Brazilian recommendations on the safety and effectiveness of the yellow fever vaccination in patients with chronic immune-mediated inflammatory diseases

Abstract Background: In Brazil, we are facing an alarming epidemic scenario of Yellow fever (YF), which is reaching the most populous areas of the country in unvaccinated people. Vaccination is the only effective tool to prevent YF. In special situations, such as patients with chronic immune-mediated inflammatory diseases (CIMID), undergoing immunosuppressive therapy, as a higher risk of severe adverse events may occur, assessment of the risk-benefit ratio of the yellow fever vaccine (YFV) should be performed on an individual level. Main body of the abstract: Faced with the scarcity of specific orientation on YFV for this special group of patients, the Brazilian Rheumatology Society (BRS) endorsed a project aiming the development of individualized YFV recommendations for patients with CIMID, guided by questions addressed by both medical professionals and patients, followed an internationally validated methodology (GIN-McMaster Guideline Development). Firstly, a systematic review was carried out and an expert panel formed to take part of the decision process, comprising BRS clinical practitioners, as well as individuals from the Brazilian Dermatology Society (BDS), Brazilian Inflammatory Bowel Diseases Study Group (GEDIIB), and specialists on infectious diseases and vaccination (from Tropical Medicine, Infectious Diseases and Immunizations National Societies); in addition, two representatives of patient groups were included as members of the panel. When the quality of the evidence was low or there was a lack of evidence to determine the recommendations, the decisions were based on the expert opinion panel and a Delphi approach was performed. A recommendation was accepted upon achieving ≥80% agreement among the panel, including the patient representatives. As a result, eight recommendations were developed regarding the safety of YFV in patients with CIMID, considering the immunosuppression degree conferred by the treatment used. It was not possible to establish recommendations on the effectiveness of YFV in these patients as there is no consistent evidence to support these recommendations. Conclusion: This paper approaches a real need, assessed by clinicians and patient care groups, to address specific questions on the management of YFV in patients with CIMID living or traveling to YF endemic areas, involving specialists from many areas together with patients, and might have global applicability, contributing to and supporting vaccination practices. We recommended a shared decision-making approach on taking or not the YFV.

Single shot of 17D vaccine may not confer life-long protection against yellow fever

The yellow fever (YF) vaccine has been used since the 1930s to prevent YF, which is a severe infectious disease caused by the yellow fever virus (YFV), and mainly transmitted by Culicidae mosquitoes from the genera Aedes and Haemagogus . Until 2013, the World Health Organization (WHO) recommended the administration of a vaccine dose every ten years. A new recommendation of a single vaccine dose to confer life-long protection against YFV infection has since been established. Recent evidence published elsewhere suggests that at least a second dose is needed to fully protect against YF disease. Here, we discuss the feasibility of administering multiple doses, the necessity for a new and modern vaccine, and recommend that the WHO conveys a meeting to discuss YFV vaccination strategies for people living in or travelling to endemic areas.

Vacuna contra fiebre amarilla para viajeros chilenos a Brasil. Consideraciones prácticas / Yellow fever vaccination for Chilean tourists visiting Brazil. Practical considerations

Resumen La aparición de fiebre amarilla en las costas brasileñas, lugares de alto interés turístico, ha provocado una alta demanda de vacunación. Este articulo entrega respuestas a las principales consultas sobre la vacuna de fiebre amarilla y puede servir como guía para médicos no expertos en Medicina del Viajero.

Due to the recent yellow fever outbreak affecting the costal region of Brazil, including main touristic destinations, there is a high demand of yellow fever vaccination. This publication addresses the most relevant practical issues regarding this vaccine for tourists visiting Brazil and aims to serve as a guideline for non-expert physicians in Chile and elsewhere.

Fiebre amarilla / Yellow fever

La fiebre amarilla representa a una de las fiebres hemorrágicas que adquieren en Venezuela y a una de las cuatro arbovirosis endémicas que tenemos. Revisando la literatura médica nacional e internacional, se actualizan aspectos relevantes de esta endemia rural. Se mencionan en la etiología las características del agente viral, que tiene ARN como componente primordial de su genoma. En la epidemiología, se menciona su prevalencia en el continente americano y africano y se evalúa su modo de transmisión. En la patogenia y la anatomía patológica se describe al hígado como órgano blanco de la infección. Se destacan en las manifestaciones clínicas los trastornos hemorrágicos y de la coagulación sanguínea. El diagnóstico como en Medicina Tropical, corresponde a un diagnóstico integral: la clínica, en primer lugar, asociada a la epidemiología y a la etiología de la enfermedad. Se establece diagnóstico diferencial con otras entidades relacionadas. El tratamiento es de soporte y en terapia intensiva. Se concluye con la profilaxis, evaluando la utilidad que sigue teniendo la vacunación.

The yelow fever represents one of the hemorrhagic fever that can be acquired in Venezuela and one of the four endemic arbovirosis we have. By reviewing the national and international medical literature. Relevant aspects of this endemic rural disease have been updated. In the etiology, several characterictics of the virus are mentioned; including the RNA as a primordial component of its genome. In the epidemiology, its prevalence on the African and American continents is mentioned, and the transmission mode es evaluated. In the pathogenesis and pathological anatomy, the liver is described as the primary organ of infection. Bleeding and blood clotting disorders are the essential clinical manifestations. Like in Tropical Medicina, The corresponding integral diagnosis is required. In the first instance, the clinical aspects, associated to the epidemiology and to the etiology of the disease are analyzed a diffential diagnosis is made with other related entities. The treatment consists of support measures and Intensive Care in the Intensive Care Unit (ICU). For the prophylaxis, we discuss the advantages of vaccination.

Serologic assessment of yellow fever immunity in the rural population of a yellow fever-endemic area in Central Brazil

Introduction The yellow fever epidemic that occurred in 1972/73 in Central Brazil surprised the majority of the population unprotected. A clinical-epidemiological survey conducted at that time in the rural area of 19 municipalities found that the highest (13.8%) number of disease cases were present in the municipality of Luziânia, State of Goiás. Methods Thirty-eight years later, a new seroepidemiological survey was conducted with the aim of assessing the degree of immune protection of the rural population of Luziânia, following the continuous attempts of public health services to obtain vaccination coverage in the region. A total of 383 volunteers, aged between 5 and 89 years and with predominant rural labor activities (75.5%), were interviewed. The presence of antibodies against the yellow fever was also investigated in these individuals, by using plaque reduction neutralization test, and correlated to information regarding residency, occupation, epidemiological data and immunity against the yellow fever virus. Results We found a high (97.6%) frequency of protective titers (>1:10) of neutralizing antibodies against the yellow fever virus; the frequency of titers of 1:640 or higher was 23.2%, indicating wide immune protection against the disease in the study population. The presence of protective immunity was correlated to increasing age. Conclusions This study reinforces the importance of surveys to address the immune state of a population at risk for yellow fever infection and to the surveillance of actions to control the disease in endemic areas. .

Aspectos críticos do controle da febre amarela no Brasil / Aspectos críticos del control de la fiebre amarilla en Brasil / Critical aspects of yellow fever control in Brazil

São apresentados aspectos epidemiológicos e do controle da febre amarela no Brasil, considerando os ciclos de transmissão silvestre e urbano. Sem registros de transmissão no Brasil desde 1942, houve casos de febre amarela urbana em 2008 no Paraguai, depois de mais de 50 anos sem essa ocorrência nas Américas. A redução do número dos casos silvestres e a manutenção da eliminação dos casos urbanos são os dois principais objetivos do controle da febre amarela no Brasil. Embora haja consenso quanto às medidas que devem ser tomadas nas áreas endêmicas para a forma silvestre, isso não ocorre em relação às áreas infestadas pelo Aedes aegypti. São discutidos argumentos favoráveis e contrários à expansão da área de vacinação. Há necessidade de estudos ambientais e entomológicos para o reconhecimento de áreas receptivas para transmissão silvestre, mesmo que estejam silentes há muitos anos.

This paper presents epidemiological and control characteristics of yellow fever in Brazil, taking its wild and urban transmission cycles into consideration. No urban cases have been reported in Brazil since 1942, but urban yellow fever cases were reported in Paraguay in 2008, after more than 50 years without registered cases in the Americas. The two main objectives of yellow fever control programs in Brazil are to reduce the number of wild cases and to maintain zero incidence of urban cases. Although there is a consensus regarding control measures that should be applied in areas endemic for the wild form, this is not so in relation to areas infested by Aedes aegypti. The arguments for and against expansion of the vaccination area are discussed. Environmental and entomological studies are needed so that areas receptive to wild-type transmission can be recognized, even if they have been silent for many years.

Se presentan aspectos epidemiológicos y del control de la fiebre amarilla en Brasil, considerando los ciclos de transmisión silvestre y urbana. Sin registros de transmisión en Brasil desde 1942, hubo casos de fiebre amarilla urbana en 2008 en Paraguay, después de más de 50 años sin ocurrir en las Américas. La reducción del número de casos silvestre y el mantenimiento de la eliminación de los casos urbanos son los dos principales objetivos del control de la fiebre amarilla en Brasil. A pesar de que exista consenso con respecto a las medidas que deben ser tomadas en las áreas endémicas para la forma silvestre, esto no ocurre con relación a las áreas infestadas por el Aedes aegypti. Son discutidos argumentos favorables y contrarios a la expansión del área de vacunación. Hay necesidad de estudios ambientales y entomológicos para el reconocimiento de áreas receptivas para transmisión silvestre, aunque se encuentren silentes desde hace muchos años.

Anticuerpos neutralizantes contra el virus de la fiebre amarilla 17 D en colombianos vacunados y no vacunados con inmunidad a dengue / Yellow fever virus 17D neutralising antibodies in vaccinated Colombian people and unvaccinated ones having immunity against dengue

Objetivo Determinar la frecuencia de título protector de anticuerpos neutralizantes contra el virus de la fiebre amarilla (AN-VFA a título >1:10) en colombianos vacunados con la cepa 17 D y conocer la magnitud de neutralización del VFA por anticuerpos contra dengue. Metodología Se colectó suero de 100 individuos con vacuna documentada por carné y de 116 residentes en municipios de Norte de Santander afectados por el brote en 2002-2003, quienes informaron haber sido vacunados. Se incluyeron sueros de individuos no vacunados con (n=61) y sin (n=16) anticuerpos contra dengue. Todos los sueros se analizaron por la prueba de neutralización para VFA por 75 por ciento de reducción de placa. Resultados AN-VFA a título >1:10 se encontraron en 90 por ciento de vacunados con carné y sin variación aparente en relación con edad. Al contrario, hubo correlación entre disminución de la frecuencia de título protector de anticuerpos e incremento del tiempo de inmunización (r=0,95; p=0,04). En residentes de Norte de Santander, AN-VFA a título >1:10 se encontraron en 92,6 por ciento adultos y 69 por ciento niños. El VFA fue neutralizado (52 -100 por ciento) por sueros de inmunes a dengue más eficientemente que por sueros de no inmunes (p<0.001). Conclusiones Vacunados con el virus 17 D podrían no estar protegidos contra fiebre amarilla: hasta 31 por ciento niños y 10 por ciento adultos. Anticuerpos contra dengue inhibieron el VFA y su significancia en términos de protección contra fiebre amarilla deberá ser investigada.

Objective Determining the frequency of yellow fever seroprotective antibody neutralising titres (YF-NT >1:10) in Colombians vaccinated with the 17 D virus and ascertaining the extent to which YF virus can be neutralised by dengue antibodies. Materials and Methods Serum samples were taken from 100 subjects who showed their vaccination record and from 116 residents in municipalities (Norte de Santander) affected by a wild YF outbreak in 2002-2003 who were reported to have been YF vaccinated. Sera from individuals with (n=61) and without (n=16) dengue antibodies who had never been YF vaccinated were included. All the sera were tested by 75 percent YF plaque-reduction neutralization test. Results YF-NT titres >1:10 were founded in 90 percent of subjects with vaccination recorded with minors variations in relation to age. In contrast, there was correlation between decrease of seroprotective YF-NT titres frequency and increase of immunization time (r=0.95; p=0.04). In residents in YF endemic area, YF-NT titres > 1.10 were founded in 92,6 percent adults and 69 percent children. YF 17 D virus was neutralized (52-100 percent) by dengue sera more efficiently than non-dengue immune sera (p<0.001). Conclusions Individuals immunised with YF vaccine 17 D could not be protected against YF: up to 31 percent children and 10 percent adults. Dengue antibodies inhibited YF virus and its significance in terms of YF protection must be investigated.

Dengue-yellow fever sera cross-reactivity; challenges for diagnosis / Reacción cruzada en sueros de Fiebre Amarilla y Dengue: desafíos para el diagnóstico

Objective The Flavivirus genera share epitopes inducing cross-reactive antibodies leading to great difficulty in differentially diagnosing flaviviral infections. This work was aimed at evaluating the complexity of dengue and yellow fever serological differential diagnosis. Material and methods Dengue antibody capture ELISA and a yellow fever neutralisation test were carried out on 13 serum samples obtained from yellow fever patients, 20 acute serum samples from dengue patients and 19 voluntan/ serum samples pre- and post-vaccination with YF vaccine. Results Dengue ELISA revealed IgM reactivity in 46,2 percent of yellow fever patients and 42 percent of vaccinees. Sixteen out of 20 dengue patients (80 percent) had high YF virus neutralisation titres. Conclusions . Such very high cross-reactivity data challenged differential laboratory diagnosis of dengue and yellow fever in áreas where both flaviviruses co-circulate. New laboratory strategies are thus needed for improving the tests and providing a specific laboratory diagnosis. Cross-reactivity between Flaviviruses represents a great difficulty for epidemiological surveillance and preventing dengue, both of which demand urgent attention.

Objetivo Los miembros del genero Flavivirus poseen epítopes inductores de anticuerpos de reactividad cruzada, lo que representa una gran dificultad en el diagnostico diferencial. En este trabajo nos propusimos evaluar la complejidad del diagnostico diferencial entre dengue y fiebre amarilla. Materiales y métodos Ensayos de ELISA de captura para dengue y de neutralización para fiebre amarilla fueron realizados en 13 muestras de suero de pacientes con fiebre amarilla, 20 muestras de pacientes con dengue en fase aguda y 19 voluntarios sanos antes y después de ser vacunados para la fiebre amarilla. Resultados Los ensayos de ELISA para IgM contra dengue mostraron reactividad cruzada en el 46,2 por ciento de los pacientes con fiebre amarilla y 42 por ciento de los vacunados. Dieciséis de los 20 pacientes con Dengue (80 por ciento) tuvieron altos títulos de anticuerpos neutralizantes para fiebre amarilla. Conclusión La alta reactividad cruzada que se encontró, representa un desafío para el diagnostico diferencial del dengue y fiebre amarilla en áreas donde co-circulan estos Flavivirus. Nuevas estrategias de diagnóstico de laboratorio son necesarias para suministrar un diagnóstico especifico. La reactividad cruzada entre Flavivirus representa un gran problema para la vigilancia epidemiológica, control y prevención del dengue, el cual debe ser solucionado.

Low frequency of side effects following an incidental 25 times concentrated dose of yellow fever vaccine

In August/1999, a group of 14 adults from the staff of a private hospital in Contagem -- Minas Gerais State, Brazil, received unintentionally a 25 times concentrated dose of the 17-DD yellow fever vaccine (Bio-Manguinhos), due to a mistake at the reconstitution step. All patients were clinically and laboratorially evaluated at days 5, 13 and 35 post vaccination. Frequency of side effects and clinical observations of this group of individuals were not different from the observed in recipients immunized with normal doses of the vaccine. At the second and third evaluation none of the subjects reported symptoms. None of the patients presented abnormalities at the physical examination at none of the time points and in all cases the blood examination was normal, except for a reduced number of platelets that was detected in one subject at the first and second evaluation and reverted to normal at third evaluation. At the first evaluation point, 8 subjects were serum negative and 6 serum positive for yellow fever at the plaque reduction neutralization test. In 5 subjects the observed titre was 10 times higher as the baseline of 2.36 Log10 mUI/ml. The samples collected at second and third evaluation (13th and 35th days) demonstrated that all subjects responded to the vaccination with the exception of one that did not present a positive result in any of the samples collected. This evaluation confirms the safety of the 17-DD yellow fever vaccine

Fatal myeloencephalitis following yellow fever vaccination in a case with HIV infection.

A 53 year old physically healthy man, unaware of any immunocompromised condition developed rapidly fatal myelomeningoencephalitis following a live-attenuated yellow fever vaccination. He was found to have asymptomatic HIV infection with high viral loads and low CD4 counts. This is the first reported case of such an incidence in the world literature. It is strongly suggested that in countries where HIV infection is endemic, an HIV blood test should be performed prior to the yellow fever vaccination and the vaccine should not be given to those immunocompromised persons.