Pandemic origins and a One Health approach to preparedness and prevention: Solutions based on SARS-CoV-2 and other RNA viruses.

COVID-19 is the latest zoonotic RNA virus epidemic of concern. Learning how it began and spread will help to determine how to reduce the risk of future events. We review major RNA virus outbreaks since 1967 to identify common features and opportunities to prevent emergence, including ancestral viral origins in birds, bats, and other mammals; animal reservoirs and intermediate hosts; and pathways for zoonotic spillover and community spread, leading to local, regional, or international outbreaks. The increasing scientific evidence concerning the origins of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is most consistent with a zoonotic origin and a spillover pathway from wildlife to people via wildlife farming and the wildlife trade. We apply what we know about these outbreaks to identify relevant, feasible, and implementable interventions. We identify three primary targets for pandemic prevention and preparedness: first, smart surveillance coupled with epidemiological risk assessment across wildlife-livestock-human (One Health) spillover interfaces; second, research to enhance pandemic preparedness and expedite development of vaccines and therapeutics; and third, strategies to reduce underlying drivers of spillover risk and spread and reduce the influence of misinformation. For all three, continued efforts to improve and integrate biosafety and biosecurity with the implementation of a One Health approach are essential. We discuss new models to address the challenges of creating an inclusive and effective governance structure, with the necessary stable funding for cross-disciplinary collaborative research. Finally, we offer recommendations for feasible actions to close the knowledge gaps across the One Health continuum and improve preparedness and response in the future.

Urgent lessons from COVID 19: why the world needs a standing, coordinated system and sustainable financing for global research and development.

The research and development (R&D) ecosystem has evolved over the past decade to include pandemic infectious diseases, building on experience from multiple recent outbreaks. Outcomes of this evolution have been particularly evident during the COVID-19 pandemic with accelerated development of vaccines and monoclonal antibodies, as well as novel clinical trial designs. These products were developed, trialled, manufactured, and authorised for use in several countries within a year of the pandemic's onset. Many gaps remain, however, that must be bridged to establish a truly efficient and effective end-to-end R&D preparedness and response ecosystem. Foremost among them is a global financing system. In addition, important changes are required for multiple aspects of enabling sciences and product development. For each of these elements we identify priorities for improved and faster functionality. There will be no better time than now to seriously address these needs, however difficult, as the ravages of COVID-19 continue to accelerate with devastating health, social, and economic consequences for the entire community of nations.

Rigorous Clinical Trial Design in Public Health Emergencies Is Essential.

Randomized clinical trials are the most reliable approaches to evaluating the effects of new treatments and vaccines. During the 2014-2015 West African Ebola epidemic, many argued that such trials were neither ethical nor feasible in an environment of limited health infrastructure and severe disease with a high fatality rate. Consensus among the numerous organizations providing help to the affected areas was never achieved, resulting in fragmented collaboration, delayed study initiation, and ultimately failure to provide definitive evidence on the efficacy of treatments and vaccines. Randomized trials were in fact approved by local ethics boards and initiated, demonstrating that randomized trials, even in such difficult circumstances, are feasible. Improved planning and collaboration among research and humanitarian organizations, and affected communities, in the interepidemic periods are needed to ensure that questions regarding the efficacy of vaccines and treatments can be definitively answered during future public health emergencies.

Environmental enteric dysfunction: pathogenesis, diagnosis, and clinical consequences.

Stunting is common in young children in developing countries, and is associated with increased morbidity, developmental delays, and mortality. Its complex pathogenesis likely involves poor intrauterine and postnatal nutrition, exposure to microbes, and the metabolic consequences of repeated infections. Acquired enteropathy affecting both gut structure and function likely plays a significant role in this outcome, especially in the first few months of life, and serve as a precursor to later interactions of infection and malnutrition. However, the lack of validated clinical diagnostic criteria has limited the ability to study its role, identify causative factors, and determine cost-effective interventions. This review addresses these issues through a historical approach, and provides recommendations to define and validate a working clinical diagnosis and to guide critical research in this area to effectively proceed. Prevention of early gut functional changes and inflammation may preclude or mitigate the later adverse vicious cycle of malnutrition and infection.

Implications of acquired environmental enteric dysfunction for growth and stunting in infants and children living in low- and middle-income countries.

Changes in small bowel function early in infancy in developing countries are increasingly being demonstrated, probably accompanied by altered mucosal architecture in most individuals, including reduced enterocyte mass and evidence of immune activation and inflammation in the mucosa. These alterations appear to be the result of factors of uncertain nature in the environment, and may be a cause of growth faltering and stunting in young children. For these reasons, this constellation of findings is being referred to as environmental enteropathy, or as we propose herein, environmental enteric dysfunction. If the causes were known and effective interventions were available, strategies and policies to intervene at--or possibly before--birth could be developed and promoted in order to prevent subsequent malnutrition and recurrent infection, which are known to interact in a cyclical and synergistic manner in a downward clinical course often ending in death. Resources would be mobilized and applied differently, and the emphasis would change from treatment to prevention. In order to move in this highly desired direction, investments in research will be required to establish the criteria to assess environmental enteric dysfunction, determine its predictive value for growth faltering and stunting, identify the causes, and propose and test potential interventions. The concepts and tools are available. What is required is the decision to move forward along this pathway to better health for infants and children in low-income countries.

New challenges in studying nutrition-disease interactions in the developing world.

Latest estimates indicate that nutritional deficiencies account for 3 million child deaths each year in less-developed countries. Targeted nutritional interventions could therefore save millions of lives. However, such interventions require careful optimization to maximize benefit and avoid harm. Progress toward designing effective life-saving interventions is currently hampered by some serious gaps in our understanding of nutrient metabolism in humans. In this Personal Perspective, we highlight some of these gaps and make some proposals as to how improved research methods and technologies can be brought to bear on the problems of undernourished children in the developing world.

Infectious Disease Threats: A Rebound To Resilience.

The US has experienced a series of epidemics during the past five decades. None has tested the nation's resilience like the coronavirus disease 2019 (COVID-19) pandemic, which has laid bare critical weaknesses in US pandemic preparedness and domestic leadership and the nation's decline in global standing in public health. Pandemic response has been politicized, proven public health measures undermined, and public confidence in a science-based public health system reduced. This has been compounded by the large number of citizens without ready access to health care, who are overrepresented among infected, hospitalized, and fatal cases. Here, as part of the National Academy of Medicine's Vital Directions for Health and Health Care: Priorities for 2021 initiative, we review the US approach to pandemic preparedness and its impact on the response to COVID-19. We identify six steps that should be taken to strengthen US pandemic resilience, strengthen and modernize the US health care system, regain public confidence in government leadership in public health, and restore US engagement and leadership in global partnerships to address future pandemic threats domestically and around the world.

The global health system: actors, norms, and expectations in transition.

In the first in a series of four articles highlighting the changing nature of global health institutions, Nicole Szlezák and colleagues outline the origin and aim of the series.

The Origin of COVID-19 and Why It Matters.

The COVID-19 pandemic is among the deadliest infectious diseases to have emerged in recent history. As with all past pandemics, the specific mechanism of its emergence in humans remains unknown. Nevertheless, a large body of virologic, epidemiologic, veterinary, and ecologic data establishes that the new virus, SARS-CoV-2, evolved directly or indirectly from a ß-coronavirus in the sarbecovirus (SARS-like virus) group that naturally infect bats and pangolins in Asia and Southeast Asia. Scientists have warned for decades that such sarbecoviruses are poised to emerge again and again, identified risk factors, and argued for enhanced pandemic prevention and control efforts. Unfortunately, few such preventive actions were taken resulting in the latest coronavirus emergence detected in late 2019 which quickly spread pandemically. The risk of similar coronavirus outbreaks in the future remains high. In addition to controlling the COVID-19 pandemic, we must undertake vigorous scientific, public health, and societal actions, including significantly increased funding for basic and applied research addressing disease emergence, to prevent this tragic history from repeating itself.

When you reach a fork in the road, take it: science and product development as linked paths.

There is a simple underlying message in this discussion, which has three parts. First, science has the capacity to generate new knowledge and harness that knowledge in the cause of developing products and technology that can reduce disease burdens among developing nation populations. Second, intellectual property is a tool to use in order to insure that new knowledge is not expropriated and exploited in a manner that threatens the ability to provide products and technology to poor people at an affordable price. Third, and finally, academic scientists need to understand that they can stride both pathways of the R&D road, remaining involved in generating basic knowledge while participating in the application of that knowledge towards product development and, through the use of best practice IP management, making it available in resource-poor environments. In order for this to happen, academia needs to maintain bridges to the private sector, while assiduously avoiding financial conflicts of interest, a topic not discussed in this paper. Academic scientists, whether already established or still completing their education, need access to training modules that allows them to define the challenges of the high disease burdens in the third world in human, and not just in consumption or dollar, terms. They also need education regarding the problems they work on, in order to engage them in the technology transfer from academia to the private sector; promote collaboration with scientists in the developing world; provide them with enough insights into the process and how it operates so that they know about the terms of any agreements with the private sector that would prevent poor people from accessing the ultimate product; and finally "reward" them in the academic system by advancement based on applied and field-based international translational and operational applied research. If these education programs develop and expand to increasing numbers of people in the research sector of academia, the number of people taking both paths described here will substantially increase. With that, the amount of research relevant to improving the health status--and indirectly, development--of developing countries will have been substantially increased.

What do -omics mean for the science and policy of the nutritional sciences?

The development of systems biology is revolutionizing the way we are studying and learning about human health. It is a way of thinking and a systematic attempt to integrate information from several fields of study (physical, biological, chemical, engineering, etc) to develop a more kinetic and real-time understanding of complex biological processes. It uses mathematical modeling tools to chart dynamic interactions between the components of a biological system, eg, genes, transcripts, proteins, metabolites, and cells, to simulate and analyze networks and pathways and the spatial and temporal relations that exist in biological systems. The term -omics represents the rigorous study of various collections of molecules, biological processes, or physiologic functions and structures as systems, represented most prominently by genomics. In the field of nutrition, had a systems approach been applied to evaluating the effect of vitamin A status on mortality rates in young children in developing countries, it might not have taken 20 y to go from the initial epidemiologic observations to global vitamin A supplementation programs. Better understanding of the functional biology of retinoids on different tissues that mediate host resistance to infection, and their synergistic interactions in biological, metabolic, and functional terms, could have provided a plausible mechanism for the observed effect on mortality. There are 3 policy take-home messages: 1) When controversies exist, invest in the science needed to sort them out. 2) Increase the amounts of money available for health research and interventions relevant to developing countries. 3) Ensure that policymakers understand the issues and why they are important and understand the science and its relevance.