Discovery and Description of Ebola Zaire Virus in 1976 and Relevance to the West African Epidemic During 2013-2016.

BACKGROUND: In 1976, the first cases of Ebola virus disease in northern Democratic Republic of the Congo (then referred to as Zaire) were reported. This article addresses who was responsible for recognizing the disease; recovering, identifying, and naming the virus; and describing the epidemic. Key scientific approaches used in 1976 and their relevance to the 3-country (Guinea, Sierra Leone, and Liberia) West African epidemic during 2013-2016 are presented. METHODS: Field and laboratory investigations started soon after notification, in mid-September 1976, and included virus cell culture, electron microscopy (EM), immunofluorescence antibody (IFA) testing of sera, case tracing, containment, and epidemiological surveys. In 2013-2016, medical care and public health work were delayed for months until the Ebola virus disease epidemic was officially declared an emergency by World Health Organization, but research in pathogenesis, clinical presentation, including sequelae, treatment, and prevention, has increased more recently. RESULTS: Filoviruses were cultured and observed by EM in Antwerp, Belgium (Institute of Tropical Medicine); Porton Down, United Kingdom (Microbiological Research Establishment); and Atlanta, Georgia (Centers for Disease Control and Prevention). In Atlanta, serological testing identified a new virus. The 1976 outbreak (280 deaths among 318 cases) stopped in <11 weeks, and basic clinical and epidemiological features were defined. The recent massive epidemic during 2013-2016 (11 310 deaths among 28 616 cases) has virtually stopped after >2 years. Transmission indices (R0) are higher in all 3 countries than in 1976. CONCLUSIONS: An international commission working harmoniously in laboratories and with local communities was essential for rapid success in 1976. Control and understanding of the recent West African outbreak were delayed because of late recognition and because authorities were overwhelmed by many patients and poor community involvement. Despite obstacles, research was a priority in 1976 and recently.

The role of research in viral disease eradication and elimination programs: lessons for malaria eradication.

By examining the role research has played in eradication or regional elimination initiatives for three viral diseases--smallpox, poliomyelitis, and measles--we derive nine cross-cutting lessons applicable to malaria eradication. In these initiatives, some types of research commenced as the programs began and proceeded in parallel. Basic laboratory, clinical, and field research all contributed notably to progress made in the viral programs. For each program, vaccine was the lynchpin intervention, but as the programs progressed, research was required to improve vaccine formulations, delivery methods, and immunization schedules. Surveillance was fundamental to all three programs, whilst polio eradication also required improved diagnostic methods to identify asymptomatic infections. Molecular characterization of pathogen isolates strengthened surveillance and allowed insights into the geographic source of infections and their spread. Anthropologic, sociologic, and behavioural research were needed to address cultural and religious beliefs to expand community acceptance. The last phases of elimination and eradication became increasingly difficult, as a nil incidence was approached. Any eradication initiative for malaria must incorporate flexible research agendas that can adapt to changing epidemiologic contingencies and allow planning for posteradication scenarios.

Prereferral rectal artesunate for treatment of severe childhood malaria: a cost-effectiveness analysis.

BACKGROUND: Severely ill patients with malaria with vomiting, prostration, and altered consciousness cannot be treated orally and need injections. In rural areas, access to health facilities that provide parenteral antimalarial treatment is poor. Safe and effective treatment of most severe malaria cases is delayed or not achieved. Rectal artesunate interrupts disease progression by rapidly reducing parasite density, but should be followed by further antimalarial treatment. We estimated the cost-effectiveness of community-based prereferral artesunate treatment of children suspected to have severe malaria in areas with poor access to formal health care. METHODS: We assessed the cost-effectiveness (in international dollars) of the intervention from the provider perspective. We studied a cohort of 1000 newborn babies until 5 years of age. The analysis assessed how the cost-effectiveness results changed with low (25%), moderate (50%), high (75%), and full (100%) referral compliance and intervention uptake. FINDINGS: At low intervention uptake and referral compliance (25%), the intervention was estimated to avert 19 disability-adjusted life-years (DALYs; 95% CI 16-21) and to cost I$1173 (95% CI 1050-1297) per DALY averted. Under the full uptake and compliance scenario (100%), the intervention could avert 967 DALYs (884-1050) at a cost of I$77 (73-81) per DALY averted. INTERPRETATION: Prereferral artesunate treatment is a cost-effective, life-saving intervention, which can substantially improve the management of severe childhood malaria in rural African settings in which programmes for community health workers are in place. FUNDING: The Disease Control Priorities Project; Fogarty International Center; US National Institutes of Health; and the Peter Paul Career Development Professorship, Boston University.

Using the entomological inoculation rate to assess the impact of vector control on malaria parasite transmission and elimination.

BACKGROUND: Prior studies have shown that annual entomological inoculation rates (EIRs) must be reduced to less than one to substantially reduce the prevalence of malaria infection. In this study, EIR values were used to quantify the impact of insecticide-treated bed nets (ITNs), indoor residual spraying (IRS), and source reduction (SR) on malaria transmission. The analysis of EIR was extended through determining whether available vector control tools can ultimately eradicate malaria. METHOD: The analysis is based primarily on a review of all controlled studies that used ITN, IRS, and/or SR and reported their effects on the EIR. To compare EIRs between studies, the percent difference in EIR between the intervention and control groups was calculated. RESULTS: Eight vector control intervention studies that measured EIR were found: four ITN studies, one IRS study, one SR study, and two studies with separate ITN and IRS intervention groups. In both the Tanzania study and the Solomon Islands study, one community received ITNs and one received IRS. In the second year of the Tanzania study, EIR was 90% lower in the ITN community and 93% lower in the IRS community, relative to the community without intervention; the ITN and IRS effects were not significantly different. In contrast, in the Solomon Islands study, EIR was 94% lower in the ITN community and 56% lower in the IRS community. The one SR study, in Dar es Salaam, reported a lower EIR reduction (47%) than the ITN and IRS studies. All of these vector control interventions reduced EIR, but none reduced it to zero. CONCLUSION: These studies indicate that current vector control methods alone cannot ultimately eradicate malaria because no intervention sustained an annual EIR less than one. While researchers develop new tools, integrated vector management may make the greatest impact on malaria transmission. There are many gaps in the entomological malaria literature and recommendations for future research are provided.

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.

Responding to the Challenge of the Dual COVID-19 and Ebola Epidemics in the Democratic Republic of Congo-Priorities for Achieving Control.

As of June 11, 2020, the Democratic Republic of the Congo (DRC) has reported 4,258 COVID-19 cases with 90 deaths. With other African countries, the DRC faces the challenge of striking a balance between easing public health lockdown measures to curtail the spread of SARS-CoV-2 and minimizing both economic hardships for large sectors of the population and negative impacts on health services for other infectious and noninfectious diseases. The DRC recently controlled its tenth Ebola virus disease (EVD) outbreak, but COVID-19 and a new EVD outbreak beginning on June 1, 2020 in the northwest Équateur Province have added an additional burden to health services. Although the epidemiology and transmission of EVD and COVID-19 differ, leveraging the public health infrastructures and experiences from coordinating the EVD response to guide the public health response to COVID-19 is critical. Building on the DRC's 40 years of experience with 10 previous EVD outbreaks, we highlight the DRC's multi-sectoral public health approach to COVID-19, which includes community-based screening, testing, contact-tracing, risk communication, community engagement, and case management. We also highlight remaining challenges and discuss the way forward for achieving control of both COVID-19 and EVD in the DRC.

Eradicating malaria.

The renewed interest in malaria research and control is based on the intolerable toll this disease takes on young children and pregnant women in Africa and other vulnerable populations; 150 to 300 children die each hour from malaria amounting to 1 to 2 million deaths yearly. Malaria-induced neurologic impairment, anemia, hypoglycemia, and low birth weight imperil normal development and survival. Resistance of Plasmodium falciparum to drugs and Anopheles mosquitoes to insecticides has stimulated discovery and development of artemisinin-based combination treatments (ACTs) and other drugs, long-lasting insecticide-treated bednets (with synthetic pyrethroids) and a search for non-toxic, long-lasting, affordable insecticides for indoor residual spraying (IRS). Malaria vaccine development and testing are progressing rapidly and a recombinant protein (RTS,S/AS02A) directed against the circumsporozoite protein is soon to be in Phase 3 trials. Support for malaria control, research, and advocacy through the Global Fund for HIV/AIDS, Tuberculosis and Malaria, the U.S. President's Malaria Initiative, the Bill & Melinda Gates Foundation, WHO and other organizations is resulting in decreasing morbidity and mortality in many malarious countries. Sustainability of effective programs through training and institution strengthening will be the key to malaria elimination coupled with improved surveillance and targeted research.

Falsified and Substandard Drugs: Stopping the Pandemic.

Falsified and substandard medicines are associated with tens of thousands of deaths, mainly in young children in poor countries. Poor-quality drugs exact an annual economic toll of up to US$200 billion and contribute to the increasing peril of antimicrobial resistance. The WHO has emerged recently as the global leader in the battle against poor-quality drugs, and pharmaceutical companies have increased their roles in assuring the integrity of drug supply chains. Despite advances in drug quality surveillance and detection technology, more efforts are urgently required in research, policy, and field monitoring to halt the pandemic of bad drugs. In addition to strengthening international and national pharmaceutical governance, in part by national implementation of the Model Law on Medicines and Crime, a quantifiable Sustainable Development Goal target and an international convention to insure drug quality and safety are urgent priorities.

Fifty Years of Supporting Global Health Research at the NIH Fogarty International Center.

For 50 years, the Fogarty International Center (FIC) has built research capacity particularly in low and middle-income countries responding to national and global public health priorities. Established in 1968 in honor of U.S. Congressman John E. Fogarty, FIC is one of 27 Institutes and Centers at the U.S. National Institutes of Health (NIH). Initially created in response to the HIV/AIDS pandemic in the 1980s and emerging infectious diseases in the 1990s, the Center provided training for approximately 6,000 health scientists from more than 100 countries including 1,000 from the U.S. Current programs are catalytic, addressing national and international institutional capacity strengthening in HIV and other infectious diseases, environmental and occupational health, research ethics, brain disorders, trauma and injury and other non-communicable diseases, tobacco, health systems implementation research, and medical education. Since 1988, FIC provided over $1.5 billion in extramural grants leveraging its relatively modest $50 million extramural budget by $20-$30 million annually. FIC-trained scientists and public health leaders led key studies about malaria vaccines and AIDS prevention trials, became directors of national HIV/AIDS programs, and achieved leadership positions such as Minister of Health. Between 2009 and 2015, FIC cited-papers averaged approximately 1.1% of the NIH total, in comparison to the FIC budget, which averaged only 0.22% of the NIH budget. While maintaining strong commitments to respond to global health threats caused by communicable diseases, FIC is training the next generation of global health researchers focusing on chronic diseases, implementation science and epidemic modeling needed to predict and help contain future global pandemics.

Advancement of global health: key messages from the Disease Control Priorities Project.

The Disease Control Priorities Project (DCPP), a joint project of the Fogarty International Center of the US National Institutes of Health, the WHO, and The World Bank, was launched in 2001 to identify policy changes and intervention strategies for the health problems of low-income and middle-income countries. Nearly 500 experts worldwide compiled and reviewed the scientific research on a broad range of diseases and conditions, the results of which are published this week. A major product of DCPP, Disease Control Priorities in Developing Countries, 2nd edition (DCP2), focuses on the assessment of the cost-effectiveness of health-improving strategies (or interventions) for the conditions responsible for the greatest burden of disease. DCP2 also examines crosscutting issues crucial to the delivery of quality health services, including the organisation, financial support, and capacity of health systems. Here, we summarise the key messages of the project.

Malaria surveillance counts.

Clinical and epidemiologic surveillance of malaria cases and deaths is required to follow the progress of the reinvigorated malaria control programs nationally and internationally. Current recording, transmittal, analysis, feedback, and use of malaria surveillance information is delayed and imprecise: substantially < 10% of the malaria cases and deaths are being reported. Improvements are occurring, but more emphasis should be placed on prompt, accurate diagnosis, patient management, and recording of clinical manifestations at hospitals. Neurologic signs, severe anemia, metabolic changes, hyperparasitemia, and concurrent sepsis are medical emergencies and require proper clinical and laboratory detection; equipment, reagents, supervision, and certification of laboratorians and clinicians are necessary. Birth weight should also be a major measure of progress in malarial control and overall prenatal care. Although malaria is the most frequent diagnosis at outpatient clinics and hospitals in Africa, co-existing conditions also mandate improved diagnosis, treatment, and registration. Monthly transmittal of information from health units and collation, analysis and feedback through electronic reporting systems using modern information technologies are necessary for resource planning and staff motivation. Denominators to compute rates of illness and death require accurate censuses of communities from which patients come to health units: specialized disease and demographic household surveys designed and performed by nationals are needed to complement hospital-based numerator data. Plasmodium falciparum and P. vivax should be distinguished in the laboratory; the former causes the greatest mortality but the latter is increasingly recognized as a major peril. Because vector control is now a major component of all malaria control programs, there is an urgent need to monitor anopheline sensitivity to insecticides and entomologic inoculation rates. Where interrupting transmission is a goal, parasite rates in groups at greatest risk should be performed. Continual monitoring of plasmodial sensitivity to drugs is necessary using WHO protocols. Human, entomological, and parasitological surveillance must be performed at the same time in the same places and the information shared widely and used for improving control strategies and tactics. These surveillance priorities require training, provision of equipment, supervision, and commitment to sustainability by national authorities and international collaborators and donors.

Dichlorodiphenyltrichloroethane (DDT) for indoor residual spraying in Africa: how can it be used for malaria control?

In 2006, the World Health Organization issued a position statement promoting the use of indoor residual spraying (IRS) with dichlorodiphenyltrichloroethane (DDT) for malaria vector control in epidemic and endemic areas. Other international organizations concurred because of the great burden of malaria and the relative ineffectiveness of current treatment and control strategies. Although the Stockholm Convention of 2001 targeted DDT as 1 of 12 persistent organic pollutants for phase-out and eventual elimination, it allowed a provision for its continued indoor use for disease vector control. Although DDT is a low-cost antimalarial tool, the possible adverse human health and environmental effects of exposure through IRS must be carefully weighed against the benefits to malaria control. This article discusses the controversy surrounding the use of DDT for IRS; its effective implementation in Africa; recommendations for deployment today, and training, monitoring, and research needs for effective and sustainable implementation. We consider the costs and cost effectiveness of IRS with DDT, alternative insecticides to DDT, and the importance of integrated vector control if toxicity, resistance, and other issues restrict its use.

The other 'neglected' eradication programme: achieving the final mile for Guinea worm disease eradication?

Guinea worm disease is one of two diseases targeted for eradication, the other being polio. Since the late 1980s, the number of new cases per year has been reduced from approximately one million to some 25 000 in 2006. However, there was an increase from 2005 owing to improved surveillance in Sudan and problems in Ghana. The International Commission argues that more resources are required to ensure that the goal of eradication is completed. Elimination of transmission throughout Asia has now been confirmed and the disease is now confined to a small number of African countries requiring increased efforts to achieve the global goal.

Building global environmental health capacity through international scientific cooperation and partnerships.

Sponsored by the Fogarty International Center, the NIEHS, and NIOSH, the International Training and Research Program in Environmental and Occupational Health (ITREOH) supports training of health professionals worldwide. The program grants awards to U.S. academic institutions, which partner with institutions in low- and middle-income countries to address health threats of regional importance.