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Background Deciding how best to invest in healthcare is never an easy task and prioritization is therefore an area of great interest for policymakers. Too low public vaccine confidence, which results in insufficient vaccine uptake, remains an area of concern for EU policy-makers. Within the European Joint action on vaccination, a work-package dedicated to research aims to define tools and methods for priority-setting in the field of vaccination research. We therefore propose a prioritization framework to identify research priorities towards generating and synthesizing evidence to support policies and strategies aiming at increasing vaccine coverage. Materials/methods We used a multi-criteria decision analysis (MCDA) method inspired by the Child Health and Nutrition Research Initiative developed by Rudan et al. This quantitative methodology follows a series of steps involving different groups of experts and relevant stakeholders. The first step consists in identifying key research questions through a broad consultation. In parallel, a first group of experts is tasked to select criteria for prioritization of research questions, taking into consideration the ultimate goal of the exercise. Another group of experts is then requested to assess a weight to each of the criteria, using pair-wise comparisons. The final step consists in gathering experts who will assess each research question against the weighted criteria. This evaluation leads to assigning a score to each individual research question, which can then be ranked in order of priority. Results We focused our work on four pre-selected pilot vaccines (pertussis, measles containing combination vaccines, influenza and HPV). The consultation generated 124 questions, which were secondarily sorted and re-worded to obtain 27 questions to be ranked. Criteria for setting priorities were the following: accessibility, answerability, deliverability, disease prevalence/incidence, effectiveness, equity, generalization, and territory. During a final face-to-face meeting international experts ranked the 27 questions and agreed on a consensual list of six top-priorities. Conclusions We have developed a transparent, evidence-based rigorous framework to defined key research questions to generate evidence towards the design of policies and strategies to increase vaccine coverage. Results were disseminated broadly and submitted to the EC for potential funding in the context of The Horizon Europe Program. The same process will be conducted in 2021 to identify vaccination research priorities regarding all vaccines used in the EU as well as COVID-19 vaccines.

International audience

Highlights • We found rVSVΔG-ZEBOV-GP to be immunogenic at 28- and 180-days post vaccination. • At 28 days post-vaccination, seroresponse rate was higher in the high-risk group. • There is a significant pairwise correlation at 28 days post-vaccination between assays. • One dose of rVSVΔG-ZEBOV-GP induces a cellular response that increased with time., Background As part of a Phase III trial with the Ebola vaccine rVSVΔG-ZEBOV-GP in Guinea, we invited frontline workers (FLWs) to participate in a sub-study to provide additional information on the immunogenicity of the vaccine. Methods We conducted an open‐label, non‐randomized, single-arm immunogenicity evaluation of one dose of rVSVΔG-ZEBOV-GP among healthy FLWs in Guinea. FLWs who refused vaccination were offered to participate as a control group. We followed participants for 84 days with a subset followed-up for 180 days. The primary endpoint was immune response, as measured by ELISA for ZEBOV-glycoprotein–specific antibodies (ELISA-GP) at 28 days. We also conducted neutralization, whole virion ELISA and enzyme-linked immunospot (ELISPOT) assay for cellular response. Results A total of 1172 participants received one dose of vaccine and were followed-up for 84 days, among them 114 participants were followed-up for 180 days. Additionally, 99 participants were included in the control group and followed up for 180 days. Overall, 86.4% (95% CI 84.1–88.4) of vaccinated participants seroresponded at 28 days post-vaccination (ELISA- GP) with 65% of these seroresponding at 14 days post-vaccination. Among those who seroresponded at 28 days, 90.7% (95% CI 82.0–95.4) were still seropositive at 180 days. The proportion of seropositivity in the unvaccinated group was 0.0% (95% CI 0.0–3.8) at 28 days and 5.4% (95% CI 2.1–13.1) at 180 days post-vaccination. We found weak correlation between ELISA-GP and neutralization at baseline but significant pairwise correlation at 28 days post-vaccination. Among samples analysed for cellular response, only 1 (2.2%) exhibited responses towards the Zaire Ebola glycoprotein (Ebola GP ≥ 10) at baseline, 10 (13.5%) at day 28 post-vaccination and 27 (48.2%) at Day 180. Conclusions We found one dose of rVSVΔG-ZEBOV-GP to be highly immunogenic at 28- and 180-days post vaccination among frontline workers in Guinea. We also found a cellular response that increased with time.

Despite successful control in many parts of the world, rabies virus continues to result in tens of thousands of deaths each year. Death from rabies can be prevented by timely and appropriate post exposure prophylaxis including wound cleaning and administration of vaccine and rabies immunoglobulin. Currently, rabies immunoglobulin is derived from the blood plasma of horses or humans and has several limitations relating to supply, cost and quality. Monoclonal antibodies produced through recombinant DNA technologies could potentially overcome these limitations. The first anti-rabies monoclonal antibody has recently gained regulatory approval in India and there are several other candidates being evaluated in clinical trials. Given the advances in the field, rabies monoclonal antibodies have been recently considered by the World Health Organization's Strategic Advisory Group of Experts on Immunization and included in updated WHO immunization policy recommendations for rabies published in April 2018. This article reviews the current landscape of the clinical trial development of anti-rabies monoclonal antibodies and the historical clinical trial pathways followed for blood-derived rabies immunoglobulin before discussing challenges in the clinical evaluation, regulatory approval, uptake and monitoring of these products.

The recombinant vaccinia–rabies vaccine, now known as Raboral®, has been widely used in Europe and North America to control/eliminate rabies in the principal wildlife vectors, and thus prevent human transmission. The origins of this vaccine are sometimes forgotten, although the formulation has not changed substantially in almost four decades. This groundbreaking vaccine was assembled by a team at a very young (at that time) genetic engineering company, Transgène, in Strasbourg, France. The joint leaders of the rabies vaccine team reflect, 36 years later, on the trials and tribulations that went hand in hand with the construction of the vaccine.

Background In October 2015, 65 people came into direct contact with a healthcare worker presenting with a late reactivation of Ebola virus disease (EVD) in the United Kingdom. Vaccination was offered to 45 individuals with an initial assessment of high exposure risk. Methods Approval for rapid expanded access to the recombinant vesicular stomatitis virus–Zaire Ebola virus (rVSV-ZEBOV) vaccine as an unlicensed emergency medicine was obtained from the relevant authorities. An observational follow-up study was carried out for 1 year following vaccination. Results Twenty-six of 45 individuals elected to receive vaccination between 10 and 11 October 2015 following written informed consent. By day 14, 39% had seroconverted, increasing to 87% by day 28 and 100% by 3 months, although these responses were not always sustained. Neutralizing antibody responses were detectable in 36% by day 14 and 73% at 12 months. Common side effects included fatigue, myalgia, headache, arthralgia, and fever. These were positively associated with glycoprotein-specific T-cell but not immunoglobulin (Ig) M or IgG antibody responses. No severe vaccine-related adverse events were reported. No one exposed to the virus became infected. Conclusions This paper reports the use of the rVSV-ZEBOV vaccine given as an emergency intervention to individuals exposed to a patient presenting with a late reactivation of EVD. The vaccine was relatively well tolerated, but a high percentage developed a fever ≥37.5°C, necessitating urgent screening for Ebola virus, and a small number developed persistent arthralgia., The rVSV-ZEBOV vaccine was used as postexposure prophylaxis in individuals exposed to Ebola virus in the United Kingdom. It was rolled out rapidly and was generally well tolerated. Side effects correlated with the magnitude of CD8+ T-cell responses.

Hongchao Pan (University of Oxford. Nuffield Department of Population Health. Medical Research Council Population Health Research Unit. Oxford, United Kingdom); Richard Peto (University of Oxford. Nuffield Department of Population Health. Medical Research Council Population Health Research Unit. Oxford, United Kingdom); Ana-Maria Henao-Restrepo (World Health Organization. Geneva, Switzerland); Marie-Pierre Preziosi (World Health Organization. Geneva, Switzerland); Vasee Sathiyamoorthy (World Health Organization. Geneva, Switzerland); Quarraisha Abdool Karim (Centre for the AIDS Programme of Research in South Africa. Durban, South Africa); Marissa M. Alejandria (University of the Philippines. National Institutes of Health. Institute of National Epidemiology. Manila, Philippines); Cesar Hernandez Garcia (Spanish Agency of Medicines and Medical Devices. Madrid, Spain / Hospital Clinico San Carlos. Madrid, Spain); Marie-Paule Kieny (Institut National de la Sante et de la Recherche Medicale. Paris, France); Reza Malekzadeh (Tehran University of Medical Sciences. Digestive Disease Research Institute. Tehran, Iran); Srinivas Murthy (University of British Columbia. Vancouver, Canada); K. Srinath Reddy (Public Health Foundation of India. New Delhi, India); Mirta Roses Periago (National Academy of Sciences of Buenos Aires. Buenos Aires, Argentina); Pierre Abi Hanna (Rafic Hariri University Hospital. Beirut, Lebanon); Florence Ader (Hospices Civils de Lyon. Lyon, France); Abdullah M. Al-Bader (Ministry of Health. Kuwait City, Kuwait); Almonther Alhasawi (Infectious Diseases Hospital. Kuwait City, Kuwait); Emma Allum (University of Bristol. Bristol, United Kingdom); Athari Alotaibi (Ministry for Preventive Health. Riyadh, Saudi Arabia); Carlos A. Alvarez-Moreno (Universidad Nacional de Colombia. Bogota, Colombia / Clinica Colsanitas. Bogota, Colombia); Sheila Appadoo (University of Bern. Bern, Switzerland); Abdullah Asiri (Ministry for Preventive Health. Riyadh, Saudi Arabia); Pal Aukrust (Oslo University Hospital. Oslo, Norway); Andreas Barratt-Due (Oslo University Hospital. Oslo, Norway); Samir Bellani (University of Bristol. Bristol, United Kingdom); Mattia Branca (University of Bern. Bern, Switzerland); Heike B.C. Cappel-Porter (University of Bristol. Bristol, United Kingdom); Nery Cerrato (Secretaria de Salud de Honduras. Tegucigalpa, Honduras); Ting S. Chow (Penang Hospital. Penang, Malaysia); Najada Como (University Hospital Center "Mother Teresa". Tirana, Albania); Joe Eustace (University College Cork. HRB Clinical Research Facility. Cork, Ireland); Patricia J. Garcia (Universidad Peruana Cayetano Heredia. Lima, Peru); Sheela Godbole (Indian Council of Medical Research. New Delhi, India / National AIDS Research Institute. Pune, Maharashtra, India); Eduardo Gotuzzo (Universidad Peruana Cayetano Heredia. Lima, Peru); Laimonas Griskevicius (Vilnius University Hospital Santaros Klinikos. Vilnius, Lithuania); Rasha Hamra (Ministry of Public Health. Beirut, Lebanon); Mariam Hassan (Shaukat Khanum Memorial Cancer Hospital and Research Centre. Lahore, Pakistan); Mohamed Hassany (National Hepatology and Tropical Medicine Research Institute. Cairo, Egypt); David Hutton (University of Bristol. Bristol, United Kingdom); Irmansyah Irmansyah (National Institute of Health Research and Development. Jakarta, Indonesia); Ligita Jancoriene (Vilnius University. Faculty of Medicine. Institute of Clinical Medicine. Vilnius, Lithuania); Jana Kirwan (University of Bristol. Bristol, United Kingdom); Suresh Kumar (Sungai Buloh Hospital. Selangor, Malaysia / Jalan Hospital. Selangor, Malaysia); Peter Lennon (Department of Health and Children. Dublin, Ireland); Gustavo Lopardo (Fundacion del Centro de Estudios Infectologicos. Buenos Aires, Argentina); Patrick Lydon (World Health Organization. Geneva, Switzerland); Nicola Magrini (Italian Medicines Agency. Rome, Italy); Teresa Maguire (Department of Health and Children. Dublin, Ireland); Suzana Manevska (Ministry of Health. Skopje, North Macedonia); Oriol Manuel (Lausanne University Hospital. Lausanne, Switzerland); Sibylle McGinty (University of Bern. Bern, Switzerland); Marco T. Medina (Universidad Nacional Autonoma de Honduras. Tegucigalpa, Honduras); Maria L. Mesa Rubio (Ministry of Health. Bogota, Colombia); Maria C. Miranda-Montoya (World Health Organization. Geneva, Switzerland); Jeremy Nel (University of the Witwatersrand. Johannesburg, South Africa); Estevao Portela Nunes (Fundacao Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil); Markus Perola (National Institute for Health and Welfare of Finland. Helsinki, Finland / University of Finland. Helsinki, Finland); Antonio Portoles (Universidade Complutense de Madrid. Madrid, Spain / Spanish Clinical Research Network. Madrid, Spain / Hospital Clinico San Carlos. Instituto de Investigacion Sanitaria San Carlos. Madrid, Spain); Menaldi R. Rasmin (Rumah Sakit Umum Pusat Persahabatan. Jakarta, Indonesia); Aun Raza (Shaukat Khanum Memorial Cancer Hospital and Research Centre. Lahore, Pakistan); Helen Rees (Wits Reproductive Health and HIV Institute. Johannesburg, South Africa); Paula P. S. Reges (Fundacao Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil); Chris A. Rogers (University of Bristol. Bristol, United Kingdom); Kolawole Salami (World Health Organization. Geneva, Switzerland); Marina I. Salvadori (Public Health Agency of Canada. Ottawa, Canada); Narvina Sinani (National Agency for Medicines and Medical Devices. Tirana, Albania); Jonathan A. C. Sterne (University of Bristol. Bristol, United Kingdom); Milena Stevanovikj (University Clinic of Infectious Diseases and Febrile Conditions. Skopje, North Macedonia); Evelina Tacconelli (University of Verona. Verona, Italy); Kari A. O. Tikkinen (Helsinki University Hospital. Helsinki, Finland / South Karelian Central Hospital. Lappeenranta, Finland); Sven Trelle (University of Bern. Bern, Switzerland); Hala Zaid (Ministry of Health and Population. Cairo, Egypt); John-Arne Rottingen (Research Council of Norway. Oslo, Norway); Soumya Swaminathan (World Health Organization. Geneva, Switzerland).

International audience

In high-income countries, there is an increased tendency to replace inactivated seasonal trivalent influenza (TIV) vaccines with quadrivalent (QIV) vaccines as these are considered to give a greater public health benefit. In addition, several recent studies from the USA and Europe indicate that replacement with QIV might also be cost-effective; however, the situation in low- and middle-income countries (LMIC) is less clear as few studies have investigated this aspect. The paper by de Boer et al. (2008) describes a dynamic modelling study commissioned by WHO that suggests that in LMICs, under certain conditions, QIV might also be more cost-effective than TIV. In this commentary, we discuss some important aspects that policymakers in LMICs might wish to take into account when considering replacing TIV by QIV. Indeed, from the data presented in the paper by de Boer et al. it can be inferred that replacing QIV for TIV would mean a 25-29% budget increase for seasonal influenza vaccination in South Africa and Vietnam, resulting in an incremental influenza-related health impact reduction of only 7-8% when a 10% symptomatic attack rate is assumed. We argue that national health budget considerations in LMIC might lead decision-makers to choose other investments with higher health impact for a budget equivalent to roughly a quarter of the yearly TIV immunization costs. In addition to an increased annual cost that would be associated with a decision to replace TIV with QIV, there would be an increased pressure on manufacturers to produce QIV in time for the influenza season requiring manufacturers to produce some components of the seasonal vaccine at risk prior to the WHO recommendations for influenza vaccines. Unless the current uncertainties, impracticalities and increased costs associated with QIVs are resolved, TIVs are likely to remain the more attractive option for many LMICs. Each country should establish its context-specific process for decision-making based on national data on disease burden and costs in order to determine whether the health gains out-weigh the additional cost of moving to QIV. For example, immunizing more people in the population, especially those in higher risk groups, with TIV might not only provide better value for money but also deliver better health outcomes in LMICs. Countries with local influenza vaccine manufacturing capacity should include in their seasonal influenza vaccine procurement process an analysis of the pros- and cons- of TIV versus QIV, to ensure both feasibility and sustainability of local manufacturing.

BACKGROUND: In March, 2016, a flare-up of Ebola virus disease was reported in Guinea, and in response ring vaccination with the unlicensed rVSV-ZEBOV vaccine was introduced under expanded access, the first time that an Ebola vaccine has been used in an outbreak setting outside a clinical trial. Here we describe the safety of rVSV-ZEBOV candidate vaccine and operational feasibility of ring vaccination as a reactive strategy in a resource-limited rural setting. METHODS: Approval for expanded access and compassionate use was rapidly sought and obtained from relevant authorities. Vaccination teams and frozen vaccine were flown to the outbreak settings. Rings of contacts and contacts of contacts were defined and eligible individuals, who had given informed consent, were vaccinated and followed up for 21 days under good clinical practice conditions. FINDINGS: Between March 17 and April 21, 2016, 1510 individuals were vaccinated in four rings in Guinea, including 303 individuals aged between 6 years and 17 years and 307 front-line workers. It took 10 days to vaccinate the first participant following the confirmation of the first case of Ebola virus disease. No secondary cases of Ebola virus disease occurred among the vaccinees. Adverse events following vaccination were reported in 47 (17%) 6-17 year olds (all mild) and 412 (36%) adults (individuals older than 18 years; 98% were mild). Children reported fewer arthralgia events than adults (one [ INTERPRETATION: The results show that a ring vaccination strategy can be rapidly and safely implemented at scale in response to Ebola virus disease outbreaks in rural settings. FUNDING:WHO, Gavi, and the World Food Programme.

Background The recent West African Ebola epidemic led to accelerated efforts to test Ebola vaccine candidates. As part of the World Health Organisation-led VSV Ebola Consortium (VEBCON), we performed a phase I clinical trial investigating rVSV-ZEBOV (a recombinant vesicular stomatitis virus-vectored Ebola vaccine), which has recently demonstrated protection from Ebola virus disease (EVD) in phase III clinical trials and is currently in advanced stages of licensing. So far, correlates of immune protection are incompletely understood and the role of cell-mediated immune responses has not been comprehensively investigated to date. Methods: We recruited 30 healthy subjects aged 18–55 into an open-label, dose-escalation phase I trial testing three doses of rVSV-ZEBOV (3 × 105 plaque-forming units (PFU), 3 × 106 PFU, 2 × 107 PFU) (ClinicalTrials.gov; NCT02283099). Main study objectives were safety and immunogenicity, while exploratory objectives included lymphocyte dynamics, cell-mediated immunity and cytokine networks, which were assessed using flow cytometry, ELISpot and LUMINEX assay. Findings: Immunization with rVSV-ZEBOV was well tolerated without serious vaccine-related adverse events. Ebola virus-specific neutralizing antibodies were induced in nearly all individuals. Additionally, vaccinees, particularly within the highest dose cohort, generated Ebola glycoprotein (GP)-specific T cells and initiated a cascade of signaling molecules following stimulation of peripheral blood mononuclear cells with Ebola GP peptides. Interpretation: In addition to a benign safety and robust humoral immunogenicity profile, subjects immunized with 2 × 107 PFU elicited higher cellular immune responses and stronger interlocked cytokine networks compared to lower dose groups. To our knowledge these data represent the first detailed cell-mediated immuneprofile of a clinical trial testing rVSV-ZEBOV, which is of particular interest in light of its potential upcoming licensure as the first Ebola vaccine. VEBCON trial Hamburg, Germany (NCT02283099)., Highlights • A phase I clinical trial was conducted to investigate the live-attenuated Ebola vaccine rVSV-ZEBOV. • Ebola-specific humoral and cell-mediated immune responses show a favorable profile for subjects immunized with 2 × 107 PFU of rVSV-ZEBOV. • The highest dose cohort induced stronger antigen-specific CTL-responses and interlocked cytokine networks compared to lower dose groups. rVSV-ZEBOV is the first Ebola vaccine with human efficacy data, currently undergoing an accelerated licensing process. Nevertheless, to date no human immunological correlate of protection has been identified and mechanisms of immune responses elicited by rVSV-ZEBOV remain incompletely understood. We conducted a phase I trial to test rVSV-ZEBOV in 30 healthy subjects using three dosage levels. We here present a comprehensive evaluation of humoral and cell-mediated responses with an in-depth analysis of signaling molecules following ex vivo stimulation with Ebola GP peptides. Our data suggest a favorable immune response profile for subjects immunized with 2 × 107 PFU. These data address critical knowledge gaps with respect to mechanisms of immuneprotection in the context of Ebola vaccines and may provide additional evidence to support the current dosage used in later stage clinical trials., Graphical Abstract Image 1

This commentary highlights the value of community-engaged social innovations to advance health care delivery in low- and middle-income countries and to accelerate universal health coverage. It emphasizes the importance of research to guide the innovators on what works, what does not work to make their innovations sustainable and to replicate and scale them up as relevant. It also helps to demonstrate impact and to enhance uptake within the health systems. Electronic supplementary material The online version of this article (10.1186/s40249-019-0586-9) contains supplementary material, which is available to authorized users.

Cost-effectiveness analysis is used to compare the costs and outcomes of alternative policy options. Each resulting cost-effectiveness ratio represents the magnitude of additional health gained per additional unit of resources spent. Cost-effectiveness thresholds allow cost-effectiveness ratios that represent good or very good value for money to be identified. In 2001, the World Health Organization's Commission on Macroeconomics in Health suggested cost-effectiveness thresholds based on multiples of a country's per-capita gross domestic product (GDP). In some contexts, in choosing which health interventions to fund and which not to fund, these thresholds have been used as decision rules. However, experience with the use of such GDP-based thresholds in decision-making processes at country level shows them to lack country specificity and this - in addition to uncertainty in the modelled cost-effectiveness ratios - can lead to the wrong decision on how to spend health-care resources. Cost-effectiveness information should be used alongside other considerations - e.g. budget impact and feasibility considerations - in a transparent decision-making process, rather than in isolation based on a single threshold value. Although cost-effectiveness ratios are undoubtedly informative in assessing value for money, countries should be encouraged to develop a context-specific process for decision-making that is supported by legislation, has stakeholder buy-in, for example the involvement of civil society organizations and patient groups, and is transparent, consistent and fair.Les analyses de rentabilité permettent de comparer les coûts et les résultats de différentes options politiques. Chaque ratio coût-efficacité qui en découle indique l'importance des avantages supplémentaires pour la santé par unité supplémentaire de ressources dépensée. Les seuils de rentabilité permettent de déterminer les ratios coût-efficacité qui représentent une bonne ou une très bonne rentabilité. En 2001, la Commission macroéconomie et santé de l'Organisation mondiale de la Santé a suggéré des seuils de rentabilité définis d'après des multiples du produit intérieur brut (PIB) par habitant d'un pays. Dans certains pays, ces seuils ont servi de règles pour décider quelles interventions financer ou non. Cependant, l'expérience d'utilisation de ces seuils fondés sur le PIB dans les processus décisionnels des pays montre qu'ils ne tiennent pas compte des spécificités des pays; cela, ajouté à une certaine incertitude concernant la modélisation des ratios coût-efficacité, peut entraîner la prise de mauvaises décisions quant à l'utilisation des ressources sanitaires. Les informations sur la rentabilité des interventions devraient être prises en compte parallèlement à d'autres considérations, comme l'impact budgétaire et la faisabilité, dans le cadre d'un processus décisionnel transparent et non de façon isolée sur la base d'une seule valeur seuil. Bien que le caractère informatif des ratios coût-efficacité soit indéniable lorsqu'il s'agit d'évaluer la rentabilité des interventions, les pays devraient être encouragés à développer un processus de prise de décision spécifique au contexte, qui soit encadré par la législation et qui ait l'adhésion des parties intéressées, avec par exemple l'implication d'organisations de la société civile et de groupes de patients, et qui soit transparent, cohérent et équitable.El análisis de rentabilidad se utiliza para comparar los costes y resultados de opciones políticas alternativas. Cada relación de rentabilidad resultante representa la magnitud de sanidad adicional obtenida por unidad adicional de recursos utilizados. Los umbrales de rentabilidad permiten la identificación de las relaciones de rentabilidad que representan un valor bueno o muy bueno del capital. En 2001, los umbrales de rentabilidad propuestos por la Comisión sobre Macroeconomía y Salud de la Organización Mundial de la Salud se basaron en múltiplos del producto interior bruto (PIB) per cápita de un país. En algunos contextos, se han utilizado estos umbrales para decidir qué intervenciones sanitarias financiar y cuáles no. No obstante, la experiencia con el uso de dichos umbrales basados en el PIB en los procesos de toma de decisiones a nivel nacional muestra la ausencia de especificidad según el país. Esto, además de la incertidumbre de las relaciones de rentabilidad modelo, puede dar lugar a una toma de decisiones equivocada sobre cómo emplear los recursos sanitarios. La información relativa a la rentabilidad debería utilizarse teniendo en cuenta otros factores (por ejemplo, el impacto presupuestario y aspectos de viabilidad) en un proceso transparente de toma de decisiones, en lugar de únicamente teniendo como referencia un solo valor del umbral. A pesar de que las relaciones de rentabilidad son indudablemente esclarecedoras a la hora de evaluar el valor del capital, es necesario fomentar que los países desarrollen un proceso específico del contexto apoyado por la legislación para tomar decisiones, como, por ejemplo, si las partes interesadas han aceptado la implicación de las organizaciones de la sociedad civil y grupos de pacientes y si es transparente, coherente y justa.تُستخدم تحاليل فعالية التكلفة للمقارنة بين التكاليف والحصائل الناتجة عن خيارات السياسات البديلة. تمثل كل نسبة من نسب فعالية التكلفة الناتجة حجم المستوى الصحي الإضافي المكتسب من استهلاك وحدة إضافية من الموارد. وتتيح القيم الحدية لفعالية التكلفة تحديد نسب فعالية التكلفة التي تمثل قيمة جيدة أو قيمة جيدة جدًا مقابل المال. وكانت اللجنة التابعة لمنظمة الصحة العالمية والمعنية بالاقتصاد الكلي في مجال الصحة قد اقترحت في عام 2001 إنشاء قيم حدية لفعالية التكلفة بناءً على مضاعفات نصيب الفرد من إجمالي الناتج المحلي (GDP) في البلاد. وفي بعض الظروف، تم استخدام هذه القيم الحدية باعتبارها قواعد لاتخاذ القرار باختيار أي التدخلات الصحية ينبغي تمويلها أو عدم تمويلها. إلا أن واقع تجربة استخدام هذه القيم الحدية المستندة إلى إجمالي الناتج المحلي في عمليات اتخاذ القرار على المستوى القطري يبين أنها تفتقر إلى التخصصية في البلدان. هذا بالإضافة إلى عدم اليقين بنسب فعالية التكلفة النموذجية يمكن أن يؤدي إلى اتخاذ قرار خاطئ بشأن طريقة استهلاك موارد الرعاية الصحية. ينبغي استخدام المعلومات المتعلقة بفعالية التكلفة، إلى جانب اعتبارات أخرى، على سبيل المثال اعتبارات تأثير الميزانية ومدى الجدوى في عملية اتخاذ قرارات تتسم بالشفافية عوضًا عن اتخاذ قرارات منعزلة مستندة إلى قيمة حدية فردية. على الرغم من أن نسب فعالية التكلفة مفيدة بلا شك في تقدير القيمة مقابل المال، ينبغي تشجيع البلدان على إعداد عمليات متناسبة مع الظروف لاتخاذ القرارات المدعومة بالتشريعات، في حال قررت الجهات المعنية، على سبيل المثال إشراك منظمات المجتمع المدني ومجموعات المرضى، وتتسم هذه القرارات بأنها شفافة ومتسقة ونزيهة.成本效益分析用于比较备选政策选项的成本及效果。 每个生成的成本效益比代表着每增加一个单位的资源投入所获得的额外健康收益的数量。 成本效益阈值确定代表物有所值或物超所值的成本效益比。 2001 年,世界卫生组织宏观经济与卫生健康委员会提出基于国家人均国内生产总值 (GDP) 倍数的成本效益阈值。 某些情况下,在选择资助和不资助哪些健康干预项目方面,这些阈值已被用作决策规则。 然而,在将这种基于 GDP 的阈值用于国家级决策过程中的经验中,显示出这些阈值缺乏国家针对性,并且——除了实现模型成本效益比的不确定性之外——这将可能导致在如何使用卫生保健资源上做出错误决策。 成本效益信息应与其他因素——如:预算影响和可行性因素——一起用于透明的决策过程当中,而不是孤立地基于一个单阈值。 尽管成本效益比在评估性价比方面无疑提供了有用信息,但应鼓励各国建立受法律支持、利益相关者认可(如:民间社会组织与患者群体的参与)、透明、一致且公正的基于具体国情的决策制定过程。.Анализ экономической эффективности применяется для сравнения затрат и результатов различных вариантов одной и той же стратегии. Во всех случаях соотношение затрат и эффективности дает представление о том, как будет происходить улучшение здоровья на единицу затраченных ресурсов. Пороговое значение экономической эффективности позволяет выявить такое соотношение затрат и эффективности, которое отвечает получению хороших или очень хороших результатов относительно затраченных средств. В 2001 году комиссия Всемирной организации здравоохранения по макроэкономике в здравоохранении порекомендовала пороговые значения экономической эффективности, основанные на параметрах валового внутреннего продукта на душу населения (ВВП) стран. В некоторых ситуациях эти пороговые значения использовались для принятия решения о том, какие меры по здравоохранению будут получать финансирование, а какие — нет. Однако опыт применения пороговых значений, основанных на величине ВВП стран, показал, что при этом не учитывается их специфика, и это в сочетании с неопределенностью в описании моделируемых затрат может способствовать принятию неверных решений о распределении средств на охрану здоровья. Информацию об экономической эффективности следует использовать с учетом других факторов, например влияния на бюджет и возможности осуществления, при этом процесс принятия решений должен быть прозрачным и выполняться не только на основе одного порогового показателя. Хотя соотношение затрат и эффективности, без сомнения, позволяет определенным образом оценить пользу от затраченных средств, следует поощрять страны на развитие прозрачным, честным и единообразным способом, учитывая их собственную ситуацию при разработке процесса принятия решений, который поддерживается законодательством и имеет заинтересованных акционеров, например гражданских ассоциаций или групп пациентов.

BACKGROUND: The replication-competent recombinant vesicular stomatitis virus (rVSV)-based vaccine expressing a Zaire ebolavirus (ZEBOV) glycoprotein was selected for rapid safety and immunogenicity testing before its use in West Africa. METHODS: We performed three open-label, dose-escalation phase 1 trials and one randomized, double-blind, controlled phase 1 trial to assess the safety, side-effect profile, and immunogenicity of rVSV-ZEBOV at various doses in 158 healthy adults in Europe and Africa. All participants were injected with doses of vaccine ranging from 300,000 to 50 million plaque-forming units (PFU) or placebo. RESULTS: No serious vaccine-related adverse events were reported. Mild-to-moderate early-onset reactogenicity was frequent but transient (median, 1 day). Fever was observed in up to 30% of vaccinees. Vaccine viremia was detected within 3 days in 123 of the 130 participants (95%) receiving 3 million PFU or more; rVSV was not detected in saliva or urine. In the second week after injection, arthritis affecting one to four joints developed in 11 of 51 participants (22%) in Geneva, with pain lasting a median of 8 days (interquartile range, 4 to 87); 2 self-limited cases occurred in 60 participants (3%) in Hamburg, Germany, and Kilifi, Kenya. The virus was identified in one synovial-fluid aspirate and in skin vesicles of 2 other vaccinees, showing peripheral viral replication in the second week after immunization. ZEBOV-glycoprotein-specific antibody responses were detected in all the participants, with similar glycoprotein-binding antibody titers but significantly higher neutralizing antibody titers at higher doses. Glycoprotein-binding antibody titers were sustained through 180 days in all participants. CONCLUSIONS: In these studies, rVSV-ZEBOV was reactogenic but immunogenic after a single dose and warrants further evaluation for safety and efficacy. (Funded by the Wellcome Trust and others; ClinicalTrials.gov numbers, NCT02283099, NCT02287480, and NCT02296983; Pan African Clinical Trials Registry number, PACTR201411000919191.).

The 2030 agenda for sustainable development is an opportunity for governments and the international community to renew their commitment to improving health as a central component of development. (1) The accompanying 17 sustainable development goals (SDGs) define the priority areas of action. (2) Goal 3 (to ensure healthy lives and promote wellbeing for all at all ages), with Target 3.8 on universal health coverage (UHC), emphasize the importance of all people and communities having access to quality health services without risking financial hardship. (2) These health services include those targeting individuals, such as curative care and population-based services, such as health promotion. (3) Achieving UHC is an important objective for all countries to attain equitable and sustainable health outcomes and improve the well-being of individuals and communities. (4,5) Health system strengthening is a means to progress towards UHC. A functioning health system is organized around the people, institutions and resources that are mandated to improve, maintain or restore the health of a given population. Health system strengthening refers to significant and purposeful effort to improve the system's performance. (6) Strengthening is one way to ensure that the system's performance embodies the intermediary objectives of most national health policies, plans and strategies--quality, equity, efficiency, accountability, resilience and sustainability (Box 1). We argue that UHC contributes to the SDGs in several ways. The impact of health system strengthening on UHC, and how health system strengthening, through UHC, contributes to different sustainable development goals is illustrated in Fig. 1. One way UHC contributes to the SDGs is by promoting global public health security and it does so by increasing the resilience of health systems to respond to health threats that spread within as well as across national borders. (6,11) The 2012 Middle East Respiratory Syndrome coronavirus, the 2013-2016 Ebola virus disease and 2015 Zika virus outbreaks prompted the international community of the financial aftermath many countries faced as a result of protracted health emergencies. The impact of humanitarian and natural disasters is exacerbated by weak health systems. (12) These recent outbreaks showed that resilience is an important feature of a health system and its effect on health workers' ability to adapt and effectively address complex challenges when responding to emergencies. Resilience should be envisaged as a critical objective of contemporary health system reforms. (13) When compared to resources spent on emergency responses, it is cost-efficient and in the long-term sustainable to invest in building resilient and functioning health systems. We claim that progress towards UHC will be essential to four specific SDG goals and the pledge to leave no one behind. First, as adults in poor health are more likely to be unemployed, when investments are made in improving health outcomes for the entire population, this can also contribute to SDG 1 (end poverty in all its forms everywhere). In addition, implementation of social protection systems to address out-of-pocket health expenditure reduces the incidence of catastrophic or impoverishing household health spending. Second, given that children anckadolescents with good health have better educational outcomes, health has an important role to play in advancing SDG 4 (ensure inclusive and equitable education and promote lifelong learning opportunities for all). Third, as women comprise over 75% of the health workforce in many countries, (14) the health system can contribute to advancing SDG 5 (achieve gender equality and empower all women and girls). Fourth, through the development of health systems that create fair, trustworthy and responsive social institutions, health system strengthening directly contributes to SDG 16 (promote inclusive societies for sustainable development, provide access to justice for all and build effective, accountable and inclusive institutions for all). …

Multilingual abstracts in the five official working languages of the United Nations. (PDF 344 kb)

The World Health Organization R&D Blueprint aims to accelerate the availability of medical technologies during epidemics by focusing on a list of prioritized emerging diseases for which medical countermeasures are insufficient or nonexistent. The prioritization process has 3 components: a Delphi process to narrow down a list of potential priority diseases, a multicriteria decision analysis to rank the short list of diseases, and a final Delphi round to arrive at a final list of 10 diseases. A group of international experts applied this process in January 2017, resulting in a list of 10 priority diseases. The robustness of the list was tested by performing a sensitivity analysis. The new process corrected major shortcomings in the pre-R&D Blueprint approach to disease prioritization and increased confidence in the results.

Background and aimThe majority of seasonal influenza vaccines are trivalent, containing two A virus strains (H1N1 and H3N2) and one B virus strain. The co-circulation of two distinct lineages of B viruses can lead to mismatch between the influenza B virus strain recommended for the trivalent seasonal vaccine and the circulating B virus. This has led some manufacturers to produce quadrivalent influenza vaccines containing one strain from each B lineage in addition to H1N1 and H3N2 strains. However, it is also important to know whether vaccines containing a single influenza B strain can provide cross-protectivity against viruses of the antigenically distinct lineage. The aim of this study was to assess in naïve ferrets the potential cross-protective activity of trivalent live attenuated influenza vaccine (T-LAIV) against challenge with a heterologous wild-type influenza B virus belonging to the genetically different lineage and to compare this activity with effectiveness of quadrivalent LAIV (Q-LAIV) in the ferret model.Methods and resultsFerrets were vaccinated with either one dose of trivalent LAIV containing B/Victoria or B/Yamagata lineage virus, or quadrivalent LAIV (containing both B lineages), or placebo. They were then challenged with B/Victoria or B/Yamagata lineage wild-type virus 28 days after vaccination. The ferrets were monitored for clinical signs and morbidity. Nasal swabs and lung tissue samples were analyzed for the presence of challenge virus. Antibody response to vaccination was assessed by routine hemagglutination inhibition assay. All LAIVs tested were found to be safe and effective against wild-type influenza B viruses based on clinical signs, and virological and histological data. The absence of interference between vaccine strains in trivalent and quadrivalent vaccine formulations was confirmed. Trivalent LAIVs were shown to have the potential to be cross-protective against infection with genetically different influenza B/Victoria and B/Yamagata lineages.ConclusionsIn this ferret model, quadrivalent vaccine provided higher protection to challenge against both B/Victoria and B/Yamagata lineage viruses. However, T-LAIV provided some cross-protection in the case of a mismatch between circulating and vaccine type B strains. Notably, B/Victoria-based T-LAIV was more protective compared to B/Yamagata-based T-LAIV.

Summary Background H7N9 avian influenza viruses characterised by high virulence and presence of mammalian adaptation markers have pandemic potential. Specific influenza vaccines remain the main defence. We assessed the safety and immunogenicity of an H7N9 live attenuated influenza vaccine (LAIV) candidate in healthy adult volunteers. Methods We did a phase 1, double-blind, randomised, placebo-controlled trial in Saint Petersburg, Russia. Eligible participants were healthy adults aged 18–49 years. The participants were randomised 3:1 to receive live vaccine or placebo, according to a computer-generated randomisation scheme. Two doses of vaccine or placebo were administered intranasally 28 days apart, each followed by 7 day stays in hospital. Immune responses were assessed in nasal swabs, saliva, and serum specimens collected before and 28 days after each vaccine dose. The primary outcome was the safety profile. This trial is registered with ClinicalTrials.gov, number NCT02480101. Findings Between Oct 21, 2014, and Oct 31, 2014, 40 adults were randomised, of whom 39 (98%) were included in the per-protocol analysis (29 in the vaccine group and ten in the placebo group). The frequency of adverse events did not differ between the vaccine and placebo groups. Seroconversion of neutralising antibodies was seen in 14 participants after the first vaccine dose (48%, 95% CI 29·4–67·5) and 21 after the second vaccine dose (72%, 52·8–87·3). Immune responses were seen in 27 of 29 recipients (93%, 95% CI 77·2–99·2). Adverse effects were seen in 19 (63%) vaccine recipients and nine (90%) placebo recipients after the first dose and in nine (31%) and four (40%), respectively, after the second dose. These effects were mainly local and all were mild. Interpretation The H7N9 LAIV was well tolerated and safe and showed good immunogenicity. Funding WHO.

Governments in low- and middle-income countries are legitimizing the implementation of universal health coverage (UHC), following a United Nation's resolution on UHC in 2012 and its reinforcement in the sustainable development goals set in 2015. UHC will differ in each country depending on country contexts and needs, as well as demand and supply in health care. Therefore, fundamental issues such as objectives, users and cost-effectiveness of UHC have been raised by policy-makers and stakeholders. While priority-setting is done on a daily basis by health authorities - implicitly or explicitly - it has not been made clear how priority-setting for UHC should be conducted. We provide justification for explicit health priority-setting and guidance to countries on how to set priorities for UHC.Les gouvernements des pays à revenu faible et intermédiaire sont en train de légitimer la mise en place de la couverture sanitaire universelle (CSU), suite à une résolution des Nations Unies de 2012 sur la CSU et à son entérinement dans les objectifs de développement durable fixés en 2015. La CSU variera selon les pays, en fonction de leur contexte et de leurs besoins, ainsi qu'en fonction de la demande et de l'offre de soins. Des questions fondamentales ont ainsi été soulevées par les responsables politiques et les parties prenantes, portant notamment sur les objectifs, les utilisateurs et le rapport coût-efficacité de la CSU. Si les autorités sanitaires déterminent quotidiennement des priorités, de façon implicite ou explicite, la marche à suivre pour définir les priorités en matière de CSU n'a pas été clairement établie. Nous justifions ici la nécessité de définir explicitement les priorités dans le domaine de la santé tout en donnant des orientations aux pays pour définir les priorités en matière de CSU.Los gobiernos de países con ingresos bajos y medios están legitimando la implementación de una cobertura sanitaria universal (CSU) tras un acuerdo de las Naciones Unidas acerca de la cobertura sanitaria universal en 2012 y su consolidación en los objetivos de desarrollo sostenible establecidos en 2015. Cada país tendrá una cobertura sanitaria universal distinta, según el contexto y las necesidades de cada uno, así como la oferta y la demanda de atención sanitaria. Por tanto, los responsables políticos y partes interesadas han abordado los asuntos fundamentales como los objetivos, los usuarios y la rentabilidad de la cobertura sanitaria universal. A pesar de que las autoridades sanitarias han establecido prioridades diarias (de forma implícita o explícita), no se ha aclarado cómo se debería gestionar el establecimiento de prioridades para la cobertura sanitaria universal. Se ofrece una justificación para el establecimiento de prioridades sanitarias explícitas y orientación a los países en la definición de prioridades para la cobertura sanitaria universal.تتولى الحكومات في الدول الأعلى دخلاً ومتوسطة الدخل سنّ تشريعات لتنفيذ التغطية الصحية الشاملة (UHC)، التزامًا منها بقرار الأمم المتحدة بشأن التغطية الصحية الشاملة الصادر في عام 2012 واستجابةً للتحفيز عليها الوارد في أهداف التنمية المستدامة التي تم وضعها في عام 2015. وستختلف التغطية الصحية الشاملة في كل دولة طبقًا لظروفها واحتياجاتها، وطبقًا لظروف العرض والطلب في مجال الرعاية الصحية. وبناءً على ذلك، طرح مقررو السياسات والجهات المعنية بعض القضايا الأساسية مثل أهداف التغطية الصحية الشاملة، والمستفيدون منها، وفاعليتها من حيث التكلفة. وبرغم التزام الجهات المسؤولة عن الناحية الصحية بتحديد الأولويات على أساس يومي، لم تتضح – سواء ضمنيًا أو صراحةً – الكيفية التي يجب من خلالها تنفيذ إجراءات تحديد الأولويات فيما يتعلق بالتغطية الصحية الشاملة. ونحن نقدم للدول المبررات اللازمة لتحديد الأولويات الصحية صراحةً، كما نقدم لها إرشادات بشأن كيفية تحديد الأولويات فيما يتعلق بالتغطية الصحية الشاملة.依据联合国 2012 年就全民医疗保险 (UHC) 提出的议案以及实施 2015 年设立的可持续发展目标，中低收入国家政府批准实施全民医疗保险 (UHC)。由于各国国情和需求，以及医疗保健的供求不同，因此 UHC 也将有所区别。因此，决策者和利益相关者提出 UHC 的目标、用户和成本效益等基本问题。尽管卫生局每日间接或直接设立优先事项，但如何确立 UHC 的优先事项仍不清楚。我们就如何确立 UHC 的优先事项，向各国政府提供明显的医疗优先事项事实和指南。.Правительства стран с низким и средним уровнями доходов узаконивают реализацию всеобщего охвата медико-санитарной помощью в соответствии с резолюцией ООН по этому вопросу, принятой в 2012 году, и с целями устойчивого развития, определенными в 2015 году, в которых она была закреплена. Прогресс в достижении всеобщего охвата медико-санитарной помощью различается в зависимости от особенностей и потребностей страны, а также от спроса и предложения в секторе здравоохранения. Поэтому лица, определяющие политику, и заинтересованные лица задаются основополагающими вопросами о целях, потребителях и экономической эффективности всеобщего охвата медико-санитарной помощью. Хотя расстановка приоритетов в явной или неявной форме осуществляется органами здравоохранения ежедневно, до сих пор не было ясно, каким образом следует определять приоритеты для достижения всеобщего охвата медико-санитарной помощью. В данной статье обосновывается целесообразность открытого определения приоритетов в области здравоохранения и приводится руководство для стран по расстановке приоритетов для достижения всеобщего охвата медико-санитарной помощью.

The Meningitis Vaccine Project (MVP), a partnership between PATH and the World Health Organization (WHO), was created in 2001 through core funding from the Bill & Melinda Gates Foundation to eliminate epidemic meningitis as a public health problem in sub-Saharan Africa through the development, testing, introduction, and widespread use of conjugate meningococcal vaccines. This project was created in response to repeated and severe group A meningococcal (MenA) meningitis epidemics in sub-Saharan Africa during the 1990s, and the potential offered by new meningococcal conjugate vaccines to prevent such epidemics. African public health leaders issued a call for action as meningitis rapidly became a public health priority given the high case fatality rates, high attack rates among young adults at the peak of their economic contributions, and the incapacitating sequelae seen in 10%–20% of survivors. Vaccination campaigns with a meningococcal C conjugate vaccine in the United Kingdom in 1999 had demonstrated that conjugate vaccines conferred herd protection within a targeted population once sufficient numbers had been vaccinated [1]. This experience demonstrated the possibility of preventing—and perhaps eliminating—MenA meningitis epidemics in the African “meningitis belt” through the development and widespread use of a MenA conjugate (PsA-TT) vaccine. Because a monovalent MenA conjugate vaccine would have limited commercial interest outside of Africa, public-sector support for vaccine development, clinical evaluation, and pilot introduction was provided through the creation of MVP [2]. Conjugate meningococcal vaccine development for Africa was initially envisaged as a partnership between MVP and a multinational “big pharma” company to produce a bivalent group A/C conjugate vaccine. In this scenario, a small MVP team at WHO and PATH would focus on managing this partnership while working to improve meningitis surveillance in Africa and planning for the vaccine's introduction in meningitis belt countries (Benin, Burkina Faso, Burundi, Cameroon, Central African Republic, Chad, Cote D'Ivoire, Democratic Republic of Congo, Ethiopia, Erithrea, Ghana, Guinea, Guinea Bissau, Kenya, Mali, Mauritania, Niger, Nigeria, Rwanda, Senegal, South Sudan, Tanzania, The Gambia, Togo, Uganda). Yet, 18 months after the project's starting date, MVP had evolved into a “virtual company” managing a new model for public sector vaccine development that linked a network of partners with unique roles and responsibilities, and sought to transfer technology and know-how for all aspects of meningococcal conjugate vaccine production to a developing country vaccine manufacturer. This article describes the maturation of MVP's vaccine development strategy, and the project structure, guiding principles, and values that ultimately led to the introduction of a safe, highly effective, and affordable MenA conjugate vaccine for sub-Saharan Africa.

Summary Background A recombinant, replication-competent vesicular stomatitis virus-based vaccine expressing a surface glycoprotein of Zaire Ebolavirus (rVSV-ZEBOV) is a promising Ebola vaccine candidate. We report the results of an interim analysis of a trial of rVSV-ZEBOV in Guinea, west Africa. Methods For this open-label, cluster-randomised ring vaccination trial, suspected cases of Ebola virus disease in Basse-Guinee (Guinea, west Africa) were independently ascertained by Ebola response teams as part of a national surveillance system. After laboratory confirmation of a new case, clusters of all contacts and contacts of contacts were defined and randomly allocated 1:1 to immediate vaccination or delayed (21 days later) vaccination with rVSV-ZEBOV (one dose of 2 × 10 7 plaque-forming units, administered intramuscularly in the deltoid muscle). Adults (age ≥18 years) who were not pregnant or breastfeeding were eligible for vaccination. Block randomisation was used, with randomly varying blocks, stratified by location (urban vs rural) and size of rings (≤20 vs >20 individuals). The study is open label and masking of participants and field teams to the time of vaccination is not possible, but Ebola response teams and laboratory workers were unaware of allocation to immediate or delayed vaccination. Taking into account the incubation period of the virus of about 10 days, the prespecified primary outcome was laboratory-confirmed Ebola virus disease with onset of symptoms at least 10 days after randomisation. The primary analysis was per protocol and compared the incidence of Ebola virus disease in eligible and vaccinated individuals in immediate vaccination clusters with the incidence in eligible individuals in delayed vaccination clusters. This trial is registered with the Pan African Clinical Trials Registry, number PACTR201503001057193. Findings Between April 1, 2015, and July 20, 2015, 90 clusters, with a total population of 7651 people were included in the planned interim analysis. 48 of these clusters (4123 people) were randomly assigned to immediate vaccination with rVSV-ZEBOV, and 42 clusters (3528 people) were randomly assigned to delayed vaccination with rVSV-ZEBOV. In the immediate vaccination group, there were no cases of Ebola virus disease with symptom onset at least 10 days after randomisation, whereas in the delayed vaccination group there were 16 cases of Ebola virus disease from seven clusters, showing a vaccine efficacy of 100% (95% CI 74·7–100·0; p=0·0036). No new cases of Ebola virus disease were diagnosed in vaccinees from the immediate or delayed groups from 6 days post-vaccination. At the cluster level, with the inclusion of all eligible adults, vaccine effectiveness was 75·1% (95% CI −7·1 to 94·2; p=0·1791), and 76·3% (95% CI −15·5 to 95·1; p=0·3351) with the inclusion of everyone (eligible or not eligible for vaccination). 43 serious adverse events were reported; one serious adverse event was judged to be causally related to vaccination (a febrile episode in a vaccinated participant, which resolved without sequelae). Assessment of serious adverse events is ongoing. Interpretation The results of this interim analysis indicate that rVSV-ZEBOV might be highly efficacious and safe in preventing Ebola virus disease, and is most likely effective at the population level when delivered during an Ebola virus disease outbreak via a ring vaccination strategy. Funding WHO, with support from the Wellcome Trust (UK); Medecins Sans Frontieres; the Norwegian Ministry of Foreign Affairs through the Research Council of Norway; and the Canadian Government through the Public Health Agency of Canada, Canadian Institutes of Health Research, International Development Research Centre, and Department of Foreign Affairs, Trade and Development.

At a recent international meeting about the Zika epidemic, experts exchanged insights, identified knowledge gaps, and agreed on a plan for accelerating product development and evaluation in the hope of controlling the spread of the virus in Brazil and elsewhere.

Summary Background The spread of antibiotic-resistant bacteria poses a substantial threat to morbidity and mortality worldwide. Due to its large public health and societal implications, multidrug-resistant tuberculosis has been long regarded by WHO as a global priority for investment in new drugs. In 2016, WHO was requested by member states to create a priority list of other antibiotic-resistant bacteria to support research and development of effective drugs. Methods We used a multicriteria decision analysis method to prioritise antibiotic-resistant bacteria; this method involved the identification of relevant criteria to assess priority against which each antibiotic-resistant bacterium was rated. The final priority ranking of the antibiotic-resistant bacteria was established after a preference-based survey was used to obtain expert weighting of criteria. Findings We selected 20 bacterial species with 25 patterns of acquired resistance and ten criteria to assess priority: mortality, health-care burden, community burden, prevalence of resistance, 10-year trend of resistance, transmissibility, preventability in the community setting, preventability in the health-care setting, treatability, and pipeline. We stratified the priority list into three tiers (critical, high, and medium priority), using the 33rd percentile of the bacterium's total scores as the cutoff. Critical-priority bacteria included carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa , and carbapenem-resistant and third-generation cephalosporin-resistant Enterobacteriaceae. The highest ranked Gram-positive bacteria (high priority) were vancomycin-resistant Enterococcus faecium and meticillin-resistant Staphylococcus aureus . Of the bacteria typically responsible for community-acquired infections, clarithromycin-resistant Helicobacter pylori , and fluoroquinolone-resistant Campylobacter spp, Neisseria gonorrhoeae , and Salmonella typhi were included in the high-priority tier. Interpretation Future development strategies should focus on antibiotics that are active against multidrug-resistant tuberculosis and Gram-negative bacteria. The global strategy should include antibiotic-resistant bacteria responsible for community-acquired infections such as Salmonella spp, Campylobacter spp, N gonorrhoeae , and H pylori . Funding World Health Organization.

Background The rVSVΔG-ZEBOV-GP vaccine prevented Ebola virus disease when used at 2 × 107 plaque-forming units (PFU) in a trial in Guinea. This study provides further safety and immunogenicity data. Methods and findings A randomised, open-label phase I trial in Lambaréné, Gabon, studied 5 single intramuscular vaccine doses of 3 × 103, 3 × 104, 3 × 105, 3 × 106, or 2 × 107 PFU in 115 adults and a dose of 2 × 107 PFU in 20 adolescents and 20 children. The primary objective was safety and tolerability 28 days post-injection. Immunogenicity, viraemia, and shedding post-vaccination were evaluated as secondary objectives. In adults, mild-to-moderate adverse events were frequent, but there were no serious or severe adverse events related to vaccination. Before vaccination, Zaire Ebola virus (ZEBOV)–glycoprotein (GP)–specific and ZEBOV antibodies were detected in 11% and 27% of adults, respectively. In adults, 74%–100% of individuals who received a dose 3 × 104, 3 × 105, 3 × 106, or 2 × 107 PFU had a ≥4.0-fold increase in geometric mean titres (GMTs) of ZEBOV-GP-specific antibodies at day 28, reaching GMTs of 489 (95% CI: 264–908), 556 (95% CI: 280–1,101), 1,245 (95% CI: 899–1,724), and 1,503 (95% CI: 931–2,426), respectively. Twenty-two percent of adults had a ≥4-fold increase of ZEBOV antibodies, with GMTs at day 28 of 1,015 (647–1,591), 1,887 (1,154–3,085), 1,445 (1,013–2,062), and 3,958 (2,249–6,967) for the same doses, respectively. These antibodies persisted up to day 180 for doses ≥3 × 105 PFU. Adults with antibodies before vaccination had higher GMTs throughout. Neutralising antibodies were detected in more than 50% of participants at doses ≥3 × 105 PFU. As in adults, no serious or severe adverse events related to vaccine occurred in adolescents or children. At day 2, vaccine RNA titres were higher for adolescents and children than adults. At day 7, 78% of adolescents and 35% of children had recombinant vesicular stomatitis virus RNA detectable in saliva. The vaccine induced high GMTs of ZEBOV-GP-specific antibodies at day 28 in adolescents, 1,428 (95% CI: 1,025–1,989), and children, 1,620 (95% CI: 806–3,259), and in both groups antibody titres increased up to day 180. The absence of a control group, lack of stratification for baseline antibody status, and imbalances in male/female ratio are the main limitations of this study. Conclusions Our data confirm the acceptable safety and immunogenicity profile of the 2 × 107 PFU dose in adults and support consideration of lower doses for paediatric populations and those who request boosting. Trial registration Pan African Clinical Trials Registry PACTR201411000919191, Sanjeev Krishna and colleagues present a phase I randomised trial for safety and immunogenicity of an Ebola vaccine in both adults and children in Gabon., Author summary Why was this study done? The worst Ebola outbreak in history ended in 2016 after killing about 11,323 individuals and infecting 28,650 individuals worldwide. This public health emergency accelerated efforts to develop a vaccine as part of the strategy to contain the outbreak. Two vaccine candidates with preclinical safety and efficacy data obtained from non-human primates entered human trials. The one used in our study is the rVSVΔG-ZEBOV-GP vaccine, containing a non-infectious portion of a gene from the Zaire Ebola virus introduced into a recombinant vesicular stomatitis virus (rVSV), which itself is unlikely to cause disease in humans. To generate data for deployment of the vaccine, several dose-ranging phase I trials were initiated across centres in the United States, Europe, and Africa. What did the researchers do and find? We allocated 115 adults aged 18–50 years to receive 1 of the 5 doses used in the trial. A single intramuscular dose ranging from 3 × 103 to 2 × 107 plaque-forming units (PFU) was given, and participants were followed up until 6 months post-injection for safety and immunogenicity. Preliminary results led to the selection of the 2 × 107 PFU dose for further development. We also included 20 adolescents (13–17 years) and 20 children (6–12 years), who received the 2 × 107 PFU dose and were followed-up in a similar way as the adults. No vaccine-related serious or severe adverse event was reported by any participant. A high proportion of our population—even though residing in an area with no history of Ebola outbreak—had pre-vaccination antibodies specific to the Zaire Ebola virus. In adults, antibodies persisted up to 6 months post-injection at doses of 3 × 105 to 2 × 107 PFU. In participants with baseline antibodies, a dose as low as 3 × 104 PFU could induce high antibody titres up to day 56 post-injection. Higher vaccine replication, leading to shedding of the vaccine in saliva and urine, occurred in children and adolescents. What do these findings mean? Our results and other findings show that this vaccine is safe and immunogenic. Lower vaccine doses may be needed in paediatric populations as well as for boosting after primary vaccination or naturally acquired immunity.

It is 20 years since an international consultation in Lejondal, Sweden, highlighted the need for more and better research "to understand and improve how societies organize themselves in achieving collective health goals, and how different actors interact in the policy and implementation processes to contribute to policy outcomes." (1) One outcome was the creation of the Alliance for Health Policy and Systems Research. (1) There have since been several important milestones on the path towards more and better health systems research. The Alliance for Health Policy and Systems Research found its home at the World Health Organization (WHO) in 1998 and subsequently issued a series of reports on health systems. (2,3) Health systems research entered the mainstream of global health policy--not only at WHO (4) and the World Bank, (5) but also with the founding of Gavi, the Vaccine Alliance, in 2000, (6) and the Global Fund to Fight AIDS, Tuberculosis and Malaria in 2002." Ministerial meetings on health research, in 2004 and 2008, (7) increased the demand for--and the national priority given to--such research. In 2010, a biennial global symposium on health systems research was initiated and this development led to the first global society of health systems researchers: Health Systems Global. More recent efforts in low- and middle-income countries--e.g. the establishment of a knowledge platform in India (8)--are indicative of a shift towards systems thinking at national level. Such encouraging developments need to be carefully balanced against areas where progress has not met expectations. The development of national capacity for financing and institutional leadership of health policy and systems research has been slow. (9) Such research also remains constrained by several common challenges--e.g. the complexity of health systems, the context specificity of research findings and the large numbers of disciplines and epistemological perspectives involved. (10) Looking forward, however, we see a brighter future for health policy and systems research. Sustainable development goal (SDG) 3--particularly its target of universal health coverage--has promoted the establishment of common performance metrics against which the relative effectiveness of alternative policies and programmes can be compared. There is a growing global interdependence in health--as reflected by infectious diseases such as the Ebola virus that requires systems' knowledge and public health investments in global readiness. The rapid growth seen in the health sector is raising systems-wide demand for knowledge and innovation to improve value for money and overcome inefficiencies related to high prices, lack of equity and poor quality. Finally, the paradigm shift towards patients being recognized as the co-designers and co-creators of their own health and health care is raising the demand for evidence that would make it possible to navigate the promises and perils of accountable care, personalized medicine and big data. How can health policy and systems research seize this favourable context and contribute more effectively to universal health coverage, greater health security, improved value in health and effective engagement of citizens? First, we need a comprehensive review of the progress that has been made and the progress that might be anticipated in the future. Second, we need to accelerate the development of capacity and opportunity for health policy and systems research in low- and middle-income countries. …

In 1960, Alphonse Chapanis, turned his attention from engineering to health care. In a study of medication-related errors in a 1100-bed hospital,1 he and his colleague identified seven sources of such errors potentially leading to harm to a patient: medicine omitted, or given to the wrong patient, at the wrong dose, as an unintended extra dose, by the wrong route, at the wrong time, or as the wrong drug entirely. Almost 60 years later, these same types of errors still happen worldwide. Later that year in a follow-up policy paper,2 Chapanis identified four areas of recommendations that could prevent harm and remain relevant today: written communication, medication procedures, the working environment, training, and education.

Summary Background rVSV-ZEBOV is a recombinant, replication competent vesicular stomatitis virus-based candidate vaccine expressing a surface glycoprotein of Zaire Ebolavirus. We tested the effect of rVSV-ZEBOV in preventing Ebola virus disease in contacts and contacts of contacts of recently confirmed cases in Guinea, west Africa. Methods We did an open-label, cluster-randomised ring vaccination trial (Ebola ca Suffit!) in the communities of Conakry and eight surrounding prefectures in the Basse-Guinee region of Guinea, and in Tomkolili and Bombali in Sierra Leone. We assessed the efficacy of a single intramuscular dose of rVSV-ZEBOV (2×10 7 plaque-forming units administered in the deltoid muscle) in the prevention of laboratory confirmed Ebola virus disease. After confirmation of a case of Ebola virus disease, we definitively enumerated on a list a ring (cluster) of all their contacts and contacts of contacts including named contacts and contacts of contacts who were absent at the time of the trial team visit. The list was archived, then we randomly assigned clusters (1:1) to either immediate vaccination or delayed vaccination (21 days later) of all eligible individuals (eg, those aged ≥18 years and not pregnant, breastfeeding, or severely ill). An independent statistician generated the assignment sequence using block randomisation with randomly varying blocks, stratified by location (urban vs rural) and size of rings (≤20 individuals vs >20 individuals). Ebola response teams and laboratory workers were unaware of assignments. After a recommendation by an independent data and safety monitoring board, randomisation was stopped and immediate vaccination was also offered to children aged 6–17 years and all identified rings. The prespecified primary outcome was a laboratory confirmed case of Ebola virus disease with onset 10 days or more from randomisation. The primary analysis compared the incidence of Ebola virus disease in eligible and vaccinated individuals assigned to immediate vaccination versus eligible contacts and contacts of contacts assigned to delayed vaccination. This trial is registered with the Pan African Clinical Trials Registry, number PACTR201503001057193. Findings In the randomised part of the trial we identified 4539 contacts and contacts of contacts in 51 clusters randomly assigned to immediate vaccination (of whom 3232 were eligible, 2151 consented, and 2119 were immediately vaccinated) and 4557 contacts and contacts of contacts in 47 clusters randomly assigned to delayed vaccination (of whom 3096 were eligible, 2539 consented, and 2041 were vaccinated 21 days after randomisation). No cases of Ebola virus disease occurred 10 days or more after randomisation among randomly assigned contacts and contacts of contacts vaccinated in immediate clusters versus 16 cases (7 clusters affected) among all eligible individuals in delayed clusters. Vaccine efficacy was 100% (95% CI 68·9–100·0, p=0·0045), and the calculated intraclass correlation coefficient was 0·035. Additionally, we defined 19 non-randomised clusters in which we enumerated 2745 contacts and contacts of contacts, 2006 of whom were eligible and 1677 were immediately vaccinated, including 194 children. The evidence from all 117 clusters showed that no cases of Ebola virus disease occurred 10 days or more after randomisation among all immediately vaccinated contacts and contacts of contacts versus 23 cases (11 clusters affected) among all eligible contacts and contacts of contacts in delayed plus all eligible contacts and contacts of contacts never vaccinated in immediate clusters. The estimated vaccine efficacy here was 100% (95% CI 79·3–100·0, p=0·0033). 52% of contacts and contacts of contacts assigned to immediate vaccination and in non-randomised clusters received the vaccine immediately; vaccination protected both vaccinated and unvaccinated people in those clusters. 5837 individuals in total received the vaccine (5643 adults and 194 children), and all vaccinees were followed up for 84 days. 3149 (53·9%) of 5837 individuals reported at least one adverse event in the 14 days after vaccination; these were typically mild (87·5% of all 7211 adverse events). Headache (1832 [25·4%]), fatigue (1361 [18·9%]), and muscle pain (942 [13·1%]) were the most commonly reported adverse events in this period across all age groups. 80 serious adverse events were identified, of which two were judged to be related to vaccination (one febrile reaction and one anaphylaxis) and one possibly related (influenza-like illness); all three recovered without sequelae. Interpretation The results add weight to the interim assessment that rVSV-ZEBOV offers substantial protection against Ebola virus disease, with no cases among vaccinated individuals from day 10 after vaccination in both randomised and non-randomised clusters. Funding WHO, UK Wellcome Trust, the UK Government through the Department of International Development, Medecins Sans Frontieres, Norwegian Ministry of Foreign Affairs (through the Research Council of Norway's GLOBVAC programme), and the Canadian Government (through the Public Health Agency of Canada, Canadian Institutes of Health Research, International Development Research Centre and Department of Foreign Affairs, Trade and Development).

The effectiveness of vaccines to mitigate the impact of annual seasonal influenza epidemics and influenza pandemics has been well documented. However, the steady increase in global capacity to produce annual seasonal influenza vaccine has not been matched with increased demand, and thus actual vaccine production. Currently, without a significant increase in demand for seasonal influenza vaccine, global capacity will be far from able to meet even the essential needs for a monovalent vaccine in the event of a severe influenza pandemic. Global commitment to the development of influenza vaccine production capacity was renewed at a consultation leading to the Second Global Action Plan on Influenza Vaccines (GAP) in July 2011. To monitor progress on the GAP, the World Health Organization has carried out periodic surveys of influenza vaccine manufacturers. This latest survey compares current maximum global capacity and actual production of seasonal influenza vaccine in 2011 with data from surveys carried out in 2009 and 2010; analyses global influenza production capacity in the context of sustainability; and discusses options to increase demand, based on strong evidence of public health benefit.

The race to develop a vaccine against Zika began in February 2016, when the unusual clustering of cases of microcephaly and other neurological disorders associated with Zika virus infection led to the declaration of a public health emergency of international concern. When the World Health Organization held its first consultation in March, 14 active vaccine projects had already been announced.1 Today, WHO’s pipeline tracker counts about 30 active projects, pursued by developers from endemic and non-endemic countries, private and public sector.2