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| ==== Structure of Yellow Fever Virus ==== | ==== Structure of Yellow Fever Virus ==== | ||
| - | The YFV is spherical in structure and is ~50 nm in diameter. It's structure is based on 3 major types of strucutral proteins that the virus codes for: Envelope (E) Proteins, Membrane (M) Proteins & Capsid (C) Proteins (Barnett, 2007). The structure is depicted in **Figure #04**. Note that the genome is housed in an icosahedral shape. | + | The YFV is spherical in structure and is ~50 nm in diameter. It's structure is based on 3 major types of strucutral proteins that the virus codes for: Envelope (E) Proteins, Membrane (M) Proteins & Capsid (C) Proteins (Barnett, 2007). The structure is depicted in **Figure #05**. Note that the genome is housed in an icosahedral shape. |
| {{:yf_-_structure_of_yfv.jpg|}} | {{:yf_-_structure_of_yfv.jpg|}} | ||
| - | **Figure #04**: Structure of the Yellow Fever Virus. Note the relationship between the structural proteins (E, M & C) as well as the spherical structure of the virus (Barnett, 2007). | + | **Figure #05**: Structure of the Yellow Fever Virus. Note the relationship between the structural proteins (E, M & C) as well as the spherical structure of the virus (Barnett, 2007). |
| ==== Genomic Structure & Sequence ==== | ==== Genomic Structure & Sequence ==== | ||
| - | The Yellow Fever Virus (YFV) is a single-stranded, positive RNA Virus. It's RNA genome is 11kb long with the 5' end having a methylated nucleated cap which allows for translation to commence on the 5' end of the genome. The 3' end is not polyadenylated and forms a loop structure (i.e. this cannot be translated into mRNA). This non-polyadenylated tail is important for nuclear export, translation and stability of the mRNA of nucleotides. (Volk et al., 2009). Interestingly, the entire YFV genome consists of only one Open Reading Frame (ORF). An ORF is a continuous stretch of codons that do not contain a stop codon and that can potentially code for proteins or peptides (Volk et al., 2009). This one ORF is depicted in **Figure #05** below and codes for 10 proteins in total: 3 structural proteins (C, M & E) and 7 non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5) which are responsible for functions ranging for translation, cytoplasmic transport and viral genome release (Patkar et al., 2007). | + | The Yellow Fever Virus (YFV) is a single-stranded, positive RNA Virus. It's RNA genome is 11kb long with the 5' end having a methylated nucleated cap which allows for translation to commence on the 5' end of the genome. The 3' end is not polyadenylated and forms a loop structure (i.e. this cannot be translated into mRNA). This non-polyadenylated tail is important for nuclear export, translation and stability of the mRNA of nucleotides. (Volk et al., 2009). Interestingly, the entire YFV genome consists of only one Open Reading Frame (ORF). An ORF is a continuous stretch of codons that do not contain a stop codon and that can potentially code for proteins or peptides (Volk et al., 2009). This one ORF is depicted in **Figure #06** below and codes for 10 proteins in total: 3 structural proteins (C, M & E) and 7 non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5) which are responsible for functions ranging for translation, cytoplasmic transport and viral genome release (Patkar et al., 2007). |
| {{:yfv_genome.png|}} | {{:yfv_genome.png|}} | ||
| - | **Figure 05**:Genomic sequence showing the genome and the structural and non-structural proteins coded for in the one ORF of the YFV (Patkar et al., 2007). | + | **Figure 06**:Genomic sequence showing the genome and the structural and non-structural proteins coded for in the one ORF of the YFV (Patkar et al., 2007). |
| By being positive-sense, the viral RNA has the ability to be directly translated into the viral protein since the RNA can be considered the mRNA as well (Rice et al., 1985). Furthermore, YFV, unlike other mosquito-borne diseases is viscerotropic, as it preferentially affects the main organs in the internal cavity of the body such as the kidneys (Rice et al., 1985). | By being positive-sense, the viral RNA has the ability to be directly translated into the viral protein since the RNA can be considered the mRNA as well (Rice et al., 1985). Furthermore, YFV, unlike other mosquito-borne diseases is viscerotropic, as it preferentially affects the main organs in the internal cavity of the body such as the kidneys (Rice et al., 1985). | ||
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| Recall that the YFV can only be spread to humans via a vector and not through any direct human-human or human-animal interaction. The virus enters the human body during a mosquito bite when the blood from an infected individual on the mouth of the mosquito enters into the blood stream of a non-affected individual. | Recall that the YFV can only be spread to humans via a vector and not through any direct human-human or human-animal interaction. The virus enters the human body during a mosquito bite when the blood from an infected individual on the mouth of the mosquito enters into the blood stream of a non-affected individual. | ||
| - | Once the YFV enters the bloodstream it is able to infect those cells that its E proteins are able to preferentially bind to. These susceptible cells are monocytes (Macrophages and / or Dendritic Cells). Once the E-proteins on the YFV binds to the receptors on these monocytes the virus is able to enter the cell via Receptor Mediated Phagocytosis. Once it enters the cell an endosome forms around the entered virus where H+ enters the endosome raising the pH of the endosome-virus vesicle. This increase in pH allows the viral RNA to be released. This viral RNA attaches onto the Rough Endoplasmic Reticulum of the cell where it begins to replicate in "sacs". | + | Once the YFV enters the bloodstream it is able to infect those cells that its E proteins are able to preferentially bind to. These susceptible cells are monocytes (Macrophages and / or Dendritic Cells) (Pulendran, 2009). Once the E-proteins on the YFV binds to the receptors on these monocytes the virus is able to enter the cell via Receptor Mediated Phagocytosis. Once it enters the cell an endosome forms around the entered virus where H+ enters the endosome raising the pH of the endosome-virus vesicle (Pulendran, 2009). This increase in pH allows the viral RNA to be released. This viral RNA attaches onto the Rough Endoplasmic Reticulum of the cell where it begins to replicate in "sacs". In order to replicate it utilizes the host's own RNA-dependent-RNA-polymerase to initiate the replication by switching the positive strand to negative strand and allowing replication to proceed (Pulendran, 2009). |
| + | Following replication, immature viral particles enter the Golgi network through vesicles in which the viral particles mature. Maturation simply implies that the viral RNA takes its icosahedron shape and the E proteins on the outer layer of the virion form a dimer. Once they have matured, the vesicles with progeny virion are released into outer environment as the vesicle fuses with the cellular membrane (Pulendran, 2009). The above process is outlined in the diagram below: | ||
| + | {{:yf_-_viral_replication.jpg|}} | ||
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| + | **Figure #07**: Diagram depicting Viral replication of the Yellow Fever Virus. | ||
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| + | ==== Immune System Response ==== | ||
| - | ====== Immune System Response ====== | ||
| Research has shown that the immune system responses to combat yellow fever can be observed after administering the yellow fever vaccine. Once an individual is vaccinated, researchers are able to analyze the types of immune cells that interact and limit the spread of yellow fever infection (Pulendran, 2009). This is possible either through using a genetic screen that identifies genes which are expressed by immune cells or using flow cytometry to determine specific proteins that are expressed by immune cells. Using these methods, the immune cells that have been identified are dendritic cells (DC), a variety of T cells and B cells (Querec et al., 2009; Gaucher et al., 2008). DCs are important for the immune response against yellow fever as they are the main activators of other adaptive immune cells that directly kill yellow fever infected cells. Research has shown that specific receptors present on the DC called toll-like receptors are able to bind to yellow fever antigens. Upon binding, the DC can then present the yellow fever antigen to naïve CD4+ T cells resulting in the activation of the apoptotic CD8+ T cells as well as neutralizing antibodies that can directly interfere with yellow fever activity in the blood. Please see Figure below for details. Ultimately, immune system recognition of yellow fever results in a well rounded and robust response that involves effective communication between multiple cell types (Pulendran, 2009). | Research has shown that the immune system responses to combat yellow fever can be observed after administering the yellow fever vaccine. Once an individual is vaccinated, researchers are able to analyze the types of immune cells that interact and limit the spread of yellow fever infection (Pulendran, 2009). This is possible either through using a genetic screen that identifies genes which are expressed by immune cells or using flow cytometry to determine specific proteins that are expressed by immune cells. Using these methods, the immune cells that have been identified are dendritic cells (DC), a variety of T cells and B cells (Querec et al., 2009; Gaucher et al., 2008). DCs are important for the immune response against yellow fever as they are the main activators of other adaptive immune cells that directly kill yellow fever infected cells. Research has shown that specific receptors present on the DC called toll-like receptors are able to bind to yellow fever antigens. Upon binding, the DC can then present the yellow fever antigen to naïve CD4+ T cells resulting in the activation of the apoptotic CD8+ T cells as well as neutralizing antibodies that can directly interfere with yellow fever activity in the blood. Please see Figure below for details. Ultimately, immune system recognition of yellow fever results in a well rounded and robust response that involves effective communication between multiple cell types (Pulendran, 2009). | ||
| {{:snip20160226_7.png|}} | {{:snip20160226_7.png|}} | ||
| - | **Figure 4: The image represents a diagram showing the different parts involved in the immune response to the Yellow Fever virus. Taken from: http://www.nature.com/nri/journal/v9/n10/full/nri2629.html** | + | **Figure #08:** The image represents a diagram showing the different parts involved in the immune response to the Yellow Fever virus (Pulendran, 2009). |
| - | ====== Yellow Fever Vaccination ====== | + | ====== Yellow Fever Treatment ====== |
| + | Currently, the only way to diagnose someone with Yellow Fever is via a blood test but unfortunately, no specific anti-viral treatment is present to treat the affected individual (Bukowski, 2015). Instead, it is treated by providing the patient with intensive and supportive care in order to allow their adaptive immune system to kick in so that it can combat the YFV (Bukowski, 2015). These care procedures include: a vasoactive medication which works as a vasoconstrictor, thus increasing the patients' blood pressure (Bukowski, 2015). Symptoms such as excessive bleeding and vomiting will cause a huge fluid imbalance in the body. However, administering intravascular fluid will keep the body hydrated and also keep the blood pressure high (Bukowski, 2015). Also, ventilator management is used to support patients' breathing, as these machines give oxygen to the lungs (Bukowski, 2015). Furthermore, you would have to administer the treatment of disseminated intravascular coagulation (DIC), hemorrhage, secondary infections, and renal and hepatic dysfunction. For actively bleeding patients, the administration of fresh frozen plasma is recommended to maintain a prothrombin time of 25-30 seconds (Bukowski, 2015). | ||
| + | ==== Yellow Fever Vaccination ==== | ||
| - | ==== Current procedures ==== | + | Yellow Fever was the first pathogenic virus for which a live-attenuated vaccine was created back in 1936 (Roukens & Visser, 2008). A live-attenuated vaccine carries a live virus however this virus has been weakened or altered so that it cannot actually infect the vaccinated individual allowing instead, the vaccinated individual to build an 'immunity' for that vaccinated virus. The first two strains created of the virus were: FNV & YF-17D, however, following their dispersion it was seen that the FNV virus caused vaccine related encephalitis and thus it was discontinued (Roukens & Visser, 2008). The YF-17D virus was further developed and today it exists in two forms: YF-17DD & YF-17D-204 (Roukens & Visser, 2008). |
| - | Yellow Fever has no cure (Bukowski, 2015). Since there is no cure, managing the disease becomes essential. Once infected, supportive care is critical and, if conditions worsen, the patients are treated in an intensive care setting (Bukowski, 2015). The infection causes a decline in blood pressure, for which the patients are given vasoactive medication which works as a vasoconstrictor, thus increasing the patients' blood pressure (Bukowski, 2015). Symptoms such as excessive bleeding and vomiting will cause a huge fluid imbalance in the body. However, administering intravascular fluid will keep the body hydrated and also keep the blood pressure high (Bukowski, 2015). Also, ventilator management is used to support patients' breathing, as these machines give oxygen to the lungs (Bukowski, 2015). Furthermore, you would have to administer the treatment of disseminated intravascular coagulation (DIC), hemorrhage, secondary infections, and renal and hepatic dysfunction. For actively bleeding patients, the administration of fresh frozen plasma is recommended to maintain a prothrombin time of 25-30 seconds (Bukowski, 2015). In patients with DIC, heparin has been a recommended for treatment (Bukowski, 2015). | + | |
| - | ==== Vaccines ==== | + | These vaccinations can prevent yellow fever and the current vaccine for yellow fever confers 95% lifelong immunity in patients (Roukens & Visser, 2008). Based on the severity of Yellow fever in certain areas, it is recommended to have routine immunization. Currently, world health organization strives for an 80% coverage for the vaccine to achieve immunity for many people to prevent an outbreak (Roukens & Visser, 2008). For travelers from non-endemic areas to endemic areas it is crucial to take this vaccine. |
| - | There are two different sub strains derived from the YF-17D, YF-17D-204 and YF-204, which are used for the production of yellow fever (Roukens & Visser, 2008). It is grown in an embryonated chicken egg, yielding 100-300 vaccines doses per egg and it should be used immediately after produced (Roukens & Visser, 2008). This vaccination can prevent yellow fever and the current vaccine for yellow fever confers 95% lifelong immunity in patients (Roukens & Visser, 2008). Based on the severity of Yellow fever in certain areas, it is recommended to have routine immunization. Currently, world health organization strives for an 80% coverage for the vaccine to achieve immunity for many people to prevent an outbreak (Roukens & Visser, 2008). For travelers from non-endemic areas to endemic areas it is crucial to take this vaccine. | + | |
| - | + | ==== Safety and Side-effects of Current Vaccination Procedures ==== | |
| - | ==== Safety ==== | + | |
| This vaccine has been administered to over 500 million people worldwide, and has been regarded as a safe drug (Roukens & Visser, 2008). The adverse effects usually occur within 2-6 days after vaccination and include low grade fever, headache, myalgia headache, and redness at the site of the injection (Roukens & Visser, 2008). Only 10-20 % of these symptoms are reported. This vaccination is advised for adults and children over the age of 9 months and under 65 years (Roukens & Visser, 2008). Furthermore, anaphylaxis can occur after vaccination with a risk of 0.8 in 100000 doses. Obtaining history on patients for hypersensitivity to eggs or egg products can reduce the risk of anaphylaxis (Roukens & Visser, 2008). The reason for this is that because this vaccine is grown in an embryonate chicken egg. To test hypersensitivity of patients with egg allergies, they give 0.1ml to patients under strict supervision (Roukens & Visser, 2008). Then a controlled saline dose is given to the other arm and both sites are checked after 30 minutes. If the diameter of the cutaneous wheal of the yellow fever virus is less than twice the control diameter, hypersensitivity to the vaccine is highly unlikely. If it exceeds the diameter two folds, the yellow fever vaccine will not be administered. Moreover, yellow fever vaccination in early pregnancy stages is safe (Roukens & Visser, 2008). | This vaccine has been administered to over 500 million people worldwide, and has been regarded as a safe drug (Roukens & Visser, 2008). The adverse effects usually occur within 2-6 days after vaccination and include low grade fever, headache, myalgia headache, and redness at the site of the injection (Roukens & Visser, 2008). Only 10-20 % of these symptoms are reported. This vaccination is advised for adults and children over the age of 9 months and under 65 years (Roukens & Visser, 2008). Furthermore, anaphylaxis can occur after vaccination with a risk of 0.8 in 100000 doses. Obtaining history on patients for hypersensitivity to eggs or egg products can reduce the risk of anaphylaxis (Roukens & Visser, 2008). The reason for this is that because this vaccine is grown in an embryonate chicken egg. To test hypersensitivity of patients with egg allergies, they give 0.1ml to patients under strict supervision (Roukens & Visser, 2008). Then a controlled saline dose is given to the other arm and both sites are checked after 30 minutes. If the diameter of the cutaneous wheal of the yellow fever virus is less than twice the control diameter, hypersensitivity to the vaccine is highly unlikely. If it exceeds the diameter two folds, the yellow fever vaccine will not be administered. Moreover, yellow fever vaccination in early pregnancy stages is safe (Roukens & Visser, 2008). | ||
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| ==== Future procedures? ==== | ==== Future procedures? ==== | ||
| Over the past 60 years the YF-17D vaccine has not changed. There are limitations on the amount of vaccinations that can be produced on a short notice. This a concern to the Global Alliance of Vaccines, which is supporting the stock pile of over 6 million doses of yellow fever vaccines (Roukens & Visser, 2008). According to the WHO, shortages in vaccine supply is soon to become a problem. In order to make it more economically friendly, they will reduce standard dosages fivefold from 0.5ml to 0.1ml (Roukens & Visser, 2008). Furthermore, injecting inactive yellow fever vaccines in people traveling to endemic areas may provide protection, as there has been trial with the inactive vaccine in mice, finding that all the mice were protected from the virus (Roukens & Visser, 2008). | Over the past 60 years the YF-17D vaccine has not changed. There are limitations on the amount of vaccinations that can be produced on a short notice. This a concern to the Global Alliance of Vaccines, which is supporting the stock pile of over 6 million doses of yellow fever vaccines (Roukens & Visser, 2008). According to the WHO, shortages in vaccine supply is soon to become a problem. In order to make it more economically friendly, they will reduce standard dosages fivefold from 0.5ml to 0.1ml (Roukens & Visser, 2008). Furthermore, injecting inactive yellow fever vaccines in people traveling to endemic areas may provide protection, as there has been trial with the inactive vaccine in mice, finding that all the mice were protected from the virus (Roukens & Visser, 2008). | ||
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| ====== Summary ====== | ====== Summary ====== | ||
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| 15. WHO (2014, March 1). Yellow Fever. Retrieved from http://www.who.int/mediacentre/factsheets/fs100/en/ | 15. WHO (2014, March 1). Yellow Fever. Retrieved from http://www.who.int/mediacentre/factsheets/fs100/en/ | ||
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| - | 10. Volk, D.E., May, F.J., Gandham, S.H., Anderson, A., Von Lindern, J.J., Beasley, D.W., Barrett, A.D., & Goreinstein, D.G. (2009). Structure of Yellow Fever Virus Envelope Protein Domain III. //US National Library of Medicine//, 394(1), 12-18. | ||
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