Applying innovative strategies to achieve Universal Health Coverage in the African Region

Universal health coverage is defined as ensuring that all people have access to needed health services of sufficient quality to be effective while ensuring that these services do not expose the user the financial hardship. Universal health coverage includes three related objectives: equity in access to health services (everyone who needs services should get them, not only those who can pay for them); the quality of health services should be good enough to improve the health of those receiving services; and people should be protected against financial risk, ensuring that the cost of using services does not put people at risk of financial harm. Africa still has a long way to go to achieve these objectives. Many barriers limit the progress of the African Region towards building the robust health systems needed for universal health coverage. Such barriers include poor infrastructure, high out-of-pocket payments and catastrophic health expenditures, shortages and inequitable distribution of qualified healthcare workers, poor quality of care delivery, high cost of quality medicines, and lack of innovative technologies appropriate to the range of settings where care is delivered, health financing and governance. This paper aims to propose innovative strategies that could be applied to improve health systems in the Africa Region, which progress towards the continent attaining universal health coverage.    &nbsp

Mechanisms of mutagenesis in Mycobacterium tuberculosis: structural and functional characterisation of the DNA polymerase accessory factors encoded by Rv3394c and Rv3395c

A thesis submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Doctor of Philosophy February 2013Mycobacterium tuberculosis is presented with environmental host assaults that damage its DNA during infection. Tubercle bacilli possess mechanisms to protect against moststresses imposed by the host, including genotoxic stress. However, tolerance of DNA lesions that have escaped the normal repair processes requires the function of specialist DNA polymerases that can introduce mutations during translesion synthesis (replication by-pass), thus leading to damage-induced mutagenesis. Mycobacteria employ a novel DNA polymerase, DnaE2, for DNA damage tolerance and induced mutagenesis. DnaE2 belongs to the C-family of DNA polymerases, which are known to replicate DNA with high fidelity, and has been implicated in virulence and the emergence of rifampicin resistance of M. tuberculosis in vivo. In this study, DnaE2 was shown to function in the same pathway as two accessory proteins, ImuB and ImuA’, for damage tolerance and induced mutagenesis in mycobacteria. In this system, DnaE2 performs the polymerase function in translesion synthesis whereas ImuB is a cryptic Y-family DNA polymerase that lacks critical active site residues. It contains a β-clamp binding motif that allows interaction with the β-clamp and presumably enables DnaE2 and ImuA’ to access the replication fork. ImuB has a C-terminal region extending from the β-clamp binding motif which contains disordered regions that allow the interaction with other proteins and is important for function. ImuA’ is also essential for damage tolerance and induced mutagenesis but its function remains unknown. This protein is structurally similar to Escherichia coli RecA protein in the N-terminus and the middle domain, but it has a distinct C-terminus that was shown to be important for the interaction with ImuB. The essential replicative, C-family polymerase, DnaE1, was shown to be upregulated in response to DNA damage and was also shown to interact with ImuB. To explore the possibility that other proteins are involved in this pathway, ImuB was Cterminally tagged for use as bait in pull-down experiments in M. smegmatis. However, introduction of the tag disrupted ImuB function, further reinforcing the importance of the Cterminal region of ImuB for the function of this protein, presumably via protein-protein interactions. In contrast, a variant of ImuA’ which was N-terminally tagged was shown to retain functionality; however, experiments using this protein as a bait for pull-down proved to be unsuccessful. Proteomic analysis of wild type M. smegmatis, a dnaE2 deletion mutant and complemented derivative was carried out on cells exposed to the same conditions as used in the pull-down assay. Base excision repair (BER) components were identified in this analysis, but did not detect ImuB and ImuA’, suggesting that the levels of expression of these proteins were comparatively lower under the conditions tested resulting in failure of the pull-down experiment. Finally, numerous attempts were made to express and purify recombinant forms of ImuB and ImuA’ in E. coli for use in structural studies. Both proteins were expressed in the soluble and insoluble fractions; however the levels of soluble protein were low, and as a result, purified protein preparations could not be obtained

Applying innovative strategies to achieve Universal Health Coverage in the African Region

Universal health coverage is defined as ensuring that all people have access to needed health services of sufficient quality to be effective while ensuring that these services do not expose the user the financial hardship. Universal health coverage includes three related objectives: equity in access to health services (everyone who needs services should get them, not only those who can pay for them); the quality of health services should be good enough to improve the health of those receiving services; and people should be protected against financial risk, ensuring that the cost of using services does not put people at risk of financial harm. Africa still has a long way to go to achieve these objectives. Many barriers limit the progress of the African Region towards building the robust health systems needed for universal health coverage. Such barriers include poor infrastructure, high out-of-pocket payments and catastrophic health expenditures, shortages and inequitable distribution of qualified healthcare workers, poor quality of care delivery, high cost of quality medicines, and lack of innovative technologies appropriate to the range of settings where care is delivered, health financing and governance. This paper aims to propose innovative strategies that could be applied to improve health systems in the Africa Region, which progress towards the continent attaining universal health coverage.    &nbsp

Development of improved cloning vectors for Bacillus and Staphylococcus species

A shuttle vector was constructed which was stably maintained in Escherichia coli, Bacillus subtilis and Staphylococcus aureus. It was made by ligating E. coli positive selection plasmid pEcoR251 and S. aureus resistance plasmid pC194 via their respective BamHI and XhoII sites. Designated pNDW1, it was shown to be effective in genomic library construction. The number of restriction sites in the EcoRI (“suicide”) gene was increased by successive addition of XbaI and XhoI using site-directed mutagenesis. SpeI, NheI and AvrII generate DNA fragments with compatible cohesive ends to XbaI while SalI digestion gives rise to ends compatible with XhoI. Therefore the number of different genomic libraries which can be made using this system is augmented by six. A principal impediment to full exploitation of these shuttle vectors is apparently the severe restriction by B. subtilis and S. aureus of DNA coming from E. coli

Randomised trials of COVID-19 vaccines in Africa – charting the path forward.

Vaccines have played a critical role in controlling disease outbreaks, hence the proliferation of the development and testing of multiple vaccine candidates during the COVID-19 pandemic. Randomised trials are gold standards for evaluating the safety and efficacy of pharmaceutical interventions such as COVID-19 vaccines. However, contextual differences may attenuate effects of COVID-19 vaccines. Thus, the need to conduct COVID-19 vaccine trials in all settings, including in Africa. We conducted a crosssectional analysis of planned, ongoing, and completed COVID-19 vaccine trials in Africa. We searched the South African National Clinical Trials Register, Pan African Clinical Trials Registry, and International Clinical Trials Registry Platform (ICTRP) on 12 January and 30 April 2022; and complemented this with a search of ClinicalTrials.gov on 17 May 2022. We screened the search output and included randomised trials with at least one recruitment site in Africa. We identified only 108 eligible trials: 90 (83%) evaluating candidate COVID-19 vaccines, 11 (10%) assessing if existing vaccines could prevent SARS-CoV-2 infection, and 7 (7%) evaluating interventions for improving COVID-19 vaccination coverage. South Africa had the highest number of trials at 58 (54%). Beyond South Africa, countries with more than 10 trial sites include Kenya, Ghana, Egypt, Uganda, and Zimbabwe. Among the trials, 14 (13%) do not have principal investigators based in Africa, 39 (30%) are funded by industry, and 91 (84%) are funded by institutions based outside the host country. COVID-19 vaccine trials with recruitment sites in Africa represented only 7% of the 1453 COVID-19 vaccine trials in the ICTRP. The paucity of COVID-19 vaccine trials conducted on the African continent is a cause for concern. This has implications for the role that Africa may play in future pandemics.Significance:• There are generally very few vaccine trials conducted in Africa, relative to the rest of the world.• The limited vaccine trials in Africa could be attributed to limited expertise and resources, both human and material, as well as lack of perceived market.• It is reassuring that many COVID-19 vaccines are planned, being conducted, or have been conducted in multiple African countries; but there is a need for more African public sector funding for vaccine trials on the continent

Clinical trial registration during COVID-19 and beyond in the African context: what have we learned?

Since the outbreak of COVID-19, many lives have been impacted especially on the African continent which is already fighting the burden of multiple diseases of poverty. However, clinical research has offered hope for treatment and prevention options for this infectious disease. Despite many COVID-19 clinical trials conducted globally, three countries in Africa account for more than 80% of all trials from the continent registered trials in clinical trial registries. This indicates geographic disparity among COVID-19 research in Africa. From the perspective of clinical trial registration, transparency in clinical research and the availability of data became important for making informed decisions to manage the pandemic. Registries serve as a source of planned, ongoing, and completed trials while allowing efficient funding allocation for research that would not duplicate efforts. Additionally, research gaps can be identified, which provide opportunities for collaboration among researchers. Therefore, a critical lesson learnt during this pandemic is that clinical trial registration is important in facilitating the process of tracking changes made to protocols and minimizing publication bias, thereby promoting and advocating for clinical research transparency. Moreover, registration in a clinical trial registry is a condition for publication and allows for trial summary results to be publicly available. Adhering to the principle of results sharing is especially important for the rapidly growing clinical research activities racing to find evidence-based interventions to end the COVID-19 pandemic

Decomposing the gap in missed opportunities for vaccination between poor and non-poor in sub-Saharan Africa : a multicountry analyses

Understanding the gaps in MOV between poor and non-poor in sub-Saharan Africa (SSA) would enable an understanding of factors associated with interventions for improving immunization coverage to achieving universal childhood immunization. We aimed to conduct a multicountry analyses to decompose the gap in MOV between poor and non-poor in SSA. We used cross-sectional data from 35 Demographic and Health Surveys in SSA conducted between 2007 and 2016. Descriptive statistics were used to understand the gap in MOV between the urban poor and non-poor, and across the selected covariates. Out of the 35 countries included in this analysis, 19 countries showed pro-poor inequality, five showed pro-non-poor inequality and remaining 11 countries showed no statistically significant inequality. Among the countries with statistically significant pro-illiterate inequality, the risk difference ranged from 4.2% in Congo DR to 20.1% in Kenya. The important factors responsible for the inequality varied across the countries. In Madagascar, the largest contributions to the inequality in MOV was media access followed by number of under-five children and maternal education. However, Liberia media access narrowed the inequality in MOV between poor and non-poor households.The findings indicate that in most SSA countries, children belonging to poor households are most likely to have MOV and that socio-economic inequality in missed opportunities for vaccination is determined not only by health system functions, but also by factors beyond the scope of health authorities and care delivery system. Suggesting the the importance of addressing the social determinants of health, particularly education

Hospital acquired COVID-19 infections amongst patients before the rollout of COVID-19 vaccinations, a scoping review

Background Hospital settings are at increased risk of spreading Coronavirus Disease 2019 (COVID-19) infections, hence non-pharmaceutical prevention interventions (NPPIs) and prioritized vaccination of healthcare workers and resident patients are critical. The status of COVID-19 hospital acquired infections (HAIs) in low-income settings is unclear. We aimed to identify and summarize the existing evidence on COVID-19 HAIs amongst patients, prior to the rollout of vaccines in countries worldwide. Methods We conducted a scoping review of English peer-reviewed literature in PubMed, Web of Science and Scopus using a combination of selected search terms. Full texts articles presenting results on COVID-19 HAIs in hospitalised patients before the rollout of vaccines in countries worldwide were eligible. Data extracted from eligible articles included estimates of COVID-19 HAIs, country, and type of hospital setting, and was summarized narratively. Quality assessment of included articles was not possible. Results Literature searches generated a total of 5920 articles, and 45 were eligible for analysis. Eligible articles were from Europe, North America, Asia, and Brazil and none were from low-income countries. The proportion of COVID-19 HAIs ranged from 0% when strict NPPIs were applied, to 65% otherwise. The estimates of COVID-19 HAIs did not differ by country but were lower in studies conducted after implementation of NPPIs and in specialized hospital settings for operative surgery. Studies conducted before the implementation of NPPIs or in long-term care and psychiatric wards often reported high estimates of HAI. Although there was no clear trend in general wards, those situated in academic hospitals managed to reduce HAI rates under strict NPPI protocols. Operative surgery settings, unlike psychiatric settings, effectively prevented COVID-19 HAI using tailored NPPIs. Conclusion The available evidence shows a high risk of COVID-19 HAIs, the feasibility of preventing HAIs in different healthcare settings and the importance of appropriately tailored NPPIs. There were no data from low-income settings, therefore, it is unclear whether the reported NPPI approaches could be equally effective elsewhere. We recommend routine monitoring of COVID-19 HAIs in countries with low vaccination coverage, to identify and close gaps in NPPIs and understand gains made from vaccinating healthcare workers and hospitalized patients

Tuberculosis treatment intervention trials in Africa: A cross-sectional bibliographic study and spatial analysis

Background Mycobacterium Tuberculosis (TB) poses a substantial burden in sub-Saharan Africa and is the leading cause of death amongst infectious diseases. Randomised controlled trials (RCTs) are regarded as the gold standard for evaluating the effectiveness of interventions. We aimed to describe published TB treatment trials conducted in Africa. Methods This is a cross-sectional study of published TB trials conducted in at least one African country. In November 2019, we searched three databases using the validated Africa search filter and Cochrane’s sensitive trial string. Published RCTs conducted in at least one African country were included for analysis. Records were screened for eligibility. Co-reviewers assisted with duplicate data extraction. Extracted data included: the country where studies were conducted, publication dates, ethics statement, trial registration number, participant’s age range. We used Cochrane’s Risk of Bias criteria to assess methodological quality. Results We identified 10,495 records; 175 trials were eligible for inclusion. RCTs were published between 1952 and 2019. The median sample size was 206 participants (interquartile range: 73–657). Most trials were conducted in South Africa (n = 83) and were drug therapy trials (n = 130). First authors were from 30 countries globally. South Africa had the most first authors (n = 55); followed by the United States of America (USA) (n = 28) and Great Britain (n = 14) with fewer other African countries contributing to the first author tally. Children under 13 years of age eligible to participate in the trials made up 17/175 trials (9.71%). International governments (n = 29) were the most prevalent funders. Ninety-four trials provided CONSORT flow diagrams. Methodological quality such as allocation concealment and blinding were poorly reported or unclear in most trials. Conclusions By mapping African TB trials, we were able to identify potential research gaps. Many of the global north’s researchers were found to be the lead authors in these African trials. Few trials tested behavioural interventions compared to drugs, and far fewer tested interventions on children compared to adults to improve TB outcomes. Lastly, funders and researchers should ensure better methodological quality reporting of trials

Creating a best practice template for participant communication plans in global health clinical studies

Background Clinical trial participants have a right to be informed throughout the entire process of human subject research. As part of this pillar of research ethics, participants and other stakeholders should be made aware of research findings after a trial has been completed. Though participants have both a right, and a desire to be informed of research outcomes, studies show that they rarely receive communication about study findings. Our aim was (1) to understand what, if any, role communication plans play in current global health clinical research protocols and (2) to use our findings to develop a communication plan template tailored to clinical research carried out in low-and-middle-income countries (LMIC) while minimizing colonial assumptions. While the template was drafted in the LMIC context, the principles are universally applicable and should be considered best practices for all global health clinical trials. Methods We carried out a mixed-method study over a period of 6 months to understand the role of communication with study participants and other stakeholders in clinical trials. The semiquantitative analysis included mining publicly available clinical trial protocols for communication-related language. Qualitative interviews (n = 7) were used to gather knowledge and insight from clinical trial experts to inform the development of a communication plan template. Results None of the 48 mined clinical trial protocols included a communication plan. Of the 48, 21% (n = 21) protocols included communication-related language, and 10% (n = 5) described plans to share trial results with participants. Conclusion The use of communication plans in global health clinical trials is lacking. To our knowledge, this is the first in-depth analysis of communication plans in clinical trials to date. We recommend that researchers utilize the developed communication plan template throughout the entire research process to ensure a human-centered approach to participant communication. This communication plan should apply to all phases of a research trial, with a particular emphasis on plans to share results in an accessible and engaging manner once the trial has been completed