Livestock network analysis for rhodesiense human African trypanosomiasis control in Uganda

Background: Infected cattle sourced from districts with established foci for Trypanosoma brucei rhodesiense human African trypanosomiasis (rHAT) migrating to previously unaffected districts, have resulted in a significant expansion of the disease in Uganda. This study explores livestock movement data to describe cattle trade network topology and assess the effects of disease control interventions on the transmission of rHAT infectiousness.Methods: Network analysis was used to generate a cattle trade network with livestock data which was collected from cattle traders (n = 197) and validated using random graph methods. Additionally, the cattle trade network was combined with a susceptible, infected, recovered (SIR) compartmental model to simulate spread of rHAT (Ro 1.287), hence regarded as “slow” pathogen, and evaluate the effects of disease interventions.Results: The cattle trade network exhibited a low clustering coefficient (0.5) with most cattle markets being weakly connected and a few being highly connected. Also, analysis of the cattle movement data revealed a core group comprising of cattle markets from both eastern (rHAT endemic) and northwest regions (rHAT unaffected area). Presence of a core group may result in rHAT spread to unaffected districts and occurrence of super spreader cattle market or markets in case of an outbreak. The key cattle markets that may be targeted for routine rHAT surveillance and control included Namutumba, Soroti, and Molo, all of which were in southeast Uganda. Using effective trypanosomiasis such as integrated cattle injection with trypanocides and spraying can sufficiently slow the spread of rHAT in the network.Conclusion: Cattle trade network analysis indicated a pathway along which T. b. rhodesiense could spread northward from eastern Uganda. Targeted T. b. rhodesiense surveillance and control in eastern Uganda, through enhanced public–private partnerships, would serve to limit its spread

Evaluating the impact of targeting livestock for the prevention of human and animal trypanosomiasis, at village level, in districts newly affected with T. b. rhodesiense in Uganda

Background: Uganda has suffered from a series of epidemics of Human African Trypanosomiasis (HAT), a tsetse transmitted disease, also known as sleeping sickness. The area affected by acute Trypanosoma brucei rhodesiense HAT (rHAT) has been expanding, driven by importation of infected cattle into regions previously free of the disease. These regions are also affected by African Animal Trypanosomiasis (AAT) demanding a strategy for integrated disease control.Methods: In 2008, the Public Private Partnership, Stamp Out Sleeping Sickness (SOS) administered a single dose of trypanocide to 31 486 head of cattle in 29 parishes in Dokolo and Kaberamaido districts. This study examines the impact of this intervention on the prevalence of rHAT and AAT trypanosomes in cattle from villages that had (HAT+ve) or had not (HAT-ve) experienced a recent case of rHAT. Cattle herds from 20 villages were sampled and screened by PCR, pre-intervention and 6-months post-intervention, for the presence or absence of: Trypanosoma brucei s.l.; human infective T. b. rhodesiense; Trypanosoma vivax; and Trypanosoma congolense savannah.Results: Post-intervention, there was a significant decrease in the prevalence of T. brucei s.l. and the human infective sub-species T. b. rhodesiense in village cattle across all 20 villages. The prevalence of T. b. rhodesiense was reduced from 2.4% to 0.74% (P < 0.0001), with the intervention showing greater impact in HAT-ve villages. The number of villages containing cattle harbouring human infective parasites decreased from 15/20 to 8/20, with T. b. rhodesiense infection mainly persisting within cattle in HAT+ve villages (six/eight). The proportion of T. brucei s.l. infections identified as human infective T. b. rhodesiense decreased after the intervention from 8.3% (95% CI = 11.1–5.9%) to 4.1% (95% CI = 6.8–2.3%). Villages that had experienced a recent human case (HAT+ve villages) showed a significantly higher prevalence for AAT both pre- and post-intervention. For AAT the prevalence of T. vivax was significantly reduced from 5.9% to 0.05% post-intervention while the prevalence of T. congolense increased from 8.0% to 12.2%.Conclusions: The intervention resulted in a significant decrease in the prevalence of T. brucei s.l., human infective T. b. rhodesiense and T. vivax infection in village cattle herds. The proportion of T. brucei s.l. that were human infective, decreased from 1:12 T. brucei s.l. infections before the intervention to 1:33 post-intervention. It is clearly more difficult to eliminate T. b. rhodesiense from cattle in villages that have experienced a human case. Evidence of elevated levels of AAT in livestock within village herds is a useful indicator of risk for rHAT in Uganda. Integrated veterinary and medical surveillance is key to successful control of zoonotic rHAT

Improving association studies and genomic predictions for climbing beans with data from bush bean populations

Common bean (Phaseolus vulgaris L.) has two major origins of domestication, Andean and Mesoamerican, which contribute to the high diversity of growth type, pod and seed characteristics. The climbing growth habit is associated with increased days to flowering (DF), seed iron concentration (SdFe), nitrogen fixation, and yield. However, breeding efforts in climbing beans have been limited and independent from bush type beans. To advance climbing bean breeding, we carried out genome-wide association studies and genomic predictions using 1,869 common bean lines belonging to five breeding panels representing both gene pools and all growth types. The phenotypic data were collected from 17 field trials and were complemented with 16 previously published trials. Overall, 38 significant marker-trait associations were identified for growth habit, 14 for DF, 13 for 100 seed weight, three for SdFe, and one for yield. Except for DF, the results suggest a common genetic basis for traits across all panels and growth types. Seven QTL associated with growth habits were confirmed from earlier studies and four plausible candidate genes for SdFe and 100 seed weight were newly identified. Furthermore, the genomic prediction accuracy for SdFe and yield in climbing beans improved up to 8.8% when bush-type bean lines were included in the training population. In conclusion, a large population from different gene pools and growth types across multiple breeding panels increased the power of genomic analyses and provides a solid and diverse germplasm base for genetic improvement of common bean

Effect of intermittent preventive treatment for malaria with dihydroartemisinin-piperaquine on immune responses to vaccines among rural Ugandan adolescents: randomised controlled trial protocol B for the 'POPulation differences in VACcine responses' (POPVAC) programme.

INTRODUCTION: Drivers of lower vaccine efficacy and impaired vaccine-specific immune responses in low-income versus high-income countries, and in rural compared with urban settings, are not fully elucidated. Repeated exposure to and immunomodulation by parasite infections may be important. We focus on Plasmodium falciparum malaria, aiming to determine whether there are reversible effects of malaria infection on vaccine responses. METHODS AND ANALYSIS: We have designed a randomised, double-blind, placebo-controlled, parallel group trial of intermittent preventive malaria treatment versus placebo, to determine effects on vaccine response outcomes among school-going adolescents (9 to 17 years) from malaria-endemic rural areas of Jinja district (Uganda). Vaccines to be studied comprise BCG vaccine on day 'zero'; yellow fever, oral typhoid and human papilloma virus vaccines at week 4; and tetanus/diphtheria booster vaccine at week 28. Participants in the intermittent preventive malaria treatment arm will receive dihydroartemisinin/piperaquine (DP) dosed by weight, 1 month apart, prior to the first immunisation, followed by monthly treatment thereafter. We expect to enrol 640 adolescents. 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. In secondary analyses, we will determine effects of monthly DP treatment (versus placebo) on correlates of protective immunity, on vaccine response waning, on whether there are differential effects on priming versus boosting immunisations, and on malaria infection prevalence. We will also conduct exploratory immunology assays among subsets of participants to further characterise effects of the intervention on vaccine responses. 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: Current Controlled Trials identifier: ISRCTN62041885

Effect of intensive treatment for schistosomiasis on immune responses to vaccines among rural Ugandan island adolescents: randomised controlled trial protocol A for the 'POPulation differences in VACcine responses' (POPVAC) programme.

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

Replication data for: Improving association studies and genomic predictions for climbing beans with data from bush bean populations

Genomic predictions for climbing beans were established. The climbing bean panel (VEC) was phenotypically and genotypically characterized. To improve association studies and predictions, contrasting bush type bean data, i.e., publicly available data as well as data from new field trials, were added to the data set

Improving Association Studies and Genomic Predictions for Climbing Beans With Data From Bush Bean Populations

Common bean (Phaseolus vulgaris L.) has two major origins of domestication, Andean and Mesoamerican, which contribute to the high diversity of growth type, pod and seed characteristics. The climbing growth habit is associated with increased days to flowering (DF), seed iron concentration (SdFe), nitrogen fixation, and yield. However, breeding efforts in climbing beans have been limited and independent from bush type beans. To advance climbing bean breeding, we carried out genome-wide association studies and genomic predictions using 1,869 common bean lines belonging to five breeding panels representing both gene pools and all growth types. The phenotypic data were collected from 17 field trials and were complemented with 16 previously published trials. Overall, 38 significant marker-trait associations were identified for growth habit, 14 for DF, 13 for 100 seed weight, three for SdFe, and one for yield. Except for DF, the results suggest a common genetic basis for traits across all panels and growth types. Seven QTL associated with growth habits were confirmed from earlier studies and four plausible candidate genes for SdFe and 100 seed weight were newly identified. Furthermore, the genomic prediction accuracy for SdFe and yield in climbing beans improved up to 8.8% when bush-type bean lines were included in the training population. In conclusion, a large population from different gene pools and growth types across multiple breeding panels increased the power of genomic analyses and provides a solid and diverse germplasm base for genetic improvement of common bean.ISSN:1664-462

Population differences in vaccine responses (POPVAC): scientific rationale and cross-cutting analyses for three linked, randomised controlled trials assessing the role, reversibility and mediators of immunomodulation by chronic infections in the tropics

Introduction Vaccine-specific immune responses vary between populations and are often impaired in low income, rural settings. Drivers of these differences are not fully elucidated, hampering identification of strategies for optimising vaccine effectiveness. We hypothesise that urban–rural (and regional and international) differences in vaccine responses are mediated to an important extent by differential exposure to chronic infections, particularly parasitic infections.Methods and analysis Three related trials sharing core elements of study design and procedures (allowing comparison of outcomes across the trials) will test the effects of (1) individually randomised intervention against schistosomiasis (trial A) and malaria (trial B), and (2) Bacillus Calmette-Guérin (BCG) revaccination (trial C), on a common set of vaccine responses. We will enrol adolescents from Ugandan schools in rural high-schistosomiasis (trial A) and rural high-malaria (trial B) settings and from an established urban birth cohort (trial C). All participants will receive BCG on day ‘0’; yellow fever, oral typhoid and human papilloma virus (HPV) vaccines at week 4; and HPV and tetanus/diphtheria booster vaccine at week 28. Primary outcomes are BCG-specific IFN-γ responses (8 weeks after BCG) and for other vaccines, antibody responses to key vaccine antigens at 4 weeks after immunisation. Secondary analyses will determine effects of interventions on correlates of protective immunity, vaccine response waning, priming versus boosting immunisations, and parasite infection status and intensity. Overarching analyses will compare outcomes between the three trial settings. Sample archives will offer opportunities for exploratory evaluation of the role of immunological and ‘trans-kingdom’ mediators in parasite modulation of vaccine-specific responses.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 numbers ISRCTN60517191, ISRCTN62041885, ISRCTN10482904

Impact of BCG revaccination on the response to unrelated vaccines in a Ugandan adolescent birth cohort: randomised controlled trial protocol C for the ‘POPulation differences in VACcine responses’ (POPVAC) programme

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