Pathophysiologic and Transcriptomic Analyses of Viscerotropic Yellow Fever in a Rhesus Macaque Model
Flora EngelmannLaurence JossetThomas GirkeByung ParkAlex BarronJesse DewaneErika HammarlundAnne D. LewisMichael K. AxthelmMark K. SlifkaIlhem Messaoudi
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Infection with yellow fever virus (YFV), an explosively replicating flavivirus, results in viral hemorrhagic disease characterized by cardiovascular shock and multi-organ failure. Unvaccinated populations experience 20 to 50% fatality. Few studies have examined the pathophysiological changes that occur in humans during YFV infection due to the sporadic nature and remote locations of outbreaks. Rhesus macaques are highly susceptible to YFV infection, providing a robust animal model to investigate host-pathogen interactions. In this study, we characterized disease progression as well as alterations in immune system homeostasis, cytokine production and gene expression in rhesus macaques infected with the virulent YFV strain DakH1279 (YFV-DakH1279). Following infection, YFV-DakH1279 replicated to high titers resulting in viscerotropic disease with ∼72% mortality. Data presented in this manuscript demonstrate for the first time that lethal YFV infection results in profound lymphopenia that precedes the hallmark changes in liver enzymes and that although tissue damage was noted in liver, kidneys, and lymphoid tissues, viral antigen was only detected in the liver. These observations suggest that additional tissue damage could be due to indirect effects of viral replication. Indeed, circulating levels of several cytokines peaked shortly before euthanasia. Our study also includes the first description of YFV-DakH1279-induced changes in gene expression within peripheral blood mononuclear cells 3 days post-infection prior to any clinical signs. These data show that infection with wild type YFV-DakH1279 or live-attenuated vaccine strain YFV-17D, resulted in 765 and 46 differentially expressed genes (DEGs), respectively. DEGs detected after YFV-17D infection were mostly associated with innate immunity, whereas YFV-DakH1279 infection resulted in dysregulation of genes associated with the development of immune response, ion metabolism, and apoptosis. Therefore, WT-YFV infection is associated with significant changes in gene expression that are detectable before the onset of clinical symptoms and may influence disease progression and outcome of infection.Keywords:
Yellow fever vaccine
Rhesus macaque
Despite the availability of an effective, live attenuated yellow fever virus (YFV) vaccine (YFV 17D), this flavivirus still causes up to ≈60,000 deaths annually. A number of new approaches are seeking to address vaccine supply issues and improve safety for the immunocompromised vaccine recipients. Herein we describe an adult female IFNAR-/- mouse model of YFV 17D infection and disease that recapitulates many features of infection and disease in humans. We used this model to evaluate a new YFV vaccine that is based on a recently described chimeric Binjari virus (BinJV) vaccine technology. BinJV is an insect-specific flavivirus and the chimeric YFV vaccine (BinJ/YFV-prME) was generated by replacing the prME genes of BinJV with the prME genes of YFV 17D. Such BinJV chimeras retain their ability to replicate to high titers in C6/36 mosquito cells (allowing vaccine production), but are unable to replicate in vertebrate cells. Vaccination with adjuvanted BinJ/YFV-prME induced neutralizing antibodies and protected mice against infection, weight loss and liver pathology after YFV 17D challenge.
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Yellow fever vaccine is a live, attenuated viral preparation from the 17D virus strain. Since 1996, 34 cases of yellow fever vaccine–associated viscerotropic disease (YEL‐AVD) have been described. We report a new case of YEL‐AVD. Given the potential risks associated with the vaccine, physicians should consider vaccination only for patients truly at risk for exposure to yellow fever, especially for primovaccination.
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Recommendations to travellers regarding yellow fever vaccination (YFV) are based on personal risk, previous vaccinations, health status of the traveller and border regulations.Recently, WHO extended the recommendation regarding protection after YFV from 10 years to lifelong.We present the results of a survey among Swiss tropical and travel medicine experts, in which they were asked to decide upon the correct vaccination approach in eight case scenarios.YFV is one of the most often administered vaccines in travel medicine [1] (40,000 doses per year in Switzerland [personal communication]).With over 600 million administered doses worldwide, only 12 yellow fever (YF) cases have been described in vaccinated persons [2].Generally, YFV is well tolerated, but severe reactions, such as yellow fever vaccination-associated viscerotropic disease (YEL-AVD) or yellow fever vaccination-associated neurotropic disease (YEL-AND) occur in around 0.5/100,000 distributed doses [3].In order to assess and harmonise indications for yellow fever vaccination, a survey was performed during a meeting of The Swiss Society of Tropical and Travel Medicine in January 2014.Experts assessed eight real and imaginary cases of travellers on whether YFV should be given, not given, or if a written exemption should be issued.Only one answer was possible and delay or cancellation of the trip was not an option.Physicians were asked to give a recommendation for two scenarios: (i.) sufficient vaccine doses available and (ii.) shortage of YFV, as this was a problem at that time.Overall, 55 questionnaires were distributed, and 43 (78%) were returned.Case descriptions, survey results and the correct options according to Swiss vaccination recommendations (version October 2013 [4]) are summarised in table 1.
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Yellow fever is a mosquito born viral illness that causes hemorrhagic fever in tropical Africa and South America. An estimated 200 000 people are still infected annually. There is no antiviral therapy available and vaccination is major strategy in the control yellow fever. From 60 years ago is available very safe and efficient vaccine. The vaccine is a live attenuated virus strain 17D. Recently identified vaccine associated viscerotropic diseases (YFV-AVD). This paper describes knowledge about yellow fever disease, vaccine associated adverse events and actually recommendation for vaccine use.
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Yellow fever outbreaks have continued to occur and caused infection and deaths in travelers from non-endemic regions. Yellow fever vaccine has proven effective, but vaccination decisions require balancing benefits with risks. Of concern is the continued vaccine shortage worldwide, including of the YF-VAX® stockout in North America, which has presented many challenges.
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Yellow fever is a viral haemorrhagic disease spread by day-biting mosquitoes. Infection can cause an acute, potentially fatal illness. Yellow fever is found in tropical regions of Africa and Central and South America and one region in the Caribbean. Avoiding mosquito bites is recommended for anyone living in or travelling to risk areas and the World Health Organization advises yellow fever vaccine is the most important way to prevent yellow fever. Risk areas and vaccine recommendations can change rapidly. Nurses advising travellers must ensure they are familiar with appropriate sources of information and stay up to date with current international yellow fever vaccine recommendations. Yellow fever vaccine is only available at designated UK Yellow Fever Vaccination Centres.
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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.
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