Incidence of Yellow Fever Vaccine-Associated Neurotropic Disease: Meningitis and Meningoencephalitis in Adults Within 30 Days of Vaccine Administration

By Michele Barry, MD, FACP, and Brian G. Blackburn, MD

Dr. Barry is the Senior Associate Dean of Global Health at Stanford University School of Medicine, Stanford, CA. Dr. Blackburn is Clinical Assistant Professor in the Division of Infectious Diseases and Geographic Medicine at Stanford University School of Medicine, Stanford, CA.

Dr. Barry serves as a consultant for the Ford Foundation, and her program receives funding from Johnson & Johnson. Dr. Blackburn reports no financial relationships relevant to this field of study.

Synopsis: A retrospective analysis was performed of all serious neurologic events that resulted in hospitalization within 30 days of yellow fever vaccination between 2000-2008.

Source: Guimard T, Minjolle S, Polard E, et al. Short report: Incidence of yellow fever vaccine-associated neurotropic disease. Am J Trop Med Hyg 2009;81:1141-1143.

Four adults with either probable or definite yellow fever (YF) vaccine-associated meningitis or meningoencephalitis were hospitalized, yielding an incidence of 9.9/100,000 vaccine doses (95% CI = 2.7-25.4/100,000). This is 10 times higher than previous estimates that did not include acute meningitis as a defining neurologic event. All patients were first-time YF vaccine recipients, and symptoms resolved in all but one, for whom cerebellar syndrome and attention deficit disorder persisted. The male-to-female ratio was 3:1, and ages ranged from 21 to 55 years.


There are three kinds of fatal adverse events caused by YF vaccine: anaphylaxis, YF vaccine -associated viscerotropic disease (YF-AVD), and YF vaccine-associated neurotropic disease (YF-AND). YF-AVD occurs in approximately 0.3-0.4 of 100,000 vaccinations, and risk factors identified to date include advanced age and history of thymus disease.1 YF-AND classically has included encephalitis, acute disseminated encephalomyelitis, and Guillain-Barré syndrome. Criteria for association with the YF vaccine when these conditions have occurred include the presence of IgM antibodies against YF in cerebrospinal fluid (CSF) or isolation of the virus from the blood or CSF. (See Table.) The incidence of YF-AND was 0.4-0.8 per 100,000 vaccinations when evaluated through a passive reporting system.1 However, active surveillance during mass vaccine campaigns in Brazil identified 12 cases of acute lymphocytic meningitis diagnosed within 30 days of vaccine administration, suggesting an incidence of 3.9/100,000 doses.2

This report of four cases of adult neurotropic disease comes from an institution that administered 40,404 vaccine doses over an eight-year period. Only severe neurologic events were captured by this retrospective study of hospitalized patients, which could have resulted in an underestimate of the number of neurologic complications of YF vaccine. Delay between YF vaccination and symptoms warranting admission ranged between 19 and 23 days, which is consistent with a previous report of 15 cases of YF-AND from the Yellow Fever Safety Working Group.3 In the current study, only one case had YF-IgM antibody documented in his CSF, and this 41-year-old had a history of testicular cancer, possibly marking him as an immunocompromised host. The other three probable cases (see Table) did not have enough CSF preserved to check CSF IgM levels. Cerebrospinal fluid examination in the four cases showed pleocytosis (10-82 cells/mm3) with 64-84% lymphocytes and slightly elevated protein levels (0.4-0.68 g/L).

The YF vaccine studied in this institution was the 17D-204 strain (StamarilR, Aventis Pasteur, Marcy L’Etoile, France) similar to YF-VaxR, the commercially available YF vaccine manufactured by Sanofi Pasteur in the United States. Of interest, all four patients with neurologic disease in the current study had received YF vaccine for the first time; patients who have developed YF-AVD to date have also been primary vaccinees. A limitation of the study was reliance on retrospective data, which included only adverse events severe enough to warrant hospitalization. Nevertheless, this report highlights the need for careful evaluation of the need for YF vaccination prior to travel. The average risk of developing YF for a non-immunized traveler during a one-month trip to endemic areas of South America and Sub-Saharan Africa is between 10 and 100 per 100,000 travelers, and this study’s incidence of neurologic events was 9.9/100,000. Fortunately, three of the four vaccine recipients who developed neurologic disease in this study experienced apparently complete recovery. Limited data are available regarding whether 17D live attenuated viruses cause residual neurologic sequelae after YF-AND. Wild-type YF virus infrequently causes encephalitis or other neurologic disease. YF vaccine-associated neurotropism causing encephalitis was first described in infants receiving the 17D-based vaccines. Fortunately, since limiting administration to persons older than 6 months of age in 1969, there have been only two neurologic fatalities: a previously healthy 3-year-old, in whose brain a mutant variant of the vaccine was isolated, and a 53-year-old man with HIV infection who died from encephalitis nine days following the vaccination.2

In conclusion, although the risk of neurologic disease after YF-vaccine is still small, it may be higher than previously recognized, and the decision to administer the vaccine to persons at risk should take into consideration epidemic YF activity, duration of travel, and the likelihood of exposure to vector mosquitoes. Clinicians who observe any neurologic symptoms within 30 days of YF vaccination, especially after primary vaccination, should report to the Vaccine Adverse Event Reporting System at Aseptic meningitis should now be considered a defining neurologic adverse event caused by YF vaccination, along with acute disseminated encephalomyelitis, Guillain-Barré syndrome, and encephalitis.


  1. Martin M, Tsai TF, Cropp B, et al. Fever and multisystem organ failure associated with 17D-204 yellow fever vaccination: A report of four cases. Lancet 2001;358:98-104.
  2. Fernandes GC, Camcho LA, Carvalho M, et al. Neurologic adverse events temporarily associated to mass vaccination against yellow fever in Juiz de Fora, Brazil 1995-2005. Vaccine 2007;25:3124-3128.
  3. McMahon A, Eidex R, Marfin A, et al. Neurologic disease associated with 17D-204 yellow fever vaccination: A report of 15 cases. Vaccine 2007;25:1727-1734.