Genomic diversity contributes to the neuroinvasiveness of the Yellow fever French neurotropic vaccine

AbstractMass vaccination with the live attenuated vaccine YF-17D is the current way to prevent infection with Yellow fever virus (YFV). However, 0.000012–0.00002% of vaccinated patients develop post-vaccination neurological syndrome (YEL-AND). Understanding the factors responsible for neuroinvasion, neurotropism, and neurovirulence of the vaccine is critical for improving its biosafety. The YF-FNV vaccine strain, known to be associated with a higher frequency of YEL-AND (0.3–0.4%) than YF-17D, is an excellent model to study vaccine neuroinvasiveness. We determined that neuroinvasiveness of YF-FNV occured both via infection and passage through human brain endothelial cells. Plaque purification and next generation sequencing (NGS) identified several neuroinvasive variants. Their neuroinvasiveness was not higher than that of YF-FNV. However, rebuilding the YF-FNV population diversity from a set of isolated YF-FNV-N variants restored the original neuroinvasive phenotype of YF-FNV. Therefore, we conclude that viral population diversity is a critical factor for YFV vaccine neuroinvasiveness.

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Safety and immunogenicity of a primary yellow fever vaccination under low-dose methotrexate therapy—a prospective multi-centre pilot study1

Journal of Travel Medicine ◽

10.1093/jtm/taaa126 ◽

2020 ◽

Vol 27 (6) ◽

Cited By ~ 1

Author(s):

Silja Bühler ◽

Veronika Katharina Jaeger ◽

Gilles Eperon ◽

Hansjakob Furrer ◽

Christoph A Fux ◽

...

Keyword(s):

Yellow Fever ◽

Neutralizing Antibodies ◽

Low Dose ◽

Yellow Fever Virus ◽

Serum Samples ◽

Post Vaccination ◽

Dose Methotrexate ◽

Yellow Fever Vaccination ◽

First Time ◽

Local Side

Abstract Background More people on immunosuppression live in or wish to travel to yellow fever virus (YFV)-endemic areas. Data on the safety and immunogenicity of yellow fever vaccination (YFVV) during immunosuppression are scarce. The aim of this study was to compare the safety and immunogenicity of a primary YFVV between travellers on methotrexate and controls. Methods We conducted a prospective multi-centre controlled observational study from 2015 to 2017 in six Swiss travel clinics. 15 adults (nine with rheumatic diseases, five with dermatologic conditions and one with a gastroenterological disease) on low-dose methotrexate (≤20 mg/week) requiring a primary YFVV and 15 age and sex-matched controls received a YFVV. Solicited/unsolicited adverse reactions were recorded, YFV-RNA was measured in serum samples on Days 3, 7, 10, 14, 28 and neutralizing antibodies on Days 0, 7, 10, 14, 28. Results Patients´ and controls’ median ages were 53 and 52 years; 9 patients and 10 controls were female. 43% of patients and 33% of controls showed local side effects (P = 0.71); 86% of patients and 66% of controls reported systemic reactions (P = 0.39). YFV-RNA was detected in patients and controls on Day 3–10 post-vaccination and was never of clinical significance. Slightly more patients developed YFV-RNAaemia (Day 3: n = 5 vs n = 2, Day 7: n = 9 vs n = 7, Day 10: n = 3 vs n = 2, all P > 0.39). No serious reactions occurred. On Day 10, a minority of vaccinees was seroprotected (patients: n = 2, controls: n = 6). On Day 28, all vaccinees were seroprotected. Conclusions First-time YFVV was safe and immunogenic in travellers on low-dose methotrexate. Larger studies are needed to confirm these promising results.

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Viral genetics as a critical factor to control the infection and dissemination of yellow fever virus inAedes aegypti

10.1603/ice.2016.95083 ◽

2016 ◽

Author(s):

Yan-Jang Scott Huang

Keyword(s):

Yellow Fever ◽

Yellow Fever Virus ◽

Critical Factor ◽

Fever Virus ◽

Viral Genetics

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Yellow fever virus isolated from a fatal post vaccination event: an experimental comparative study with the 17DD vaccine strain in the Syrian hamster (Mesocricetus auratus)

Revista da Sociedade Brasileira de Medicina Tropical ◽

10.1590/s0037-86822004000700011 ◽

2004 ◽

Vol 37 (suppl 2) ◽

pp. 69-74 ◽

Cited By ~ 6

Author(s):

Sueli Guerreiro Rodrigues ◽

Amélia Paes de Andrade Travassos da Rosa ◽

Ricardo Galler ◽

Vera Lúcia Reis de Souza Barros ◽

Conceição de Maria Almeida Vieira ◽

...

Keyword(s):

Yellow Fever ◽

Vaccine Strain ◽

Yellow Fever Virus ◽

Mesocricetus Auratus ◽

Virus Antigen ◽

Fever Virus ◽

Wild Type ◽

Post Vaccination ◽

The Brain ◽

Virus Strains

In order to investigate the pathogenicity of the virus strain GOI 4191 that was isolated from a fatal adverse event after yellow fever virus (YFV) vaccination, an experimental assay using hamsters (Mesocricetus auratus) as animal model and YFV 17DD vaccine strain as virus reference was accomplished. The two virus strains were inoculated by intracerebral, intrahepatic and subcutaneous routes. The levels of viremia, antibody response, and aminotransferases were determined in sera; while virus, antigen and histopathological changes were determined in the viscera. No viremia was detected for either strain following infection; the immune response was demonstrated to be more effective to strain GOI 4191; and no significant aminotransferase levels alterations were detected. Strain GOI 4191 was recovered only from the brain of animals inoculated by the IC route. Viral antigens were detected in liver and brain by immunohistochemical assay. Histothological changes in the viscera were characterized by inflammatory infiltrate, hepatocellular necrosis, and viral encephalitis. Histological alterations and detection of viral antigen were observed in the liver of animals inoculated by the intrahepatic route. These findings were similar for both strains used in the experiment; however, significant differences were observed from those results previously reported for wild type YFV strains.

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Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine

Journal of Experimental Medicine ◽

10.1084/jem.20202486 ◽

2021 ◽

Vol 218 (4) ◽

Author(s):

Paul Bastard ◽

Eleftherios Michailidis ◽

Hans-Heinrich Hoffmann ◽

Marwa Chbihi ◽

Tom Le Voyer ◽

...

Keyword(s):

Yellow Fever ◽

Yellow Fever Virus ◽

Previous History ◽

Type I ◽

Live Attenuated Vaccine ◽

Attenuated Vaccine ◽

Type I Ifns ◽

Individual Type ◽

Life Threatening

Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine–associated disease. One 13-yr-old patient had AR complete IFNAR2 deficiency. Three other patients vaccinated at the ages of 47, 57, and 64 yr had high titers of circulating auto-Abs against at least 14 of the 17 individual type I IFNs. These antibodies were recently shown to underlie at least 10% of cases of life-threatening COVID-19 pneumonia. The auto-Abs were neutralizing in vitro, blocking the protective effect of IFN-α2 against YFV vaccine strains. AR IFNAR1 or IFNAR2 deficiency and neutralizing auto-Abs against type I IFNs thus accounted for more than half the cases of life-threatening YFV vaccine-associated disease studied here. Previously healthy subjects could be tested for both predispositions before anti-YFV vaccination.

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Post-Vaccination Yellow Fever Antibodies Enhance Zika Virus Infection in Embryoid Bodies

10.20944/preprints202007.0105.v1 ◽

2020 ◽

Author(s):

Emily M. Schultz ◽

TyAnthony J. Jones ◽

Kelli L. Barr

Keyword(s):

Yellow Fever ◽

Zika Virus ◽

Yellow Fever Virus ◽

Embryoid Body ◽

Embryoid Bodies ◽

Post Inoculation ◽

Culture Methods ◽

Zikv Infection ◽

Post Vaccination ◽

The Impact

Zika virus (ZIKV) is a flavivirus that originated in Africa but emerged in Latin America in 2015. In this region, other flaviviruses such as Dengue (DENV), West Nile, and Yellow Fever Virus (YFV) also circulate, allowing for possible antigenic cross-reactivity to impact viral infections and immune responses. Studies have found antibody mediated enhancement between DENV and ZIKV, but the impact of YFV antibodies on ZIKV infection has not been fully explored. ZIKV infections cause congenital syndromes, such as microcephaly, necessitating further research into ZIKV vertical transmission through the placental barrier. Recent advancements in biomedical engineering have generated co-culture methods that allow for in vitro recapitulation of the maternal: fetal interface. This study utilized a transwell assay, which is a co-culture model utilizing human placental syncytiotrophoblasts, fetal umbilical cells, and a differentiating embryoid body to replicate the maternal: fetal axis. To determine if cross reactive YFV vaccine antibodies impact the pathogenesis of ZIKV across the maternal fetal axis, maternal syncytiotrophoblasts were inoculated with ZIKV or ZIKV incubated with YFV vaccine anti-sera, and viral load was measured 72 hours post inoculation. Here we report that BeWo and HUVEC cells are permissive to ZIKV and that the impact of YFV post-vaccination antibodies on ZIKV replication is cell line dependent. Embryoid bodies are also permissive to ZIKV and the presence of YFV antibodies collected 1 to 6 months post vaccination enhances ZIKV infection. Our data show that each of the cell lines and EBs have a unique response to ZIKV complexed with post-vaccination serum suggesting there may be cell-specific mechanisms that impact congenital ZIKV infections. Since ZIKV infections can cause severe congenital syndromes, it is crucial to understand any potential enhancement or protection offered from cross-reactive, post-vaccination antibodies.

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Post-Vaccination Yellow Fever Antiserum Reduces Zika Virus in Embryoid Bodies When Placental Cells are Present

Vaccines ◽

10.3390/vaccines8040752 ◽

2020 ◽

Vol 8 (4) ◽

pp. 752

Author(s):

Emily M. Schultz ◽

TyAnthony J. Jones ◽

Hannah K. Hopkins ◽

Jingmei Zeng ◽

Kelli L. Barr

Keyword(s):

Yellow Fever ◽

Zika Virus ◽

Yellow Fever Virus ◽

Embryoid Body ◽

Embryoid Bodies ◽

Post Inoculation ◽

Zikv Infection ◽

Post Vaccination ◽

Placental Cells ◽

The Impact

Zika virus (ZIKV) is a flavivirus that originated in Africa but emerged in Latin America in 2015. In this region, other flaviviruses such as Dengue (DENV), West Nile, and Yellow Fever virus (YFV) also circulate, allowing for possible antigenic cross-reactivity to impact viral infections and immune responses. Studies have found antibody-mediated enhancement between DENV and ZIKV, but the impact of YFV antibodies on ZIKV infection has not been fully explored. ZIKV infections cause congenital syndromes, such as microcephaly, necessitating further research into ZIKV vertical transmission through the placental barrier. Recent advancements in biomedical engineering have generated co-culture methods that allow for the in vitro recapitulation of the maternal–fetal interface. This study utilized a transwell assay, which was a co-culture model utilizing human placental syncytiotrophoblasts, fetal umbilical cells, and a differentiating embryoid body, to replicate the maternal–fetal axis. To determine if cross-reactive YFV vaccine antibodies impacted the pathogenesis of ZIKV across the maternal–fetal axis, syncytiotrophoblasts were inoculated with ZIKV or ZIKV incubated with YFV vaccine antisera, and the viral load was measured 72 h post-inoculation. Here, we report that BeWo and HUVEC cells were permissive to ZIKV and that the impact of YFV post-vaccination antibodies on ZIKV replication was cell line-dependent. Embryoid bodies were also permissive to ZIKV, and the presence of YFV antibodies collected 4–14 months post-vaccination reduced ZIKV infection when placental cells were present. However, when directly infected with ZIKV, the embryoid bodies displayed significantly increased viral loads in the presence of YFV antiserum taken 30 days post-vaccination. The data show that each of the cell lines and EBs have a unique response to ZIKV complexed with post-vaccination serum, suggesting there may be cell-specific mechanisms that impact congenital ZIKV infections. Since ZIKV infections can cause severe congenital syndromes, it is crucial to understand any potential enhancement or protection offered from cross-reactive, post-vaccination antibodies.

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What Does the Future Hold for Yellow Fever Virus? (I)

10.20944/preprints201805.0099.v1 ◽

2018 ◽

Author(s):

Raphaëlle Klitting ◽

Ernest A. Gould ◽

Christophe Paupy ◽

Xavier de Lamballerie

Keyword(s):

Yellow Fever ◽

Yellow Fever Virus ◽

Mosquito Species ◽

Central Africa ◽

Fever Virus ◽

Control Measures ◽

Live Attenuated Vaccine ◽

Tropical Regions ◽

The Individual ◽

Vaccination Campaigns

The recent resurgence of yellow fever virus (YFV) activity in the tropical regions of Africa and South America has sparked renewed interest in this infamous arboviral disease. YFV had been a human plague for centuries prior to the identification of its urban transmission vector, the Aedes aegypti mosquito species, and the development of an efficient live-attenuated vaccine, the YF-17D strain. The combination of vector-control measures and vaccination campaigns drastically reduced YFV incidence in humans on many occasions, but the virus never ceased to circulate in the forest, through its sylvatic invertebrate vector(s) and vertebrate host(s). Outbreaks recently reported in Central Africa (2015-2016) and Brazil (since late 2016), reached considerable proportions in terms of spatial distribution and total numbers of cases, with multiple exports, including to China. In turn, questions regarding the likeliness of occurrence of large urban YFV outbreaks in the Americas or of a successful import of YFV to Asia are currently resurfacing. This two-part review describes the current state of knowledge and gaps regarding the molecular biology and transmission dynamics of YFV, along with an overview of the tools that can be used to manage the disease at the individual, local and global levels.

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Exploratory re-encoding of Yellow Fever Virus genome: new insights for the design of live-attenuated viruses

10.1101/256610 ◽

2018 ◽

Author(s):

R. Klitting ◽

T. Riziki ◽

G. Moureau ◽

G. Piorkowski ◽

E. A. Gould ◽

...

Keyword(s):

Yellow Fever ◽

Yellow Fever Virus ◽

Fever Virus ◽

Coding Region ◽

Live Attenuated Vaccine ◽

Replicative Fitness ◽

Synonymous Mutations ◽

Attenuated Viruses

AbstractVirus attenuation by genome re-encoding is a pioneering approach for generating effective live-attenuated vaccine candidates. Its core principle is to introduce a large number of synonymous substitutions into the viral genome to produce stable attenuation of the targeted virus. Introduction of large numbers of mutations has also been shown to maintain stability of the attenuated phenotype by lowering the risk of reversion and recombination of re-encoded genomes. Identifying mutations with low fitness cost is pivotal as this increases the number that can be introduced and generates more stable and attenuated viruses. Here, we sought to identify mutations with low deleterious impact on thein vivoreplication and virulence of yellow fever virus (YFV). Following comparative bioinformatic analyses of flaviviral genomes, we categorized synonymous transition mutations according to their impact on CpG/UpA composition and secondary RNA structures. We then designed 17 re-encoded viruses with 100-400 synonymous mutations in the NS2A-to-NS4B coding region of YFVAsibiandAp7M(hamster-adapted) genomes. Each virus contained a panel of synonymous mutations designed according to the above categorisation criteria. The replication and fitness characteristics of parent and re-encoded viruses were comparedin vitrousing cell culture competition experiments.In vivolaboratory hamster models were also used to compare relative virulence and immunogenicity characteristics. Most of the re-encoded strains showed no decrease in replicative fitnessin vitro. However, they showed reduced virulence and, in some instances, decreased replicative fitnessin vivo. Importantly, the most attenuated of the re-encoded strains induced robust, protective immunity in hamsters following challenge withAp7M, a virulent virus. Overall, the introduction of transitions with no or a marginal increase in the number of CpG/UpA dinucleotides had the mildest impact on YFV replication and virulencein vivo. Thus, this strategy can be incorporated in procedures for the finely tuned creation of substantially re-encoded viral genomes.

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The Analysis of Live-Attenuated Piscirickettsia salmonis Vaccine Reveals the Short-Term Upregulation of Innate and Adaptive Immune Genes in Atlantic Salmon (Salmo salar): An In Situ Open-Sea Cages Study

Microorganisms ◽

10.3390/microorganisms9040703 ◽

2021 ◽

Vol 9 (4) ◽

pp. 703

Author(s):

Deborah Vargas ◽

Eva Vallejos-Vidal ◽

Sebastián Reyes-Cerpa ◽

Aarón Oyarzún-Arrau ◽

Claudio Acuña-Castillo ◽

...

Keyword(s):

Immune Response ◽

Atlantic Salmon ◽

Salmo Salar ◽

Cellular Response ◽

Short Term ◽

Live Attenuated Vaccine ◽

Gene Markers ◽

Post Vaccination ◽

Atlantic Salmon Salmo Salar ◽

Piscirickettsia Salmonis

Piscirickettsia salmonis, the etiological agent of the Salmon Rickettsial Septicemia (SRS), is one the most serious health problems for the Chilean salmon industry. Typical antimicrobial strategies used against P. salmonis include antibiotics and vaccines, but these applications have largely failed. A few years ago, the first attenuated-live vaccine against SRS (ALPHA JECT LiVac® SRS vaccine) was released to the market. However, there is no data about the agents involved in the activation of the immune response induced under field conditions. Therefore, in this study we evaluated the expression profile of a set of gene markers related to innate and adaptive immunity in the context of a cellular response in Atlantic salmon (Salmo salar) reared under productive farm conditions and immunized with a live-attenuated vaccine against P. salmonis. We analyzed the expression at zero, 5-, 15- and 45-days post-vaccination (dpv). Our results reveal that the administration of the attenuated live SRS LiVac vaccine induces a short-term upregulation of the cellular-mediated immune response at 5 dpv modulated by the upregulation of ifnα, ifnγ, and the cd4 and cd8α T cell surface markers. In addition, we also registered the upregulation of il-10 and tgfβ. Altogether, the results suggest that a balanced activation of the immune response took place only at early times post-vaccination (5 dpv). The scope of this short-term upregulation of the cellular-mediated immune response against a natural outbreak in fish subjected to productive farm conditions deserves further research.

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