Philip C Hill

McMaster University, Hamilton, Ontario, Canada

Are you Philip C Hill?

Claim your profile

Publications (99)539.38 Total impact

  • Source
    Article: Immunology
    [show abstract] [hide abstract]
    ABSTRACT: Early clearance (EC) is the successful eradication of inhaled Mycobacterium tuberculosis before an adaptive immune response develops. Evidence for early clearance comes from case contact studies that consistently show a proportion of heavily exposed individuals do not develop M. tuberculosis infection. Further support for the existence of this phenotype comes from genetic loci associated with tuberculin reactivity. In this review we discuss aspects of the innate response that may underpin EC and hypotheses that can be tested through field laboratory link studies in M. tuberculosis case contacts. Specifically, we consider mechanisms whereby alveolar macrophages recognize and kill intracellular M. tuberculosis, and how other cell types, such as neutrophils, NK T cells, MAIT and γδ T cells may assist. How EC maybe impaired by HIV infection or vitamin D deficiency is also explored. As EC is a form of protective immunity, further study may advance the development of vaccines and immunotherapies to prevent M. tuberculosis infection.
    Immunology 12/2013; · 3.71 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Early clearance (EC) is the successful eradication of inhaled Mycobacterium tuberculosis before an adaptive immune response develops. Evidence for early clearance comes from case contact studies that consistently show a proportion of heavily exposed individuals do not develop M. tuberculosis infection. Further support for the existence of this phenotype comes from genetic loci associated with tuberculin reactivity. In this review we discuss aspects of the innate response that may underpin EC and hypotheses that can be tested through field laboratory link studies in M. tuberculosis case contacts. Specifically, we consider mechanisms whereby alveolar macrophages recognize and kill intracellular M. tuberculosis, and how other cell types, such as neutrophils, NK T cells, MAIT and γδ T cells may assist. How EC maybe impaired by HIV infection or vitamin D deficiency is also explored. As EC is a form of protective immunity, further study may advance the development of vaccines and immunotherapies to prevent M. tuberculosis infection. This article is protected by copyright. All rights reserved.
    Immunology 12/2013; · 3.71 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: To investigate qualitatively and quantitatively the performance of a programme for managing the child contacts of adult tuberculosis patients in Indonesia. A public health evaluation framework was used to assess gaps in a child contact management programme at a lung clinic. Targets for programme performance indicators were derived from established programme indicator targets, the scientific literature and expert opinion. Compliance with tuberculosis screening, the initiation of isoniazid preventive therapy in children younger than 5 years, the accuracy of tuberculosis diagnosis and adherence to preventive therapy were assessed in 755 child contacts in two cohorts. In addition, 22 primary caregivers and 34 clinic staff were interviewed to evaluate knowledge and acceptance of child contact management. The cost to caregivers was recorded. Gaps between observed and target indicator values were quantified. THE GAPS BETWEEN OBSERVED AND TARGET PERFORMANCE INDICATORS WERE: 82% for screening compliance; 64 to 100% for diagnostic accuracy, 50% for the initiation of preventive therapy, 54% for adherence to therapy and 50% for costs. Many staff did not have adequate knowledge of, or an appropriate attitude towards, child contact management, especially regarding isoniazid preventive therapy. Caregivers had good knowledge of screening but not of preventive therapy and had difficulty travelling to the clinic and paying costs. The study identified widespread gaps in the performance of a child contact management system in Indonesia, all of which appear amenable to intervention. The public health evaluation framework used could be applied in other settings where child contact management is failing.
    Bulletin of the World Health Organisation 12/2013; 91(12):932-941A. · 5.25 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Defaulting from anti-tuberculosis treatment hinders tuberculosis (TB) control. To identify potential defaulters. We conducted a cohort study in newly diagnosed Indonesian TB patients. We administered a questionnaire, prospectively identified defaulters (discontinued treatment ≥2 weeks) and assessed risk factors using Cox's regression. Of 249 patients, 39 (16%) defaulted, 61% in the first 2 months. Default was associated with liver disease (HR 3.40, 95%CI 1.02-11.78), chest pain (HR 2.25, 95%CI 1.06-4.77), night sweats (HR 1.98, 95%CI 1.03-3.79), characteristics of the head of the household (self-employed, HR 2.47, 95%CI 1.15-5.34; patient's mother, HR 7.72, 95%CI 1.66-35.88), household wealth (HR 4.24, 95%CI 1.12-16.09), walking to clinic (HR 4.53, 95%CI 1.39-14.71), being unaccompanied at diagnosis (HR 30.49, 95%CI 7.55-123.07) or when collecting medication (HR 3.34, 95%CI 1.24-8.98) and low level of satisfaction with the clinic (HR 3.85, 95%CI 1.17-12.62) or doctors (HR 2.45, 95%CI 1.18-5.10). Health insurance (HR 0.24, 95%CI 0.07-0.74) and paying for diagnosis (HR 0.14, 95%CI 0.04-0.48) were protective. Defaulting is common and occurs early. Interventions that improve clinic services, strengthen patient support and increase insurance coverage may reduce default in Indonesia.
    The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease 10/2013; 17(10):1304-9. · 2.61 Impact Factor
  • PLoS ONE 09/2013; 8(9). · 3.73 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Diarrheal disease causes ∼1.34 million deaths per year among children under 5 years of age globally. We conducted a Health Care Utilization and Attitude Survey of 1,012 primary caregivers of children ages 0-11, 12-23, and 24-59 months randomly selected from a Demographic Surveillance population in rural Gambia. Point prevalence of diarrhea was 7.7% (95% confidence interval [CI] = 6.1-9.8); 23.3% had diarrhea within the previous 2 weeks. Caregivers of 81.5% of children with diarrhea sought healthcare outside their home, but only 48.4% of them visited a health center. Only 17.0% (95% CI = 12.1-23.2) of children with diarrhea received oral rehydration solution (ORS) at home. Abbreviated surveys conducted on six occasions over the subsequent 2 years showed no change in prevalence or treatment-seeking behavior. Diarrhea remains a significant problem in rural young Gambian children. Encouraging care-seeking behavior at health centers and promoting ORS use can reduce mortality and morbidity in this population.
    The American journal of tropical medicine and hygiene 04/2013; · 2.53 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: BACKGROUND: The two major class A scavenger receptors are scavenger receptor A (SRA), which is constitutively expressed on most macrophage populations, and macrophage receptor with collagenous structure (MARCO), which is constitutively expressed on a more restricted subset of macrophages, (e.g. alveolar macrophages) but whose expression increases on most macrophages during the course of infection. Although the primary role of SRA appears to be clearance of modified host proteins and lipids, mice defective in expression of either MARCO or SRA are immunocompromised in multiple models of infection and in vitro assays, the scavenger receptors have been demonstrated to bind bacteria and to enhance pro-inflammatory signalling to many bacterial lung pathogens; however their importance in Mycobacterium tuberculosis infection, is less clear. METHODS: To determine whether polymorphisms in either SRA or MARCO were associated with tuberculosis, a case--control study of was performed. DNA samples from newly-detected, smear-positive, pulmonary tuberculosis cases were collected from The Gambia. Controls for this study consisted of DNA from cord bloods obtained from routine births at local Gambian health clinics. Informed written consent was obtained from patients or their parents or guardians. Ethical approval was provided by the joint The Gambian Government/MRC Joint Ethics Committee. RESULTS: We studied the frequencies of 25 polymorphisms of MSR1 (SRA) and 22 in MARCO in individuals with tuberculosis (n=1284) and matched controls (n=1349). No SNPs within the gene encoding or within 1 kb of the promoter sequence of MSR1 were associated with either susceptibility or resistance to tuberculosis. Three SNPS in MARCO (rs4491733, Mantel-Haenszel 2x2 chi2 = 6.5, p = 0.001, rs12998782, Mantel-Haenszel 2x2 chi2 = 6.59, p = 0.001, rs13389814 Mantel-Haenszel 2x2 chi2 = 6.9, p = 0.0009) were associated with susceptibility to tuberculosis and one (rs7559955, Mantel-Haenszel 2x2 chi2 = 6.9, p = 0.0009) was associated with resistance to tuberculosis. CONCLUSIONS: These findings identify MARCO as a potentially important receptor in the host response to tuberculosis.
    BMC Medical Genetics 04/2013; 14(1):47. · 2.54 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: A village-randomized trial of a seven-valent pneumococcal-conjugate-vaccine (PCV-7) conducted in rural Gambia showed a decrease of vaccine-type (VT) and a non-significant increase in non-vaccine-type (NVT) nasopharyngeal carriage of pneumococci two years after vaccination. Here, we report findings four years after vaccination. PCV-7 was given to all children below 30 months of age enrolled in the trial and to those born during its course in all study villages. Villages were randomized (older children and adults) to receive PCV-7 (wholly vaccinated villages) or serogroup-C-meningococcal-conjugate-vaccine (partly vaccinated villages). Cross-sectional surveys (CSS) to collect nasopharyngeal swabs were conducted before and at various intervals after vaccination. Sixteen of these randomized villages (8 wholly vaccinated and 8 partly vaccinated) participated in a CSS conducted four years after vaccination started. Four years after vaccination, the prevalence of VT pneumococcal carriage was slightly higher in partly than in wholly vaccinated villages [6.4% versus 3.9% (p = 0.120)] compared to 24.4% in the pre-vaccination CSS (p<0.001). Prevalence of NVT four years after vaccination was similar between study groups [32.7% versus 29.8% (p = 0.392), respectively] compared to 51.1% in the pre-vaccination CSS (p<0.001). Four years after vaccination started, lower prevalence of serotype 6A was detected in wholly vaccinated than in partly vaccinated villages (1.6% versus 3.5%, p = 0.093) whilst the prevalence of serotype 19A was similar between groups (2.9% versus 2.5%, p = 0.779). The most prevalent serotype 19A clone was ST 847. The most prevalent serotype 6A clone before vaccination was ST3324 whilst after vaccination ST913 and ST1737 predominated. Fourteen out of 26 STs detected among the serotype 6A isolates were new while no new 19A serotype ST was found. The decline in prevalence of VT pneumococci seen shortly after PCV-7 vaccination was sustained four years later with only a small difference between study arms. No significant serotype replacement was detected. ClinicalTrials.gov ISRCTN51695599.
    PLoS ONE 01/2013; 8(9):e72198. · 3.73 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: A number of childhood vaccination programmes have recently introduced vaccination against Streptococcus pneumoniae, the pneumococcus, a major cause of pneumonia and meningitis. The pneumococcal conjugate vaccines (PCVs) that are currently in use only protect against some serotypes of the bacterium, and there is now strong evidence that those serotypes not included in the vaccine increase in prevalence among most vaccinated populations. We present a mathematical model for the dynamics of nasopharyngeal carriage of S. pneumoniae that allows for carriage with multiple serotypes. The model is used to predict the prevalence of vaccine type (VT) and non-VT (NVT) serotypes following the introduction of PCV. Parameter estimates for the model are obtained by maximum likelihood using pre-vaccination data from The Gambia. The model predicts that low (1, 6A and 9V) and medium (4, 5, 7F, 14, 18C, 19A and 19F) prevalence serotypes can be eliminated through vaccination, but that the overall prevalence of carriage will be reduced only slightly because of an increase in the prevalence of NVT serotypes. Serotype replacement will be sequential, with high and medium prevalence NVT serotypes dominating initially, followed by an increase of serotypes of low prevalence. We examine the impact of a hypothetical vaccine that provides partial protection against all serotypes, and find that this reduces overall carriage, but is unable to eliminate low or medium prevalence serotypes.
    Journal of The Royal Society Interface 01/2013; 10(89):20130786. · 4.91 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Rationale Biomarkers that can be used to evaluate new interventions against latent tuberculosis infection (LTBI) and predict reactivation TB disease are urgently required. Objectives To measure Isoniazid induced qualitative and quantitative reversion of positive ESAT-6 and CFP-10 (EC) Interferon gamma ELISPOT tests in LTBI. Methods This was a randomized, blinded and placebo controlled trial of Isoniazid (INH) in ESAT-6 and CFP-10 (EC) ELISPOT and Mantoux test positive participants. Measurements and Main Results Participants received a 6-month course of 900mg INH twice weekly or a matching placebo. INH acetylator genotypes were determined and urine tests for INH metabolites to confirm adherence. The proportion of positive responders for CFP-10 and ESAT-6, between treatment arms were compared using mixed effects logistic regression models. A Tweedie (compound Poisson) model fitted using the R package cplm to allow for zero inflation and over dispersion of qualitative response. This trial was registered with ClinicalTrials.gov (NCT00130325). The proportions of EC ELISPOT positive subjects reduced over time (p <0.001) but did not differ by study arm (p=0.36). Median spot forming units (SFUs) for ESAT-6 and CFP-10 also declined significantly with time (p<0.001) but did not differ by study arm (p=0.74 and 0.71 respectively). There was no evidence of an interaction between acetylator status and INH treatment with respect to ELISPOT results over time. Conclusions In contacts with LTBI, Isoniazid therapy plays no role in observed decreases in M. tuberculosis antigen-specific T-cell responses over time. Interferon gamma ELISPOT is probably not a useful biomarker of treatment efficacy in LTBI.
    American Journal of Respiratory and Critical Care Medicine 12/2012; · 11.04 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: SETTING AND OBJECTIVES: Young children living with infectious tuberculosis (TB) cases are at high risk of infection and disease, and screening is recommended. This is rarely conducted in resource-limited settings. Identifying children most at risk of infection may be useful for setting practical screening policies. Child contacts of smear-positive adult TB patients were invited for Mycobacterium tuberculosis infection and disease screening by symptoms, tuberculin skin test (TST), QuantiFERON®-TB Gold In-Tube assay (QFT-GIT) and chest X-ray. Risk factors for infection were collected using a questionnaire and were calculated separately for TST, for QFT-GIT and for both tests combined. Of 304 screened children 145/302 (48%) were positive using TST, 152/299 (51%) by QFT-GIT and 180/304 (59%) were positive using either or both tests. Positivity for both tests was associated with index case infectivity (acid-fast bacilli [AFB] 3+ vs. AFB 1+: TST OR 2.93, 95%CI 1.59-5.39; QFT-GIT OR 2.28, 95%CI 1.06-4.90) and exposure (child contact's parent is the index case: TST OR 7.04, 95%CI 2.23-22.28; QFT-GIT OR 4.30, 95%CI 1.48-12.45). M. tuberculosis infection according to either test was high, supporting screening and preventive treatment. Children of smear-positive TB cases who accompany their parents to the clinic should be prioritised for immediate screening.
    The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease 12/2012; 16(12):1594-9. · 2.61 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: OBJECTIVE To evaluate the effectiveness of Sprinkles alongside infant and young child feeding (IYCF) education compared with IYCF education alone on anemia, deficiencies in iron, vitamin A, and zinc, and growth in Cambodian infants. DESIGN Cluster-randomized effectiveness study. SETTING Cambodian rural health district. PARTICIPANTS Among 3112 infants aged 6 months, a random subsample (n = 1350) was surveyed at baseline and 6-month intervals to age 24 months. INTERVENTION Daily micronutrient Sprinkles alongside IYCF education vs IYCF education alone for 6 months from ages 6 to 11 months. MAIN OUTCOME MEASURES Prevalence of anemia; iron, vitamin A, and zinc deficiencies; and growth via biomarkers and anthropometry. RESULTS Anemia prevalence (hemoglobin level <11.0 g/dL [to convert to grams per liter, multiply by 10.0]) was reduced in the intervention arm compared with the control arm by 20.6% at 12 months (95% CI, 9.4-30.2; P = .001), and the prevalence of moderate anemia (hemoglobin level <10.0 g/dL) was reduced by 27.1% (95% CI, 21.0-31.8; P < .001). At 12 and 18 months, iron deficiency prevalence was reduced by 23.5% (95% CI, 15.6-29.1; P < .001) and 11.6% (95% CI, 2.6-17.9; P = .02), respectively. The mean serum zinc concentration was increased at 12 months (2.88 μg/dL [to convert to micromoles per liter, multiply by 0.153]; 95% CI, 0.26-5.42; P = .03). There was no statistically significant difference in the prevalence of zinc and vitamin A deficiencies or in growth at any time. CONCLUSIONS Sprinkles reduced anemia and iron deficiency and increased the mean serum zinc concentration in Cambodian infants. Anemia and zinc effects did not persist beyond the intervention period. TRIAL REGISTRATION anzctr.org.au Identifier: ACTRN12608000069358.
    Archives of pediatrics & adolescent medicine 09/2012; 166(9):842-50. · 3.73 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Young children living with a tuberculosis patient are at high risk of Mycobacterium tuberculosis infection and disease. WHO guidelines promote active screening and isoniazid (INH) preventive therapy (PT) for such children under 5 years, yet this well-established intervention is seldom used in endemic countries. We review the literature regarding barriers to implementation of PT and find that they are multifactorial, including difficulties in screening, poor adherence, fear of increasing INH resistance and poor acceptability among primary caregivers and healthcare workers. These barriers are largely resolvable, and proposed solutions such as the adoption of symptom-based screening and shorter drug regimens are discussed. Integrated multicomponent and site-specific solutions need to be developed and evaluated within a public health framework to overcome the policy-practice gap and provide functional PT programmes for children in endemic settings.
    Tropical Medicine & International Health 08/2012; · 2.94 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Objective: To evaluate the effectiveness of Sprinkles alongside infant and young child feeding (IYCF) educa-tion compared with IYCF education alone on anemia, de-ficiencies in iron, vitamin A, and zinc, and growth in Cambodian infants. Design: Cluster-randomized effectiveness study. Setting: Cambodian rural health district. Participants: Among 3112 infants aged 6 months, a ran-dom subsample (n = 1350) was surveyed at baseline and 6-month intervals to age 24 months. Intervention: Daily micronutrient Sprinkles along-side IYCF education vs IYCF education alone for 6 months from ages 6 to 11 months. Main Outcome Measures: Prevalence of anemia; iron, vitamin A, and zinc deficiencies; and growth via bio-markers and anthropometry. Results: Anemia prevalence (hemoglobin level 11.0 g/dL [to convert to grams per liter, multiply by 10.0]) was reduced in the intervention arm compared with the control arm by 20.6% at 12 months (95% CI, 9.4-30.2; P = .001), and the prevalence of moderate anemia (he-moglobin level 10.0 g/dL) was reduced by 27.1% (95% CI, 21.0-31.8; P .001). At 12 and 18 months, iron de-ficiency prevalence was reduced by 23.5% (95% CI, 15.6-29.1; P.001) and 11.6% (95% CI, 2.6-17.9; P=.02), re-spectively. The mean serum zinc concentration was increased at 12 months (2.88 µg/dL [to convert to mi-cromoles per liter, multiply by 0.153]; 95% CI, 0.26-5.42; P =.03). There was no statistically significant dif-ference in the prevalence of zinc and vitamin A deficiencies or in growth at any time. Conclusions: Sprinkles reduced anemia and iron defi-ciency and increased the mean serum zinc concentra-tion in Cambodian infants. Anemia and zinc effects did not persist beyond the intervention period.
    Archives of Pediatrics and Adolescent Medicine 07/2012; · 4.28 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: This study evaluated the impact of age and pneumococcal vaccination on the density of pneumococcal nasopharyngeal carriage. A cluster-randomized trial was conducted in rural Gambia. In 11 villages (the vaccine group), all residents received 7-valent pneumococcal conjugate vaccine (PCV-7), while in another 10 villages (the control group), only children <30 months old or born during the study period received PCV-7. Cross-sectional surveys (CSSs) were conducted to collect nasopharyngeal swabs before vaccination (baseline CSS) and 4, 12, and 22 months after vaccination. Pneumococcal density was defined using a semiquantitative classification (range, 1-4) among colonized individuals. An age-trend analysis of density was conducted using data from the baseline CSS. Mean pneumococcal density was compared in CSSs conducted before and after vaccination. Mean bacterial density among colonized individuals in the baseline CSS was 2.57 for vaccine-type (VT) and non-vaccine-type (NVT) pneumococci; it decreased with age (P < .001 for VT and NVT). There was a decrease in the density of VT carriage following vaccination in individuals older than 5 years (from 2.44 to 1.88; P = .001) and in younger individuals (from 2.57 to 2.11; P = .070) in the vaccinated villages. Similar decreases in density were observed with NVT within vaccinated and control villages. No significant differences were found between vaccinated and control villages in the postvaccination comparisons for either VT or NVT. A high density of carriage among young subjects might partly explain why children are more efficient than adults in pneumococcal transmission. PCV-7 vaccination lowered the density of VT and of NVT pneumococcal carriage in the before-after vaccination analysis. Clinical Trials Registration: ISRCTN51695599.
    Clinical Infectious Diseases 06/2012; 55(6):816-24. · 9.37 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: SETTING AND OBJECTIVES: The tuberculin skin test (TST) has limitations in diagnosing latent tuberculosis (TB) infection (LTBI). Interferon-gamma release assays may improve diagnostic accuracy. We compared QuantiFERON®-TB Gold In-Tube (QFT-GIT) and TST in Indonesian children. Children aged from 6 months to 9 years exposed to a TB case at household and neighbourhood levels were recruited. The children underwent QFT-GIT and TST. Test responsiveness was assessed according to an exposure gradient. A total of 299 household-exposed and 72 neighbourhood-exposed children were analysed. Overall, respectively 46% and 41% were positive using QFT-GIT and the TST. Test positivity increased with exposure (QFT-GIT P value for trend <0.001, and TST P < 0.001); however, only QFT-GIT responded significantly to a 'within-household' gradient. The TST was less likely to be positive than the QFT-GIT in neighbourhood-exposed children (P = 0.05). BCG-vaccinated children were less likely to be QFT-GIT-positive, while older children were more likely to be QFT-GIT-positive. Both tests had increasing positivity with increasing smear grade. QFT-GIT performed similarly to the TST in Indonesian children living with an infectious TB case. Test accuracy was not compromised by young age or BCG vaccination. Our findings suggest that QFT-GIT offers little advantage over the TST in this population. High rates of LTBI diagnosed in household-exposed children by both tests support preventive therapy.
    The international journal of tuberculosis and lung disease: the official journal of the International Union against Tuberculosis and Lung Disease 02/2012; 16(4):496-502. · 2.61 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: It is recommended that young child contacts of sputum smear positive tuberculosis cases receive isoniazid preventive therapy (IPT) but reported adherence is low and risk factors for poor adherence in children are largely unknown. We prospectively determined rates of IPT adherence in children < 5 yrs in an Indonesian lung clinic. Possible risk factors for poor adherence, defined as ≤3 months prescription collection, were calculated using logistic regression. To further investigate adherence barriers in-depth interviews were conducted with caregivers of children with good and poor adherence. Eighty-two children eligible for IPT were included, 61 (74.4%) of which had poor adherence. High transport costs (OR 3.3, 95% CI 1.1-10.2) and medication costs (OR 20.0, 95% CI 2.7-414.5) were significantly associated with poor adherence in univariate analysis. Access, medication barriers, disease and health service experience and caregiver TB and IPT knowledge and beliefs were found to be important determinants of adherence in qualitative analysis. Adherence to IPT in this setting in Indonesia is extremely low and may result from a combination of financial, knowledge, health service and medication related barriers. Successful reduction of childhood TB urgently requires evidence-based interventions that address poor adherence to IPT.
    BMC Research Notes 01/2012; 5:7.
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: The monocyte chemotactic protein-1 (MCP-1) is a chemokine that plays an important role in the recruitment of monocytes to M. tuberculosis infection sites, and previous studies have reported that genetic variants in MCP1 are associated with differential susceptibility to pulmonary tuberculosis (PTB). We examined eight MCP1 single nucleotide polymorphisms (SNPs) in a multi-ethnic, case-control design that included: 321 cases and 346 controls from Guinea-Bissau, 258 cases and 271 controls from The Gambia, 295 cases and 179 controls from the U.S. (African-Americans), and an additional set of 237 cases and 144 controls of European ancestry from the U.S. and Argentina. Two locus interactions were also examined for polymorphisms in MCP1 and interleukin 12B (IL12B), another gene implicated in PTB risk. Examination of previously associated MCP1 SNPs rs1024611 (-2581A/G), rs2857656 (-362G/C) and rs4586 (+900C/T) did not show evidence for association. One interaction between rs2857656 and IL12B SNP rs2288831 was observed among Africans but the effect was in the opposite direction in Guineans (OR = 1.90, p = 0.001) and Gambians (OR = 0.64, p = 0.024). Our data indicate that the effect of genetic variation within MCP1 is not clear cut and additional studies will be needed to elucidate its role in TB susceptibility.
    PLoS ONE 01/2012; 7(2):e32275. · 3.73 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Gambian infants frequently acquire Streptococcus pneumoniae soon after birth. We investigated the indirect effect of 7-valent pneumococcal conjugate vaccine (PCV-7) on pneumococcal acquisition in newborn Gambian babies. Twenty-one villages were randomised to receive PCV-7 to all subjects (11 vaccinated villages) or to infants aged 2-30 months (10 control villages). Other control villagers received Meningococcal C conjugate vaccine. From 328 babies born during the trial, nasopharyngeal swabs were collected after birth, then weekly until 8 weeks of age when they received their first dose of PCV-7. Pneumococcal carriage and acquisition rates were compared between the study arms and with a baseline study. 57.4% of 2245 swabs were positive for S. pneumoniae. Overall carriage was similar in both arms. In vaccinated villages fewer infants carried pneumococci of vaccine serotypes (VT) (16.9% [31/184] vs. 37.5% [54/144], p<0.001) and more carried pneumococci of non-vaccine serotypes (NVT) (80.9% [149/184] vs. 75.7% [109/144], p = 0.246). Infants from vaccinated villages had a significantly lower acquisition rate of VT (HR 0.39 [0.26-0.58], p<0.001) and increased acquisition of NVT (HR 1.16 [0.87-1.56], p = 0.312). VT carriage (51.6% vs. 37.5%, p = 031 in control and 46.1% vs. 16.8%, p<0.001 in vaccinated villages) and acquisition rates (HR 0.68 [0.50-0.92], p = 0.013 in control villages and HR 0.31 [0.19-0.50], p<.001 in vaccinated villages) were significantly lower in both study arms than in the baseline study. NVT carriage (63.2% vs. 75.7%, p = 0.037 in control and 67.2% vs. 75.3%, p = 0.005 in vaccinated villages) and acquisition rates (HR 1.48 [1.06-2.06], p = 0.022) and (HR 1.52 [1.11-2.10], p = 0.010 respectively) were significantly higher. PCV-7 significantly reduced carriage of VT pneumococci in unvaccinated infants. This indirect effect likely originated from both the child and adult vaccinated populations. Increased carriage of NVT pneumococci needs ongoing monitoring. ISRCTN Register 51695599.
    PLoS ONE 01/2012; 7(11):e49143. · 3.73 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: A recent trial with PCV-7 in a rural Gambian community showed reduced vaccine-type pneumococcal carriage in fully vaccinated compared with control communities. We measured pneumococcal polysaccharide antibody concentrations in this trial to understand further the mechanisms underlying the observed changes. A single-blind, cluster-randomized (by village) trial was conducted in 21 Gambian villages. In 11 villages, all residents received PCV-7 (Vaccine group); in 10 control villages only children <30 months old or those born during the study received PCV-7. Subjects over the age of 30 months resident in vaccine villages received a single dose of PCV-7 whilst those in control villages received a single dose of a serogroup C meningococcal conjugate vaccine. Serum antibody concentrations against specific pneumococcal polysaccharides were measured in approximately 200 age-stratified subjects before, 4-6, 12 and 24 months following vaccination. Baseline pneumococcal antibody concentrations were generally high and increased with age up to 10 years. One dose of PCV-7 increased geometric mean antibody concentrations (GMC) in vaccinated versus control villages for vaccine serotypes 6B and 18C, and 4 and 18C, in the young (under 5 years) and older age groups (5+ years) respectively. There were significantly higher proportions of subjects in the vaccinated than in the control communities with an antibody concentration believed to protect against carriage (>5.0 µg/mL) for all but serotype 9V of the PCV-7 serotypes in the older group, but not in the younger age group. Higher antibodies in vaccinated communities provide an explanation for the lower pneumococcal carriage rates in fully vaccinated compared to control communities. Controlled-Trials.com ISRCTN51695599 51695599.
    PLoS ONE 01/2012; 7(8):e42997. · 3.73 Impact Factor

Publication Stats

2k Citations
539.38 Total Impact Points

Institutions

  • 2013
    • McMaster University
      • McMaster Immunology Research Centre (MIRC)
      Hamilton, Ontario, Canada
  • 2009–2013
    • University of Otago
      • • Centre for International Health
      • • Department of Preventive & Social Medicine
      Taieri, Otago Region, New Zealand
    • Max Planck Institute for Infection Biology
      • Department of Immunology
      Berlín, Berlin, Germany
    • CUNY Graduate Center
      New York City, New York, United States
    • National Veterinary Research Institute, Vom
      Vom, Plateau, Nigeria
  • 2012
    • University of Miami
      • Dr. John T. Macdonald Foundation Department of Human Genetics
      Coral Gables, FL, United States
  • 2005–2012
    • Medical Research Council Unit, The Gambia Unit
      Bakau, Banjul, Gambia
    • Leiden University Medical Centre
      • Department of Immunhematology and Blood Transfusion
      Leyden, South Holland, Netherlands
  • 2010
    • Bernhard Nocht Institute for Tropical Medicine
      • Department of Molecular Medicine
      Hamburg, Hamburg, Germany
  • 2006
    • Mulago Hospital
      Kampala, Central Region, Uganda