Viscerotropic disease following yellow fever vaccination in Peru
Introduction
Yellow fever virus (YFV) is transmitted in tropical sylvatic areas of South America and Africa, and can spread into urban areas infested with the mosquito Aedes aegypti. In recent years over one-third of yellow fever cases in South America have been reported in the Amazon forest of Peru. In 2007–2008, yellow fever transmission intensified in Brazil, northern Argentina, and Paraguay where urban transmission was reported near Asuncion [1].
Yellow fever can be prevented by vaccination with live, attenuated 17D yellow fever vaccine. Over 500 million doses of 17D vaccine have been safely administered to humans since its development in 1937. However starting in 2001, reports emerged of rare but serious, often fatal adverse reactions to the vaccine that mimicked naturally acquired yellow fever [2], [3], [4], [5], [6]. The incidence of this yellow fever vaccine-associated viscerotropic disease (YEL-AVD) is unknown but has been estimated at 0.4 cases per 100,000 doses administered [7]. The risk of YEL-AVD appears to be higher among people over 60 years of age and those who have had thymic disease or a thymectomy [7], [8]. It seems likely that a rare genetic predisposition to YEL-AVD exists but no common genetic risk factor has yet been determined [9], [10]. Although single point mutations in the single-stranded RNA genome of yellow fever vaccine virus (YFVV) can alter virulence, no important changes in consensus gene sequence or viral virulence have been found in multiple YEL-AVD cases that have been studied [5], [11]. Cases of YEL-AVD have been reported from Brazil, United States, Australia, China, Spain, Colombia, Great Britain, Japan, Switzerland, France, Germany, and Belgium, and have been associated with vaccine lots of both YFVV substrains (17D and 17DD) and with lots from multiple manufacturers [5], [9], [10], [12]. Of 36 cases reported worldwide, the ages ranged from 4 to 79 years with a median of 60 years; the male to female ratio was 2:1 [5]. The median age of female cases was 22 years compared to 63 years for male cases. Onset of YEL-AVD occurred an average of 4 days after vaccination; the case fatality rate was 50% [5].
From September 23 to October 6, 2007, following a destructive earthquake, a mass immunization campaign was conducted in Ica Department, Peru. Yellow fever is not endemic in Ica but yellow fever vaccination was included as part of the post-disaster response. Two lots, 050VFA121Z (121Z) and 050VFA123Z (123Z), of 17DD vaccine manufactured at Bio-Manguinhos in Brazil, were used. Reports of serious adverse events following immunization (AEFI) led to cessation of the campaign. The Ministry of Health's Epidemiologic Surveillance Network detected 5 cases of suspected YEL-AVD, yielding an incidence of 7.9 per 100,000 doses. This was the first time that more than two YEL-AVD cases had clustered within a short time and delimited space. Four of the five persons died and all five received the same vaccine lot (121Z) administered to 42,742 people (lot-specific YEL-AVD incidence in Ica of 11.7 per 100,000 doses). In Venezuela, 73,000 doses from lot 121Z had previously been administered without reports of YEL-AVD. An additional 20,432 people were vaccinated in Ica with a different lot (123Z), and no YEL-AVD was reported in this group.
Section snippets
Methods
Medical records of all five case–patients were reviewed. Diagnostic blood and tissue samples were tested at the Instituto Nacional de Salud (INS) in Lima, Peru; U.S. Naval Medical Research Center Detachment (NMRCD) also in Lima; Centers for Disease Control and Prevention (CDC) Division of Vector-Borne Infectious Diseases in Fort Collins, Colorado; and CDC's Infectious Disease Pathology Activity in Atlanta, Georgia for evidence of YFV or YFVV and for other possible etiologies of each patient's
Case 1
A 23-year-old female medical student was vaccinated on September 27. Her past medical history was remarkable only for acne rosacea. No data were available regarding her history of previous vaccination against yellow fever, any regular medications, allergies, any acute illnesses in the previous month, or recent travel. One day after vaccination, she developed generalized malaise, fever, headache, arthralgias and myalgias. She took paracetamol and a nonsteroidal anti-inflammatory drug (NSAID).
Discussion
This cluster of YEL-AVD is unprecedented in the known history of yellow fever vaccination. The finding that four confirmed cases of YEL-AVD and one probable case all received the same lot of vaccine whereas no cases were ascribed to the other lot used in Ica raised suspicion that lot 121Z had increased viscerotropism, possibly through mutation during manufacture. However the results presented here do not support that conclusion. Given an expected rate of 0.4 YEL-AVD cases per 100,000 vaccine
Acknowledgements
The authors gratefully acknowledge the work and help of the following people and agencies in carrying out the investigation of this unusual cluster of YEL-AVD: José Aguilar, Inés Caro, Juan Carlos Tirado, and Eduardo Gotuzzo, who were non-author members of the National Committee for AEFI Case Classification in Peru; Christopher Paddock and Wun-Ju Shieh from CDC, Atlanta; Víctor Aquije, Rómulo Cahua, Lita del Río and Tania Alarcón from Ica Region, Peru; Paul Pachas, José Bolarte, from Dirección
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