The impact of maternal infection with Mycobacterium tuberculosis on the infant response to bacille Calmette-Guérin immunization.

Bacille Calmette-Guérin (BCG) immunization provides variable protection against tuberculosis. Prenatal antigen exposure may have lifelong effects on responses to related antigens and pathogens. We therefore hypothesized that maternal latent Mycobacterium tuberculosis infection (LTBI) influences infant responses to BCG immunization at birth. We measured antibody (n = 53) and cellular (n = 31) responses to M. tuberculosis purified protein derivative (PPD) in infants of mothers with and without LTBI, in cord blood and at one and six weeks after BCG. The concentrations of PPD-specific antibodies declined between birth (median [interquartile range (IQR)]) 5600 ng ml(-1) [3300-11 050] in cord blood) and six weeks (0.00 ng ml(-1) [0-288]). Frequencies of PPD-specific IFN-γ-expressing CD4(+)T cells increased at one week and declined between one and six weeks (p = 0.031). Frequencies of IL-2- and TNF-α-expressing PPD-specific CD4(+)T cells increased between one and six weeks (p = 0.019, p = 0.009, respectively). At one week, the frequency of PPD-specific CD4(+)T cells expressing any of the three cytokines, combined, was lower among infants of mothers with LTBI, in crude analyses (p = 0.002) and after adjusting for confounders (mean difference, 95% CI -0.041% (-0.082, -0.001)). In conclusion, maternal LTBI was associated with lower infant anti-mycobacterial T-cell responses immediately following BCG immunization. These findings are being explored further in a larger study

Continuous research monitoring improves the quality of research conduct and compliance among research trainees: internal evaluation of a monitoring programme.

Background: Research site monitoring (RSM) is an effective way to ensure compliance with Good Clinical Practice (GCP). However, RSM is not offered to trainees (investigators) at African Institutions routinely. The Makerere University/Uganda Virus Research Institute Centre of Excellence in Infection and Immunity Research and Training (MUII-Plus) introduced internal monitoring to promote the quality of trainees' research projects. Here, we share our monitoring model, experiences and achievements, and challenges encountered. Methods: We analysed investigators' project reports from monitoring visits undertaken from April 2017 to December 2019. Monitors followed a standard checklist to review investigator site files and record forms, and toured site facilities. We planned four monitoring visits for each trainee: one at site initiation, two interim, and a closeout monitoring visit. A team of two monitors conducted the visits. Results: We monitored 25 out of the 26 research projects in progress between April 2017 and December 2019. Compliance with protocols, standard operating procedures, GCP, and GCLP improved with each monitoring visit. Median (IQR) compliance rate was 43% (31%, 44%) at site initiation visit for different monitoring items, 70% (54%, 90%) at the 1st interim monitoring visit, 100% (92%, 100%) at 2nd interim monitoring visit and all projects achieved 100% compliance at site closeout.  All investigators had good work ethics and practice, and appropriate facilities. Initially, some investigators' files lacked essential documents, and informed consent processes needed to be improved. We realized that non-compliant investigators had not received prior training in GCP/GCLP, so we offered them this training. Conclusions: Routine monitoring helps identify non-compliance early and improves the quality of research. We recommend continuous internal monitoring for all research studies. Investigators conducting research involving human subjects should receive GCP/GCLP training before commencing their projects. Institutional higher degrees and research ethics committees should enforce this as a requirement for project approvals

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

Lessons from the first clinical trial of a non-licensed vaccine among Ugandan adolescents: a phase II field trial of the tuberculosis candidate vaccine, MVA85A

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 03/06/201

The Lake Victoria Island Intervention Study on Worms and Allergy-related diseases (LaVIISWA): study protocol for a randomised controlled trial.

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

The Impact of Intensive Versus Standard Anthelminthic Treatment on Allergy-related Outcomes, Helminth Infection Intensity, and Helminth-related Morbidity in Lake Victoria Fishing Communities, Uganda: Results From the LaVIISWA Cluster-randomized Trial.

BACKGROUND: The prevalence of allergy-related diseases is increasing in low-income countries. Parasitic helminths, common in these settings, may be protective. We hypothesized that intensive, community-wide, anthelminthic mass drug administration (MDA) would increase allergy-related diseases, while reducing helminth-related morbidity. METHODS: In an open, cluster-randomized trial (ISRCTN47196031), we randomized 26 high-schistosomiasis-transmission fishing villages in Lake Victoria, Uganda, in a 1:1 ratio to receive community-wide intensive (quarterly single-dose praziquantel plus albendazole daily for 3 days) or standard (annual praziquantel plus 6 monthly single-dose albendazole) MDA. Primary outcomes were recent wheezing, skin prick test positivity (SPT), and allergen-specific immunoglobulin E (asIgE) after 3 years of intervention. Secondary outcomes included helminths, haemoglobin, and hepatosplenomegaly. RESULTS: The outcome survey comprised 3350 individuals. Intensive MDA had no effect on wheezing (risk ratio [RR] 1.11, 95% confidence interval [CI] 0.64-1.93), SPT (RR 1.10, 95% CI 0.85-1.42), or asIgE (RR 0.96, 95% CI 0.82-1.12). Intensive MDA reduced Schistosoma mansoni infection intensity: the prevalence from Kato Katz examinations of single stool samples from each patient was 23% versus 39% (RR 0.70, 95% CI 0.55-0.88), but the urine circulating cathodic antigen test remained positive in 85% participants in both trial arms. Hookworm prevalence was 8% versus 11% (RR 0.55, 95% CI 0.31-1.00). There were no differences in anemia or hepatospenomegaly between trial arms. CONCLUSIONS: Despite reductions in S. mansoni intensity and hookworm prevalence, intensive MDA had no effect on atopy, allergy-related diseases, or helminth-related pathology. This could be due to sustained low-intensity infections; thus, a causal link between helminths and allergy outcomes cannot be discounted. Intensive community-based MDA has a limited impact in high-schistosomiasis-transmission fishing communities, in the absence of other interventions. CLINICAL TRIALS REGISTRATION: ISRCTN47196031

Role of Phosphorus and Inoculation with Bradyrhizobium in Enhancing Soybean Production

Soybean (Glycine max L. Merril) is among the key oil seed crops worldwide, providing several benefits from human consumption to the enhancement of soil productivity. In Uganda, legumes are cultivated on roughly 1.5 million ha, with soybean being produced on a lower production area of 150,000 ha compared to beans (925,000 ha) and groundnuts (253,000 ha). In terms of achievable yield, soybean emerges the highest at 1.2 t·ha−1 as compared to beans (0.5 t·ha−1) and groundnuts (0.7 t·ha−1). Despite the smallest production coverage area, the crop’s feasible grain yield is projected at 4.6 t·ha−1 under optimal environmental conditions. The major bottleneck to the crop’s production is the decreasing soil fertility, mainly caused by low nitrogen (N) but also phosphorus (P) levels in the soil. There is a high potential for supplying N from the atmosphere through biological N fixation (BNF), a natural process mediated by the symbiotic bacteria Bradyrhizobium japonicum, which requires optimum P levels for effective N fixation and increased yield. The current work reviews the present status of soybean production in Uganda, highlights its ecological requirements, importance, and constraints, and proposes the use of inoculation and P application to boost its production

Nutraceutical properties and secondary metabolites of quinoa (Chenopodium quinoa Willd.): a review

ABSTRACTQuinoa is a food grain crop that has gained popularity in recent years due to its high nutrient content, phytochemical qualities, and health advantages. Quinoa grain has a high concentration of amino acids, fiber, minerals, vitamins, saponins, and phenolics that can help alleviate various biological diseases in the human body. It contains a variety of biological components and nutraceutical compounds that promote human health. It is an extremely nutritious, gluten-free wonder grain and has the potential to be utilized as biomedicine owing to the existence of functional chemicals that may aid in the prevention of various chronic illnesses. Quinoa has gained popularity in recent years due to its excellent nutritional content and as a component in gluten-free food. It could help to guide the population toward better health. Due to its higher nutritional and health benefits compared to traditional cereal grains, including its high protein concentration, tocopherols, fatty acids, phenolic compounds, phytosterols, low glycemic index, and gluten-free status, it is a promising grain for human consumption and nutrition around the world. The present review paper has been undertaken to provide an overview of the nutrient composition and valuable nutraceutical properties of quinoa

Internal monitoring within MUII-plus for research capacity development

A dataset on 25 projects that provided data on an internal monitoring evaluation of the Makerere University-Uganda Virus Research Institute Centre of Excellence for Infection and Immunity Research and Training (MUII-plus) research programme. The dataset contains 75 variables on projects adherence to the approved protocol, Standard Operating Procedures (SOPs), Good Clinical Practices (GCP) and Good Clinical Laboratory Practices (GCLP), other applicable regulatory requirements, study related training and presence of adequate facilities required for study related procedures

After abduction: exploring access to reintegration programs and mental health status among young female abductees in Northern Uganda

Background: Reintegration programs are commonly offered to former combatants and abductees to acquire civilian status and support services to reintegrate into post-conflict society. Among a group of young female abductees in northern Uganda, this study examined access to post-abduction reintegration programming and tested for between group differences in mental health status among young women who had accessed reintegration programming compared to those who self-reintegrated. Methods This cross-sectional study analysed interviews from 129 young women who had previously been abducted by the Lords Resistance Army (LRA). Data was collected between June 2011-January 2012. Interviews collected information on abduction-related experiences including age and year of abduction, manner of departure, and reintegration status. Participants were coded as ‘reintegrated’ if they reported ≥1 of the following reintegration programs: traditional cleansing ceremony, received an amnesty certificate, reinsertion package, or had gone to a reception centre. A t-test was used to measure mean differences in depression and anxiety measured by the Acholi Psychosocial Assessment Instrument (APAI) to determine if abductees who participated in a reintegration program had different mental status from those who self-reintegrated. Results From 129 young abductees, 56 (43.4%) had participated in a reintegration program. Participants had been abducted between 1988–2010 for an average length of one year, the median age of abduction was 13 years (IQR:11–14) with escaping (76.6%), being released (15.6%), and rescued (7.0%) being the most common manner of departure from the LRA. Traditional cleansing ceremonies (67.8%) were the most commonly accessed support followed by receiving amnesty (37.5%), going to a reception centre (28.6%) or receiving a reinsertion package (12.5%). Between group comparisons indicated that the mental health status of abductees who accessed ≥1 reintegration program were not significantly different from those who self-reintegrated (p > 0.05). Conclusions Over 40% of female abductees in this sample had accessed a reintegration program, however significant differences in mental health were not observed between those who accessed a reintegration program and those who self-reintegrated. The successful reintegration of combatants and abductees into their recipient community is a complex process and these results support the need for gender-specific services and ongoing evaluation of reintegration programming.Liu Institute for Global IssuesMedicine, Department ofPopulation and Public Health (SPPH), School ofNon UBCArts, Faculty ofMedicine, Faculty ofReviewedFacult