Bi-isotype immunoglobulins enhance antibody-mediated neutrophil activity against Plasmodium falciparum parasites.

Background: Malaria remains a major global health priority, and monoclonal antibodies (mAbs) are emerging as potential new tools to support efforts to control the disease. Recent data suggest that Fc-dependent mechanisms of immunity are important mediators of protection against the blood stages of the infection, but few studies have investigated this in the context of mAbs. We aimed to isolate mAbs agnostic to cognate antigens that target whole merozoites and simultaneously induce potent neutrophil activity measured by the level of reactive oxygen species (ROS) production using an antibody-dependent respiratory burst (ADRB) assay. Methods: We used samples from semi-immune adults living in coastal Kenya to isolate mAbs that induce merozoite-specific ADRB activity. We then tested whether modifying the expressed IgG1 isotype to an IgG-IgA Fc region chimera would enhance the level of ADRB activity. Results: We isolated a panel of nine mAbs with specificity to whole merozoites. mAb J31 induced ADRB activity in a dose-dependent fashion. Compared to IgG1, our modified antibody IgG-IgA bi-isotype induced higher ADRB activity across all concentrations tested. Further, we observed a negative hook effect at high IgG1 mAb concentrations (i.e., >200 µg/mL), but this was reversed by Fc modification. We identified MSP3.5 as the potential cognate target of mAb J31. Conclusions: We demonstrate an approach to engineer mAbs with enhanced ADRB potency against blood-stage parasites.

Designing and delivering bioinformatics project-based learning in East Africa.

BACKGROUND: The Eastern Africa Network for Bioinformatics Training (EANBiT) has matured through continuous evaluation, feedback, and codesign. We highlight how the program has evolved to meet challenges and achieve its goals and how experiential learning through mini projects enhances the acquisition of skills and collaboration. We continued to learn and grow through honest feedback and evaluation of the program, trainers, and modules, enabling us to provide robust training even during the Coronavirus disease 2019 (COVID-19) pandemic, when we had to redesign the program due to restricted travel and in person group meetings. RESULTS: In response to the pandemic, we developed a program to maintain "residential" training experiences and benefits remotely. We had to answer the following questions: What must change to still achieve the RT goals? What optimal platforms should be used? How would we manage connectivity and data challenges? How could we avoid online fatigue? Going virtual presented an opportunity to reflect on the essence and uniqueness of the program and its ability to meet the objective of strengthening bioinformatics skills among the cohorts of students using different delivery approaches. It allowed an increase in the number of participants. Evaluating each program component is critical for improvement, primarily when feedback feeds into the program's continuous amendment. Initially, the participants noted that there were too many modules, insufficient time, and a lack of hands-on training as a result of too much focus on theory. In the subsequent iterations, we reduced the number of modules from 27 to five, created a harmonized repository for the materials on GitHub, and introduced project-based learning through the mini projects. CONCLUSION: We demonstrate that implementing a program design through detailed monitoring and evaluation leads to success, especially when participants who are the best fit for the program are selected on an appropriate level of skills, motivation, and commitment.

Anti-merozoite antibodies induce natural killer cell effector function and are associated with immunity against malaria.

Natural killer (NK) cells are potent immune effectors that can be activated via antibody-mediated Fc receptor engagement. Using multiparameter flow cytometry, we found that NK cells degranulate and release IFN-γ upon stimulation with antibody-opsonized Plasmodium falciparum merozoites. Antibody-dependent NK (Ab-NK) activity was largely strain transcending and enhanced invasion inhibition into erythrocytes. Ab-NK was associated with the successful control of parasitemia after experimental malaria challenge in African adults. In an independent cohort study in children, Ab-NK increased with age, was boosted by concurrent P. falciparum infections, and was associated with a lower risk of clinical episodes of malaria. Nine of the 14 vaccine candidates tested induced Ab-NK, including some less well-characterized antigens: P41, P113, MSP11, RHOPH3, and Pf_11363200. These data highlight an important role of Ab-NK activity in immunity against malaria and provide a potential mechanism for evaluating vaccine candidates.

A framework for managing health research capacity strengthening consortia: addressing tensions and enhancing capacity outcomes.

There has been a steady increase in health research capacity strengthening (HRCS) consortia and programmes. However, their structures and management practices and the effect on the capacity strengthening outcomes have been underexamined. We conducted a case study involving three HRCS consortia where we critically examined the consortia's decision-making processes, strategies for resolving management tensions and the potential implications for consortia outcomes. We conducted 44 in-depth interviews with a range of consortia members and employed the framework method to analyse the data. We assessed the extent to which consortia's management practices and strategies enabled or hindered research capacity strengthening using a capacity development lens. At the heart of consortium management is how tensions are navigated and the resolution strategies adopted. This study demonstrates that the management strategies adopted by consortia have capacity strengthening consequences. When deciding on tension management strategies, trade-offs often occur, sometimes to the detriment of capacity strengthening aims. When management strategies align with capacity development principles, consortium management processes become capacity strengthening mechanisms for participating individuals and institutions. Such alignment enhances programme effectiveness and value for money. Drawing on these findings, we propose an evidence-informed management framework that consortia leaders can use in practice to support decision-making to optimise research capacity gains. Considering the increasing investment in HRCS consortia, leveraging all consortium processes towards capacity strengthening will maximise the returns on investments made.

Consortium management structures, processes, and approaches: The DELTAS Africa example.

Background: Global efforts to strengthen health research capacity in low- and middle-income countries (LMICs) have intensified in the past few decades, and these efforts are often implemented by consortia. Our review of the literature indicated that reports on health research capacity strengthening (HRCS) consortia have primarily focused on programme outputs and outcomes while management processes and their contributions to consortia goals have received little attention. This qualitative study sought to identify the consortium management processes employed by 10 DELTAS Africa consortia, factors influencing these processes, and leaders' consortium management experiences. Methods: We conducted 24 key informant interviews with the directors and programme managers of all the 10 DELTAS Africa consortia, and funding actors who worked closely with the consortia. The interviews were supplemented by reviews of DELTAS and consortium-specific documents. Data were analysed using the content analysis approach. Results: The consortia studied employed similar management processes but adopted different strategies in executing these processes. Study results indicate that decision-making in consortia is not always a straightforward process as leaders were often faced with dilemmas when determining management strategies to adopt, and often tried to balance multiple factors which were not always aligned. This was demonstrated as consortia selected partners, determined goals and activities, assigned roles and responsibilities, allocated resources, established governance and partner management systems, and coordinated and monitored consortia activities. Factors that influenced the choice of processes and approaches included previous experiences, funders expectations, and the pressure to deliver research outputs. Consortia's unique approaches to management were due to varying contexts and influences and indicate that management decisions are nuanced and cannot easily be formularized. Conclusion: The study has highlighted the importance of flexibility in consortium management and the need to generate research capacity strengthening (RCS)-specific guidance that can assist consortia in resolving dilemmas and making appropriate management decisions.

Considerations for an integrated population health databank in Africa: lessons from global best practices.

Background: The rising digitisation and proliferation of data sources and repositories cannot be ignored. This trend expands opportunities to integrate and share population health data. Such platforms have many benefits, including the potential to efficiently translate information arising from such data to evidence needed to address complex global health challenges. There are pockets of quality data on the continent that may benefit from greater integration. Integration of data sources is however under-explored in Africa. The aim of this article is to identify the requirements and provide practical recommendations for developing a multi-consortia public and population health data-sharing framework for Africa. Methods: We conducted a narrative review of global best practices and policies on data sharing and its optimisation. We searched eight databases for publications and undertook an iterative snowballing search of articles cited in the identified publications. The Leximancer software © enabled content analysis and selection of a sample of the most relevant articles for detailed review. Themes were developed through immersion in the extracts of selected articles using inductive thematic analysis. We also performed interviews with public and population health stakeholders in Africa to gather their experiences, perceptions, and expectations of data sharing. Results: Our findings described global stakeholder experiences on research data sharing. We identified some challenges and measures to harness available resources and incentivise data sharing.  We further highlight progress made by the different groups in Africa and identified the infrastructural requirements and considerations when implementing data sharing platforms. Furthermore, the review suggests key reforms required, particularly in the areas of consenting, privacy protection, data ownership, governance, and data access. Conclusions: The findings underscore the critical role of inclusion, social justice, public good, data security, accountability, legislation, reciprocity, and mutual respect in developing a responsive, ethical, durable, and integrated research data sharing ecosystem.

Cadmium tolerance pathway in Anopheles gambiae senso stricto.

Cadmium is one of the widely used heavy metals (HM) in commercial and industrial products and contributes to environmental contamination in an urban setting. In our previous studies, we established that An. gambiae sensu stricto, a vector of malaria, had adapted to HM pollutants in nature despite their proclivity for unpolluted aquatic habitats. We further demonstrated that heavy metal tolerance adaptation process impacts a biological cost to the fitness of the mosquito and potentially involves the induction of specific HM-responsive transcripts and proteins. Here we interrogated differential proteomic profiles of the cadmium tolerant vs. naïve strains of An. gambiae to shed light on proteomic processes that underpinned biological cost to fitness. We identified a total of 1067 larval proteins and observed significant down-regulation of proteins involved in larval immune responses, energy metabolism, antioxidant enzymes, protein synthesis, and proton transport. Our results suggest that mosquitoes can adjust their biological program through proteome changes to counter HM pollution. Since our study was done in controlled laboratory settings, we acknowledge this may not wholly represent the conditions HM polluted environments. Nevertheless, mosquitoes deploying this strategy have the potential of creating an urban enclave for breeding and thrive and become agents of sporadic malaria epidemics.

Managing health research capacity strengthening consortia: a systematised review of the published literature.

BACKGROUND: Locally relevant research is considered critical for advancing health and development in low- and middle-income countries (LMICs). Accordingly, health research capacity strengthening (HRCS) efforts have intensified, increasingly through consortia. Yet, the knowledge base for managing such consortia is not well defined. This review aimed to ascertain the scope and quality of published literature on HRCS consortium management processes, management-related factors influencing consortium operations and outcomes, and the knowledge gaps. METHODS: Given the paucity of published HRCS literature, a 'systematised review' as outlined by Grant and Booth was conducted, modelling the systematic review process without restriction to research-based publications. A systematic search in PubMed and Scopus was carried out coupled with a manual search for papers using reference checking and citation searching. A quality appraisal of eligible articles using the Mixed Method Appraisal Tool was undertaken. Thematic synthesis was used to analyse the extracted data. RESULTS: The search identified 55 papers, made up of 18 empirical papers and 37 commentaries focusing on consortium-based HRCS initiatives involving LMICs and reporting management-related data. The review indicates increasing efforts being made in the HRCS field in reporting consortia outcomes. However, it highlights the dearth of high-quality empirical research on HRCS consortium management and the nascent nature of the field with most papers published after 2010. The available literature highlights the importance of relational management factors such as equity and power relations in influencing consortium success, though these factors were not explored in depth. Operational management processes and their role in the capacity strengthening pathway were rarely examined. CONCLUSION: Findings indicate a weak evidence base for HRCS consortium management both in terms of quantity and conceptual depth, demonstrating the need for an expanded research effort to inform HRCS practice.

Analysis of immunity to febrile malaria in children that distinguishes immunity from lack of exposure.

In studies of immunity to malaria, the absence of febrile malaria is commonly considered evidence of "protection." However, apparent "protection" may be due to a lack of exposure to infective mosquito bites or due to immunity. We studied a cohort that was given curative antimalarials before monitoring began and documented newly acquired asymptomatic parasitemia and febrile malaria episodes during 3 months of surveillance. With increasing age, there was a shift away from febrile malaria to acquiring asymptomatic parasitemia, with no change in the overall incidence of infection. Antibodies to the infected red cell surface were associated with acquiring asymptomatic infection rather than febrile malaria or remaining uninfected. Bed net use was associated with remaining uninfected rather than acquiring asymptomatic infection or febrile malaria. These observations suggest that most uninfected children were unexposed rather than "immune." Had they been immune, we would have expected the proportion of uninfected children to rise with age and that the uninfected children would have been distinguished from children with febrile malaria by the protective antibody response. We show that removing the less exposed children from conventional analyses clarifies the effects of immunity, transmission intensity, bed nets, and age. Observational studies and vaccine trials will have increased power if they differentiate between unexposed and immune children.

Evidence for over-dispersion in the distribution of clinical malaria episodes in children.

BACKGROUND: It may be assumed that patterns of clinical malaria in children of similar age under the same level of exposure would follow a Poisson distribution with no over-dispersion. Longitudinal studies that have been conducted over many years suggest that some children may experience more episodes of clinical malaria than would be expected. The aim of this study was to identify this group of children and investigate possible causes for this increased susceptibility. METHODOLOGY AND PRINCIPAL FINDINGS: Using Poisson regression, we chose a group of children whom we designated as 'more susceptible' to malaria from 373 children under 10 years of age who were followed up for between 3 to 5 years from 1998-2003. About 21% of the children were categorized as 'more susceptible' and although they contributed only 23% of the person-time of follow-up, they experienced 55% of total clinical malaria episodes. Children that were parasite negative at all cross-sectional survey were less likely to belong to this group [AOR = 0.09, (95% CI: 0.14-0.61), p = 0.001]. CONCLUSIONS AND SIGNIFICANCE: The pattern of clinical malaria episodes follows a negative binomial distribution. Use of lack of a clinical malaria episode in a certain time period as endpoints for intervention or immunological studies may not adequately distinguish groups who are more or less immune. It may be useful in such studies, in addition to the usual endpoint of the time to first episode, to include end points which take into account the total number of clinical episodes experienced per child.

Transient cross-reactive immune responses can orchestrate antigenic variation in malaria.

The malaria parasite Plasmodium falciparum has evolved to prolong its duration of infection by antigenic variation of a major immune target on the surface of the infected red blood cell. This immune evasion strategy depends on the sequential, rather than simultaneous, appearance of immunologically distinct variants. Although the molecular mechanisms by which a single organism switches between variants are known in part, it remains unclear how an entire population of parasites within the host can synchronize expression to avoid rapidly exhausting the variant repertoire. Here we show that short-lived, partially cross-reactive immune responses to parasite-infected erythrocyte surface antigens can produce a cascade of sequentially dominant antigenic variants, each of which is the most immunologically distinct from its preceding types. This model reconciles several previously unexplained and apparently conflicting epidemiological observations by demonstrating that individuals with stronger cross-reactive immune responses can, paradoxically, be more likely to sustain chronic infections. Antigenic variation has always been seen as an adaptation of the parasite to evade host defence: we show that the coordination necessary for the success of this strategy might be provided by the host.