Abstract The world has faced many infectious disease emergencies during this century and is certain to see more in the decades ahead. Urgent research to study new pathogens and how to control and counter them is now increasingly being integrated into global response to infectious diseases to chronicle their clinical presentation, identify treatment alternatives, and develop approaches to prevention or control—and to do so with the urgency befitting a pandemic with many lives at stake. The recent Ebola outbreaks in Africa and the coronavirus disease 2019 (COVID-19) pandemic have spurred more coordination on response among global stakeholders. However, they also revealed many shortcomings and spurred movement toward a global framework providing more consistent resources, coordination, and governance. A well thought-out, realistic framework is needed not only for more effective scientific research including clinical trials, but to better account for popular perceptions of and reactions to events, and to ensure that the products of emergency research are equitably distributed among the world’s population. The key elements of the research ecosystem must be in place before a new infectious disease appears.

Abstract This chapter offers a historical introduction and perspective for many of the subjects explored in detail in further chapters of the book. Efforts to discover which medical treatments are safe and effective and which are not date back many centuries. But it has only been 75 years since the current scientifically and ethically sound clinical research gold standard, the randomly controlled, double-blind clinical trial, was widely adopted, representing the maturation of biostatistically based trial design and the development of modern concepts of medical ethics. We are now on the cusp of another revolution as new circumstances highlight the need for innovative, adaptive research models. For example, the need to design and implement clinical trials quickly during an infectious disease outbreak is now an accepted element of response, even—or especially—in countries with limited health resources and research capacity. The 2014–2016 Ebola outbreak in West Africa clearly demonstrated a new set of constraints and the need to initiate research both swiftly and safely. Innovative trial designs such as multi-arm, adaptive trials offer great advantages in certain contexts, but require more sophisticated statistical analysis and currently are more difficult for communities and even review boards to understand. The need for community inclusion in clinical trial implementation is now universally recognized, but how to accomplish it, and the degree to which researchers are committed to it, remains a work in progress. The fundamental ethical and scientific principles of clinical research may seem well established but continue to challenge research study design and the agencies that provide funding for large clinical trials. The combined impacts of innovations in technology and trial design, the need to carry out research on an expedited basis when novel pathogens arise, and the flowering of misinformation in the current media environment make emergency research not only essential, but an exciting and challenging field as well.

Threatening the Future of Global Health A new policy for foreign subrecipients of NIH funding departs sharply from decades of efforts to promote research integrity and build research capacity globally - and may have wide-ranging negative consequences.

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.

We agree with Carel IJsselmuiden and colleagues that research and development (R&D) systems of low-income and middle-income countries (LMICs) need to be strengthened for pandemic preparedness and response to succeed. Solving the financing challenge is central to closing what we called “the R&D equity gap”.1Lurie N Keusch GT Dzau VJ Urgent lessons from COVID 19: why the world needs a standing, coordinated system and sustainable financing for global research and development.Lancet. 2021; 397: 1229-1236Summary Full Text Full Text PDF PubMed Scopus (15) Google Scholar This task includes establishing research hubs on each continent committed “to equity of opportunity” for scientists in LMICs who must be central to all aspects of the R&D ecosystem.1Lurie N Keusch GT Dzau VJ Urgent lessons from COVID 19: why the world needs a standing, coordinated system and sustainable financing for global research and development.Lancet. 2021; 397: 1229-1236Summary Full Text Full Text PDF PubMed Scopus (15) Google Scholar A global financing system is essential to support the broad components of the R&D ecosystem of the future. Distributed modern manufacturing capacity, including in LMICs, and procurement and distribution of the products of R&D are integral to this. Eliminating the “immoral inequity” of vaccine access that IJsselmuiden and colleagues refer to depends on sufficient manufacturing capacity to address the needs of all countries simultaneously. We are heartened by the call of the Africa Centres for Disease Control and Prevention to establish more vaccine manufacturing capacity on the African continent.2Africa Centres for Disease Control and PreventionAfrican Union and Africa CDC launches Partnerships for African Vaccine Manufacturing (PAVM) framework to achieve it and signs 2 MoUs.https://africacdc.org/wp-content/uploads/2021/04/post-summit-comunique-African-Union-and-Africa-CDC-launches-Partnerships-for-African-Vaccine-Manufacturing.pdfDate: April 13, 2021Date accessed: May 12, 2021Google Scholar LMICs also need to invest their own resources; indeed, in the Money & Microbes report,3International Vaccines Task ForceMoney & microbes: strengthening clinical research capacity to prevent epidemics. The World Bank, Washington, DC2018Google Scholar the World Bank's International Vaccines Task Force notes the importance of national investments to “motivate young investigators to pursue clinical research careers, and…to choose to use those skills in-country”. Providing the quality education and infrastructure cutting-edge scientists require will make it easier to retain talented young scientists and attract nationals who wish to return home after their education and training abroad. While the world cannot wait for these goals to be achieved to improve the R&D preparedness and response ecosystem, we can ensure that national and international investments and a solid financing system will leave us better positioned to achieve both equity of opportunity and equity of outcomes. We must use this time during the COVID-19 crisis to make solid progress towards that end. GTK is a member of the Lancet Task Force on the Origins and Early Spread of COVID-19 & One Health Solutions to Future Pandemic Threats. NL and VJD declare no competing interests. Urgent lessons from COVID 19: why the world needs a standing, coordinated system and sustainable financing for global research and developmentThe 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. Full-Text PDF Should global financing be the main priority for pandemic preparedness?Nicole Lurie and colleagues1 argue that “[m]any gaps…must be bridged to establish a truly efficient and effective end-to-end R&D [research and development] preparedness and response ecosystem. Foremost among them is a global financing system”. While obviously essential, it is unlikely that global financing, in itself, will address the immoral inequity on display in the global distribution of COVID-19 vaccines.2 The R&D systems of low-income and middle-income countries (LMICs) need to be strengthened with equal force and funding for pandemic preparedness to succeed. Full-Text PDF

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.

On Feb 19, 2020, we, a group of physicians, veterinarians, epidemiologists, virologists, biologists, ecologists, and public health experts from around the world, joined together to express solidarity with our professional colleagues in China.1Calisher C Carroll D Colwell R et al.Statement in support of the scientists, public health professionals, and medical professionals of China combatting COVID-19.Lancet. 2020; 395: E42-E43Summary Full Text Full Text PDF PubMed Scopus (169) Google Scholar Unsubstantiated allegations were being raised about the source of the COVID-19 outbreak and the integrity of our peers who were diligently working to learn more about the newly recognised virus, SARS-CoV-2, while struggling to care for the many patients admitted to hospital with severe illness in Wuhan and elsewhere in China. It was the beginning of a global tragedy, the COVID-19 pandemic. According to WHO, as of July 2, 2021, the pandemic has resulted in 182 101 209 confirmed cases and 3 950 876 deaths, both undoubtedly underestimates of the real toll. The impact of the pandemic virtually everywhere in the world has been far worse than even these numbers suggest, with unprecedented additional social, cultural, political, and economic consequences that have exposed numerous flaws in our epidemic and pandemic preparedness and in local and global political and economic systems. We have observed escalations of conflicts that pit many parties against one another, including central government versus local government, young versus old, rich versus poor, people of colour versus white people, and health priorities versus the economy. The crisis has highlighted the urgent need to build a better understanding of how science proceeds and the complex, but critical, links science has with health, public health, and politics. Recently, many of us have individually received inquiries asking whether we still support what we said in early 2020.1Calisher C Carroll D Colwell R et al.Statement in support of the scientists, public health professionals, and medical professionals of China combatting COVID-19.Lancet. 2020; 395: E42-E43Summary Full Text Full Text PDF PubMed Scopus (169) Google Scholar The answer is clear: we reaffirm our expression of solidarity with those in China who confronted the outbreak then, and the many health professionals around the world who have since worked to exhaustion, and at personal risk, in the relentless and continuing battle against this virus. Our respect and gratitude have only grown with time. The second intent of our original Correspondence was to express our working view that SARS-CoV-2 most likely originated in nature and not in a laboratory, on the basis of early genetic analysis of the new virus and well established evidence from previous emerging infectious diseases, including the coronaviruses that cause the common cold as well as the original SARS-CoV and MERS-CoV.2Forni D Cagliani R Clerici M Sironi M Molecular evolution of human coronavirus genomes.Trends Microbiol. 2017; 25: 35-48Summary Full Text Full Text PDF PubMed Scopus (519) Google Scholar Opinions, however, are neither data nor conclusions. Evidence obtained using the scientific method must inform our understanding and be the basis for interpretation of the available information. The process is not error-free, but it is self-correcting as good scientists endeavour to continually ask new questions, apply new methodologies as they are developed, and revise their conclusions through an open and transparent sharing of data and ongoing dialogue. The critical question we must address now is, how did SARS-CoV-2 reach the human population? This is important because it is such insights that will drive what the world must urgently do to prevent another tragedy like COVID-19. We believe the strongest clue from new, credible, and peer-reviewed evidence in the scientific literature3Wacharapluesadee S Tan CW Maneeorn P et al.Evidence for SARS-CoV-2 related coronaviruses circulating in bats and pangolins in southeast Asia.Nat Comms. 2021; 12: 972Crossref PubMed Scopus (228) Google Scholar, 4Zhou H Ji J Chen X et al.Identification of novel bat coronaviruses sheds light on the evolutionary origins of SARS-CoV-2 and related viruses.Cell. 2021; (in press)https://doi.org/10.1016/j.cell.2021.06.008Summary Full Text Full Text PDF Scopus (206) Google Scholar, 5Garry RF Early appearance of two distinct genomic lineages of SARS-CoV-2 in different Wuhan wildlife markets suggests SARS-CoV-2 has a natural origin.https://virological.org/t/early-appearance-of-two-distinct-genomic-lineages-of-sars-cov-2-in-different-wuhan-wildlife-markets-suggests-sars-cov-2-has-a-natural-origin/691Date: May 12, 2021Date accessed: June 15, 2021Google Scholar, 6Latinne A Hu B Olival KJ et al.Origin and cross-species transmission of bat coronaviruses in China.Nat Comms. 2020; 114235Crossref PubMed Scopus (223) Google Scholar is that the virus evolved in nature, while suggestions of a laboratory-leak source of the pandemic remain without scientifically validated evidence that directly supports it in peer-reviewed scientific journals.7Maxmen A Mallapaty S The COVID lab-leak hypothesis: what scientists do and don't know.Nature. 2021; 594: 313-315Crossref PubMed Scopus (61) Google Scholar, 8Ling H The lab leak theory doesn't hold up. The rush to find a conspiracy around the COVID-19 pandemic's origins is driven by narrative, not evidence.https://foreignpolicy.com/2021/06/15/lab-leak-theory-doesnt-hold-up-covid-china/Date: June 15, 2021Date accessed: June 15, 2021Google Scholar Careful and transparent collection of scientific information is essential to understand how the virus has spread and to develop strategies to mitigate the ongoing impact of COVID-19, whether it occurred wholly within nature or might somehow have reached the community via an alternative route, and prevent future pandemics. Allegations and conjecture are of no help, as they do not facilitate access to information and objective assessment of the pathway from a bat virus to a human pathogen that might help to prevent a future pandemic. Recrimination has not, and will not, encourage international cooperation and collaboration.9NatureProtect scientific collaboration from geopolitics.Nature. 2021; 593: 477Crossref PubMed Scopus (13) Google Scholar New viruses can emerge anywhere, so maintaining transparency and cooperation between scientists everywhere provides an essential early warning system. Cutting professional links and reducing data sharing will not make us safer. We welcome calls for scientifically rigorous investigations.10Bloom JD Chan YA Baric RS et al.Investigate the origins of COVID-19.Science. 2021; 372: 694Crossref PubMed Scopus (84) Google Scholar, 11McNutt M Anderson JL Dzau VJ Let scientific evidence determine origin of SARS-CoV-2, urge Presidents of the National Academies.https://www.nationalacademies.org/news/2021/06/let-scientific-evidence-determine-origin-of-sars-cov-2-urge-presidents-of-the-national-academiesDate: June 15, 2021Date accessed: June 15, 2021Google Scholar To accomplish this, we encourage WHO and scientific partners across the world to expeditiously move to continue and further extend their initial investigation with experts in China and the Chinese Government. WHO's report from March, 2021,12Joint WHO-China studyWHO-convened global study of origins of SARS-CoV-2: China part.https://www.who.int/publications/i/item/who-convened-global-study-of-origins-of-sars-cov-2-china-partDate: March 30, 2021Date accessed: June 15, 2021Google Scholar must be considered the beginning rather than the end of an inquiry, and we strongly support the G7 leaders' call for "a timely, transparent, expert-led, and science-based WHO-convened phase 2 COVID-19 origins study".13G7 Cornwall UK 2021Carbis Bay G7 Summit communiqué. Our shared agenda for global action to build back better.https://www.g7uk.org/wp-content/uploads/2021/06/Carbis-Bay-G7-Summit-Communique-PDF-430KB-25-pages-3.pdfDate: June 13, 2021Date accessed: June 15, 2021Google Scholar We also understand that it might take years of field and laboratory study to assemble and link the data essential to reach rational and objective conclusions, but that is what the global scientific community must strive to do. It is time to turn down the heat of the rhetoric and turn up the light of scientific inquiry if we are to be better prepared to stem the next pandemic, whenever it comes and wherever it begins. Meanwhile, people around the world continue to be infected by SARS-CoV-2, many are suffering severe disease and long-term sequelae, and too many are dying. Too many populations lack access to SARS-CoV-2 testing, COVID-19 treatments, and safe and effective vaccines, which will inevitably perpetuate the pandemic and its consequences. At the very least, we owe it to all who have suffered from COVID-19, as well as our families and the global community, to work collaboratively to end the pandemic and support international efforts to ensure vaccine equity, even as we prepare for the next pandemic.14Lurie N Keusch GT Dzau VJ Urgent lessons from COVID 19: why the world needs a standing, coordinated system and sustainable financing for global research and development.Lancet. 2021; 397: 1229-1236Summary Full Text Full Text PDF PubMed Scopus (50) Google Scholar Having robust surveillance and detection systems in place across the globe is essential to detect and report new or evolving pathogens that can potentially unleash the next local or global threat, as required by the International Health Regulations. Equally essential will be ensuring that the field workforce, laboratory facilities, and the health-care community can all work under the safest conditions. Until this pandemic ends, we ask, as we did in February, 2020,1Calisher C Carroll D Colwell R et al.Statement in support of the scientists, public health professionals, and medical professionals of China combatting COVID-19.Lancet. 2020; 395: E42-E43Summary Full Text Full Text PDF PubMed Scopus (169) Google Scholar for solidarity and rigorous scientific data. PD's remuneration is paid solely in the form of a salary from EcoHealth Alliance, a 501(c)(3) non-profit organisation. EcoHealth Alliance's mission is to develop science-based solutions to prevent pandemics and promote conservation. Funding for this work comes from a range of US Government funding agencies and non-governmental sources. All past and current funders are listed publicly, and full financial accounts are filed annually and published. EcoHealth Alliance's work in China was previously funded by the US National Institutes of Health (NIH) and the United States Agency for International Development (USAID). Neither PD nor EcoHealth Alliance have received funding from the People's Republic of China. PD joined the WHO–China joint global study on the animal origins of SARS-CoV-2 towards the end of 2020 and is currently a member. As per WHO rules, this work is undertaken as an independent expert in a private capacity, not as an EcoHealth Alliance staff member. The work conducted by this study was published in March, 2021. EcoHealth Alliance's work in China includes collaboration with a range of universities and governmental health and environmental science organisations, all of which are listed in prior publications, three of which received funding from US federal agencies as part of EcoHealth Alliance grants or cooperative agreements, as publicly reported by NIH. EcoHealth Alliance's work in China is currently unfunded. All federally funded subcontractees are assessed and approved by the respective US federal agencies in advance and all funding sources are acknowledged in scientific publications as appropriate. EcoHealth Alliance's work in China involves assessing the risk of viral spillover across the wildlife–livestock–human interface, and includes behavioural and serological surveys of people, and ecological and virological analyses of animals. This work includes the identification of viral sequences in bat samples, and has resulted in the isolation of three bat SARS-related coronaviruses that are now used as reagents to test therapeutics and vaccines. It also includes the production of a small number of recombinant bat coronaviruses to analyse cell entry and other characteristics of bat coronaviruses for which only the genetic sequences are available. NIH reviewed the planned recombinant virus work and deemed it does not meet the criteria that would warrant further specific review by its Potential Pandemic Pathogen Care and Oversight (P3CO) committee. All of EcoHealth Alliance's work is reviewed and approved by appropriate research ethics committees, the Institutional Animal Care and Use Committee, institutional review boards for biomedical research involving human subjects, P3CO oversight administrators, and biosafety committees, as listed on all relevant publications. JMH is a member of the board of directors of EcoHealth Alliance. JL is a former Chief Veterinary Officer of the UN Food and Agriculture Organization. JSM is a member of the WHO International Health Regulations Emergency Committee for COVID-19, a member of the One Health High Level Expert Panel that advises the Food and Agriculture Organization of the UN, the World Organisation for Animal Health, the United Nations Environment Programme, and WHO, and a past member of the scientific advisory committee for the Center for Emerging Infectious Diseases of the Wuhan Institute of Virology (2008–11). JKM receives funding from USAID to the University of California at Davis, where she is a Principle Investigator, for the PREDICT Project, which funded viral detection and discovery capacity strengthening, One Health education, and global health capability strengthening around the world, including China and the Wuhan Institute of Virology. JKM is also a voluntary board member, with no compensation or financial interest, for the following not-for-profit collaborative consortia advocating for social and environmental equity, conservation, and global viral discovery in order to mitigate risks from viral spillover and pandemics: Global Virome Project, Gorilla Doctors, Bay Area Global Health Alliance, and UC Global Health Institute. JKM has reviewed for and consulted with numerous US state and federal agencies, including the NIH, Department of Defence, USAID, Food and Drug Administration, as well as non-governmental organisation such as the National Academies of Science, Engineering & Medicine and the American Association of Academic Medical Centers. JKM has ongoing collaborations with organisations, scientists, and other professionals in at least 40 countries, including China and the Wuhan Institute of Virology. JKM declares that her spouse owns and operates BHM Construction and A&J Investments, is an investor in VSP, and is a board member for San Francisco Achievers. SMP receives funding from an NIH grant for a project about SARS-CoV and host cell interactions and vaccine development. LE, HF, AEG, JKM, JSM, SMP, and LP have past or ongoing academic and scientific collaborations on coronavirus biology with colleagues in China and several other countries. LP directs a WHO COVID-19 Reference Laboratory. PD, HF, GTK, SKL, SMP, and LS are members of the Lancet Task Force on the Origins and Early Spread of COVID-19 & One Health Solutions to Future Pandemic Threats. JL is a member of the Lancet One Health Commission. All authors contributed to the 2020 Correspondence in The Lancet in support of the scientists, public health professionals, and medical professionals of China combatting COVID-19. Statement in support of the scientists, public health professionals, and medical professionals of China combatting COVID-19We are public health scientists who have closely followed the emergence of 2019 novel coronavirus disease (COVID-19) and are deeply concerned about its impact on global health and wellbeing. We have watched as the scientists, public health professionals, and medical professionals of China, in particular, have worked diligently and effectively to rapidly identify the pathogen behind this outbreak, put in place significant measures to reduce its impact, and share their results transparently with the global health community. Full-Text PDF An appeal for an objective, open, and transparent scientific debate about the origin of SARS-CoV-2On July 5, 2021, a Correspondence was published in The Lancet called "Science, not speculation, is essential to determine how SARS-CoV-2 reached humans".1 The letter recapitulates the arguments of an earlier letter (published in February, 2020) by the same authors,2 which claimed overwhelming support for the hypothesis that the novel coronavirus causing the COVID-19 pandemic originated in wildlife. The authors associated any alternative view with conspiracy theories by stating: "We stand together to strongly condemn conspiracy theories suggesting that COVID-19 does not have a natural origin". Full-Text PDF An appeal for an objective, open, and transparent scientific debate about the origin of SARS-CoV-2 – Authors' replyWe write on behalf of our coauthors1 to agree with Jacques van Helden and colleagues that scientists "need to evaluate all hypotheses on a rational basis, and to weigh their likelihood based on facts and evidence, devoid of speculation concerning possible political impacts". Scientific knowledge is essential to effectively guide future efforts to reduce the chance of another pandemic,1,2 including by mitigating or blocking all relevant pathways for a pathogen to host-shift from natural hosts to humans. Full-Text PDF

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.

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 β-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.

We are public health scientists who have closely followed the emergence of 2019 novel coronavirus disease (COVID-19) and are deeply concerned about its impact on global health and wellbeing. We have watched as the scientists, public health professionals, and medical professionals of China, in particular, have worked diligently and effectively to rapidly identify the pathogen behind this outbreak, put in place significant measures to reduce its impact, and share their results transparently with the global health community. This effort has been remarkable. We sign this statement in solidarity with all scientists and health professionals in China who continue to save lives and protect global health during the challenge of the COVID-19 outbreak. We are all in this together, with our Chinese counterparts in the forefront, against this new viral threat. The rapid, open, and transparent sharing of data on this outbreak is now being threatened by rumours and misinformation around its origins. We stand together to strongly condemn conspiracy theories suggesting that COVID-19 does not have a natural origin. Scientists from multiple countries have published and analysed genomes of the causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),1Gorbalenya AE Baker SC Baric RS et al.Severe acute respiratory syndrome-related coronavirus: the species and its viruses—a statement of the Coronavirus Study Group.bioRxiv. 2020; (published online Feb 11. DOI: 2020.02.07.937862 (preprint).)Google Scholar and they overwhelmingly conclude that this coronavirus originated in wildlife,2Zhou P Yang X-L Wang X-G et al.A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature. 2020; (published online Feb 3.)DOI:10.1038/s41586-020-2012-7Crossref Scopus (14410) Google Scholar, 3Lu R Zhao X Li J et al.Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding.Lancet. 2020; (published online Jan 30.)https://doi.org/10.1016/S0140-6736(20)30251-8Summary Full Text Full Text PDF Scopus (8212) Google Scholar, 4Zhu N Zhang D Wang W et al.A novel coronavirus from patients with pneumonia in China, 2019.NEJM. 2020; (published online Jan 24.)DOI:10.1056/NEJMoa2001017Crossref PubMed Scopus (18588) Google Scholar, 5Ren L Wang Y-M Wu Z-Q et al.Identification of a novel coronavirus causing severe pneumonia in humans: a descriptive study.Chin Med J. 2020; (published online Feb 11.)DOI:10.1097/CM9.0000000000000722Crossref Scopus (862) Google Scholar, 6Paraskevis D Kostaki EG Magiorkinis G Panayiotakopoulos G Tsiodras S Full-genome evolutionary analysis of the novel corona virus (2019-nCoV) rejects the hypothesis of emergence as a result of a recent recombination event.Infect Genet Evol. 2020; (published online Jan 29.)DOI:10.1016/j.meegid.2020.104212Crossref PubMed Scopus (496) Google Scholar, 7Benvenuto D Giovanetti M Ciccozzi A Spoto S Angeletti S Ciccozzi M The 2019-new coronavirus epidemic: evidence for virus evolution.J Med Virol. 2020; (published online Jan 29.)DOI:10.1002/jmv.25688Crossref Scopus (452) Google Scholar, 8Wan Y Shang J Graham R Baric RS Li F Receptor recognition by novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS.J Virol. 2020; (published online Jan 29.)DOI:10.1128/JVI.00127-20Crossref Scopus (3161) Google Scholar, 9US Center for Disease Control and PreventionCoronavirus disease 2019 (COVID-19) situation summary.https://www.cdc.gov/coronavirus/2019-nCoV/summary.htmlDate: Feb 16, 2020Date accessed: February 8, 2020Google Scholar, 10Andersen KG Rambaut A Lipkin WI Holmes EC Garry RF The proximal origin of SARS-CoV-2.http://virological.org/t/the-proximal-origin-of-sars-cov-2/398Date: Feb 16, 2020Date accessed: February 17, 2020Google Scholar as have so many other emerging pathogens.11Bengis R Leighton F Fischer J Artois M Morner T Tate C The role of wildlife in emerging and re-emerging zoonoses.Rev Sci Tech. 2004; 23: 497-512PubMed Google Scholar, 12Woolhouse ME Gowtage-Sequeria S Host range and emerging and reemerging pathogens.Emerg Infect Dis. 2005; 11: 1842-1847Crossref PubMed Scopus (1029) Google Scholar This is further supported by a letter from the presidents of the US National Academies of Science, Engineering, and Medicine13NASEMThe National Academies of Science Engineering and Medicine of the USA. NAS, NAE, and NAM presidents' letter to the White House Office of Science and Technology Policy.https://www.nationalacademies.org/includes/NASEM%20Response%20to%20OSTP%20re%20Coronavirus_February%206,%202020.pdfDate: Feb 6, 2020Date accessed: February 7, 2020Google Scholar and by the scientific communities they represent. Conspiracy theories do nothing but create fear, rumours, and prejudice that jeopardise our global collaboration in the fight against this virus. We support the call from the Director-General of WHO to promote scientific evidence and unity over misinformation and conjecture.14WHODirector-General's remarks at the media briefing on 2019 novel coronavirus on 8 February 2020.https://www.who.int/dg/speeches/detail/director-general-s-remarks-at-the-media-briefing-on-2019-novel-coronavirus---8-february-2020Date: Feb 8, 2020Date accessed: February 18, 2020Google Scholar We want you, the science and health professionals of China, to know that we stand with you in your fight against this virus. We invite others to join us in supporting the scientists, public health professionals, and medical professionals of Wuhan and across China. Stand with our colleagues on the frontline! We speak in one voice. To add your support for this statement, sign our letter online. LM is editor of ProMED-mail. We declare no competing interests. Download .pdf (.12 MB) Help with pdf files Chinese translation of full text Addendum: competing interests and the origins of SARS-CoV-2In February, 2020, 27 public health experts co-authored a Correspondence in The Lancet ("Statement in support of the scientists, public health professionals, and medical professionals of China combatting COVID-19"),1 supporting health professionals and physicians in China during the early stages of the COVID-19 pandemic. In this letter, the authors declared no competing interests. Some readers have questioned the validity of this disclosure, particularly as it relates to one of the authors, Peter Daszak. Full-Text PDF Science, not speculation, is essential to determine how SARS-CoV-2 reached humansOn Feb 19, 2020, we, a group of physicians, veterinarians, epidemiologists, virologists, biologists, ecologists, and public health experts from around the world, joined together to express solidarity with our professional colleagues in China.1 Unsubstantiated allegations were being raised about the source of the COVID-19 outbreak and the integrity of our peers who were diligently working to learn more about the newly recognised virus, SARS-CoV-2, while struggling to care for the many patients admitted to hospital with severe illness in Wuhan and elsewhere in China. Full-Text PDF

This chapter describes the effects of malnutrition on the thymus gland, T lymphocytes, and cell-mediated immunity in humans. The size of the thymus gland relative to body weight is greatest at birth, and although total thymus mass increases slightly during the first year of life, its size stabilizes even as the progressive process of physiological involution begins. A study of thymus pathology in malnourished children from Senegal used microscopic examination with an image analyzer to quantify the fibrous tissue invading the gland and employed this criterion, in addition to descriptions of architecture and density of lymphoid cells and Hassal's corpuscles, to classify the degree of involution in malnourished subjects. Available human data demonstrate that protein-energy malnutrition causes major changes in thymus gland structure, with marked decreases in the number of cortical lymphocytes, fatty infiltration, fibrosis, and diminution and alteration of Hassal's corpuscles.

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.

1 Department of Philosophy, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America, 2 Institute of Child Health, University of Ibadan, Ibadan, Nigeria, 3 School of Law and School of Medicine, Stanford University, Stanford, California, United States of America, 4 National Emerging Infectious Diseases Laboratory, Boston University, Boston, Massachusetts, United States of America

The west African epidemic of Ebola virus disease in 2014–15 became a major tragedy because the global system under the International Health Regulations and the governance of research related to epidemics both failed to function as needed. Research started too late and yielded only one vaccine candidate with probable effectiveness.1US National Academies of Sciences, Engineering, and MedicineCommittee on Clinical Trials During the 2014–2015 Ebola Outbreak. Integrating clinical research into epidemic response: the Ebola experience. The National Academies Press, Washington, DC2017https://www.nap.edu/catalog/24739/integrating-clinical-research-into-epidemic-response-the-ebolaexperienceGoogle Scholar Today, the international framework for epidemic preparedness and response still does not include a role for research.2WHOInternational Health Regulations (2005). 3rd edn. World Health Organization, Geneva2016Google Scholar Future cross-national epidemics and Public Health Emergencies of International Concern are likely to involve pathogens that have no proven effective vaccines or specific therapeutics.3WHOEmergencies preparedness, response: priority diseases needing R&D actions.http://www.who.int/blueprint/priority-diseases/en/Date: 2017Google Scholar, 4Woolhouse MEJ Brierley L McCaffery C Lycett S Assessing the epidemic potential of RNA and DNA Viruses.Emerg Infect Dis. 2016; 22: 2037-2044Crossref PubMed Scopus (50) Google Scholar What can be done now to improve the prospects for scientific learning in the next epidemic? Concerned agencies have taken steps to better incorporate research into epidemic preparedness since the recent Ebola epidemic. These include the WHO R&D Blueprint with a priority list of diseases,3WHOEmergencies preparedness, response: priority diseases needing R&D actions.http://www.who.int/blueprint/priority-diseases/en/Date: 2017Google Scholar consultations to establish a Global Coordination Mechanism for research and development to prevent and respond to epidemics,5Chatham HouseEstablishing a global coordination mechanism for research and development to prevent and respond to epidemics: scoping meeting. Center on Global Health Security.https://www.chathamhouse.org/sites/files/chathamhouse/events/2016-11-10-Global-Coordination-Meeting-Summary.pdfDate: Nov 10, 2016Google Scholar and an International Working Group on Financing Preparedness.6International Working Group on Financing PreparednessFrom panic and neglect to investing in health security: financing pandemic preparedness at a national level. World Bank, Wellcome Trust, Conference edition.http://documents.worldbank.org/curated/en/979591495652724770/pdf/115271-REVISED-PUBLIC-IWG-Report-Conference-Edition-8-10-2017-low-res.pdfDate: May, 2017Google Scholar These are welcome actions, but not sufficient because global health governance arrangements do not deliver what is needed. A key challenge is to create more inclusive arrangements that involve a broader range of actors with interests that cross or ignore state boundaries, so that collective action can be taken through agreed rules and institutions.7Dodgson R Lee K Drager N Global health governance: a conceptual review. World Health Organization, Department of Health and Development, and London School of Hygiene & Tropical Medicine Discussion Paper, 2002http://apps.who.int/iris/bitstream/10665/68934/1/a85727_eng.pdfCrossref Google Scholar For research related to epidemics, key actors include not only national governments, but also WHO, other multilateral organisations, humanitarian organisations, philanthropic foundations, academic institutions, pharmaceutical and diagnostic companies, civil society organisations, and individual experts. These stakeholders were not well coordinated during the Ebola outbreak.1US National Academies of Sciences, Engineering, and MedicineCommittee on Clinical Trials During the 2014–2015 Ebola Outbreak. Integrating clinical research into epidemic response: the Ebola experience. The National Academies Press, Washington, DC2017https://www.nap.edu/catalog/24739/integrating-clinical-research-into-epidemic-response-the-ebolaexperienceGoogle Scholar They are connected in many formal and ad-hoc ways, yet have their own vested interests, ideologies, capabilities, mandates, and authorities. New governance models should be developed that account for these realities. A recent US National Academies of Sciences, Engineering, and Medicine committee report on clinical research in the Ebola epidemic includes recommendations to build workable governance and implementation arrangements for research during major epidemics—specifically for collaborative planning and coordination mechanisms between epidemics, and for rapid research response during an outbreak.1US National Academies of Sciences, Engineering, and MedicineCommittee on Clinical Trials During the 2014–2015 Ebola Outbreak. Integrating clinical research into epidemic response: the Ebola experience. The National Academies Press, Washington, DC2017https://www.nap.edu/catalog/24739/integrating-clinical-research-into-epidemic-response-the-ebolaexperienceGoogle Scholar, 8Keusch GT McAdam KPWJ Clinical trials during epidemics.Lancet. 2017; 389: 2455-2457Summary Full Text Full Text PDF PubMed Scopus (10) Google Scholar Building on principles for the governance of evidence,9Parkhurst J The politics of evidence: from evidence-based policy to the good governance of evidence. Routledge, New York, NY2017Google Scholar there remain important issues to address. Clarification of goals with the full range of key stakeholders is essential. Broad agreement must be reached on the importance of collecting valid clinical data and integrating research into emergency preparedness and response. Agreement on other goals may be difficult but important for determining the scope of the epidemic research agenda; building capacity for disease surveillance and response and country-level management of scientific, ethical, and legal review of research; ensuring that the complete set of costs and benefits are shared fairly; and holding organisations accountable for research and epidemic preparedness and response actions. Concerned agencies also need to agree on working principles. For interepidemic prioritisation and planning activities, it is important to use consensus building and deliberative processes that demonstrate legitimacy, inclusiveness, authority, and public accountability. These attributes build trust and help to raise and distribute funding for governance and implementation activities. Agreement on goals and working principles provides a basis for developing and deploying a much-needed rapid research and response capability in an emergency. Rapid response depends on abilities to coordinate operations and bring in specialised expertise, and the capability to support or undertake research during crisis.1US National Academies of Sciences, Engineering, and MedicineCommittee on Clinical Trials During the 2014–2015 Ebola Outbreak. Integrating clinical research into epidemic response: the Ebola experience. The National Academies Press, Washington, DC2017https://www.nap.edu/catalog/24739/integrating-clinical-research-into-epidemic-response-the-ebolaexperienceGoogle Scholar Conflicts of interest in research leadership functions were also highlighted during the Ebola outbreak, and should be addressed before the next crisis. The figure highlights pairs of research leadership functions that present conflicts of interest when done by the same organisation. Conflicts of interest arguably occurred during the Ebola outbreak (appendix). Should an agency that funds research on human beings lead the ethical review of the study, or conduct the study, or be involved in analysing the results? Should those conducting research lead in policy decision making or access to medical products? Future governance arrangements should not leave any organisation to have leadership roles that have intrinsic conflicts of interest. These are some of the questions that will be debated at the joint US National Academy of Medicine and Wellcome Trust meeting on Integrating Clinical Research into Epidemic Response in London, UK, on Oct 9, 2017. The Ebola epidemic teaches us that we should not reinforce business as usual in global health governance, with a sometimes unruly melange of global actors often jockeying for prominence.10Buse K Walt G An unruly mélange? Coordinating external resources to the health sector: a review.Soc Sci Med. 1997; 45: 449-463Crossref PubMed Scopus (85) Google Scholar Better coordinated and transparent processes are needed that will engage a broader range of stakeholders and facilitate efforts to agree on goals and working principles. The governance arrangements should distribute responsibilities to those agencies best positioned to lead key areas, while respecting national leadership, limiting conflicts of interest, and taking into consideration the interests, ideologies, power, and accountabilities of key stakeholders. The processes need to reinforce consensus building and learning, and provide a platform for decisive action during a crisis. The pathway will not be easy. But to fail is to invite chaos to the next global health crisis. GTK and KPWJM were Co-Chairs, and DHP, JC, SD, JL, MMM, OO, and FW-M were members, of the National Academies of Sciences, Engineering, and Medicine's Committee on Clinical Trials During the 2014–2015 Ebola Outbreak. We declare no other competing interests. Download .pdf (.24 MB) Help with pdf files Supplementary appendix

The consensus report of the US National Academies of Sciences, Engineering and Medicine for the first time evaluates the clinical trials on Ebola therapeutics and vaccines in Guinea, Sierra Leone, and Liberia during 2014–15. 1 US National Academies of Sciences, Engineering and MedicineCommittee on Clinical Trials During the 2014–2015 Ebola Outbreak. Integrating clinical research into epidemic response: the Ebola experience. The National Academies Press, Washington, DC2017https://www.nap.edu/catalog/24739/integrating-clinical-research-into-epidemic-response-the-ebola-experience Google Scholar The report presents seven recommendations for both interepidemic and epidemic periods to improve the likelihood that important new information on therapeutics and vaccines can be obtained during future epidemics (panel). This information is especially critical for infections such as Ebola virus disease because the only time efficacy and safety of drugs or vaccines can be studied in infected or at-risk human beings is during an outbreak. The recommendations are based on analysis of what happened in west Africa, and fall into three main categories: capacity strengthening, engaging communities, and international coordination and collaboration. PanelRecommendations by the Committee on Clinical Trials During the 2014–2015 Ebola Outbreak 1 US National Academies of Sciences, Engineering and MedicineCommittee on Clinical Trials During the 2014–2015 Ebola Outbreak. Integrating clinical research into epidemic response: the Ebola experience. The National Academies Press, Washington, DC2017https://www.nap.edu/catalog/24739/integrating-clinical-research-into-epidemic-response-the-ebola-experience Google Scholar 1Support the development of sustainable health systems and research capacities in low-income countries 2 •Develop memoranda of understanding to facilitate data collection and sharing •Provide resources to enable data collection and sharing at the start of an epidemic 3Facilitate capacity for rapid ethics reviews and legal agreements 4Ensure that capacity-strengthening efforts benefit the local population during an epidemic 5Enable the incorporation of research into national health systems 6 •Prioritise community engagement in research and response during an epidemic •Fund training and research into community engagement and communication for research and response 7 •Coordinate international efforts in research and development for infectious disease pathogens •Establish and implement a cooperative international clinical research agenda at the outset of an epidemic 1Support the development of sustainable health systems and research capacities in low-income countries 2 •Develop memoranda of understanding to facilitate data collection and sharing •Provide resources to enable data collection and sharing at the start of an epidemic 3Facilitate capacity for rapid ethics reviews and legal agreements 4Ensure that capacity-strengthening efforts benefit the local population during an epidemic 5Enable the incorporation of research into national health systems 6 •Prioritise community engagement in research and response during an epidemic •Fund training and research into community engagement and communication for research and response 7 •Coordinate international efforts in research and development for infectious disease pathogens •Establish and implement a cooperative international clinical research agenda at the outset of an epidemic Recognition matters: only one in ten awards given to womenReceiving an award is an accolade. Awards validate and bring visibility, help attract funding, hasten career advancement, and can consolidate career accomplishments. Yet, in the fields of public health and medicine, few women receive them. Between seven public health and medicine awards from diverse countries, the chances of a woman receiving a prize was nine out of 100 since their inception (appendix). Full-Text PDF WHO R&D Blueprint: a global coordination mechanism for R&D preparednessA report1 by the National Academies of Sciences, Engineering, and Medicine and the Comment in today's issue of The Lancet by Gerald T Keusch and colleagues2 outline how to improve the speed and effectiveness of clinical trial research before and during an epidemic. The report uses key lessons learned from the Ebola epidemic in west Africa. Full-Text PDF