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INTRODUCTION: There is evidence that BCG immunisation may protect against unrelated infectious illnesses. This has led to the postulation that administering BCG before unrelated vaccines may enhance responses to these vaccines. This might also model effects of BCG on unrelated infections. METHODS AND ANALYSIS: To test this hypothesis, we have designed a randomised controlled trial of BCG versus no BCG immunisation to determine the effect of BCG on subsequent unrelated vaccines, among 300 adolescents (aged 13-17 years) from a Ugandan birth cohort. Our schedule will comprise three main immunisation days (week 0, week 4 and week 28): BCG (or no BCG) revaccination at week 0; yellow fever (YF-17D), oral typhoid (Ty21a) and human papillomavirus (HPV) prime at week 4; and HPV boost and tetanus/diphtheria (Td) boost at week 28. Primary outcomes are anti-YF-17D neutralising antibody titres, Salmonella typhi lipopolysaccharide-specific IgG concentration, IgG specific for L1-proteins of HPV-16/HPV-18 and tetanus and diphtheria toxoid-specific IgG concentration, all assessed at 4 weeks after immunisation with YF, Ty21a, HPV and Td, respectively. Secondary analyses will determine effects on correlates of protective immunity (where recognised correlates exist), on vaccine response waning and on whether there are differential effects on priming versus boosting immunisations. We will also conduct exploratory immunology assays among subsets of participants to further characterise effects of BCG revaccination on vaccine responses. Further analyses will assess which life course exposures influence vaccine responses in adolescence. ETHICS AND DISSEMINATION: Ethics approval has been obtained from relevant Ugandan and UK ethics committees. Results will be shared with Uganda Ministry of Health, relevant district councils, community leaders and study participants. Further dissemination will be done through conference proceedings and publications. TRIAL REGISTRATION NUMBER: ISRCTN10482904.
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Vacuna BCG , Tétanos , Adolescente , Humanos , Inmunización Secundaria , Ensayos Clínicos Controlados Aleatorios como Asunto , Uganda , VacunaciónRESUMEN
INTRODUCTION: Several licensed and investigational vaccines have lower efficacy, and induce impaired immune responses, in low-income versus high-income countries and in rural, versus urban, settings. Understanding these population differences is essential to optimising vaccine effectiveness in the tropics. We suggest that repeated exposure to and immunomodulation by chronic helminth infections partly explains population differences in vaccine response. METHODS AND ANALYSIS: We have designed an individually randomised, parallel group trial of intensive versus standard praziquantel (PZQ) intervention against schistosomiasis, to determine effects on vaccine response outcomes among school-going adolescents (9-17 years) from rural Schistosoma mansoni-endemic Ugandan islands. Vaccines to be studied comprise BCG on day 'zero'; yellow fever, oral typhoid and human papilloma virus (HPV) vaccines at week 4; and HPV and tetanus/diphtheria booster vaccine at week 28. The intensive arm will receive PZQ doses three times, each 2 weeks apart, before BCG immunisation, followed by a dose at week 8 and quarterly thereafter. The standard arm will receive PZQ at week 8 and 52. We expect to enrol 480 participants, with 80% infected with S. mansoni at the outset.Primary outcomes are BCG-specific interferon-γ ELISpot responses 8 weeks after BCG immunisation and for other vaccines, antibody responses to key vaccine antigens at 4 weeks after immunisation. Secondary analyses will determine the effects of intensive anthelminthic treatment on correlates of protective immunity, on waning of vaccine response, on priming versus boosting immunisations and on S. mansoni infection status and intensity. Exploratory immunology assays using archived samples will enable assessment of mechanistic links between helminths and vaccine responses. ETHICS AND DISSEMINATION: Ethics approval has been obtained from relevant ethics committes of Uganda and UK. Results will be shared with Uganda Ministry of Health, relevant district councils, community leaders and study participants. Further dissemination will be done through conference proceedings and publications. TRIAL REGISTRATION NUMBER: ISRCTN60517191.
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Esquistosomiasis , Adolescente , Animales , Humanos , Inmunidad , Islas , Praziquantel , Ensayos Clínicos Controlados Aleatorios como Asunto , UgandaRESUMEN
BACKGROUND: The prevalence of allergy-related diseases (ARDs), including rhinitis, allergic conjunctivitis and eczema, is on the increase globally. The causes of this increase are not well established. OBJECTIVES: To investigate the risk factors associated with ARDs among schoolchildren in Uganda. METHODS: We conducted a secondary data analysis of a large asthma case-control study involving 1700 schoolchildren, 5-17 years, in urban Uganda. ARDs were defined according to the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Skin prick testing (SPT) was conducted using standard procedures and allergen-specific IgE (asIgE) using ImmunoCAP® . We employed inverse probability weighted analysis to generate estimated prevalence data and weighted odds ratios. RESULTS: The lifetime estimated weighted prevalence of reported rhinitis, allergic conjunctivitis and eczema was 43.3%, 39.5% and 13.5%; weighted prevalence in 12 months was 10.1%, 9.1% and 2.3%, respectively. There was overlap of ARDs, with 66.3% of 1193 schoolchildren who reported having ever an ARDs (including asthma) reporting two or more. Risk factors associated with reported rhinitis in the last 12 months were city residence at birth [adjusted odds ratio (95% confidence interval) 2.66 (1.42-4.99) compared to rural]; father's [2.62 (1.79-3.83)] and mother's history of allergic disease [2.12 (1.48-3.02)]; frequent de-worming in the last 12 months [2.01 (1.30-3.11), ≥2 versus none]; current high frequency of 'trucks passing on the street near home' [2.59 (1.48-4.52), 'almost all the time' versus rarely] and positive SPT [1.54 (1.09-2.18)] but not asIgE [1.38 (0.60-3.15)]. The same pattern of risk factors was observed for allergic conjunctivitis and eczema. CONCLUSION: We found extensive multi-morbidity of, and overlap in the risk factors for, rhinitis, conjunctivitis and eczema-similar to asthma risk factors-among schoolchildren in urban Uganda. This suggests a similar underlying cause for all ARDs, associated with exposure to urban lifestyles and environment in Uganda.
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Conjuntivitis Alérgica/epidemiología , Dermatitis Atópica/epidemiología , Dinámica Poblacional/estadística & datos numéricos , Rinitis Alérgica/epidemiología , Población Urbana/estadística & datos numéricos , Adolescente , Asma/epidemiología , Estudios de Casos y Controles , Niño , Preescolar , Comorbilidad , Femenino , Humanos , Masculino , Padres , Prevalencia , Rinitis/epidemiología , Factores de Riesgo , Uganda/epidemiologíaRESUMEN
Data on asthma aetiology in Africa are scarce. We investigated the risk factors for asthma among schoolchildren (5-17 years) in urban Uganda. We conducted a case-control study, among 555 cases and 1115 controls. Asthma was diagnosed by study clinicians. The main risk factors for asthma were tertiary education for fathers (adjusted OR (95% CI); 2.32 (1.71-3.16)) and mothers (1.85 (1.38-2.48)); area of residence at birth, with children born in a small town or in the city having an increased asthma risk compared to schoolchildren born in rural areas (2.16 (1.60-2.92)) and (2.79 (1.79-4.35)), respectively; father's and mother's history of asthma; children's own allergic conditions; atopy; and cooking on gas/electricity. In conclusion, asthma was associated with a strong rural-town-city risk gradient, higher parental socio-economic status and urbanicity. This work provides the basis for future studies to identify specific environmental/lifestyle factors responsible for increasing asthma risk among children in urban areas in LMICs.
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Contaminantes Atmosféricos/efectos adversos , Alérgenos/efectos adversos , Asma/diagnóstico , Asma/epidemiología , Adolescente , Contaminantes Atmosféricos/inmunología , Alérgenos/inmunología , Asma/etiología , Asma/inmunología , Estudios de Casos y Controles , Niño , Preescolar , Escolaridad , Femenino , Humanos , Estilo de Vida , Masculino , Padres/educación , Factores de Riesgo , Población Rural , Uganda/epidemiología , Población Urbana , UrbanizaciónRESUMEN
Background: Children from low- and middle-income countries have poor asthma control, mainly because of poor management. The extent of this problem in Uganda is not well known, but such information would be useful to guide policy and practice. We therefore conducted a cross-sectional study among schoolchildren with asthma in urban Uganda, to assess the level of asthma control and management. Methods: Schoolchildren aged 5-17 years were enrolled, asthma was diagnosed by the study medical team. Asthma control was assessed using the Asthma Control Test and the childhood Asthma Control Test. Data on previous asthma management was obtained using interviewer-led questionnaires. Data were analysed using multiple linear and multiple logistic regression. Results: We enrolled 561 children with asthma, of whom only 56% had ever had an asthma diagnosis. We categorised asthma as well-controlled (55.5%), partly-controlled (29.5%) and poorly-controlled (15.0%). Poor asthma control was associated with increasing age (adjusted regression coefficient [95% confidence interval], p-value: -1.07 [-1.20, -0.94], p<0.0001), concurrent allergic rhinitis (-1.33 [-2.28, -0.38], p=0.006), and city residence in early life (-1.99 [-3.69, -0.29], p=0.06). Regular use of inhaled asthma medication in the last 12 months was very low; 18.1% for salbutamol and 6.7% for inhaled corticosteroids. The main barriers to inhaled asthma medication use were lack of prescription (47.6%) and inaccurate diagnosis (38.8%). Increased inhaler use was associated with tertiary education of the fathers (adjusted odds ratio [95% confidence interval], p-value: 5.19 [2.39-11.28], p<0.0001), city residence in early life (4.66 [1.79-12.43], 0.002) and an asthma diagnosis prior to enrolment (11.39 [6.35-20.43], p<0.0001). Conclusions: This study confirms that children with asthma in Uganda generally have inadequate asthma control, which is attributable to poor asthma management. This could be improved through re-training of medical workers and patient education, and by increasing availability and affordability of essential asthma medications.
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Background: A more effective vaccine for tuberculosis (TB) is a global public health priority. Vaccines under development will always need evaluation in endemic settings, most of which have limited resources. Adolescents are an important target population for a new TB vaccine and for other vaccines which are relevant at school-age. However, in most endemic settings there is limited experience of trials of investigational products among adolescents, and adolescents are not routinely vaccinated. Methods: We used Modified vaccinia Ankara-expressing Ag85A (MVA85A), a well-tolerated candidate vaccine for tuberculosis, to assess the effect of Schistosoma mansoni infection on vaccine immunogenicity among Ugandan adolescents in primary school. We describe here the challenges and lessons learned in designing and implementing this first clinical trial among Ugandan adolescents using a non-licensed vaccine. Results: The school based immunization study was feasible and adhered to Good Clinical Practice principles. Engagement with the community and all stakeholders was critical for successful implementation of the trial. Creative and adaptable strategies were used to address protocol-specific, operational and logistical challenges. This study provided lessons and solutions that can be applied to other trials among adolescents in similar settings elsewhere, and to school-based immunization programs. Conclusion: Sufficient time and resources should be planned for community preparation and sensitization to ensure buy in and acceptance of a project of this kind. This trial shows that challenges to implementing early field trials in Africa are not insurmountable and that necessary well-planned high-quality ethical trials are feasible and should be encouraged. Trial Registration: ClinicalTrials.gov NCT02178748 03/06/2014.
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BACKGROUND: The Hygiene Hypothesis proposes that infection exposure protects against inflammatory conditions. Helminths possess allergen-like molecules and may specifically modulate allergy-related immunological pathways to inhibit responses which protect against them. Mass drug administration is recommended for helminth-endemic communities to control helminth-induced pathology, but may also result in increased rates of inflammation-mediated diseases in resource-poor settings. Immunological studies integrated with implementation of helminth control measures may elucidate how helminth elimination contributes to ongoing epidemics of inflammatory diseases. We present the design of the Lake Victoria Island Intervention Study on Worms and Allergy-related diseases (LaVIISWA), a cluster-randomised trial evaluating the risks and benefits of intensive versus standard anthelminthic treatment for allergy-related diseases and other health outcomes. METHODS/DESIGN: The setting is comprised of island fishing communities in Mukono district, Uganda. Twenty-six communities have been randomised in a 1:1 ratio to receive standard or intensive anthelminthic intervention for a three-year period. Baseline characteristics were collected immediately prior to intervention rollout, commenced in February 2013. Primary outcomes are reported wheeze in the past 12 months and atopy (skin prick test response and allergen-specific immunoglobulin (asIg) E concentration). Secondary outcomes are visible flexural dermatitis, helminth infections, haemoglobin, growth parameters, hepatosplenomegaly, and responses to vaccine antigens. The trial provides a platform for in-depth analysis of clinical and immunological consequences of the contrasting interventions. DISCUSSION: The baseline survey has been completed successfully in a challenging environment. Baseline characteristics were balanced between trial arms. Prevalence of Schistosoma mansoni, hookworm, Strongyloides stercoralis and Trichuris trichiura was 52%, 23%, 13%, and 12%, respectively; 31% of Schistosoma mansoni infections were heavy (>400 eggs/gram). The prevalence of reported wheeze and positive skin prick test to any allergen was 5% and 20%, respectively. Respectively, 77% and 87% of participants had Dermatophagoides- and German cockroach-specific IgE above 0.35 kUA/L. These characteristics suggest that the LaVIISWA study will provide an excellent framework for investigating beneficial and detrimental effects of worms and their treatment, and the mechanisms of such effects. TRIAL REGISTRATION: This trial was registered with Current Controlled Trials (identifier: ISRCTN47196031) on 7 September 2012.