower number of T regulatory cells (36), the immunological cross-talk between S. haematobium and P.

falciparum in this population is worthy of further investigation.

Author statement

Valentina D. Mangano conceptualization, methodology, formal analysis, investigation, resources, data curation, writing-original draft, visualization, supervision, project administration, funding acquisition Claretta Bianchi investigation Mireille Ouedraogo investigation Youssouf Kabore investigation Patrick Corran methodology, investigation, resources Nilupa Silva investigation Sodiomon B. Sirima investigation, resources Issa Nebie investigation, resources, validation, writing - review & editing Fabrizio Bruschi conceptualization, resources, validation, writing - review & editing David Modiano conceptualization, resources, validation, writing - review & editing, visualization, supervision, project administration, funding acquisition

Declaration of interests

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

REFERENCES

1.

WHO. World Malaria Report 2017. Geneva, Switzerland; 2017.

2.

Jourdan PM, Lamberton PHL, Fenwick A, Addiss DG. Soil-transmitted helminth infections. Lancet. 2018 Jan 4;391(10117):252–65.

3.

Taylor MJ, Hoerauf A, Bockarie M. Lymphatic filariasis and onchocerciasis. Lancet. Elsevier; 2010 Oct 2;376(9747):1175–85.

4.

Colley DG, Bustinduy AL, Secor WE, King CH. Human schistosomiasis. Lancet. 2014 Jun 28;383(9936):2253–64.

5.

Hotez PJ, Kamath A. Neglected Tropical Diseases in Sub-Saharan Africa: Review of Their Prevalence, Distribution, and Disease Burden. Cappello M, editor. PLoS Negl Trop Dis. 2009 Aug 25;3(8):e412.

6.

Salgame P, Yap GS, Gause WC. Effect of helminth-induced immunity on infections with microbial pathogens. Nat Immunol. 2013 Nov;14(11):1118–26.

7.

Modiano D, Petrarca V, Sirima BS, Nebié I, Diallo D, Esposito F, et al. Different response to Plasmodium falciparum malaria in west African sympatric ethnic groups. Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13206–11.

8.

Mangano VD, Kabore Y, Bougouma EC, Verra F, Sepulveda N, Bisseye C, et al. Novel Insights into the Protective Role of Hemoglobin S and C Against Plasmodium falciparum Parasitemia. J Infect Dis. 2015;212(4).

9.

Bisoffi Z, Buonfrate D, Sequi M, Mejia R, Cimino RO, Krolewiecki AJ, et al. Diagnostic

Accuracy of Five Serologic Tests for Strongyloides stercoralis Infection. Siddiqui AA, editor. PLoS Negl Trop Dis. 2014 Jan 9;8(1):e2640. 10.

Gueglio B, Bordier C, Marjolet M. Mise au point d’un test Elisa pour le diagnostic des filarioses humaines. Bull la société Française Parasitol. 1995;

11.

Mutapi F, Ndhlovu PD, Hagan P, Woolhouse ME. A comparison of humoral responses to Schistosoma haematobium in areas with low and high levels of infection. Parasite Immunol. 1997 Jun;19(6):255–63.

12.

Shelton JMG, Corran P, Risley P, Silva N, Hubbart C, Jeffreys A, et al. Genetic determinants of anti-malarial acquired immunity in a large multi-centre study. Malar J. 2015 Dec 28;14(1):333.

13.

Brooker S, Hotez PJ, Bundy DAP. The Global Atlas of Helminth Infection: Mapping the Way Forward in Neglected Tropical Disease Control. Aksoy S, editor. PLoS Negl Trop Dis. 2010 Jul 27;4(7):e779.

14.

GAHI. Distribution of soil transmitted helminth survey data and average districtlevel prevalence in Burkina Faso [Internet]. Available from: http://www.thiswormyworld.org/maps/distribution-of-soil-transmitted-helminthsurvey-data-in-burkina-faso

15.

WHO. Global programme to eliminate lymphatic filariasis: Progress report on mass drug administration in 2009. 2010.

16.

GAHI. Distribution of pre-control LF survey data in Burkina Faso [Internet]. Available from: http://www.thiswormyworld.org/maps/distribution-of-pre-control-lf-

survey-data-in-burkina-faso 17.

GAHI. Distribution of contemporary LF survey data in Burkina Faso [Internet]. Available from: http://www.thiswormyworld.org/maps/distribution-ofcontemporary-lf-survey-data-in-burkina-faso

18.

Traore LK, Ouedraogo LH, Pietra V, Nacoulma I, Nebie B PF. Prevalence de l’infection a schistosoma haematobium et relations bilharziose hematurie dans deux villages du Burkina Faso. Med Afr Noire. 1990;37:100–7.

19.

GAHI. Prevalence and location of Schistosoma haematobium parasitological surveys and average district-level prevalence in Burkina Fasp [Internet]. Available from: http://www.thiswormyworld.org/maps/distribution-of-s-haematobium-surveydata-in-burkina-faso

20.

Clements ACA, Garba A, Sacko M, Touré S, Dembelé R, Landouré A, et al. Mapping the probability of schistosomiasis and associated uncertainty, West Africa. Emerg Infect Dis. 2008 Oct;14(10):1629–32.

21.

King CH, Keating CE, Muruka JF, Ouma J, Houser H, Siongok TKA, et al. Urinary Tract Morbidity in Schistosomiasis Haematobia: Associations with Age and Intensity of Infection in an Endemic Area of Coast Province, Kenya. Am J Trop Med Hyg. The American Society of Tropical Medicine and Hygiene; 1988 Oct 1;39(4):361–8.

22.

Woolhouse ME. Immunoepidemiology of intestinal helminths: pattern and process. Parasitol Today. 1992 Apr;8(4):111.

23.

Kapito-Tembo AP, Mwapasa V, Meshnick SR, Samanyika Y, Banda D, Bowie C, et al.

Prevalence distribution and risk factors for Schistosoma hematobium infection among school children in Blantyre, Malawi. PLoS Negl Trop Dis. 2009;3(1):e361. 24.

Negussu N, Wali M, Ejigu M, Debebe F, Aden S, Abdi R, et al. Prevalence and distribution of schistosomiasis in afder and gode zone of somali region, ethiopia. J Glob Infect Dis. 2013 Oct;5(4):149–52.

25.

Imai N, Rujeni N, Nausch N, Bourke CD, Appleby LJ, Cowan G, et al. Exposure, infection, systemic cytokine levels and antibody responses in young children concurrently exposed to schistosomiasis and malaria. Parasitology. 2011;138(12):1519–33.

26.

Wami WM, Nausch N, Bauer K, Midzi N, Gwisai R, Simmonds P, et al. Comparing parasitological vs serological determination of Schistosoma haematobium infection prevalence in preschool and primary school-aged children: implications for control programmes. Parasitology. 2014;141(14):1962–70.

27.

Jarrett E, Bazin H. Elevation of total serum IgE in rats following helminth parasite infection. Nature. 1974 Oct 18;251(5476):613–4.

28.

Bell RG. IgE, allergies and helminth parasites: a new perspective on an old conundrum. Immunol Cell Biol. 1996 Aug;74(4):337–45.

29.

Cooper PJ, Alexander N, Moncayo A-L, Benitez SM, Chico ME, Vaca MG, et al. Environmental determinants of total IgE among school children living in the rural Tropics: importance of geohelminth infections and effect of anthelmintic treatment. BMC Immunol. 2008 Jun 27;9(1):33.

30.

Mulu A, Kassu A, Legesse M, Erko B, Nigussie D, Shimelis T, et al. Helminths and malaria co-infections are associated with elevated serum IgE. Parasit Vectors. BioMed Central; 2014 May 23;7(1):240.

31.

Stevens WJ, Feldmeir H, Bridts CH, Daffalla AA. IgG and IgE circulating immune complexes, total serum IgE and parasite related IgE in patients with mono- or mixed infection with Schistosoma mansoni and/or S. haematobium. Influence of therapy. Clin Exp Immunol. 1983 Apr;52(1):144–52.

32.

Arnold BF, van der Laan MJ, Hubbard AE, Steel C, Kubofcik J, Hamlin KL, et al. Measuring changes in transmission of neglected tropical diseases, malaria, and enteric pathogens from quantitative antibody levels. Picardeau M, editor. PLoS Negl Trop Dis. 2017 May 19;11(5):e0005616.

33.

Priest JW, Jenks MH, Moss DM, Mao B, Buth S, Wannemuehler K, et al. Integration of Multiplex Bead Assays for Parasitic Diseases into a National, Population-Based Serosurvey of Women 15-39 Years of Age in Cambodia. Mutapi F, editor. PLoS Negl Trop Dis. Public Library of Science; 2016 May 3;10(5):e0004699.

34.

Mangano VD, Modiano D. Host genetics and parasitic infections. Clin Microbiol Infect. 2014;20(12).

35.

Degarege A, Degarege D, Veledar E, Erko B, Nacher M, Beck-Sague CM, et al. Plasmodium falciparum Infection Status among Children with Schistosoma in SubSaharan Africa: A Systematic Review and Meta-analysis. PLoS Negl Trop Dis. 2016;10(12):1–18.

36.

Torcia MG, Santarlasci V, Cosmi L, Clemente A, Maggi L, Mangano VD, et al. Functional deficit of T regulatory cells in Fulani, an ethnic group with low susceptibility to Plasmodium falciparum malaria. Proc Natl Acad Sci U S A. 2008;105(2).