Transmission-reducing and -enhancing monoclonal antibodies against Plasmodium vivax gamete surface protein Pvs48/45.

Gamete surface protein P48/45 has been shown to be important for male gamete fertility and a strong candidate for the development of a malaria transmission-blocking vaccine (TBV). However, TBV development for Plasmodium vivax homolog Pvs48/45 has been slow because of a number of challenges: availability of conformationally suitable recombinant protein; the lack of an in vivo challenge model; and the inability to produce P. vivax gametocytes in culture to test transmission-blocking activity of antibodies. To support ongoing efforts to develop Pvs48/45 as a potential vaccine candidate, we initiated efforts to develop much needed reagents to move the field forward. We generated monoclonal antibodies (mAbs) directed against Pvs48/45 and characterized putative functional domains in Pvs48/45 using recombinant fragments corresponding to domains D1-D3 and their biological functionality through ex vivo direct membrane feeding assays (DMFAs) using P. vivax parasites from patients in a field setting in Brazil. While some mAbs partially blocked oocyst development in the DMFA, one mAb caused a significant enhancement of the infectivity of gametocytes in the mosquitoes. Individual mAbs exhibiting blocking and enhancing activities recognized non-overlapping epitopes in Pvs48/45. Further characterization of precise epitopes recognized by transmission-reducing and -enhancing antibodies will be crucial to design an effective immunogen with optimum transmission-reducing potential.

Immune mechanisms targeting malaria transmission: opportunities for vaccine development.

INTRODUCTION: Malaria continues to remain a major global health problem with nearly a quarter of a billion clinical cases and more than 600,000 deaths in 2022. There has been significant progress toward vaccine development, however, poor efficacy of approved vaccines requiring multiple immunizing doses emphasizes the need for continued efforts toward improved vaccines. Progress to date, nonetheless, has provided impetus for malaria elimination. AREAS COVERED: In this review we will focus on diverse immune mechanisms targeting gametocytes in the human host and gametocyte-mediated malaria transmission via the mosquito vector. EXPERT OPINION: To march toward the goal of malaria elimination it will be critical to target the process of malaria transmission by mosquitoes, mediated exclusively by the sexual stages, i.e. male, and female gametocytes, ingested from infected vertebrate host. Studies over several decades have established antigens in the parasite sexual stages developing in the mosquito midgut as attractive targets for the development of transmission blocking vaccines (TBVs). Immune clearance of gametocytes in the vertebrate host can synergize with TBVs and directly aid in maintaining effective transmission reducing immune potential.

Assets for integrating task-sharing strategies for hypertension within HIV clinics: Stakeholder's perspectives using the PEN-3 cultural model.

BACKGROUND: Access to antiretroviral therapy has increased life expectancy and survival among people living with HIV (PLWH) in African countries like Nigeria. Unfortunately, non-communicable diseases such as cardiovascular diseases are on the rise as important drivers of morbidity and mortality rates among this group. The aim of this study was to explore the perspectives of key stakeholders in Nigeria on the integration of evidence-based task-sharing strategies for hypertension care (TASSH) within existing HIV clinics in Nigeria. METHODS: Stakeholders representing PLWH, patient advocates, health care professionals (i.e. community health nurses, physicians and chief medical officers), as well as policymakers, completed in-depth qualitative interviews. Stakeholders were asked to discuss facilitators and barriers likely to influence the integration of TASSH within HIV clinics in Akwa Ibom, Nigeria. The interviews were transcribed, keywords and phrases were coded using the PEN-3 cultural model as a guide. Framework thematic analysis guided by the PEN-3 cultural model was used to identify emergent themes. RESULTS: Twenty-four stakeholders participated in the interviews. Analysis of the transcribed data using the PEN-3 cultural model as a guide yielded three emergent themes as assets for the integration of TASSH in existing HIV clinics. The themes identified are: 1) extending continuity of care among PLWH; 2) empowering health care professionals and 3) enhancing existing workflow, staff motivation, and stakeholder advocacy to strengthen the capacity of HIV clinics to integrate TASSH. CONCLUSION: These findings advance the field by providing key stakeholders with knowledge of assets within HIV clinics that can be harnessed to enhance the integration of TASSH for PLWH in Nigeria. Future studies should evaluate the effect of these assets on the implementation of TASSH within HIV clinics as well as their effect on patient-level outcomes over time.

Dissemination and implementation research coordination and training to improve cardiovascular health in people living with HIV in sub-Saharan Africa: the research coordinating center of the HLB-SIMPLe Alliance.

As global adoption of antiretroviral therapy extends the lifespan of People Living with HIV (PLHIV) through viral suppression, the risk of comorbid conditions such as hypertension has risen, creating a need for effective, scalable interventions to manage comorbidities in PLHIV. The Heart, Lung, and Blood Co-morbiditieS Implementation Models in People Living with HIV (HLB-SIMPLe) Alliance has been funded by the National Heart, Lung, and Blood Institute (NHLBI) and the Fogarty International Center (FIC) since September 2020. The Alliance was created to conduct late-stage implementation research to contextualize, implement, and evaluate evidence-based strategies to integrate the diagnosis, treatment, and control of cardiovascular diseases, particularly hypertension, in PLHIV in low- and middle-income countries (LMICs).The Alliance consists of six individually-funded clinical trial cooperative agreement research projects based in Botswana, Mozambique, Nigeria, South Africa, Uganda, and Zambia; the Research Coordinating Center; and personnel from NIH, NHLBI, and FIC (the Federal Team). The Federal Team works together with the members of the seven cooperative agreements which comprise the alliance. The Federal Team includes program officials, project scientists, grant management officials and clinical trial specialists. This Alliance of research scientists, trainees, and administrators works collaboratively to provide and support venues for ongoing information sharing within and across the clinical trials, training and capacity building in research methods, publications, data harmonization, and community engagement. The goal is to leverage shared learning to achieve collective success, where the resulting science and training are greater with an Alliance structure rather than what would be expected from isolated and unconnected individual research projects.In this manuscript, we describe how the Research Coordinating Center performs the role of providing organizational efficiencies, scientific technical assistance, research capacity building, operational coordination, and leadership to support research and training activities in this multi-project cooperative research Alliance. We outline challenges and opportunities during the initial phases of coordinating research and training in the HLB-SIMPLe Alliance, including those most relevant to dissemination and implementation researchers.

Research opportunities for the primordial prevention of rheumatic fever and rheumatic heart disease-streptococcal vaccine development: a national heart, lung and blood institute workshop report.

Streptococcus pyogenes, also known as group A streptococcus (StrepA), is a bacterium that causes a range of human diseases, including pharyngitis, impetigo, invasive infections, and post-infection immune sequelae such as rheumatic fever and rheumatic heart disease. StrepA infections cause some of the highest burden of disease and death in mostly young populations in low-resource settings. Despite decades of effort, there is still no licensed StrepA vaccine, which if developed, could be a cost-effective way to reduce the incidence of disease. Several challenges, including technical and regulatory hurdles, safety concerns and a lack of investment have hindered StrepA vaccine development. Barriers to developing a StrepA vaccine must be overcome in the future by prioritising key areas of research including greater understanding of StrepA immunobiology and autoimmunity risk, better animal models that mimic human disease, expanding the StrepA vaccine pipeline and supporting vaccine clinical trials. The development of a StrepA vaccine is a complex and challenging process that requires significant resources and investment. Given the global burden of StrepA infections and the potential for a vaccine to save lives and livelihoods, StrepA vaccine development is an area of research that deserves considerable support. This report summarises the findings of the Primordial Prevention Working Group-VAX, which was convened in November 2021 by the National Heart, Lung, and Blood Institute. The focus of this report is to identify research gaps within the current StrepA vaccine landscape and find opportunities and develop priorities to promote the rapid and successful advancement of StrepA vaccines.