The effect of current Schistosoma mansoni infection on the immunogenicity of a candidate TB vaccine, MVA85A, in BCG-vaccinated adolescents: An open-label trial.

INTRODUCTION: Helminth infection may affect vaccine immunogenicity and efficacy. Adolescents, a target population for tuberculosis booster vaccines, often have a high helminth burden. We investigated effects of Schistosoma mansoni (Sm) on the immunogenicity and safety of MVA85A, a model candidate tuberculosis vaccine, in BCG-vaccinated Ugandan adolescents. METHODS: In this phase II open label trial we enrolled 36 healthy, previously BCG-vaccinated adolescents, 18 with no helminth infection detected, 18 with Sm only. The primary outcome was immunogenicity measured by Ag85A-specific interferon gamma ELISpot assay. Tuberculosis and schistosome-specific responses were also assessed by whole-blood stimulation and multiplex cytokine assay, and by antibody ELISAs. RESULTS: Ag85A-specific cellular responses increased significantly following immunisation but with no differences between the two groups. Sm infection was associated with higher pre-immunisation Ag85A-specific IgG4 but with no change in antibody levels following immunisation. There were no serious adverse events. Most reactogenicity events were of mild or moderate severity and resolved quickly. CONCLUSIONS: The significant Ag85A-specific T cell responses and lack of difference between Sm-infected and uninfected participants is encouraging for tuberculosis vaccine development. The implications of pre-existing Ag85A-specific IgG4 antibodies for protective immunity against tuberculosis among those infected with Sm are not known. MVA85A was safe in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT02178748

Tuberculosis knowledge, attitudes and health-seeking behaviour in rural Uganda

OBJECTIVES: To assess tuberculosis (TB) knowledge, attitudes and health-seeking behaviour to inform the design of communication and social mobilisation interventions. SETTING: Iganga/Mayuge Demographic Surveillance Site, Uganda. DESIGN: Between June and July 2008, 18 focus group discussions and 12 key informant interviews were conducted, including parents of infants and adolescents and key informant interviews with community leaders, traditional healers and patients with TB. RESULTS: People viewed TB as contagious, but not necessarily an airborne pathogen. Popular TB aetiologies included sharing utensils, heavy labour, smoking, bewitchment and hereditary transmission. TB patients were perceived to seek care late or to avoid care. Combining care from traditional healers and the biomedical system was common. Poverty, drug stock-outs, fear of human immunodeficiency virus (HIV) testing and length of TB treatment negatively affect health-seeking behaviour. Stigma and avoidance of persons with TB often reflects an assumption of HIV co-infection. CONCLUSION: The community's concerns about pill burden, quality of care, financial barriers, TB aetiology, stigma and preference for pluralistic care need to be addressed to improve early detection. Health education messages should emphasise the curability of TB, the feasibility of treatment and the engagement of traditional healers as partners in identifying cases and facilitating adherence to treatment

Trees improve water storage and reduce soil evaporation in agroforestry systems on bench terraces in SW Uganda

The success of agroforestry in semi-arid areas depends on efficient use of available water and effective strategies to limit tree/crop competition and maximise productivity. On hillsides, planting improved tree fallows on the degraded upper section of bench terraces is a recommended practice to improve soil fertility while cropping continues on the lower terrace to maintain food production. This study examined the influence of tree fallows on soil water content (θ w ) and evaporation (E s ). Alnus acuminata Kunth (alnus), Calliandra calothyrsus Meissner (calliandra), Sesbania sesban L. (sesbania), a mixture of all three species, or sole crops (beans (Phaseolus vulgaris L.) or maize (Zea mays L.)) were grown on the upper terrace. The same sole crops were grown on the lower terrace. Four management regimes (unpruned, root, shoot and root + shoot pruned) were applied to the tree rows adjacent to the cropping area. Neutron probe and microlysimeter approaches were used to determine θ w and E s when the trees were c. 3.5 years old. Sesbania and alnus increased θ w by 9–18 % in the cropping area on the lower terrace but calliandra reduced θ w by 3–15 %. After heavy rain, E s comprised 29–38 % of precipitation in the tree-based treatments and 53 % under sole crops. Absolute values declined as rainfall decreased, but E s as a proportion of rainfall increased to 39–45 % in the tree-based treatments and 62 % for sole crops. Root + shoot pruning of alnus and the tree mixture increased θ w in the cropping area but had no significant effect in the other tree-based treatments. The results suggest that sesbania and alnus can be planted on smallholdings without compromising water supply to adjacent crops, whereas calliandra decreased water availability despite reducing E s . These results provide a mechanistic understanding of reported effects on crop yield in the same site

Activation of beta-chemokines and CCR5 in persons infected with human immunodeficiency virus type 1 and tuberculosis

Tuberculosis (TB) in human immunodeficiency virus type 1 (HIV-1)-infected persons is associated with progression of HIV-1 disease. The expression of macrophage inflammatory protein (MIP)-1alpha and CCR5 was assessed in HIV-1-infected patients with pulmonary TB (HIV-1/PTB) and without PTB (HIV-1/C), PTB patients not infected with HIV-1 (PTB), and control subjects. Mycobacterium tuberculosis (MTB)-induced MIP-1alpha production was lower in peripheral blood mononuclear cells (PBMC) of HIV-1/PTB patients than in those of PTB patients (P< .05) and was lower in PBMC of HIV-1/C patients than in those of control subjects (P< .005). However, MIP-1alpha production was higher in PBMC of HIV/PTB patients than in those of HIV-1/C patients (P< .01). The pattern of MTB-induced RANTES production was similar to that of MIP-1alpha. However, MTB induced greater expression of mRNA for CCR5 in PBMC of HIV-1/PTB patients than in those of HIV-1/C patients (P< .04). Furthermore, the MTB-induced HIV p24 antigen level in PBMC of HIV-1/PTB patients with a CD4 cell count <500 cells/microL was higher (P< .05) than that in HIV-1/C patients. Thus, perturbations in chemokine pathways in HIV-1/PTB patients may accelerate HIV-1 disease

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 03/06/2014</p

Ethical and scientific considerations on the establishment of a controlled human infection model for schistosomiasis in Uganda: report of a stakeholders’ meeting held in Entebbe, Uganda

Controlled human infection (CHI) models are gaining recognition as an approach to accelerating vaccine development, for use in both non-endemic and endemic populations: they can facilitate identification of the most promising candidate vaccines for further trials and advance understanding of protective immunity. Helminths present a continuing health burden in sub-Saharan Africa. Vaccine development for these complex organisms is particularly challenging, partly because protective responses are akin to mechanisms of allergy. A CHI model for Schistosoma mansoni (CHI-S) has been developed at Leiden University Medical Centre, the Netherlands. However, responses to schistosome infections, and candidate vaccines, are likely to be different among people from endemic settings compared to schistosome-naïve Dutch volunteers. Furthermore, among volunteers from endemic regions who have acquired immune responses through prior exposure, schistosome challenge can be used to define responses associated with clinical protection, and thus to guide vaccine development. To explore the possibility of establishing the CHI-S in Uganda, a Stakeholders’ Meeting was held in Entebbe in 2017. Regulators, community members, researchers and policy-makers discussed implementation challenges and recommended preparatory steps: risk assessment; development of infrastructure and technical capacity to produce the infectious challenge material in Uganda; community engagement from Parliamentary to grass-roots level; pilot studies to establish approaches to assuring fully informed consent and true voluntariness, and strategies for selection of volunteers who can avoid natural infection during the 12-week CHI-S; the building of regulatory capacity; and the development of study protocols and a product dossier in close consultation with ethical and regulatory partners. It was recommended that, on completion, the protocol and product dossier be reviewed for approval in a joint meeting combining ethical, regulatory and environment management authorities. Most importantly, representatives of schistosomiasis-affected communities emphasised the urgent need for an effective vaccine and urged the research community not to delay in the development process. Keyword

Establishing a single-sex controlled human Schistosoma mansoni infection model for Uganda: protocol for safety and dose-finding trial

Control of schistosomiasis depends on a single drug, praziquantel, with variable cure rates, high reinfection rates, and risk of drug resistance. A vaccine could transform schistosomiasis control. Preclinical data show that vaccine development is possible, but conventional vaccine efficacy trials require high incidence, long-term follow-up, and large sample size. Controlled human infection studies (CHI) can provide early efficacy data, allowing the selection of optimal candidates for further trials. A Schistosoma CHI has been established in the Netherlands but responses to infection and vaccines differ in target populations in endemic countries. We aim to develop a CHI for Schistosoma mansoni in Uganda to test candidate vaccines in an endemic setting. This is an open-label, dose-escalation trial in two populations: minimal, or intense, prior Schistosoma exposure. In each population, participants will be enrolled in sequential dose-escalating groups. Initially, three volunteers will be exposed to 10 cercariae. If all show infection, seven more will be exposed to the same dose. If not, three volunteers in subsequent groups will be exposed to higher doses (20 or 30 cercariae) following the same algorithm, until all 10 volunteers receiving a particular dose become infected, at which point the study will be stopped for that population. Volunteers will be followed weekly after infection until CAA positivity or to 12 weeks. Once positive, they will be treated with praziquantel and followed for one year. The trial registry number is ISRCTN14033813 and all approvals have been obtained. The trial will be subjected to monitoring, inspection, and/or audits. Host-parasite interactio

T cell activation, apoptosis and cytokine dysregulation in the (co)pathogenesis of HIV and pulmonary tuberculosis (TB)

Immune parameters were compared in four groups of Ugandan subjects: HIV− and HIV+ adult patients with active pulmonary TB (HIV− PTB n = 38; HIV+ PTB n = 28), patients with HIV infection only (n = 26) and PPD+ healthy controls (n = 25). Compared with healthy controls, CD4 and CD8 T cells from patients with HIV and/or PTB expressed more activation markers (HLA-DR, CD38); their CD8 T cells expressed more CD95 (pre-apoptosis) and less CD28 (co-stimulatory receptor). Peripheral blood mononuclear cells (PBMC) of patients with either HIV or PTB were impaired in interferon-gamma (IFN-γ) production upon antigenic stimulation. PTB (with or without HIV) was characterized by monocytosis, granulocytosis, increased transforming growth factor-beta 1 production and PPD-induced apoptosis. In vivo CD4 T cell depletion, in vitro increased spontaneous CD4 T cell apoptosis and defects in IFN-γ responses upon mitogenic stimulation were restricted to HIV+ subjects (with or without PTB). Overlapping and distinctive immune alterations, associated with PTB and HIV, might explain mutual unfavourable influences of both diseases