Yellow Fever Update

Conference Coverage

By Lin H. Chen, MD

At the 51st meeting of the American Society of Tropical Medicine and Hygiene in Denver, November 10-14, 2002, a full symposium was devoted to yellow fever (YF). In Morbidity and Mortality Weekly Report (November 8, 2002) the CDC published additional adverse events associated with the 17D YF vaccine in the United States as well as the Recommendations of the Advisory Committee on Immunization Practices (ACIP) on Yellow Fever. This timely symposium addressed important issues regarding the assessment of YF fever risks in travelers vs the risks from YF vaccination.

Dr. Tom Monath provided an overview of YF risk in unvaccinated travelers. It is estimated that 9 million travelers visit endemic countries each year. In Africa, travelers can encounter increased mosquito activity in rainy and early dry season (July to October), during rural exposures, in moist savannas, and unfortunately YF risk exists in both cities and towns. During epidemic periods there is extreme risk. Surveillance is simply not sensitive; outbreaks occur 1-2 months before recognition and reporting. The ratio of reported vs actual cases is up to 1 in 300. The risk to the traveler spending 1 week in an epidemic region is 1:280. In an endemic region, 1-2% of the local population is infected annually, and the risk to the traveler spending 1 week in an endemic region is estimated to be 1:4200.

There have been 10 reported cases of YF in travelers since 1979. Six cases occurred in the last 5 years, or 0.03/100,000. In comparison, the risk of typhoid fever is 0.03%, and the risk of hepatitis A is 0.3%. South America has reported about 500 cases per year, mostly jungle YF. In 2001, jungle YF occurred in Minas Gerais, near Belo Horizonte.

Dr. Marty Cetron from the CDC discussed YF vaccine safety. The Asibi YF strain from Nigeria (1927) was the original virus used in the development of the vaccine. The seed lot for 17D YF virus strain has been used for the vaccine since 1942. The 17DD, 17D-204, and 17D-213 are all derived from the 17D strain. Adverse events were initially reported from the United States in 4 recipients aged 63-79 years of age, with an onset between 2-5 days. Additional cases were reported from Brazil in a 5-year-old girl from Goias and a 22-year-old woman from Sao Paolo, and from Australia in a 53-year-old man. Six of the 7 patients died, and vaccine type YF was isolated in 5 of 5 samples obtained.

Since the original reports of YF vaccine-associated viscerotropic disease (YEL-AVD), previously called multiorgan systemic failure, 2 additional cases have been reported from the United States. These patients were a 25-year-old man (April 2001) and a 70-year-old man (March 2002). A third possible case involved a 56-year-old recipient in 1999. Three other cases were described in the letters to Lancet; among these are: 45-year-old British male, 50-year-old Swiss male, and 71-year-old German male. Case fatality rates were 54%, and all cases occurred in people receiving their primary vaccinations.

The syndrome has been renamed 17D YEL-AVD. Onset of the syndrome occurs within 2-5 days of vaccination with YF and is associated with fever, myalgia, arthralgia, increased liver enzymes and bilirubin, sometimes with liver failure, thrombocytopenia, DIC, lymphocytopenia.

Through the Vaccine Adverse Event Reporting System (VAERS), increased surveillance has detected 4 cases of neurotropic adverse events following YF vaccination in 2001-2002. These cases presented with meningitis or meningoencephalitis, in which CSF pleocytosis and CSF IgM for YF were detected. Case fatality rates for neurotropic events had been < 5%. Reversion to neurovirulence has an onset from 4-23 days. Previously called postvaccinal encephalitis, the syndrome is called YF vaccine-associated neurotropic disease (YEL-AND) and is associated with a greater risk for children younger than 6 months old.

What is the risk of YEL-AVD? Approximately 200,000 doses of YF vaccines were sold to civilians and 800,000 doses to the military each year; A total of 3-5.5 million doses were distributed to civilians from 1996-2002. Two to 3 cases of YEL-AVD occurred per 1,000,000 doses during this period. Risk by age groups indicated a greater risk in those older than 50.

17D YEL-AVD is a newly recognized syndrome, and 17D YEL-AND is possibly re-emerging. 17D YEL-AVD is not caused by the emergence of wild-type YF clone, nor due to vaccine-type virus mutation. It is most likely a result of idiosyncratic host responses, and it appears to be age-related. To date, 17D YEL-AVD has only occurred with primary YF vaccination. Host susceptibility genes may be playing a role, and there can be acquired cofactors or confounders. For example, ISG (ISG) was in much wider use before 1996 and may have played some role. The true incidence of adverse events is unknown but is probably in the range of 3-5 per million for viscerotropic events and 2-3 per million for neurotropic events. Revised guidelines are available via the CDC web site: www.cdc.gov. Enhanced surveillance is done by reporting to www.vaers.org (800-822-7967). Additional information is available from the CDC at www.cdc.gov/ncidod/dvbid/yellowfever/index.htm (970-221-6400 or 404-498-1600).

Dr. Anthony Marfin discussed current research needs to define YF vaccine risks and benefits. He pointed out the rising interest in YF vaccination as a result of growth in general tourism, ecotourism, sports vacations, and lumber/oil development. In addition, the first YF case to be imported to the United States in 72 years occurred in 1996. At the same time, an increased range for the mosquito vector, Aedes aegypti, is evident along with increased interest in vector-borne diseases, especially in flaviviruses, since the emergence of West Nile Virus. Future research must focus on the true risk of vaccine, the true risk of YF in travelers to areas, and its pathophysiology.

Dr. Mary Wilson addressed means to raise awareness and risk communication. Specifically, how do we save the greatest number of lives given the current vaccine? Risk of paralytic polio after the first dose of oral polio vaccine is approximately 1:750,000. The risk of death from motor vehicle accident is approximately 1:6700. The risk from YF itself appears to be greater than both, and the risk of adverse events from YF vaccine is smaller than that of death from motor vehicle accident.

Dr. Chen, Clinical Instructor, Harvard Medical School, Director, Travel Resource Center, Mt. Auburn Hospital, Cambridge, Mass., is Associate Editor of Travel Medicine Advisor.

References

1. CDC. Adverse events associated with 17D-derived yellow fever vaccination—United States, 2001-2002. MMWR Morb Mortal Wkly Rep. 2002;51(44):989-993.

2. CDC. Yellow fever vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2002. MMWR Morb Mortal Wkly Rep. 2002; 51(RR-17):1-12.