Yellow Fever Vaccine—Adverse Events

Abstracts & Commentary

Synopsis: Yellow fever vaccine has been one of the most extensively used vaccines in the world during much of the 20th century. Recent evidence, however, indicates an increased risk of adverse events in the elderly.

Sources: Martin M, et al. Lancet. 2001;358:98-104; Vasconcelos PFC, et al. Lancet. 2001;358:91-97; Chan RC, et al. Lancet. 2001;358:121-122.

While serious adverse events associated with yellow fever (YF) vaccination remain rare, several recent reports have raised concern. YF remains a serious risk in South America and Africa, and vaccination for persons at risk should be continued. However, physicians should be vigilant in detecting and reporting adverse events associated with YF vaccination, and the safety of the vaccine is being further evaluated.

Seven cases of serious adverse events in YF vaccinees were reported in the July 14, 2001, issue of the Lancet. Four cases occurred in the United States, and 1 in Australia following use of the 17D-204 vaccine. Two cases were reported from Brazil, following use of the 17DD vaccine.

In US and Australian patients, illness occurred 2-5 days after administration of the 17D-204 YF vaccine. All US patients were older than 62 years of age, and the Australian patient was 56 years old. All cases presented with fever and subsequently developed thrombocytopenia, lymphopenia, bandemia, significant hyperbilirubinemia, and hypotension. All patients developed renal failure, respiratory failure, or both. The vaccine strain of YF virus was isolated from the serum of 2 US patients and the cerebrospinal fluid of 1 US patient. One patient’s liver biopsy, performed 28 days after vaccination, showed YF fever virus antigen by immunohistochemical assay. The Australian patient’s serum samples as well as multiple organs showed the vaccine strain of YF virus.

The 2 Brazilian cases presented similarly with fevers, myalgia, and vomiting. Following immunization with the 17DD YF vaccine, the patients developed icterus, hemorrhage, and multi-organ involvement. In contrast to the other patients, the Brazilian patients were only 5 and 22 years old. None of the patients were known to be immunosuppressed at the time of vaccination. YF virus was isolated from blood and multiple organs in both patients.

Comment by Lin H. Chen, MD

Yellow fever virus is an enveloped, single-stranded RNA virus in the Flaviviridae family. The vectors are tree hole-breeding mosquitoes, which feed primarily on monkeys in the jungle, and Aedes aegypti, a domestic mosquito that thrives in urban settings. YF occurs only in sub-Saharan Africa and parts of South America. It has never occurred in Asia, the Indian subcontinent, the Middle East, and Australia, although the mosquito vector is present.

The incidence of YF is thought to be greater than 200,000 cases annually in Africa, with a case-fatality rate of 23%.1 In comparison, the incidence in South America is estimated to be 1000-20,000 cases annually, with a case-fatality rate of 65%.1 Epidemics in the 1990s, which occurred in Nigeria, Cameroon, Ghana, Liberia, Gabon, Senegal, Benin, and Kenya, have contributed to a resurgence of YF.1,2

Clinical presentation for YF is variable, ranging from an influenza-like illness to hemorrhagic fevers. Following the bite of an infected mosquito, the infection incubates for 3-6 days before fever develops. Patients then enter a "period of infection" in which they are viremic up to several days.1 Symptoms during this period include fever, chills, malaise, headache, myalgia, nausea, and anorexia. Findings include toxic appearance, conjunctival congestion, pointed red tongue with a central white coating, relative bradycardia, leukopenia, and neutropenia. A "period of remission" follows and lasts 2-24 hours.1 Some patients may recover at this point, but many go on to a "period of intoxication" where fever increases along with nausea, vomiting, abdominal pain, jaundice, renal failure, and hemorrhages.1 A "terminal period" follows with death occurring on the 7th to 10th day of illness.1

A diagnosis of YF may be made by culturing the virus from blood or serum during the first 4 days of symptoms.1 Serologic studies with the enzyme-linked immunosorbent assay (ELISA), especially the IgM-capture immunoassay, can also establish a diagnosis. Postmortem diagnosis can be made by histopathology as well as immunocytochemical staining of liver tissue sections to detect YF antigen. Biopsy of the liver is, however, often precluded by the presence of a coagulopathy.

The YF vaccine has long been considered a safe vaccine, and it has been successful in controlling YF. Live attenuated vaccines were developed shortly after isolation of the YF virus in 1927, and the 17D vaccine has been in use since 1937. The 17D-204 and 17DD vaccines are substrains derived from the 17D strain. Approximately 300 million doses of the 17D YF vaccines have been administered in endemic areas, and approximately 8 million US travelers have been vaccinated since 1965.3 The World Health Organization estimated that 54 million doses of the vaccine were administered in Brazil in the past 4 years, during which the 2 cases of serious adverse events were reported.4

Adverse events following administration of the 17D vaccines have been reported in the past, although most have been mild. These include fever, headache, backache, local reactions, and mild flu-like symptoms.5 Encephalitis following vaccination has occurred rarely and primarily in very young infants, with an estimated incidence of 0.5-4/1000,5 which is the reason the vaccine is generally not recommended for children younger than 9 months of age. Allergic reactions associated with the 17D vaccine have been reported, and the incidence is estimated at 5-20 per million doses.5

The reported rate for YF vaccine-associated serious illness appears to be higher in the elderly. The rate is estimated to be 3.5 per 100,000 among people 65-75 years old and 9.1 per 100,000 for people 75 or older.6 However, the overall systemic adverse events are still rare at 2.4 per 100,000 doses in the United States.6 The itinerary of each traveler should be carefully assessed for necessity of the vaccine. YF remains a serious threat to travelers going to endemic areas in Africa and South America, and vaccination should be continued for the travelers at risk.

VAERS report forms can be obtained by telephone (800-822-7967) or at Reports can be submitted by fax (877-721-0366), mail (P.O. Box 1100, Rockville, MD 20849-1100), or e-mail ( The CDC will perform virologic and immunohistochemical studies on specimens available.


1. Monath TP. Yellow fever. In: Guerrant RL, et al (eds). Tropical Infectious Diseases. Philadelphia, Pa: Churchill Livingstone; 1999:1253-1264.

2. Robertson SE, et al. JAMA. 1996;276(14):1157-1162.

3. CDC. MMWR Morb Mortal Wkly Rep. 2001;50(30):643-645.

4. World Health Organization. Wkly Epidemiol Rec. 2001;29(76):217-218.

5. Monath TP. Yellow Fever. In: Plotkin SA, Orenstein WA (eds). Vaccines. 3rd ed. Philadelphia, Pa: WB Saunders; 1999:815-879.

6. Martin M, et al. Emerg Infect Dis. (To be published Nov-Dec 2001);7(6). Available via

7. Marianneau P, et al. Lancet. 2001;358:84-85.

Dr. Chen is Clinical Instructor, Harvard Medical School and Travel/Tropical Medicine Clinic, Lahey Clinic Medical Center, Burlington, Mass.