Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe.

Yellow fever (YF) was one of the most dangerous infectious diseases of the 18th and 19th centuries, resulting in mass casualties in Africa and the Americas. The etiologic agent is yellow fever virus (YFV), and its live-attenuated form, YFV-17D, remains one of the most potent vaccines ever developed. During the first half of the 20th century, vaccination combined with mosquito control eradicated YFV transmission in urban areas. However, the recent 2016-2018 outbreaks in areas with historically low or no YFV activity have raised serious concerns for an estimated 400-500 million unvaccinated people who now live in at-risk areas. Once a forgotten disease, we highlight here that YF still represents a very real threat to human health and economies. As many gaps remain in our understanding of how YFV interacts with the human host and causes disease, there is an urgent need to address these knowledge gaps and propel YFV research forward.

The Yellow Fever Vaccine Misadventure of 1942.

In 1942, a hepatitis B outbreak occurred in the US Army after vaccination with contaminated lots of 17D yellow fever vaccine; long-term sequelae were surprisingly limited, and retrospective studies of carrier rates, cirrhosis, and hepatocellular carcinoma were found to be minimal. Later studies identified the contaminant as hepatitis B virus (HBV) in the human serum component of the vaccine. Other than 2 follow-up studies of long-term sequelae and reports within US Military archives, the event has never been fully elucidated in its proper historical context in the medical literature available through MEDLINE (PubMed). The outbreak resulted in nearly 50 000 clinical cases, including 29 000 cases of overt jaundice. More than 300 000 troops may have been infected with HBV. The decision to immunize troops received criticism, but the decision may have been reasonable, given the exigencies of an impending war and the possibility that yellow fever could spread to future theaters of war. The epidemic was the largest and most well-documented vaccine-related epidemic in history. Today, independent of war, globalization has actually increased the likelihood of yellow fever importations to vulnerable areas of the world.

How Brazil joined the quest for a yellow fever vaccine. Interview by Claudia Jurberg and Julia D'Aloisio..

Brazil recently announced an agreement between its Bio-Manguinhos vaccine unit and two US companies to research and develop a new yellow fever vaccine. Claudia Jurberg and Julia D'Aloisio talk to Jaime Benchimol about the controversial history of the development of the vaccine that benefits millions of people today.

Mortality and morbidity among military personnel and civilians during the 1930s and World War II from transmission of hepatitis during yellow fever vaccination: systematic review.

During World War II, nearly all US and Allied troops received yellow fever vaccine. Until May 1942, it was both grown and suspended in human serum. In April 1942, major epidemics of hepatitis occurred in US and Allied troops who had received yellow fever vaccine. A rapid and thorough investigation by the US surgeon general followed, and a directive was issued discontinuing the use of human serum in vaccine production. The large number of cases of hepatitis caused by the administration of this vaccine could have been avoided. Had authorities undertaken a thorough review of the literature, they would have discovered published reports, as early as 1885, of postvaccination epidemics of hepatitis in both men and horses. It would take 4 additional decades of experiments and epidemiological research before viruses of hepatitis A, B, C, D, and E were identified, their modes of transmission understood, and their genomes sequenced.

The yellow fever vaccine: a history.

After failed attempts at producing bacteria-based vaccines, the discovery of a viral agent causing yellow fever and its isolation in monkeys opened new avenues of research. Subsequent advances were the attenuation of the virus in mice and later in tissue culture; the creation of the seed lot system to avoid spontaneous mutations; the ability to produce the vaccine on a large scale in eggs; and the removal of dangerous contaminants. An important person in the story is Max Theiler, who was Professor of Epidemiology and Public Health at Yale from 1964-67, and whose work on virus attenuation created the modern vaccine and earned him the Nobel Prize.

[Cycles of German yellow fever research in the first half of the 20th century: protagonists and interests]. / Konjunkturen der deutschen Gelbfieberforschung in der ersten Hälfte des 20. Jahrhunderts: Akteure und Interessen.

This article examines for the case of yellow fever research in Germany in the first half of the 20th century how political and military conditions affected the interests of scientific research. As a tropical disease, yellow fever was unknown in Germany and very rare in the German colonies and thus of little scientific or political interest. But this changed once the National Socialists began pursuing their wars of conquest. In preparation for a new colonial empire and a military mission in Africa, yellow fever research became increasingly important. The chief beneficiary of this development was the Robert Koch-Institute in Berlin, where Eugen Haagen worked after his time as a researcher in the Yellow Fever Laboratory in New York. In collaboration with the army and the industry, he used human experiments in his efforts to develop a vaccine for mass production. Ultimately, the vaccine's application was prevented by the German surrender in North Africa.

Yellow fever and Max Theiler: the only Nobel Prize for a virus vaccine.

In 1951, Max Theiler of the Rockefeller Foundation received the Nobel Prize in Physiology or Medicine for his discovery of an effective vaccine against yellow fever--a discovery first reported in the JEM 70 years ago. This was the first, and so far the only, Nobel Prize given for the development of a virus vaccine. Recently released Nobel archives now reveal how the advances in the yellow fever vaccine field were evaluated more than 50 years ago, and how this led to a prize for Max Theiler.

[Yellow fever]. / La febbre amarilla.

After the discovery of the New World, yellow fever proved to be an important risk factor of morbidity and mortality for Caribbean populations. In the following centuries epidemic risk, expanded by sea trade and travel, progressively reached the settlements in North America and Brazil as well as the Atlantic seaboard of tropical and equatorial Africa. In the eighteenth century and the first half of the nineteenth century epidemics of yellow fever were reported in some coastal towns in the Iberian peninsula, French coast, Great Britain and Italy, where, in 1804 at Leghorn, only one epidemic was documented. Prevention and control programs against yellow fever, developed at the beginning of the twentieth century in Cuba and in Panama, were a major breakthrough in understanding definitively its aetiology and pathogenesis. Subsequently, further advances in knowledge of yellow fever epidemiology were obtained when French scientists, working in West and Central Africa, showed that monkeys were major hosts of the yellow fever virus (the wild yellow fever virus), besides man. In addition, advances in research, contributing to the development of vaccines against the yellow fever virus in the first half of the nineteenth century, are reported in this paper.

A vacina contra a febre amarela: uma longa história inacabada / Yellow fever vaccine: a long unfinished story

Mostra como a história da vacina contra a febre amarela é uma história que deságua em pontas inacabadas: iniciou-se, do ponto de vista institucional, com a Fundação Rockefeller, teve sua continuidade garantida pelo Instituto Oswaldo Cruz, e foi herdada por Bio-Manguinhos que se empenha para assegurar a transmissão desse legado.

A vacina contra a febre amarela: uma longa história inacabada / Yellow fever vaccine: a long unfinished story

Mostra como a história da vacina contra a febre amarela é uma história que deságua em pontas inacabadas: iniciou-se, do ponto de vista institucional, com a Fundação Rockefeller, teve sua continuidade garantida pelo Instituto Oswaldo Cruz, e foi herdada por Bio-Manguinhos que se empenha para assegurar a transmissão desse legado.

Yellow fever: the recurring plague.

Despite the availability of a safe and efficacious vaccine, yellow fever (YF) remains a disease of significant public health importance, with an estimated 200,000 cases and 30,000 deaths annually. The disease is endemic in tropical regions of Africa and South America; nearly 90% of YF cases and deaths occur in Africa. It is a significant hazard to unvaccinated travelers to these endemic areas. Virus transmission occurs between humans, mosquitoes, and monkeys. The mosquito, the true reservoir of YF, is infected throughout its life, and can transmit the virus transovarially through infected eggs. Man and monkeys, on the other hand, play the role of temporary amplifiers of the virus available for mosquito infection. Recent increases in the density and distribution of the urban mosquito vector, Aedes aegypti, as well as the rise in air travel increase the risk of introduction and spread of yellow fever to North and Central America, the Caribbean, the Middle East, Asia, Australia, and Oceania. It is an acute infectious disease characterized by sudden onset with a two-phase development, separated by a short period of remission. The clinical spectrum of yellow fever varies from very mild, nonspecific, febrile illness to a fulminating, sometimes fatal disease with pathognomic features. In severe cases, jaundice, bleeding diathesis, with hepatorenal involvement are common. The case fatality rate of severe yellow fever is 50% or higher. The pathogenesis and pathophysiology of the disease are poorly understood and have not been the subject of modern clinical research. There is no specific treatment for YF, making the management of YF patients extremely problematic. YF is a zoonotic disease that cannot be eradicated, therefore instituting preventive vaccination through routine childhood vaccination in endemic countries, can significantly reduce the burden of the disease. The distinctive properties of lifelong immunity after a single dose of yellow fever vaccination are the basis of the new applications of yellow fever 17D virus as a vector for foreign genes, "the chimeric vaccine,' and the promise of developing new vaccines against other viruses, and possibly against cancers.

De ratones, vacunas y hombres: el programa de fiebre amarilla de la Fundación Rockefeller en Colombia, 1932-1948 / On mice, vaccines and men: the yellow fever program of the Rockefeller Foundation in Colombia, 1932-1948

Explora las actividades del programa cooperativo de fiebre amarilla de la Fundación Rockefeller en Colombia y sus alcances y muestra cómo la FR construyó a la fiebre amarilla como un problema continental y una prioridad de salud pública de los países americanos, presionando así la inversión en la investigación básica en la que estaba interesada, a costa de otras acciones de salud pública más urgentes. Por su parte, las autoridades de salud pública emplearon el prestigio y los recursos del programa para consolidar su posición frente al estado y fortalecer el papel de la investigación en salud pública. (AU)