WHO target product profiles to shape global research and development.

Research and development leading to new and improved health products is essential for achieving healthier lives for populations worldwide. However, new products in development do not always match the global need for products for neglected diseases and populations. To promote research, provide an incentive for investment and align products with the needs of end-users, research needs to be better coordinated and prioritized. The World Health Organization (WHO) has developed target product profiles that define the characteristics required in new health products to address the greatest public health needs. A WHO target product profile document presents a need and provides guidance on what to include to consider access and equity as part of the research and development plan from the outset. WHO has also set up the Target Product Profile Directory, a free-to-use online database of characteristics used to describe desired health products, including medicines, vaccines, diagnostic tools and medical equipment. Here we describe the process of developing a WHO target product profile, and the benefits of this type of guidance. We urge product developers to share product profiles addressing unmet needs in public health, to help in progress towards global targets for better health and well-being.

Promouvoir la santé des populations à travers le monde va de pair avec la recherche-développement responsable de la conception et de l'optimisation de produits sanitaires. Pourtant, les nouveaux produits à l'étude ne répondent pas toujours aux exigences mondiales des populations et maladies négligées. En vue de promouvoir la recherche, de favoriser les investissements et d'aligner les produits sur les besoins des utilisateurs finaux, les travaux doivent être mieux coordonnés et leurs priorités, mieux définies. L'Organisation mondiale de la Santé (OMS) a donc élaboré des profils de produits cibles qui déterminent les caractéristiques requises pour les nouveaux produits sanitaires, afin qu'ils correspondent davantage aux besoins les plus criants en matière de santé publique. Un profil de produit cible établi par l'OMS est un document qui met en évidence un besoin et fournit des indications sur les aspects à prendre en compte pour garantir l'accès et l'équité dès le départ dans le plan de recherche-développement. L'OMS a également publié un Répertoire des profils de produits cibles, une base de données en ligne consultable gratuitement qui reprend les caractéristiques employées pour décrire les produits sanitaires souhaités (médicaments, vaccins, outils diagnostiques et équipements médicaux). Dans le présent document, nous détaillons le processus de développement d'un profil de produit cible par l'OMS, mais aussi les avantages que comportent de telles indications. Nous encourageons vivement les laboratoires à partager les profils de produits qui répondent à des besoins non satisfaits en matière de santé publique, afin de contribuer à avancer vers les objectifs mondiaux de santé et de bien-être.

La investigación y el desarrollo de productos sanitarios nuevos y mejorados son esenciales para que las poblaciones de todo el mundo vivan más sanas. Sin embargo, los productos nuevos en desarrollo no siempre se ajustan a las necesidades mundiales de productos para enfermedades y poblaciones desatendidas. Para promover la investigación, incentivar la inversión y adaptar los productos a las necesidades de los usuarios finales, es necesario coordinar mejor la investigación y establecer prioridades. La Organización Mundial de la Salud (OMS) ha elaborado perfiles de productos específicos que definen las características que deben reunir los productos sanitarios nuevos para satisfacer las principales necesidades de salud pública. Un documento de perfil de producto específico de la OMS presenta una necesidad y ofrece orientación sobre lo que debe incluirse para tener en cuenta el acceso y la equidad como parte del plan de investigación y desarrollo desde el principio. La OMS también ha creado el Directorio de Perfiles de Productos Específicos, una base de datos en línea de uso gratuito con las características utilizadas para describir los productos sanitarios deseados, incluidos medicamentos, vacunas, herramientas de diagnóstico y equipos médicos. En el presente documento, describimos el proceso de elaboración de un perfil de producto específico de la OMS y las ventajas de este tipo de orientación. Instamos a los desarrolladores de productos a compartir perfiles de productos que aborden necesidades no cubiertas en salud pública para contribuir al avance hacia los objetivos mundiales de mejora de la salud y el bienestar.

Tracking global resources and capacity for health research: time to reassess strategies and investment decisions.

The COVID-19 pandemic and more recently the Monkeypox outbreak emphasize the urgency and importance of improving the availability and equitable distribution of resources for health research across rich and poor countries. Discussions about the persistent imbalances in resource allocation for health research between rich and poor countries are not new, but little or no progress has been made in redressing these imbalances over the years. This is critical not only for emergency preparedness, but for the worlds' ability to improve population health in an equitable manner. Concerned with the lack of progress in this area, Member States of the World Health Organization requested the establishment of a Global Observatory on Health Research and Development, with the aim of consolidating, monitoring and analyzing relevant information on health research and development, with a view to informing the coordination and prioritization of new investments. In this commentary, we highlight some of the striking disparities from the Observatory's analysis over the 5 years since its establishment and reflect on what is needed to overturn stagnant progress.

Oversight of Dual-Use Research: What Role for Ethics Committees?

The World Health Organization (WHO) Global Guidance Framework for the Responsible Use of the Life Sciences addresses the governance of biorisks, including dual-use research, for countries. It emphasizes engaging multisectoral stakeholders such as governments, scientific bodies, health and research institutes, standard-setting organizations, funding bodies, and others. Ethics constitutes a key component of the framework. Given the high social impact of such research and the importance of trust, risk, and benefit, national ethics committees could make a valuable contribution by providing ethical guidance in the decisionmaking process. The purpose of this study was to examine the role of national ethics committees in the context of governance and oversight of dual-use research at the national level. We conducted a landscape analysis of the activities of ethics committees in dual-use research oversight. We also searched the WHO database on National Ethics Committees for publications related to dual-use research and/or misuse of life sciences research and gathered additional documentation from national ethics committees websites and through author contacts. Results showed that in the context of the wide range of oversight mechanisms for dual-use research in countries, national ethics committees have contributed to guiding policy and assessing dual-use research risks in only a limited number of countries. Recommendations from those countries include establishing a multistakeholder, coordinated oversight mechanism at the country level; strengthening international linkages to guide, harmonize, and reinforce national and international efforts; and involving ethics committees as an expert resource in the governance and oversight process.

Towards an HIV cure: science and debate from the International AIDS Society 2013 symposium.

The International AIDS Society convened the multi-stakeholder "Towards an HIV Cure" symposium in Kuala Lumpur, Malaysia in 2013 to address the significant research challenges posed by the search for a cure for HIV infection. Current antiretroviral regimens select for a small reservoir of cells that harbour latent HIV provirus, produce few or no HIV virions, and resist detection or clearance by host immunity. The symposium examined basic molecular science and animal model data, and emerging and ongoing clinical trial results to prioritise strategies and determine the viral and immune responses that could lead to HIV remission without ART. Here we review the presentations that scrutinized the molecular mechanisms controlling virus expression from proviral DNA, and the intrinsic cellular restriction and immune mechanisms preventing viral production. Insights from the basic science have translated into new therapeutic strategies seeking HIV remission without ongoing therapy, and much interest was focused on these ongoing trials. We also summarise the emerging ethical issues and patient expectations as concepts move into the clinic.

Proteasome-independent degradation of HIV-1 in naturally non-permissive human placental trophoblast cells.

BACKGROUND: The human placenta-derived cell line BeWo has been demonstrated to be restrictive to cell-free HIV-1 infection. BeWo cells are however permissive to infection by VSV-G pseudotyped HIV-1, which enters cells by a receptor-independent mechanism, and to infection by HIV-1 via a cell-to-cell route. RESULTS: Here we analysed viral entry in wild type BeWo (CCR5+, CXCR4+) and BeWo-CD4+ (CD4+, CCR5+, CXCR4+) cells. We report that HIV-1 internalisation is not restricted in either cell line. Levels of internalised p24 antigen between VSV-G HIV-1 pseudotypes and R5 or X4 virions were comparable. We next analysed the fate of internalised virions; X4 and R5 HIV-1 virions were less stable over time in BeWo cells than VSV-G HIV-1 pseudotypes. We then investigated the role of the proteasome in restricting cell-free HIV-1 infection in BeWo cells using proteasome inhibitors. We observed an increase in the levels of VSV-G pseudotyped HIV-1 infection in proteasome-inhibitor treated cells, but the infection by R5-Env or X4-Env pseudotyped virions remains restricted. CONCLUSION: Collectively these results suggest that cell-free HIV-1 infection encounters a surface block leading to a non-productive entry route, which either actively targets incoming virions for non-proteasomal degradation, and impedes their release into the cytoplasm, or causes the inactivation of mechanisms essential for viral replication.

The Self-Testing AfRica (STAR) Initiative: accelerating global access and scale-up of HIV self-testing.

INTRODUCTION: HIV self-testing (HIVST) was first proposed as an additional option to standard HIV testing services in the 1980s. By 2015, two years after the first HIVST kit was approved for the American market and the year in which Unitaid invested in the "HIV Self-Testing AfRica (STAR) Initiative," HIVST remained unexplored with negligible access in low- and middle-income countries (LMIC). However, rapid progress had been made. This commentary outlines the interlinked market, regulatory and policy barriers that had inhibited product development and kept HIVST out of LMIC policy. We detail the components of STAR that enabled rapid HIVST scale-up, including critical investments in implementation, research, market forecasting, and engagement with manufacturers and regulators. DISCUSSION: The STAR Initiative has generated crucial information about how to distribute HIVST products effectively, ethically and efficiently. Service delivery models range from clinic-based distribution to workplace and partner-delivered approaches to reach first-time male testers, to community outreach to sex workers and general population "hotspots." These data directly informed supportive policy, notably the 2016 WHO guidelines strongly recommending HIVST as an additional testing approach, and regulatory change through support for WHO prequalification of the first HIVST kit in 2017. In July 2015, only two countries had national HIVST policies and were implementing HIVST. Three years later, 59 countries have policies, actively implemented in 28, with an additional 53 countries reporting policies under development. By end-November 2018 several quality-assured HIVST products had been registered, including two WHO prequalified tests. STAR Initiative countries have drafted regulations governing in vitro diagnostics, including HIVST products. With enabling policies, pre-qualification and regulations in place, donor procurement of kits has increased rapidly, to a forecasted estimate of 16 million HIVST kits procured by 2020. CONCLUSIONS: The STAR Initiative provided a strong foundation to introduce HIVST in LMICs and allow for rapid scale-up based on the wealth of multi-country evidence gathered. Together with sustained coordination and acceleration of market development work, HIVST can help address the testing gap and provide a focused and cost-effective means to expand access to treatment and prevention services.

Vertebrate DNA damage tolerance requires the C-terminus but not BRCT or transferase domains of REV1.

REV1 is central to the DNA damage response of eukaryotes through an as yet poorly understood role in translesion synthesis. REV1 is a member of the Y-type DNA polymerase family and is capable of in vitro deoxycytidyl transferase activity opposite a range of damaged bases. However, non-catalytic roles for REV1 have been suggested by the Saccharomyces cerevisiae rev1-1 mutant, which carries a point mutation in the N-terminal BRCT domain, and the recently demonstrated ability of the mammalian protein to interact with each of the other translesion polymerases via its extreme C-terminus. Here, we show that a region adjacent to this polymerase interacting domain mediates an interaction with PCNA. These C-terminal domains of REV1 are necessary, although not sufficient, for effective tolerance of DNA damage in the avian cell line DT40, while the BRCT domain and transferase activity are not directly required. Together these data provide strong support for REV1 playing an important non-catalytic role in coordinating translesion synthesis. Further, unlike in budding yeast, rad18 is not epistatic to rev1 for DNA damage tolerance suggesting that REV1 and RAD18 play largely independent roles in the control of vertebrate translesion synthesis.

Analysis of DNA replication damage bypass and its role in immunoglobulin repertoire development.

Cells possess very effective mechanisms for repairing DNA damage. However, in some circumstances repair cannot be carried out before passage of a replication fork, leading to polymerase stalling and an unreplicated gap. Left unrepaired, such gaps will lead to misegregation of genetic information or apoptosis. Cells can ensure that replication is completed by bypassing the damaged bases in the DNA template either directly by translesion synthesis or indirectly by employing an alternative undamaged template. This cellular activity, originally termed post-replication repair is now often referred to as replication damage bypass. Extensively studied in bacteria and yeast, replication damage bypass is now receiving much attention in higher eukaryotes because of its close link to mutagenesis and genetic instability. Work in DT40 has given many insights into the roles of and relationships between the genes involved in DNA damage tolerance and recombination, not least because the cell line can tolerate disruption of many genes that result in early embryonic lethality in mice. In this review we examine current thinking about vertebrate replication damage bypass in the context of studies in bacteria and yeast. We focus particularly on the contribution made by DT40 to these studies and discuss how immunoglobulin diversification in this cell line can contribute to our understanding of replication damage bypass in vertebrates.

The catalytic activity of REV1 is employed during immunoglobulin gene diversification in DT40.

REV1 plays a key role in vertebrate translesion synthesis. Although its deoxycytidyl transferase activity is dispensable for tolerance of DNA damage caused by a number of mutagens, its extreme C terminus, which interacts with other translesion polymerases and PCNA, is essential. By examining immunoglobulin diversification in the genetically tractable chicken cell line DT40 we show that the generation of non-templated point mutations from C/G to G/C does require the catalytic activity of REV1. This provides the first clear evidence that the catalytic activity of REV1 is utilised in vivo in higher eukaryotes and is involved in immunoglobulin diversification. Although rev1 DT40 cells incorporate few point mutations, a mutant lacking the C terminus of REV1 exhibits a similar level to that seen in wild-type cells. Thus, the polymerase selection or stabilisation role of REV1 does not appear to play a major role in the bypass of AID-dependent abasic sites.

Ending AIDS as a public health threat by 2030: Scientific Developments from the 2016 INTEREST Conference in Yaoundé, Cameroon.

The underpinning theme of the 2016 INTEREST Conference held in Yaoundé, Cameroon, 3-6 May 2016 was ending AIDS as a public health threat by 2030. Focused primarily on HIV treatment, pathogenesis and prevention research in resource-limited settings, the conference attracted 369 active delegates from 34 countries, of which 22 were in Africa. Presentations on treatment optimization, acquired drug resistance, care of children and adolescents, laboratory monitoring and diagnostics, implementation challenges, HIV prevention, key populations, vaccine and cure, hepatitis C, mHealth, financing the HIV response and emerging pathogens, were accompanied by oral, mini-oral and poster presentations. Spirited plenary debates on the UNAIDS 90-90-90 treatment cascade goal and on antiretroviral pre-exposure prophylaxis took place. Joep Lange career guidance sessions and grantspersonship sessions attracted early career researchers. At the closing ceremony, the Yaoundé Declaration called on African governments; UNAIDS; development, bilateral, and multilateral partners; and civil society to adopt urgent and sustained approaches to end HIV by 2030.

Towards Multidisciplinary HIV-Cure Research: Integrating Social Science with Biomedical Research.

The quest for a cure for HIV remains a timely and key challenge for the HIV research community. Despite significant scientific advances, current HIV therapy regimens do not completely eliminate the negative impact of HIV on the immune system; and the economic impact of treating all people infected with HIV globally, for the duration of their lifetimes, presents significant challenges. This article discusses, from a multidisciplinary approach, critical social, behavioral, ethical, and economic issues permeating the HIV-cure research agenda. As part of a search for an HIV cure, both the perspective of patients/participants and clinical researchers should be taken into account. In addition, continued efforts should be made to involve and educate the broader community.

International AIDS Society global scientific strategy: towards an HIV cure 2016.

Antiretroviral therapy is not curative. Given the challenges in providing lifelong therapy to a global population of more than 35 million people living with HIV, there is intense interest in developing a cure for HIV infection. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. This Perspective summarizes the group's strategy.

Progress towards an HIV cure: update from the 2014 International AIDS Society Symposium.

Biomedical research has led to profound advances in the treatment of HIV infection. Combination antiretroviral therapy (ART) now provides the means to readily control viral infection, and people living with HIV who receive timely and effective ART can expect to benefit from a life expectancy comparable to uninfected individuals. Nevertheless, despite effective treatment, ART does not fully restore the immune system and importantly HIV persists indefinitely in latent reservoirs, resulting in the need for life-long treatment. The challenges and limits of life-long treatment have spurred significant scientific interest and global investment into research towards an HIV cure. The International AIDS Society (IAS) 2014 Towards an HIV cure symposium brought together researchers and community to discuss the most recent advances in our understanding of latency and HIV reservoirs, and the clinical approaches towards an HIV cure under current investigation. This report summarizes and reviews some of the major findings discussed during the symposium.

The HIV Cure Research Agenda: The Role of Mathematical Modelling and Cost-Effectiveness Analysis.

The research agenda towards an HIV cure is building rapidly. In this article, we discuss the reasons for and methodological approach to using mathematical modeling and cost-effectiveness analysis in this agenda. We provide a brief description of the proof of concept for cure and the current directions of cure research. We then review the types of clinical economic evaluations, including cost analysis, cost-benefit analysis, and cost-effectiveness analysis. We describe the use of mathematical modeling and cost-effectiveness analysis early in the HIV epidemic as well as in the era of combination antiretroviral therapy. We then highlight the novel methodology of Value of Information analysis and its potential role in the planning of clinical trials. We close with recommendations for modeling and cost-effectiveness analysis in the HIV cure agenda.

Past, present and future: 30 years of HIV research.

This year marks the thirtieth anniversary of the publication of the study that first reported the isolation of HIV-1. In this Timeline article, we provide a historical perspective of some of the major milestones in HIV science, highlighting how translational research has affected treatment and prevention of HIV. Finally, we discuss some of the current research directions and the scientific challenges ahead, in particular in the search for a cure for HIV.

Progress towards development of an HIV vaccine: report of the AIDS Vaccine 2009 Conference.

The search for an HIV/AIDS vaccine is steadily moving ahead, generating and validating new concepts in terms of novel vectors for antigen delivery and presentation, new vaccine and adjuvant strategies, alternative approaches to design HIV-1 antigens for eliciting protective cross-neutralising antibodies, and identification of key mechanisms in HIV infection and modulation of the immune system. All these different perspectives are contributing to the unprecedented challenge of developing a protective HIV-1 vaccine. The high scientific value of this massive effort is its great impact on vaccinology as a whole, providing invaluable scientific information for the current and future development of new preventive vaccine as well as therapeutic knowledge-based infectious-disease and cancer vaccines.

RAD18-independent ubiquitination of proliferating-cell nuclear antigen in the avian cell line DT40.

Ubiquitination of proliferating-cell nuclear antigen (PCNA) at K164 by RAD6/RAD18 has a key role in DNA damage tolerance in yeast. Here, we report on the first genetic study of this modification in a vertebrate cell. As in yeast, mutation of K164 of PCNA to arginine in the avian cell line DT40 results in sensitivity to DNA damage but, by contrast, the DT40 pcnaK164R mutant is more sensitive than the rad18 mutant. Consistent with this, we show the presence of residual ubiquitination of PCNA at K164 in the absence of functional RAD18, suggesting the presence of an alternate PCNA ubiquitinating enzyme in DT40. Furthermore, RAD18 and PCNA K164 have non-overlapping roles in the suppression of sister chromatid exchange in DT40, showing that RAD18 has other functions that do not involve the ubiquitination of PCNA.