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1.  Factors affecting the infant antibody response to measles immunisation in Entebbe-Uganda 
BMC Public Health  2013;13:619.
Background
Vaccine failure is an important concern in the tropics with many contributing elements. Among them, it has been suggested that exposure to natural infections might contribute to vaccine failure and recurrent disease outbreaks. We tested this hypothesis by examining the influence of co-infections on maternal and infant measles-specific IgG levels.
Methods
We conducted an observational analysis using samples and data that had been collected during a larger randomised controlled trial, the Entebbe Mother and Baby Study (ISRCTN32849447). For the present study, 711 pregnant women and their offspring were considered. Helminth infections including hookworm, Schistosoma mansoni and Mansonella perstans, along with HIV, malaria, and other potential confounding factors were determined in mothers during pregnancy and in their infants at age one year. Infants received their measles immunisation at age nine months. Levels of total IgG against measles were measured in mothers during pregnancy and at delivery, as well as in cord blood and from infants at age one year.
Results
Among the 711 pregnant women studied, 66% had at least one helminth infection at enrolment, 41% had hookworm, 20% M. perstans and 19% S. mansoni. Asymptomatic malaria and HIV prevalence was 8% and 10% respectively. At enrolment, 96% of the women had measles-specific IgG levels considered protective (median 4274 mIU/ml (IQR 1784, 7767)). IgG levels in cord blood were positively correlated to maternal measles-specific IgG levels at delivery (r = 0.81, p < 0.0001). Among the infants at one year of age, median measles-specific IgG levels were markedly lower than in maternal and cord blood (median 370 mIU/ml (IQR 198, 656) p < 0.0001). In addition, only 75% of the infants had measles-specific IgG levels considered to be protective. In a multivariate regression analysis, factors associated with reduced measles-specific antibody levels in infancy were maternal malaria infection, infant malaria parasitaemia, infant HIV and infant wasting. There was no association with maternal helminth infection.
Conclusion
Malaria and HIV infection in mothers during pregnancy, and in their infants, along with infant malnutrition, may result in reduction of the antibody response to measles immunisation in infancy. This re-emphasises the importance of malaria and HIV control, and support for infant nutrition, as these interventions may have benefits for vaccine efficacy in tropical settings.
doi:10.1186/1471-2458-13-619
PMCID: PMC3733798  PMID: 23816281
Infections; Co-infections; Measles; Helminth; Malaria; HIV; Maternal; Infants; Pregnancy; Immunisation
2.  The effect of anthelminthic treatment during pregnancy on HIV plasma viral load; results from a randomised, double blinded, placebo-controlled trial in Uganda 
Background
To investigate the effect of helminth infections and their treatment during pregnancy on HIV load, we conducted a 2×2 factorial randomised controlled trial of albendazole versus placebo and praziquantel versus placebo in pregnant women in Entebbe, Uganda
Methods
Two hundred and sixty-four HIV-infected women from the Entebbe Mother and Baby Study (ISRCTN32849447) were included in this analysis. Women were tested for helminth infections at enrolment and mean HIV load was compared between infected and uninfected groups. The effect of anthelminthic treatment on HIV load was evaluated at six weeks post-treatment and at delivery using linear regression and adjusting for enrolment viral load.
Results
Hookworm and Trichuris infections were associated with higher mean viral load at enrolment (adjusted mean difference 0.24log10 copies/ml, 95% confidence interval (CI): 0.01 to 0.47, p=0.03 and 0.37log10 copies/ml, 95%CI: 0.00 to 0.74, p=0.05, respectively). There were no associations between viral load and other helminth species. There was some evidence that albendazole reduced viral load at six weeks post-treatment (adjusted mean difference −0.17, 95% CI: −0.36 to 0.01, p=0.07), however this effect did not differ according to mother’s hookworm infection status and had diminished at delivery (adjusted mean difference −0.11, 95% CI: −0.28 to 0.07, p=0.23). There was no effect of praziquantel treatment on HIV load at any time point.
Conclusions
Infection with some soil-transmitted helminth species is associated with increased HIV load in pregnancy. Treatment with albendazole causes a small decrease in HIV load, however this may not represent a direct effect of worm removal.
doi:10.1097/QAI.0b013e3182511e42
PMCID: PMC3383620  PMID: 22728750
HIV; viral load; helminths; anthelminthic treatment; clinical trial
3.  Impact of Anthelminthic Treatment in Pregnancy and Childhood on Immunisations, Infections and Eczema in Childhood: A Randomised Controlled Trial 
PLoS ONE  2012;7(12):e50325.
Background
Helminth infections may modulate immune responses to unrelated pathogens and allergens; these effects may commence prenatally. We addressed the hypothesis that anthelminthic treatment in pregnancy and early childhood would improve responses to immunisation and modulate disease incidence in early childhood with both beneficial and detrimental effects.
Methods and Findings
A randomised, double-blind, placebo-controlled trial was conducted in Entebbe, Uganda [ISRCTN32849447]. In three independent randomisations, 2507 pregnant women were allocated to receive single-dose albendazole or placebo, and praziquantel or placebo; 2016 of their offspring were randomised to receive quarterly single-dose albendazole or placebo from age 15 months to 5 years. Primary outcomes were post-immunisation recall responses to BCG and tetanus antigens, and incidence of malaria, diarrhoea, and pneumonia; incidence of eczema was an important secondary outcome. Analysis was by intention-to-treat. Of 2345 live births, 1622 (69%) children remained in follow-up at age 5 years. 68% of mothers at enrolment, and 11% of five-year-olds, had helminth infections. Maternal hookworm and Schistosoma mansoni were effectively treated by albendazole and praziquantel, respectively; and childhood hookworm and Ascaris by quarterly albendazole. Incidence rates of malaria, diarrhoea, pneumonia, and eczema were 34, 65, 10 and 5 per 100 py, respectively. Albendazole during pregnancy caused an increased rate of eczema in the children (HR 1.58 (95% CI 1.15–2.17), p = 0.005). Quarterly albendazole during childhood was associated with reduced incidence of clinical malaria (HR 0.85 (95% CI 0.73–0.98), p = 0.03). There were no consistent effects of the interventions on any other outcome.
Conclusions
Routine use of albendazole in pregnancy may not always be beneficial, even in tropical developing countries. By contrast, regular albendazole treatment in preschool children may have an additional benefit for malaria control where helminths and malaria are co-endemic. Given the low helminth prevalence in our children, the effect of albendazole on malaria is likely to be direct.
Trial registration
Current Controlled Trials ISRCTN32849447
doi:10.1371/journal.pone.0050325
PMCID: PMC3517620  PMID: 23236367
4.  Determining Mycobacterium tuberculosis Infection among BCG-Immunised Ugandan Children by T-SPOT.TB and Tuberculin Skin Testing 
PLoS ONE  2012;7(10):e47340.
Background
Children with latent tuberculosis infection (LTBI) represent a huge reservoir for future disease. We wished to determine Mycobacterium tuberculosis (M.tb) infection prevalence among BCG-immunised five-year-old children in Entebbe, Uganda, but there are limited data on the performance of immunoassays for diagnosis of tuberculosis infection in children in endemic settings. We therefore evaluated agreement between a commercial interferon gamma release assay (T-SPOT.TB) and the tuberculin skin test (TST; 2 units RT-23 tuberculin; positive defined as diameter ≥10 mm), along with the reproducibility of T-SPOT.TB on short-term follow-up, in this population.
Methodology/Principal Findings
We recruited 907 children of which 56 were household contacts of TB patients. They were tested with T-SPOT.TB at age five years and then re-examined with T-SPOT.TB (n = 405) and TST (n = 319) approximately three weeks later. The principal outcome measures were T-SPOT.TB and TST positivity. At five years, 88 (9.7%) children tested positive by T-SPOT.TB. More than half of those that were T-SPOT.TB positive at five years were negative at follow-up, whereas 96% of baseline negatives were consistently negative. We observed somewhat better agreement between initial and follow-up T-SPOT.TB results among household TB contacts (κ = 0.77) than among non-contacts (κ = 0.39). Agreement between T-SPOT.TB and TST was weak (κ = 0.28 and κ = 0.40 for T-SPOT.TB at 5 years and follow-up, respectively). Of 28 children who were positive on both T-SPOT.TB tests, 14 (50%) had a negative TST. Analysis of spot counts showed high levels of instability in responses between baseline and follow-up, indicating variability in circulating numbers of T cells specific for certain M.tb antigens.
Conclusions/Significance
We found that T-SPOT.TB positives are unstable over a three-week follow-up interval, and that TST compares poorly with T-SPOT.TB, making the categorisation of children as TB-infected or TB-uninfected difficult. Existing tools for the diagnosis of TB infection are unsatisfactory in determining infection among children in this setting.
doi:10.1371/journal.pone.0047340
PMCID: PMC3471887  PMID: 23077594
5.  Low avidity of human papillomavirus (HPV) type 16 antibodies is associated with increased risk of low-risk but not high-risk HPV type prevalence 
BMC Research Notes  2011;4:170.
Background
Low avidity of antibodies against viral, bacterial and parasitic agents has been used for differential diagnosis of acute versus recent/past infections. The low-avidity antibodies may however, persist for a longer period in some individuals.
Findings
We studied the association of human papillomavirus (HPV) type 16 antibody avidity with seroprevalence to HPV types 6/11/18/31/33/45. Antibody avidity was analysed for 365 HPV16 seropositive pregnant Finnish and Ugandan women using a modified ELISA.
Low avidity of HPV16 antibodies was found in 15% of Finnish and 26% of Ugandan women. Ugandan women with low-avidity HPV16 antibodies had an increased risk estimate for HPV6/11 (odds ratio, OR 2.9; 95%CI 1.01-8.4) seropositivity but not to high-risk HPV types 18/31/33/45.
Conclusion
Association of the low avidity HPV16 antibody "phenotype" with possible susceptibility to infections with other HPV types warrants investigation.
doi:10.1186/1756-0500-4-170
PMCID: PMC3118998  PMID: 21645376
antibody; avidity; genital infection; HPV; prevalence
6.  Effect of single-dose anthelmintic treatment during pregnancy on an infant's response to immunisation and on susceptibility to infectious diseases in infancy: a randomised, double-blind, placebo-controlled trial 
Lancet  2011;377(9759):52-62.
Summary
Background
Helminth infections affect the human immune response. We investigated whether prenatal exposure to and treatment of maternal helminth infections affects development of an infant's immune response to immunisations and unrelated infections.
Methods
In this randomised, double-blind, placebo-controlled trial, we enrolled 2507 women in the second or third trimester of pregnancy who were planning to deliver in Entebbe General Hospital, Entebbe, Uganda. With a computer-generated random number sequence in blocks of 100, we assigned patients to 440 mg albendazole and 40 mg/kg praziquantel (n=628), 440 mg albendazole and a praziquantel-matching placebo (n=625), 40 mg/kg praziquantel and an albendazole-matching placebo (n=626), or an albendazole-matching placebo and praziquantel-matching placebo (n=628). All participants and hospital staff were masked to allocation. Primary outcomes were immune response at age 1 year to BCG, tetanus, and measles immunisation; incidence of infectious diseases during infancy; and vertical HIV transmission. Analysis was by intention-to-treat. This trial is registered, number ISRCTN32849447.
Findings
Data were available at delivery for 2356 women, with 2345 livebirths; 2115 (90%) of liveborn infants remained in follow-up at 1 year of age. Neither albendazole nor praziquantel treatments affected infant response to BCG, tetanus, or measles immunisation. However, in infants of mothers with hookworm infection, albendazole treatment reduced interleukin-5 (geometric mean ratio 0·50, 95% CI 0·30–0·81, interaction p=0·02) and interleukin-13 (0·52, 0·34–0·82, 0·0005) response to tetanus toxoid. The rate per 100 person-years of malaria was 40·9 (95% CI 38·3–43·7), of diarrhoea was 134·1 (129·2–139·2), and of pneumonia was 22·3 (20·4–24·4). We noted no effect on infectious disease incidence for albendazole treatment (malaria [hazard ratio 0·95, 95% CI 0·79–1.14], diarrhoea [1·06, 0·96–1·16], pneumonia [1·11, 0·90–1·38]) or praziquantel treatment (malaria [1·00, 0·84–1·20], diarrhoea [1·07, 0·98–1·18], pneumonia [1·00, 0·80–1·24]). In HIV-exposed infants, 39 (18%) were infected at 6 weeks; vertical transmission was not associated with albendazole (odds ratio 0·70, 95% CI 0·35–1·42) or praziquantel (0·60, 0·29–1·23) treatment.
Interpretation
These results do not accord with the recently advocated policy of routine antenatal anthelmintic treatment, and the value of such a policy may need to be reviewed.
Funding
Wellcome Trust.
doi:10.1016/S0140-6736(10)61457-2
PMCID: PMC3018567  PMID: 21176950
7.  Uptake of HIV and syphilis testing of pregnant women and their male partners in a programme for prevention of mother-to-child HIV transmission in Uganda 
Objective
To describe uptake of HIV and syphilis testing in a prevention of mother-to-child HIV transmission programme in Uganda.
Methods
Analysis of data from routine HIV and syphilis testing at Entebbe Hospital antenatal services.
Results
A total of 20 738 women attended antenatal services. Exactly 62.8% of women, but only 1.8% of their male partners, accepted testing for HIV; 82.2% of women, but only 1.1% of their male partners accepted syphilis testing. Partners of women with positive HIV results were more likely to come for subsequent testing. Of 200 couples whose partners accepted HIV-testing within 30 days of one another, 19 (9.5%) were HIV-discordant, representing 65.5% of couples with at least one partner HIV-positive. HIV prevalence was 12.6% for women and 10.8% for men; syphilis prevalence was 4.0% for women and 6.2% for men.
Conclusion
Uptake of HIV and syphilis testing was fairly good among pregnant women attending antenatal clinics at Entebbe Hospital, but very low among their male partners. The level of HIV-discordant couples was high. These clinics should be made more couples-friendly to identify both HIV-positive men for treatment and discordant couples for HIV prevention.
doi:10.1111/j.1365-3156.2008.02052.x
PMCID: PMC2592475  PMID: 18331533
HIV; PMTCT; Uganda; pregnant; couple; syphilis
8.  Associations between mild-to-moderate anaemia in pregnancy and helminth, malaria and HIV infection in Entebbe, Uganda 
Summary
It is suggested that helminths, particularly hookworm and schistosomiasis, may be important causes of anaemia in pregnancy. We assessed the associations between mild-to-moderate anaemia (haemoglobin >8.0 g/dl and <11.2 g/dl) and helminths, malaria and HIV among 2507 otherwise healthy pregnant women at enrolment to a trial of deworming in pregnancy in Entebbe, Uganda. The prevalence of anaemia was 39.7%. The prevalence of hookworm was 44.5%, Mansonella perstans 21.3%, Schistosoma mansoni 18.3%, Strongyloides 12.3%, Trichuris 9.1%, Ascaris 2.3%, asymptomatic Plasmodium falciparum parasitaemia 10.9% and HIV 11.9%. Anaemia showed little association with the presence of any helminth, but showed a strong association with malaria (adjusted odds ratio (AOR) 3.22, 95% CI 2.43–4.26) and HIV (AOR 2.46, 95% CI 1.90–3.19). There was a weak association between anaemia and increasing hookworm infection intensity. Thus, although highly prevalent, helminths showed little association with mild-to-moderate anaemia in this population, but HIV and malaria both showed a strong association. This result may relate to relatively good nutrition and low helminth infection intensity. These findings are pertinent to estimating the disease burden of helminths and other infections in pregnancy. [Clinical Trial No. ISRCTN32849447]
doi:10.1016/j.trstmh.2007.03.017
PMCID: PMC1950430  PMID: 17555783
Anaemia; Helminth; Pregnancy; HIV; Malaria; Uganda
9.  Treatment with anthelminthics during pregnancy: what gains and what risks for the mother and child? 
Parasitology  2011;138(12):1499-1507.
SUMMARY
In 1994 and 2002, respectively, the World Health Organisation proposed that treatment for hookworm and schistosomiasis could be provided during pregnancy. It was hoped that this might have benefits for maternal anaemia, fetal growth and perinatal mortality; a beneficial effect on the infant response to immunisation was also hypothesised. Three trials have now been conducted. Two have examined the effects of benzimidazoles; one (the Entebbe Mother and Baby Study) the effects of albendazole and praziquantel. All three were conducted in settings of high prevalence but low intensity helminth infection. Results suggest that, in such settings and given adequate provision of haematinics, the benefit of routine anthelminthics during pregnancy for maternal anaemia may be small; none of the other expected benefits has yet been demonstrated. The Entebbe Mother and Baby Study found a significant adverse effect of albendazole on the incidence of infantile eczema in the whole study population, and of praziquantel on the incidence of eczema among infants of mothers with Schistosoma mansoni. Further studies are required in settings that differ in helminth species and infection intensities. Further research is required to determine whether increased rates of infantile eczema translate to long-term susceptibility to allergy, and to explore the underlying mechanisms of these effects. The risks and benefits of routine anthelminthic treatment in antenatal clinics may need to be reconsidered.
doi:10.1017/S0031182011001053
PMCID: PMC3178871  PMID: 21810307
Anthelminthic; pregnancy; albendazole; praziquantel; hookworm; Schistosoma mansoni; atopic eczema; anaemia

Results 1-9 (9)