Abstract:Yellow fever (YF) is a mosquito-borne viral hemorrhagic fever, which is a serious and potentially fatal disease with no specific antiviral treatment that can be effectively prevented by an attenuated vaccine (YEL). Despite the long history of safe and efficacious YF vaccination, sporadic case reports of serious adverse events (SAEs) have been reported, including yellow fever vaccine-associated neurotropic disease (YEL-AND). YEL-AND usually appears within one month of YF vaccination, manifesting as meningoencep… Show more
“…We also carried out a short review using the main databases (PubMed, Lilacs, and Medline) using the keywords “YELLOW FEVER” AND “NEUROTROPIC” or “YELLOW FEVER VACCINE” AND ”NEUROLOGICAL” AND ” ADVERSE EVENT”, resulting in 24 articles reporting several cases of YEL-AND summarized in Table A1 [ 11 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. The data showed that adults and the elderly had a higher risk for development of SAEs, and the highest occurrence of SAEs were associated with the 17D-204 vaccine and presented after administration of the first dose [ 11 , 15 , 16 ].…”
The disease burden of yellow fever virus infection (YFV) is quite high in the tropics where vaccination coverage is low. To date, vaccination is the most effective control strategy to mitigate and eliminate the burden of YF disease. The licensed YF vaccines are safe and effective and serious adverse events are rare. Herein, we report three cases of neurological syndrome, compatible with meningoencephalitis following 17DD vaccination. In all cases, YFV-specific IgM antibodies were detected in the cerebrospinal fluid. Our observations confirm the development of YF vaccine-associated neurotropic disease, a rare serious adverse event, from which all three patients have fully recovered without any long-term sequelae. This report reinforces the need for awareness among health professionals to recognize and effectively manage such events in a timely manner.
“…We also carried out a short review using the main databases (PubMed, Lilacs, and Medline) using the keywords “YELLOW FEVER” AND “NEUROTROPIC” or “YELLOW FEVER VACCINE” AND ”NEUROLOGICAL” AND ” ADVERSE EVENT”, resulting in 24 articles reporting several cases of YEL-AND summarized in Table A1 [ 11 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. The data showed that adults and the elderly had a higher risk for development of SAEs, and the highest occurrence of SAEs were associated with the 17D-204 vaccine and presented after administration of the first dose [ 11 , 15 , 16 ].…”
The disease burden of yellow fever virus infection (YFV) is quite high in the tropics where vaccination coverage is low. To date, vaccination is the most effective control strategy to mitigate and eliminate the burden of YF disease. The licensed YF vaccines are safe and effective and serious adverse events are rare. Herein, we report three cases of neurological syndrome, compatible with meningoencephalitis following 17DD vaccination. In all cases, YFV-specific IgM antibodies were detected in the cerebrospinal fluid. Our observations confirm the development of YF vaccine-associated neurotropic disease, a rare serious adverse event, from which all three patients have fully recovered without any long-term sequelae. This report reinforces the need for awareness among health professionals to recognize and effectively manage such events in a timely manner.
“…According to the CDC diagnostic criteria, this patient would not have met the criteria for a suspect case, as although he had clinical signs of encephalitis he did not have neuroimaging consistent with inflammation or an EEG consistent with an encephalopathy (box 1). We still consider this case to represent a suspect case of YEL-AND, as there are case reports of patients classified as definite YEL-AND who do not have neuroimaging consistent with inflammation,6 12 therefore the absence of abnormal imaging results does not preclude the diagnosis.CDC’s Yellow Fever Vaccine Safety Working Group case definition for yellow fever vaccine-associated neurological disease. (Box adapted from Staples et al 1)
‘Suspect’ neurotropic disease
Neurological disease presenting with one or more of the following:Fever, focal neurological dysfunction, mental status change, seizures, cerebrospinal fluid (CSF) pleocytosis, elevated CSF protein.One or more of the following:Neuroimaging consistent with inflammation.Electroencephalogram finding consistent with encephalopathy.Symptoms occur within 1 and 30 days of vaccination with yellow fever (YF) vaccine, either given alone or in combination with other vaccinations.No evidence of other diagnoses.
‘Probable’ neurotropic disease
Fulfils criteria for suspect neurotropic disease.One or more of the following:YF vaccine strain isolated from blood (>7 days postvaccination).YF vaccine virus concentration in serum >1000 pfu/mL (on any day).
‘Definite’ neurotropic disease
Fulfils criteria for suspect neurotropic disease.One or more of the following:YF vaccine strain isolated from CSF.YF-specific IgM detected in CSF.Amplification of YF vaccine strain from CSF.
A 35-year-old man presented to his optician with sudden onset diplopia and a 1-week history of headaches. He was noted to have sixth nerve palsy. The following day he was admitted to hospital with confusion and expressive dysphasia. He had been due to travel to Ghana on business and had received yellow fever (YF) vaccination 18 days prior to onset of headaches. His initial cerebrospinal fluid (CSF) revealed elevated protein, increased white cell count but was PCR negative for standard viral pathogens. Herpes simplex virus (HSV)-1 was detected by PCR in CSF at a very low level from a second lumbar puncture performed 6 days later, and the patient was treated for HSV meningoencephalitis. However, retrospective investigation for yellow fever vaccine-associated neurological disease revealed increasing titres of YF IgG in three serial CSF samples, and no evidence of HSV antibodies in CSF or plasma, ruling out HSV encephalitis.
“…A single immunization with YF17D can provide lifetime protection in up to 99% of vaccinees (8). However, vaccine-associated viscerotropic disease and neurotropic disease have been reported in recent years (9)(10)(11)(12)(13)(14). The mechanism of action behind these serious adverse effects remains largely unknown.…”
Yellow fever virus (YFV) is a re-emerging flavivirus, which can lead to severe clinical manifestations and high mortality, with no specific antiviral therapies available. The live-attenuated yellow fever vaccine 17D (YF17D) has been widely used for over eighty years. However, the emergence of yellow fever vaccine-associated viscerotropic disease (YFL-AVD) and yellow fever vaccine-associated neurotropic disease (YFL-AND) raised non-negligible concerns. Additionally, the attenuation mechanism of YF17D is still unclear. Thus, the development of convenient models is crucial to understand the mechanisms behind YF17D attenuation and its adverse effects. In this work, we generated a reporter YF17D expressing nano-luciferase (NLuc).
In vitro
and
in vivo
characterization demonstrated that the NLuc-YF17D shared similar biological properties with its parental strain and the NLuc activity can reflect viral infectivity reliably. Combined with
in vivo
bioluminescence imaging, a series of mice models of YF17D infection was established, which will be useful for the evaluation of antiviral medicines and novel vaccine candidates. Especially, we demonstrated that intraperitoneally (i.p.) infection of NLuc-YF17D in type I interferon receptor-deficient mice A129 resulted in outcomes resembling YEL-AVD and YEL-AND, evidenced by viral replication in multiple organs and invasion of the central neuronal system. Finally,
in vitro
and
in vivo
assays based on this reporter virus were established to evaluate the antiviral activities of validated antiviral agents. In conclusion, the bioluminescent reporter virus described herein provides a powerful platform to study YF17D attenuation and vaccine-associated diseases as well as to develop novel countermeasures against YFV.
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