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Yellow Fever: Past and Present

1942, Innoculating eggs with yellow fever vaccine. USPHS (United States Public Health Service) Rocky Mountain Laboratory, Hamilton, Montana
Inoculating eggs with yellow fever vaccine, 1942. USPHS (the United States Public Health Service) Rocky Mountain Laboratory, Hamilton, Montana. Photographer: John Vachon


written by Dr. Jaclynn Moskow

What is Yellow Fever?

The yellow fever virus, a flavivirus, is transmitted via the bites of various mosquito species. The disease has an average incubation period of 3 to 6 days. The clinical presentation of yellow fever can vary greatly, ranging from a self-limited flu-like illness to overwhelming hemorrhagic fever – with a case fatality rate of 50%. Approximately 55% of yellow fever infections are asymptomatic, 33% are categorized as mild, and 12% severe (1).

Diagram of Symptoms of Yellow fever patient

Yellow fever generally manifests with the acute onset of fever, headache, backache, myalgia, and vomiting. Conjunctival infection may be seen, accompanied by facial flushing, relative bradycardia (Faget’s sign), and leukopenia. In some cases, fever and other symptoms may remit for a few hours to several days. Upon return of symptoms, icteric hepatitis and a hemorrhagic diathesis may follow with epistaxis, bleeding from the gums and gastrointestinal tract, and petechial and purpuric hemorrhages. Weakness, prostration, protracted vomiting, and albuminuria may also be noted. At this stage, patients will experience renal failure, myocardial dysfunction, necro-hemorrhagic pancreatitis, and seizures.

Yellow fever has a case fatality rate of 10 to 60% within 7 days of disease onset (1).



The Origin and Spread of Yellow Fever

Phylogenetic analyses indicate that yellow fever originated in Africa within the last 1,500 years. Its spread to the Americas coincided with the trans-Atlantic slave trade that began during the 16th century. It is likely that mosquitoes carrying yellow fever were imported into the Americas via slave ships (2). Significant outbreaks followed as the virus was introduced into populations with no pre-existing immunity. During the 18th and 19th centuries, approximately 25 major outbreaks claimed the lives of hundreds of thousands in New York City, Philadelphia, Baltimore, and New Orleans (3). Yellow fever also arrived in Europe during this time, with notable outbreaks occurring at Spanish, Portuguese, French, and British seaports (4).

It is estimated that for every soldier who died in battle during the Spanish-American War, 13 died of yellow fever (5). Yellow fever also killed many thousands during the construction of the Panama Canal. 

William C. Gorgas (1854-1920), on the site of Panama Canal construction.
William C. Gorgas (1854-1920), on the site of Panama Canal construction. As a U.S. Army surgeon during the Spanish American War, he established methods for eradicating mosquitoes hence reducing yellow fever and malaria among soldiers in Cuba. In 1904 he applied these techniques to control disease among the Panama Canal workers. Ca. 1910.



Development of a Vaccine for Yellow Fever

USA - CIRCA 1940: A stamp printed in USA shows portrait of Dr. Walter Reed, series Scientists, circa 1940

Early attempts to develop a vaccine for yellow fever resulted in the deaths of several test subjects and researchers. In 1900, a team led by Major Walter Reed traveled to Cuba to study the disease. At this point, the medical community was largely dismissive of the theory that mosquitos were the vectors of transmission for yellow fever. Working under the assumption that the mosquito theory was indeed incorrect, Reed’s team began experimenting with mosquitos and volunteers. After receiving criticism about using human test subjects, some team members decided to instead experiment on themselves. Unfortunately, this resulted in the death of physician-scientist Dr. Jesse Lazear – but with his death, the mosquito theory began to gain acceptance (6). 

Despite the death of Dr. Lazear, yellow fever research on human test subjects continued. The Reed team conducted a second and third set of mosquito experiments, offering financial compensation in the form of gold to study participants (6). After learning that none of these latest Reed study participants had died, Cuban physician Dr. John Guiteras began his own experiments. Unfortunately, three of his 42 test subjects succumbed to the illness, and with this, yellow fever research in Cuba came to a halt (7).

Subsequent efforts to control yellow fever centered on reducing mosquito populations as opposed to vaccine development, until 1918 when the Rockefeller Foundation began conducting yellow fever research. Within a year, Japanese scientist Dr. Hideyo Noguchi, who was working with the Foundation, announced that he had successfully developed a vaccine. Individuals in the United States, Latin America, and the French African colonies began receiving his vaccine, but the legitimacy of the studies leading to its development were soon called into question, and ultimately the vaccine was pulled (7).

The Rockefeller Foundation continued its efforts, and in 1925, they sent investigators to Lagos to determine if the African and South American diseases were caused by the same pathogen. Unfortunately, this trip resulted in three more investigators contracting and dying from yellow fever, including Dr. Noguchi. Nonetheless, the Rockefeller Foundation persisted, and a few years later, another candidate vaccine was developed – this time from efforts led by Dr. Max Theiler (7).

Despite the history of physician deaths related to yellow fever experimentation, Brazilian physician Dr. Bruce Wilson volunteered to receive the first dose of the Theiler vaccine. It was designated a success, and mass production began. Soon after, the Pasteur Institute developed their own vaccine, and for the next several years, the Rockefeller Foundation vaccine was used in the West as well as in England, and the Pasteur Institute vaccine used in France and its African colonies (7).

During World War II, the Rockefeller Foundation vaccine was given to almost all US soldiers. Unfortunately, the vaccine contained blood serum, and vaccination efforts resulted in approximately 330,000 soldiers contracting hepatitis B virus infection (8). Blood serum was subsequently removed as a component of the vaccine, and in 1953 a yellow fever vaccine was licensed for civilian use in the US (9). Use of the Pasteur Institute vaccine eventually ceased due to cases of postvaccinal encephalitis, but a variant of the Rockefeller foundation vaccine is still used today. Dr. Theiler received the Nobel Prize in Physiology or Medicine for his critical role in its development.


Yellow Fever in 2021

Yellow fever vaccination est. coverage 1980 - 2019

Today, the Centers for Disease Control and Prevention (CDC) recommends vaccination against yellow fever for individuals 9 months and older and who are traveling to or living in areas at risk in Africa and South America (10). It is a live attenuated vaccine, and thus contraindicated in patients who are immunocompromised. The vaccine is highly effective, with a median seroconversion rate of 99% (range 81–100%) in clinical trials (11).

Yellow fever is currently estimated to affect 200,000 people each year, resulting in 30,000 deaths, with 90% of cases occurring in Africa (12). Recent outbreaks have occurred in Brazil, Angola, Nigeria, and the Democratic Rep. of Congo. If you have a GIDEON account, click here to explore the Yellow Fever outbreak map. There are ongoing efforts to expand accessibility to the vaccine in these regions, as well as to implement additional vector control programs. 

The last outbreak of Yellow Fever in the United States occurred in 1905 (13). Yellow fever outbreaks ceased in Europe after World War II, when, for unknown reasons, the Aedes aegypti mosquito disappeared (14).

The absence of yellow fever in Asia is not fully understood. Some have speculated that differences in mosquito species may play a role. Another theory is that there may be a cross-immunity between yellow fever and other flaviviruses endemic to Asia, such as dengue fever. A third theory is that yellow fever has simply never been introduced into Asia (2).




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(1) “Yellow fever”, GIDEON Informatics, Inc, 2021. [Online]. Available:

(2) Cathey and J. Marr, “Yellow fever, Asia and the East African slave trade”, Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 108, no. 5, pp. 252-257, 2014. Available: 10.1093/trstmh/tru043 

(3) F. Douam and A. Ploss, “Yellow Fever Virus: Knowledge Gaps Impeding the Fight Against an Old Foe”, Trends in Microbiology, vol. 26, no. 11, pp. 913-928, 2018. Available: 10.1016/j.tim.2018.05.012 

(4) M. Morillon, B. Marfart, and T. Matton, “Yellow fever in Europe in 19th Century”, Ecological Aspects of Past Settlement in Europe. P. Bennike, pp. 211-222, 2002.

(5) Staples, “Yellow Fever: 100 Years of Discovery”, JAMA, vol. 300, no. 8, p. 960, 2008. Available: 10.1001/jama.300.8.960 

(6) “Politics of Participation: Walter Reed’s Yellow-Fever Experiments”, AMA Journal of Ethics, vol. 11, no. 4, pp. 326-330, 2009. Available: 10.1001/virtualmentor.2009.11.4.mhst1-0904

(7) J. Frierson. “The yellow fever vaccine: a history”, Yale J Biol Med, vol. 83, no. 2, pp. 77-85, 2010

(8) M. Furmanski. “Unlicensed vaccines and bioweapon defense in World War II”, JAMA, vol. 282, no. 9, p. 822, 1999

(9) “Historic Dates and Events Related to Vaccines and Immunization”,, 2021. [Online]. Available:

(10)”Yellow Fever Vaccine Recommendations”, Centers for Disease Control and Prevention, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Division of Vector-Borne Diseases (DVBD), 2021. [Online]. Available:

(11) J. Staples, A. Barrett, A. Wilder-Smith and J. Hombach, “Review of data and knowledge gaps regarding yellow fever vaccine-induced immunity and duration of protection”, npj Vaccines, vol. 5, no. 1, 2020. Available: 10.1038/s41541-020-0205-6 

(12) “Yellow Fever”, Centers for Disease Control and Prevention, Global Health, 2018. [Online]. Available:

(13) K. Patterson, “Yellow fever epidemics and mortality in the United States, 1693–1905”, Social Science & Medicine, vol. 34, no. 8, pp. 855-865, 1992. Available: 10.1016/0277-9536(92)90255-o 

(14) “Facts about yellow fever”, European Centre for Disease Prevention and Control, 2021. [Online]. Available:



Histoplasmosis in Travelers

In 2019, several Canadian tourists acquired histoplasmosis while exploring caves in Cuba.  The Gideon database maintains an ongoing record of all cross-border Infectious Diseases events, including importation of animals and foods associated with zoonotic disease. [1-3]

As of 2019, 76 episodes of histoplasmosis had been associated with travel, involving at least 574 individual cases (8 fatal).  18 of these events were related to cave exposure, including two involving caves in Cuba.  Four publications described acquisition of histoplasmosis by Canadian travelers – two involving cave exposure.

In the following screen-shot, the frame to the left displays an interactive chronicle of cross-border histoplasmosis.  Users can sort data by year of event, country of exposure / origin, etc.  In this example I’ve selected “Setting” in order to study cases related to “cave exposure.”  Additional details and electronically-linked references appear when the user clicks on “Show event notes”


  1. Gideon Online.
  2. Berger S. Histoplasmosis: Global Status, 2019. Gideon e-books,
  3. Berger S. GIDEON Guide to Cross Border Infections, 2019. 256 pages, 134 tables, 4,543 references.

Note featured on ProMED

African Trypanosomiasis: Crossing Borders

141 individual importations (193 patients) of African trypanosomiasis are listed by Gideon  Ten of these patients acquired the disease in Zambia, and 27 were treated in South Africa.

As of February, 2019 the Gideon web application and e-book series [1,2] list 2,718 individual cross-border events, arranged in 134 charts – by disease and country.  Charts also include importation of infected animals (ie, rabid dogs) and contaminated foods and other vehicles which resulted in outbreaks.  Charts in the web application are interactive, and allow the user to sort data according to country, year, number of cases, etc.  In the following screen shots, I have sorted the African trypanosomiasis chart to display cases originating in Zambia (upper box) and cases imported into South Africa (lower box)


  1. Berger S. GIDEON Guide to Cross Border Infections, 2019. 256 pages , 134 tables , 4,543 references. Gideon e-books,
  2. Berger S. African Trypanosomiasis: Global Status, 2019. 84 pages , 40 graphs , 906 references. Gideon e-books,


Mayaro Virus Disease and Travel

As of April, 2018 eleven cases of travel-associated Mayaro virus infection have been reported (see chart below). [1,2]  The current report on ProMED is the third to have originated in Peru.  A user-generated Gideon chart comparing the clinical features of several mosquito-borne viral diseases of Peru (Dengue, Chikungunya, Oropouche, Mayaro, Group C viruses and Zika) is also displayed.

                                                            Note:  Group C  zoonotic viruses of Peru = Ataqui, Iataya, Murutucu, Caraparu and Apeu


  1. Berger SA. Gideon Guide to Cross Border Infections, 2018. 237 pages, 133 tables, 4,061 references. Gideon e-books,
  2. Berger SA. Infectious Diseases of Peru, 2018. 367 pages, 100 graphs, 1,089 references. Gideon e-books,

New Video tutorials for Outbreaks, Surveys and Cross Border Events

Dr. Steve Berger has release new videos to review how to use the Outbreaks, Surveys and Cross Border Events Public Health features of GIDEON.

They are included below:

Crimean-Congo Hemorrhagic Fever and Travel

Reports of Crimean-Congo hemorrhagic fever (CCHF) related to travel are rare. The following chronology is abstracted from Gideon and the Gideon e-book series. [1]

1985 – South Africa ex. Democratic Republic of Congo (fatal).
1986 – South Africa ex. Tanzania (nonfatal)
1997 – An English traveler died of probable CCHF contracted in Zimbabwe.
2001 – A German tourist acquired Crimean-Congo hemorrhagic fever in Bulgaria.
2004 – A case of imported Crimean-Congo hemorrhagic fever (nonfatal) was reported in a traveler returning to France from Senegal. Infection in a second French national was diagnosed locally in Senegal.
2009 – An American soldier died in a hospital in Germany after contracting Crimean-Congo hemorrhagic fever in Afghanistan.
2011 – An outbreak (4 cases) in a Pakistan hospital was related to an index patient who had arrived from Afghanistan.
2012 – A patient died of Crimean-Congo hemorrhagic fever in Scotland following acquisition of the disease in Afghanistan.
2013 – A woman died of Crimean-Congo hemorrhagic fever in Uganda following contact with her infected husband in South Sudan.
2014 – A British traveler acquired Crimean-Congo hemorrhagic fever in Bulgaria.

1. Berger SA. Crimean-Congo Hemorrhagic Fever: Global Status, 2014. 41 pages, 21 graphs, 658 references. Gideon e-books,

Note featured on ProMED

Microbiology References and Vaccination schedules

Over the past couple of months, we have rolled out a number of product updates to the GIDEON web app.

Microbiology References
References have been added to the improved notes and ecology sections for most organisms in the Microbiology sub-modules of Bacteria, Mycobacteria and Yeasts.

Vaccine Schedules
Vaccine schedules for each country have typically appeared in a number of notes in the Diseases module. These vaccine schedules have now been added to the Travel section, so it’s very easy to scroll through countries and compare their vaccination schedules.

For example see the initial travel note for Australia:
Australia vaccination schedule

With easy access to the vaccine abbreviations:

Vaccine abbreviations

Shigellosis Outbreaks Among Travelers

Although sporadic cases of shigellosis are common among travelers and expatriates, overt outbreaks are relatively uncommon. The following chronology was abstracted from reference [1]. Primary references are available on request.

1969 (publication year) – An outbreak of shigellosis was reported among Australian soldiers in Vietnam.
1976 – An outbreak (386 cases) of diarrhea due to Salmonella, Vibrio, Shigella, ETEC and EIEC was reported among passengers of a cruise ship following a visit to Haiti.
1987 – An outbreak (15 cases) of Shigella dysenteriae infection was reported among American tourists in Mexico.
1988 – An outbreak (240 cases) of shigellosis was reported among domestic and international passengers aboard an airline based in the United States.
1989 – An outbreak (84 cases) of Shigella flexneri infection aboard an American cruise ship was caused by contaminated potato salad.
1991 (publication year) – An outbreak (11 cases) of Shigella sonnei infection was reported among children from a Danish day-care institution on tour in Sweden.
1992 – An outbreak of shigellosis was reported among passengers on a cruise ship following a restaurant meal in Saint Lucia.
1994 – An outbreak (610 cases, 1 fatal) of Shigella flexneri infection occurred on a cruise ship sailing between California and Mexico.
1994 – An outbreak (1,062 cases) was reported among Rwandan refugees in Dem. Rep. Congo. A parallel outbreak (77 cases) involved Dutch military personnel who had eaten at an on-site hotel.
1996 – An outbreak (350 cases) was reported on a cruise ship en route from Venice to Crete.
2001 – Outbreaks (30 cases) were reported among travelers returning to New Zealand from Samoa.
2002 – An outbreak (78 cases) of food-borne Shigella sonnei infection was reported among tourists at a hotel resort in the Turks and Caicos Islands.
2003 – An outbreak (99 cases) was reported among Taiwanese tourists on tour in Indonesia.
2004 – An outbreak (45 cases) of Shigella sonnei infection in the United States, Japan, Australia and American Samoa was associated with food served on air flights serviced by a supplier in Hawaii.
2005 – An outbreak (71 cases) was reported among Irish tourists in Egypt.
2005 – An outbreak (6 cases) was reported among Japanese students and family members traveling to Malaysia and Singapore.
2005 (publication year) – An outbreak (14 cases) was reported among tourists at a rural hotel in the Canary Islands.
2006 – An outbreak (23 cases) of Shigella sonnei infection was reported among passengers on a bus from Norway to the Russian Federation.
2008 – Outbreaks (18 cases) were reported among tourists from Hong Kong in Cambodia (11 cases) and Egypt (7 cases).

1. Berger SA. Shigellosis: Global Status. 150 pp., 891 refs. 2010, Gideon e-book series

Update: Posted in ProMED

Legionellosis in Spain

A recent outbreak in Alcoy reminds us that rates of legionellosis have been increasing in Spain. The following background data are abstracted from the GIDEON e-book series. [1,2]

Graph 1 summarizes disease incidence and rates per 100,000 population.

Graph Notes:
1. 47 cases were reported in the Balearic Islands during 2001 to 2003.
2. 460 cases were reported among Spanish tourists during 2002 to 2006; 30 in 2005; 73 in 2006.
Individual years:
1993 – Included 57 cases in Cataluna
2003 – 5.82 per 100,000 in the Balearic Islands

As seen in Graph 2, this increase has also affected tourists in Spain.

Graph Notes:
1. 281 cases were acquired by foreign tourists in Spain during 1987 to 1995 – 67% of these from Great Britain. 37% of these were acquired in the Balearic Islands.
2. 627 cases were acquired by foreign tourists in Spain during 1989 to 2001.
3. 6,411 cases of legionellosis were reported during 1999 to 2004 – 565 (9%) involving Spanish travelers, and 426 involving foreign travelers in Spain.
4. 73 travel-associated cases were reported in 2006; 68 in 2007.
Individual years:
2003 – Included nine Spanish citizens touring within Spain.

Legionellosis accounts for 3% of community-acquired pneumonia in Palma de Mallorca (1992 to 1994)

Outbreaks – an overview:
– 1989 to 1998 – 55 outbreaks of legionellosis were reported – 36 of these associated with tourism, 11 nosocomial and 8 community-acquired.
– A single hotel in Benidorm was implicated in the infection of 3 tourists in 1989, 1 in 1990, 2 in 1995, 1 in 1996; 3 in 1997; 8 (1 fatal) in 1998.
– 1990 to 1991 – 54 outbreaks involving 805 cases (and additional 1,358 sporadic cases) were reported.
– 1990 to 2004 – 118 outbreaks involving 690 patients were reported in Catalonia – 35.6% involving water towers, and 14.4% involving water distribution systems in public buildings.
– 1999 to 2001 – Four outbreaks affected over 160 people in Alcoy.
– 2000 – Seven outbreaks were reported – 4 of these nosocomial. An additional 4 clusters were reported among tourists to Spain.
– 2000 – Girona reported 32 cases (3 fatal); Barcelona 48 (1 fatal); Vigo 30 (4 fatal) and Alcala de Henares 249 (11 fatal).
– 2001 to 2003 – 135 cases (10 fatal) in 46 clusters were acquired by European travelers to Spain, including 85 in 2002
– 1999 to 2003 – Eight outbreaks (approximately 300 cases) were reported in Alcoy, Alicante.
– 2003 – 55 outbreaks (247 cases) were reported.

Notable outbreaks:
1973 – An outbreak (89 cases, 3 fatal) was associated with a hotel in Benidorm.
1978 (publication year) – An outbreak (2 fatal cases) was associated with a hotel in Benidorm.
1983 – An outbreak (35 cases) in Valencia was related to contaminated shower heads and toilet tanks.
1984 (publication year) – An outbreak was reported in Los Castillejos.
1984 – An outbreak (32 cases) was reported among Dutch tourists at a hotel in Pineda de Mar (Barcelona region, Spain).
1988 – An outbreak (56 cases) was reported in Barcelona.
1992 (publication year) – An outbreak (6 cases) in a private apartment building in Zaragoza was associated with potable water.
1992 (publication year) – An outbreak was reported in a hospital in Badalona.
1993 – An outbreak (4 British tourists and 1 French tourist) was reported at a hotel in Spain.
1994 – An outbreak (20 cases) was reported in L’Espluga de Francoli, Tarragona.
1996 – An outbreak (260 cases, 197 hospitalized, 14 fatal) was reported in Madrid region (Alcala de Henares). This was the largest outbreak reported in Europe to date.
1996 – An outbreak (4 cases) was reported among British tourists at a hotel in Minorca.
1998 – An outbreak (3 cases, all fatal) was reported in a hospital in Zaragoza.
1999 – An outbreak (6 cases) was reported among foreign tourists to a spa in Cestona (Guipuzcoa Province).
1999 – An outbreak (7 cases, 1 fatal) was associated with a hotel outbreak in Benidorm.
2000 – An outbreak (70 cases, 2 fatal) was reported in Alcoy (Valencia region).
2000 – An outbreak (28 cases) was associated with a cooling tower in the region of a hospital in Vigo (Galicia).
2000 – An outbreak (54 cases, 17 hospitalized, 3 fatal) was reported in the “La Barceloneta” district of Barcelona.
2001 (publication year) – An outbreak (2 cases, both fatal) was reported among mechanics working on a cargo ship in the port of Barcelona.
2001 – An outbreak of 751 clinical cases (449 confirmed, 2 fatal) was reported in Santa Maria de Gracia (Murcia) – the world’s largest recorded outbreak to that time. The source of infection was an outdoor hospital cooling tower.
2001 – An outbreak (18 cases, 3 fatal) was reported from a hospital in Pamplona. A contaminated hot water system was implicated.
2002 – An outbreak (124 cases, 2 fatal) in Matara, Catalonia was related to a local cooling tower.
2003 – Outbreaks (25 total cases, 1 fatal) were reported in Valencia.
2003 – An outbreak (4 cases) was reported at a spa on Tenerife. An additional suspect case was reported in a Venezuelan visitor to the spa.
2004 – An outbreak (28 confirmed cases, 1 fatal) was reported at a hospital in Zaragoza. Contaminated cooling towers were implicated.
2004 – An outbreak (33 cases, 2 fatal) in Vallarca, Barcelona was caused by a contaminated air conditioning system at a private clinic.
2005 – An outbreak (19 cases, 3 fatal) was reported in Barcelona.
2005 – An outbreak (28 cases, including 21 foreigners – 0 fatal) was associated with a shopping center in Torrevieja.
2005 – An outbreak (55 cases, 3 fatal) was associated with a cooling tower in Catalonia.
2006 – An outbreak (146 cases, 0 fatal) in Pamplona was ascribed to contaminated cooling towers.
2006 – An outbreak (5 cases) was reported among ceramic workers in Castellon.
2006 – An outbreak (12 cases) in Catalonia was related to a contaminated mist machine.
2007 (publication year) – An outbreak of Legionnaires’ disease was reported among immunosuppressed patients at a cancer centre in Barcelona.
2007 to 2008 – An outbreak (3 cases) on a hospital surgical ward was associated with a contaminated oxygen humidifier.

1. Berger SA. Infectious Diseases of Spain, 516 pp. Gideon Informatics, Inc. 2010,
2. Berger SA. Legionellosis: Global Status, 84 pp. Gideon Informatics, Inc. 2010,

GIDEON review in Travel Medicine and Infectious Disease

Dr. Stephen Toovey wrote a nice review of GIDEON in the Travel Medicine and Infectious Disease journal. He says “…there is no doubt that travel medicine practitioners, infectious disease physicians and microbiologists in need of a serious database will have to consider Gideon”