An mRNA technology transfer programme and economic sustainability in health care.

The World Health Organization (WHO) set up the messenger ribonucleic acid (mRNA) technology transfer programme in June 2021 with a development hub in South Africa and 15 partner vaccine producers in middle-income countries. The goal was to support the sustainable development of and access to life-saving vaccines for people in these countries as a means to enhance epidemic preparedness and global public health. This initiative aims to build resilience and strengthen local vaccine research, and development and manufacturing capacity in different regions of the world, especially those areas that could not access coronavirus disease 2019 (COVID-19) vaccines in a timely way. This paper outlines the current global vaccine market and summarizes the findings of a case study on the mRNA technology transfer programme conducted from November 2022 to May 2023. The study was guided by the vision of the WHO Council on the Economics of Health for All to build an economy for health using its four work streams of value, finance, innovation and capacity. Based on the findings of the study, we offer a mission-oriented policy framework to support the mRNA technology transfer programme as a pilot for transformative change towards an ecosystem for health innovation for the common good. Parts of this vision have already been incorporated into the governance of the mRNA technology transfer programme, while other aspects, especially the common good approach, still need to be applied to achieve the goals of the programme.

L'Organisation mondiale de la Santé (OMS) a lancé le Programme de transfert de la technologie de l'acide ribonucléique messager (ARNm) en juin 2021, assorti d'un centre de développement en Afrique du Sud et de 15 fabricants de vaccins partenaires dans des pays à revenu intermédiaire. L'objectif consistait à soutenir la pérennisation et l'accès à des vaccins d'importance vitale pour les populations de ces pays en vue d'améliorer la préparation aux épidémies et la santé publique mondiale. Cette initiative vise à accroître la résilience et à renforcer la recherche vaccinale locale, ainsi que les capacités de conception et de fabrication dans différentes régions du monde, en particulier dans celles qui n'ont pas pu obtenir des vaccins contre la maladie à coronavirus 2019 (COVID-19) en temps utile. Le présent document décrit l'actuel marché mondial des vaccins et résume les résultats d'une étude de cas consacrée au Programme de transfert de la technologie ARNm et menée de novembre 2022 à mai 2023. L'étude s'inspire de la vision du Conseil de l'OMS sur l'économie de la santé pour tous, qui consiste à construire une économie allant dans le sens de la santé selon quatre axes de travail: valeur, finances, innovation et capacité. En nous fondant sur les résultats de l'étude, nous proposons un cadre stratégique orienté vers un but précis: soutenir le Programme de transfert de la technologie ARNm en tant que projet pilote afin d'évoluer vers un écosystème d'innovation en matière de santé dédié au bien commun. Certains aspects de cette vision ont déjà été intégrés dans les principes de gouvernance du Programme de transfert de la technologie ARNm tandis que d'autres, en particulier l'approche liée au bien commun, doivent encore être appliqués pour atteindre les objectifs du programme.

La Organización Mundial de la Salud (OMS) creó el programa de transferencia de tecnología de ácido ribonucleico mensajero (ARNm) en junio de 2021 con un centro de desarrollo en Sudáfrica y 15 productores de vacunas asociados en países de ingresos medios. El objetivo era apoyar el desarrollo sostenible y el acceso a las vacunas que salvan vidas para la población de estos países como medio para mejorar la preparación ante epidemias y la salud pública mundial. Con esta iniciativa se pretende crear resiliencia y reforzar la capacidad local de investigación, desarrollo y fabricación de vacunas en distintas regiones del mundo, especialmente en aquellas áreas que no pudieron acceder oportunamente a las vacunas contra la enfermedad por coronavirus de 2019 (COVID-19). Este documento describe el actual mercado mundial de vacunas y resume las conclusiones de un estudio de caso sobre el programa de transferencia de tecnología de ARNm realizado entre noviembre de 2022 y mayo de 2023. El estudio se guió por la visión del Consejo de la OMS sobre la Economía de la Salud para Todos de crear una economía de la salud utilizando sus cuatro líneas de trabajo: valor, financiación, innovación y capacidad. A partir de las conclusiones del estudio, ofrecemos un marco político orientado a la misión para apoyar el programa de transferencia de tecnología de ARNm como piloto para un cambio transformador hacia un ecosistema de innovación sanitaria para el bien común. Algunas partes de esta visión ya se han incorporado a la gobernanza del programa de transferencia de tecnología de ARNm, mientras que otros aspectos, en especial el enfoque del bien común, aún deben aplicarse para alcanzar los objetivos del programa.

Global challenges in preparedness and response to epidemic infectious diseases.

Lessons drawn from successes and failures with coronavirus disease 2019 (COVID-19) and Ebola virus disease (EVD) should help shaping a robust health innovation system for infectious disease epidemics. Epidemic response research and development (R&D) can be mobilized quickly for public health priorities and yield medicinal products within months. However, to resolve epidemics, technological advances must be equitably accessible and deployed, and these examples expose the limitations of a supply-driven, fragmented R&D ecosystem relying primarily on the private sector to deliver health products. Efficient epidemic response requires a coordinated public health-focused, end-to-end R&D ecosystem for the development, registration, availability, and use of pharmaceutical products. Because pivotal clinical trials can only be conducted during outbreaks, significant preparation must be done beforehand: strengthening clinical research capacity and developing pre-positioned trial protocols and clinical characterization protocols, as well as conducting discovery and pre-clinical research, manufacturing, and early clinical testing of candidate products. This will allow for speedy execution of clinical research early into an outbreak and delivering products within a short time. Effective interventions should be adopted and deployed ensuring equitable access during the ongoing outbreak. Measures to make products available where and when needed must be integrated throughout the R&D value chain.

Business-as-Usual will not Deliver the COVID-19 Vaccines We Need.

Governments must become active shapers of medical innovation and drive the development of critical health technologies as global health commons. The 'race' for COVID-19 vaccines is exposing the deficiencies of a business-as-usual medical innovation ecosystem driven by corporate interests, not health outcomes. Instead of bolstering collective intelligence, it relies on competition between proprietary vaccines and allows the bar on safety and efficacy to be lowered, risking people's health and undermining their trust.

An open source pharma roadmap.

In an Essay, Matthew Todd and colleagues discuss an open source approach to drug development.

Engaging Human Rights in the Response to the Evolving Zika Virus Epidemic.

In late 2015, an increase in the number of infants born with microcephaly in poor communities in northeast Brazil prompted investigation of antenatal Zika infection as the cause. Zika now circulates in 69 countries, and has affected pregnancies of women in 29 countries. Public health officials, policymakers, and international organizations are considering interventions to address health consequences of the Zika epidemic. To date, public health responses have focused on mosquito vector eradication, sexual and reproductive health services, knowledge and technology including diagnostic test and vaccine development, and health system preparedness. We summarize responses to date and apply human rights and related principles including nondiscrimination, participation, the legal and policy context, and accountability to identify shortcomings and to offer suggestions for more equitable, effective, and sustainable Zika responses.

Global health security: the wider lessons from the west African Ebola virus disease epidemic.

The Ebola virus disease outbreak in West Africa was unprecedented in both its scale and impact. Out of this human calamity has come renewed attention to global health security--its definition, meaning, and the practical implications for programmes and policy. For example, how does a government begin to strengthen its core public health capacities, as demanded by the International Health Regulations? What counts as a global health security concern? In the context of the governance of global health, including WHO reform, it will be important to distil lessons learned from the Ebola outbreak. The Lancet invited a group of respected global health practitioners to reflect on these lessons, to explore the idea of global health security, and to offer suggestions for next steps. Their contributions describe some of the major threats to individual and collective human health, as well as the values and recommendations that should be considered to counteract such threats in the future. Many different perspectives are proposed. Their common goal is a more sustainable and resilient society for human health and wellbeing.

Why are our medicines so expensive? Spoiler: Not for the reasons you are being told .

Often described as a natural economic trend, the prices that pharmaceutical companies charge for new medicines have skyrocketed in recent years. Companies claim these prices are justified because of the 'value' new treatments represent or that they reflect the high costs and risks associated with the research and development process. They also claim that the revenues generated through these high prices are required to pay for continued innovation.This paper argues that high prices are not inevitable but the result of a societal and political choice to rely on a for-profit business model for medical innovation, selling medicines at the highest price possible. Instead of focusing on therapeutic advances, it prioritises profit maximisation to benefit shareholders and investors over improving people's health outcomes or equitable access.As a result, people and health systems worldwide struggle to pay for the increasingly expensive health products, with growing inequities in access to even life-saving medicines while the biopharmaceutical industry and its financiers are the most lucrative business sectors.As the extreme COVID-19 vaccine inequities once again highlighted, we urgently need to reform the social contract between governments, the biopharmaceutical industry, and the public and restore its original health purpose. Policymakers must redesign policies and financing of the pharmaceutical research and development ecosystem such that public and private sectors work together towards the shared objective of responding to public health and patients' needs, rather than maximising financial return because medicines should not be a luxury.

Elucidating the migrations of European seabass from the southern north sea using mark-recapture data, acoustic telemetry and data storage tags.

The movement ecology of European seabass, Dicentrarchus labrax, remains poorly understood, especially in the northern ranges of its distribution. To investigate migration patterns of seabass from the southern North Sea, we combined data from different projects from four countries using various tagging techniques. This resulted in 146 recaptures (out of 5598 externally marked seabass), 138 detected animals (out of 162 seabass fitted with an acoustic transmitter) and 76 archived depth and temperature series (out of 323 seabass with an archival tag). Using geolocation modelling, we distinguished different migration strategies, whereby individual fish migrated to the eastern English Channel (15.1%), the western English Channel (28.3%), the Celtic Sea and the norther part of the Bay of Biscay (17.0%), or stayed in the North Sea (39.6%). A high number of seabass exhibited fidelity to the North Sea (90.5% of recaptures, 55.3% for acoustic transmitters and 44.7% of archival tags). Although seabass are generally considered to migrate southwards in winter, a large number of individuals (n = 62) were observed in the southern North Sea, where spawning might potentially occur in a particular deep location along the coast of Norfolk in the UK. Our results highlight the need to consider fine-scaled population structuring in fisheries assessment, and indicate that current seasonal fisheries closures are not aligned with the ecology of seabass in the North Sea.

Nipah virus disease: what can we do to improve patient care?

The year 2023 marked the 25th anniversary of the first detected outbreak of Nipah virus disease. Despite Nipah virus being a priority pathogen in the WHO Research and Development blueprint, the disease it causes still carries high mortality, unchanged since the first reported outbreaks. Although candidate vaccines for Nipah virus disease exist, developing new therapeutics has been underinvested. Nipah virus disease illustrates the typical market failure of medicine development for a high-consequence pathogen. The unpredictability of outbreaks and low number of infections affecting populations in low-income countries does not make an attractive business case for developing treatments for Nipah virus disease-a situation compounded by methodological challenges in clinical trial design. Nipah virus therapeutics development is not motivated by commercial interest. Therefore, we propose a regionally led, patient-centred, and public health-centred, end-to-end framework that articulates a public health vision and a roadmap for research, development, manufacturing, and access towards the goal of improving patient outcomes. This framework includes co-creating a regulatory-compliant, clinically meaningful, and context-specific clinical development plan and establishing quality standards in clinical care and research capabilities at sites where the disease occurs. The success of this approach will be measured by the availability and accessibility of improved Nipah virus treatments in affected communities and reduced mortality.

Breakthrough treatments for Ebola virus disease, but no access-what went wrong, and how can we do better?

Three years since proving effective for Ebola virus disease in a clinical trial, two breakthrough treatments are registered and stockpiled in the USA but still not registered and generally available in the countries most affected by this deadly infection of epidemic potential. Analysing the reasons for this, we see a fragmentation of the research and development value chain, with different stakeholders taking on different steps of the research and development process, without the public health-focused leadership needed to ensure the end goal of equitable access in countries where Ebola virus disease is prevalent. Current financial incentives for companies to overcome market failures and engage in epidemic-prone diseases are geared towards registration and stockpiling in the USA, without responsibility to provide access where and when needed. Ebola virus disease is the case in point, but not unique-a situation seen again for mpox and likely to occur again for other epidemics primarily affecting disempowered communities. Stronger leadership in African countries will help drive drug development efforts for diseases that primarily affect their communities, and ensure all partners align with and commit to an end-to-end approach to pharmaceutical development and manufacturing that puts equitable access when and where needed at its core.

The Future of Epidemic and Pandemic Vaccines to Serve Global Public Health Needs.

This Review initiates a wide-ranging discussion over 2023 by selecting and exploring core themes to be investigated more deeply in papers submitted to the Vaccines Special Issue on the "Future of Epidemic and Pandemic Vaccines to Serve Global Public Health Needs". To tackle the SARS-CoV-2 pandemic, an acceleration of vaccine development across different technology platforms resulted in the emergency use authorization of multiple vaccines in less than a year. Despite this record speed, many limitations surfaced including unequal access to products and technologies, regulatory hurdles, restrictions on the flow of intellectual property needed to develop and manufacture vaccines, clinical trials challenges, development of vaccines that did not curtail or prevent transmission, unsustainable strategies for dealing with variants, and the distorted allocation of funding to favour dominant companies in affluent countries. Key to future epidemic and pandemic responses will be sustainable, global-public-health-driven vaccine development and manufacturing based on equitable access to platform technologies, decentralised and localised innovation, and multiple developers and manufacturers, especially in low- and middle-income countries (LMICs). There is talk of flexible, modular pandemic preparedness, of technology access pools based on non-exclusive global licensing agreements in exchange for fair compensation, of WHO-supported vaccine technology transfer hubs and spokes, and of the creation of vaccine prototypes ready for phase I/II trials, etc. However, all these concepts face extraordinary challenges shaped by current commercial incentives, the unwillingness of pharmaceutical companies and governments to share intellectual property and know-how, the precariousness of building capacity based solely on COVID-19 vaccines, the focus on large-scale manufacturing capacity rather than small-scale rapid-response innovation to stop outbreaks when and where they occur, and the inability of many resource-limited countries to afford next-generation vaccines for their national vaccine programmes. Once the current high subsidies are gone and interest has waned, sustaining vaccine innovation and manufacturing capability in interpandemic periods will require equitable access to vaccine innovation and manufacturing capabilities in all regions of the world based on many vaccines, not just "pandemic vaccines". Public and philanthropic investments will need to leverage enforceable commitments to share vaccines and critical technology so that countries everywhere can establish and scale up vaccine development and manufacturing capability. This will only happen if we question all prior assumptions and learn the lessons offered by the current pandemic. We invite submissions to the special issue, which we hope will help guide the world towards a global vaccine research, development, and manufacturing ecosystem that better balances and integrates scientific, clinical trial, regulatory, and commercial interests and puts global public health needs first.

From private incentives to public health need: rethinking research and development for pandemic preparedness.

Pandemic preparedness and response have relied primarily on market dynamics to drive development and availability of new health products. Building on calls for transformation, we propose a new value proposition that instead prioritises equity from the research and development (R&D) stage and that strengthens capacity to control outbreaks when and where they occur. Key elements include regional R&D hubs free to adapt well established technology platforms, and independent clinical trials networks working with researchers, regulators, and health authorities to better study questions of comparative benefit and real-world efficacy. Realising these changes requires a shift in emphasis: from pandemic response to outbreak control, from one-size-fits-all economies of scale to R&D and manufacture for local need, from de novo product development to last-mile innovation through adaptation of existing technologies, and from proprietary, competitive R&D to open science and financing for the common good that supports collective management and sharing of technology and know-how.

Genotoxicity profile of fexinidazole--a drug candidate in clinical development for human African trypanomiasis (sleeping sickness).

The parasitic disease human African trypanomiasis (HAT), also known as sleeping sickness, is a highly neglected fatal condition endemic in sub-Saharan Africa, which is poorly treated with medicines that are toxic, no longer effective or very difficult to administer. New, safe, effective and easy-to-use treatments are urgently needed. Many nitroimidazoles possess antibacterial and antiprotozoal activity and examples such as tinidazole are used to treat trichomoniasis and guardiasis, but concerns about toxicity including genotoxicity limit their usefulness. Fexinidazole, a 2-substituted 5-nitroimidazole rediscovered by the Drugs for Neglected Diseases initiative (DNDi) after extensive compound mining of public and pharmaceutical company databases, has the potential to become a short-course, safe and effective oral treatment, curing both acute and chronic HAT. This paper describes the genotoxicity profile of fexinidazole and its two active metabolites, the sulfoxide and sulfone derivatives. All the three compounds are mutagenic in the Salmonella/Ames test; however, mutagenicity is either attenuated or lost in Ames Salmonella strains that lack one or more nitroreductase(s). It is known that these enzymes can nitroreduce compounds with low redox potentials, whereas their mammalian cell counterparts cannot, under normal conditions. Fexinidazole and its metabolites have low redox potentials and all mammalian cell assays to detect genetic toxicity, conducted for this study either in vitro (micronucleus test in human lymphocytes) or in vivo (ex vivo unscheduled DNA synthesis in rats; bone marrow micronucleus test in mice), were negative. Thus, fexinidazole does not pose a genotoxic hazard to patients and represents a promising drug candidate for HAT. Fexinidazole is expected to enter Phase II clinical trials in 2012.

Antitrypanosomal activity of fexinidazole, a new oral nitroimidazole drug candidate for treatment of sleeping sickness.

Fexinidazole is a 5-nitroimidazole drug currently in clinical development for the treatment of human sleeping sickness (human African trypanosomiasis [HAT]), caused by infection with species of the protozoan parasite Trypanosoma brucei. The compound and its two principal metabolites, sulfoxide and sulfone, have been assessed for their ability to kill a range of T. brucei parasite strains in vitro and to cure both acute and chronic HAT disease models in the mouse. The parent molecule and both metabolites have shown trypanocidal activity in vitro in the 0.7-to-3.3 µM (0.2-to-0.9 µg/ml) range against all parasite strains tested. In vivo, fexinidazole is orally effective in curing both acute and chronic diseases in the mouse at doses of 100 mg/kg of body weight/day for 4 days and 200 mg/kg/day for 5 days, respectively. Pharmacokinetic data indicate that it is likely that the sulfoxide and sulfone metabolites provide most, if not all, of the in vivo killing activity. Fexinidazole and its metabolites require up to 48 h exposure in order to induce maximal trypanocidal efficacy in vitro. The parent drug and its metabolites show no in vitro cross-reactivity in terms of trypanocidal activity with either themselves or other known trypanocidal drugs in use in humans. The in vitro and in vivo antitrypanosomal activities of fexinidazole and its two principal metabolites provide evidence that the compound has the potential to be an effective oral treatment for both the T. b. gambiense and T. b. rhodesiense forms of human sleeping sickness and both stages of the disease.