Yellow fever virus: Infectious substances pathogen safety data sheet

For more information on yellow fever virus, see the following:

• Yellow fever
• Information for Travellers Going to Yellow Fever Areas
• Rapid risk assessment: the risk of Yellow fever (YF) to Canadians
• Yellow fever vaccine: Canadian Immunization Guide

Section I – Infectious agent

Name

Yellow fever virus

Agent type

Virus

Taxonomy

Family

Flaviviridae

Genus

Orthoflavivirus

Species

Orthoflavivirus flavi^{Footnote 1}

Synonym or cross-reference

Causative agent of yellow fever, previously known as black vomit^{Footnote 2}, yellow jack^{Footnote 3}, yellow plague, Bronze John, Bulam fever, and saffron scourge^{Footnote 4}.

Characteristics

Brief description

Yellow fever virus (YFV) is an icosahedral enveloped virus with a diameter of approximately 40 nm. The viral envelope is derived from the host plasma membrane and is embedded with dimers of the viral envelope (E) glycoprotein and membrane (M) proteins that protrude up to 10 nm^{Footnote 5}. The viral genome is a single-stranded, positive-sense RNA molecule, approximately 11 kb in length, with a cap structure at the 5'-end and a very stable, highly conserved stem-loop structure at the 3'-end which acts to stabilize the genome and provides signals for initiation of translation and RNA synthesis^{Footnote 5Footnote 6}.

Properties

YFV can tolerate and replicate at temperatures between 20–37°C (optimum 37°C) in mosquito salivary glands^{Footnote 7}. After inoculation, the virus is able to replicate in a susceptible host^{Footnote 8}. It does so by first infecting dendritic cells in the skin, which are also susceptible to virus infection in vitro. The lymphatic vessels then drain these cells to lymph nodes, where the virus is replicated and released into the bloodstream, causing initial viremia. Once in the hematogenous route, the virus infects the liver, kidneys, heart, spleen and other organs.

Section II – Hazard identification

Pathogenicity and toxicity

YFV causes yellow fever (YF), a disease described as the original viral hemorrhagic fever^{Footnote 5Footnote 9}. Reports from West African outbreaks suggest that the ratio of symptomatic to asymptomatic cases of YFV infection is 1 in 3.8 to 1 in 7.4, suggesting that clinically overt disease occurs in 12-21% of YFV infections^{Footnote 10}. The clinical course of YF is classically described in three phases. The infection phase is typically abrupt in onset and is characterized by flu-like symptoms such as fever with measured temperatures of up to 41°C in adults, myalgia, headache, joint pain and nausea^{Footnote 11}. Patients are usually viremic during this stage of the illness, with high viral titers of up to 10⁵ to 10⁶ viral particles/mL^{Footnote 9}. This may be followed by a short remission phase (2 to 48 hours in duration), with resolution of fever and improvement in clinical symptoms. Patients with mild disease may recover at this phase, without subsequent progression to more severe disease. Approximately 12–20% of YFV-infected individuals progress to the intoxication phase, which occurs within 3 to 6 days after onset of initial symptoms and is characterized by the recurrence of high fever, as well as abdominal pain, nausea, vomiting, renal failure, oliguria, and jaundice^{Footnote 5Footnote 11Footnote 12}. Hemorrhagic manifestations occur during this phase and include petechiae, ecchymoses, epistaxis (nosebleeds), oozing of blood from gums and needle puncture sites, hematuria (blood in urine), melena (blood in the stool), hematemesis (vomiting of blood), and metrorrhagia (prolonged menstrual bleeding)^{Footnote 5Footnote 9Footnote 13}. Notably, myocardial injury, represented via wave abnormalities on electrocardiograms, has also been reported in patients^{Footnote 9}. Encephalopathy and other changes in the brain can also be reported and are often due to increased cerebrospinal pressure and edema rather than viral encephalitis^{Footnote 9}, although encephalitis due to YFV is extremely rare^{Footnote 14}. Symptoms of encephalopathy include delirium, stupor, coma, Cheyne-Stokes respirations, metabolic acidosis, hyperkalemia, hypoglycemia, and hypothermia^{Footnote 15Footnote 16}. Based off a systematic literature review, the case fatality rate of YFV is estimated to be approximately 39%^{Footnote 17}. An estimated 20 to 50% of YF patients with hepatorenal involvement during the disease (i.e., progression to the period of intoxication) have a fatal outcome^{Footnote 9}.

Epidemiology

YFV is currently endemic in 34 countries in Africa and 13 countries in South America^{Footnote 18}. The virus can be classified into two major clades: the first clade encompasses four genotypes, two in West Africa and two in South America, whereas the second clade includes three genotypes identified in Central/East Africa^{Footnote 18}. The virus is maintained in nature by transmission between non-human primates (NHPs), horizontal transmission via blood-feeding mosquitoes, and transovarial transmission in competent vectors^{Footnote 18}. There are 3 transmission cycles; sylvatic (or jungle), urban, and intermediate (savannah)^{Footnote 19}. The sylvatic cycle involves the transmission of the virus between non-human primates and tree-hole breeding mosquitoes, such as Aedes africanus, A. luteocephalus, A. opok, and the A. simpsoni group in Africa and Haemagogus species in South America^{Footnote 19Footnote 20}. The urban cycle is less common but was responsible for historical outbreaks in Europe and North America and involves the transmission in densely populated regions between humans and domesticated mosquitoes like A. aegypti^{Footnote 5Footnote 16}. The intermediate cycle occurs only in Africa, and is between humans living close to jungle boarders and tree-hole-breeding anthropophilic mosquito species such as A. africanus, A. luteocephalus, A. opok, and the A. simpsoni group^{Footnote 16Footnote 21}. Since NHPs represent one of the reservoirs, YFV cannot be eradicated. In addition, infected humans can also contribute to YFV transmission, infecting mosquitoes during periods of viremia. There is an estimated 200,000 cases of YF and 30,000 deaths every year, 90% of which occur in Africa^{Footnote 22}.

From 2016-2018, YFV outbreaks were reported in both endemic and non-endemic areas in Africa and South America with historically low vaccination coverage^{Footnote 23}. The largest YF outbreak in 30 years was reported in Angola in 2016-2017, an endemic area where YFV activity is infrequent and the vaccination coverage is lower than in West Africa, with subsequent spread to the Democratic Republic of Congo and possibly Uganda. From December 2015 to October 2016, 884 confirmed cases and 121 deaths were reported in these countries, triggering the mass vaccination of 30 million people. The largest YFV outbreak recorded in Africa occurred along the River Omo, in southwestern Ethiopia, between 1960 and 1962, resulting in approximately 200,000 cases and 30,000 deaths^{Footnote 21}. In 1966, YFV appeared in Arba Minch in South Ethiopia, in an area previously unaffected in the 1960 epidemic, and therefore was excluded from the mass vaccination campaign at the time. During this outbreak, 2200 cases and 450 deaths were reported and the outbreak was confirmed through serological testing^{Footnote 24}. YFV then re-emerged in South Omo in 2012-2014, and more recently in October 2018 in South West Ethiopia^{Footnote 21}.

Individuals participating in occupational or recreational activities in forests have an increased risk of YFV infection via the sylvatic cycle^{Footnote 16Footnote 25}. Infection is also more commonly reported in men than in women, likely due to the overrepresentation of men in these professions^{Footnote 9}.

Individuals older than 40 years were found to be more likely to succumb to YF than individuals under 40 years^{Footnote 26}.

Host range

Natural host(s)

Humans, NHPs, and mosquitoes are the natural hosts^{Footnote 27}. Susceptible animal species in Africa include monkeys of the genus Cercopithecus, chimpanzees (Pan spp.), mangabey (Cercocebus spp.), baboons (Papio spp.), bush babies (Galaga spp.), and possibly hedgehogs (Erinaceus spp.), whereas in Central and South America, YFV infection has been reported in capuchin, spider, howler, titi, and night monkeys, marmosets, and tamarins^{Footnote 28Footnote 29Footnote 30}.

Other host(s)

Mice and hamsters are experimentally infected hosts^{Footnote 31}.

Infectious dose

Unknown for humans. Generally, the infectious dose for causative agents of viral hemorrhagic fever is approximately 1–10 organisms by aerosol in humans^{Footnote 32}. Experimental evidence indicates that the 50% lethal dose in monkeys is less than 1 plaque-forming unit^{Footnote 9}.

Incubation period

YF has an incubation period of 3 to 6 days^{Footnote 5}.

Communicability

The preferred mode of transmission is injection of infectious material via the bite of a YFV-infected mosquito^{Footnote 5}. Although there are no reported naturally acquired cases of YFV infection via contact with intact skin in humans or animals, historical experimental evidence in monkeys, suggested that YFV might be transmitted through the skin, although high viral titers would be necessary^{Footnote 33}. Contact of infectious material with mucous membranes or damaged skin is another possible route of transmission^{Footnote 34}. Experimental evidence in monkeys suggests that YFV can be transmitted via aerosols and by ingestion^{Footnote 34Footnote 35Footnote 36}. Human-to-human transmission can occur via intimate direct contact through organ transplantation, blood transfusion^{Footnote 37}, and vertical transmission^{Footnote 34Footnote 38Footnote 39}. Although YFV was shown not to be transmitted between individuals via contact with beddings of infected individuals^{Footnote 40}, laboratory-acquired cases of infection have been reported after handling contaminated patient/animal materials, suggesting that indirect contact via fomites may be a rare route of human-to-human transmission^{Footnote 34}.

Section III – Dissemination

Reservoir

Humans in the urban cycle; NHPs in the sylvatic cycle; humans and NHPs in the intermediate cycle^{Footnote 18}. In a serological survey conducted in French Guiana, anti-YFV antibodies were detected in 10 wild mammalian species of various orders or superorders, namely golden-handed tamarin, white-faced saki, and red howler monkeys (primates); agoutis and porcupines (Rodentia); collared peccary (artiodactyl); tayra (Carnivora); two-toed and three-toed sloths, and anteaters (Xenarthra), suggesting that non-primate mammalian species may play a role in transmission^{Footnote 41}.

Zoonosis

Indirect zoonosis occurs in the sylvatic cycle, which involves transmission of YFV between NHPs and tree-hole breeding mosquitoes, where humans may be sporadically infected when bitten by a YFV-infected mosquito^{Footnote 11}.

Vectors

The principal arthropod vectors of YFV differ depending on geographical location and transmission cycle^{Footnote 42}. The urban transmission cycle is mediated by domesticated mosquito vectors, such as Aedes aegypti^{Footnote 5}. In the sylvatic cycle, YFV is transmitted between NHPs and tree-hole breeding mosquito species, including Aedes africanus in Africa, and Haemogogus spp. and Sabethes spp. in South America^{Footnote 19Footnote 20}. The intermediate cycle occurs only in Africa and involves transmission between humans and NHPs, and tree-hole breeding anthropophilic Aedes spp., including A. africanus, A. furcifer-taylori, A. bromeliae, A. metallicus, and A. luteocephalis^{Footnote 19Footnote 43}.

Section IV – Stability and viability

Drug susceptibility/resistance

YFV is susceptible to high, and potentially cytotoxic, concentrations of ribavirin in vitro^{Footnote 44}. Sofosbuvir has also shown antiviral activity against YFV^{Footnote 45}. Some 2-indolinone compounds exhibited nontoxic and selective antiviral activity against YFV in vitro, with 1-benxyl and 5-halogen or nitro-substituted compounds being most effective against YFV^{Footnote 46}.

Susceptibility to disinfectants

YFV is inactivated by 2% glutaraldehyde, beta-propioacetone, 2-3% hydrogen peroxide, 70% ethanol, 500-5000 ppm chlorine, 3-8% formaldehyde, 1% iodine and phenol iodophors, and 0.5% phenol with detergent^{Footnote 47}.

Physical inactivation

YFV may be inactivated by heat treatment at temperatures >50°C for 30 minutes and by gamma irradiation^{Footnote 47}.

Survival outside host

Low temperatures preserve infectivity, with stability being greatest below -60°C^{Footnote 48}. YFV is viable for up to 90 days when air-dried on filter paper and maintained at room temperature^{Footnote 49}. In a case of YF vaccine virus transmission via blood transfusion, an individual received a red blood cell (RBC) transfusion from a donor that had been recently vaccinated with attenuated vaccine^{Footnote 37}. The transfusion occurred 24 days after blood donation, suggesting that YF vaccine virus may be viable in stored RBC products for at least 24 days.

Section V – First aid/medical

Surveillance

The most widespread diagnostic method is detection of anti-YFV IgM antibodies by enzyme-linked immunosorbent assays (ELISA), although this may be complicated by cross-reactivity among other flaviviruses^{Footnote 47}. The plaque reduction neutralization (PRNT) assay, or virus neutralization test (VNT), is the most specific method for the detection of anti-YFV antibodies. Other tests that are currently used for detection of IgM and IgG antibodies against YFV include in house indirect immunofluorescence methods (IIF), which require well-trained personnel for correct interpretation, and ELISA, MAC-ELISA, and ELISA inhibition tests. More recently, a multiplex microsphere immunoassay (MIA) test has been described for the detection of arboviral antibodies, including those against YFV^{Footnote 47}.

Note: The specific recommendations for surveillance in the laboratory should come from the medical surveillance program, which is based on a local risk assessment of the pathogens and activities being undertaken, as well as an overarching risk assessment of the biosafety program as a whole. More information on medical surveillance is available in the Canadian Biosafety Handbook.

First aid/treatment

Treatment for YF is supportive as there are no therapies currently available^{Footnote 50}. Observation, rest, fluids and acetaminophen for pain and fever are recommended. Nonsteroidal anti-inflammatory drugs and aspirin should be avoided, given the risk of hemorrhagic shock. Persons with YF should be protected from mosquito bites for 5 days after fever onset to avoid infecting naïve mosquitoes and contributing to the transmission cycle.

Note: The specific recommendations for first aid/treatment in the laboratory should come from the post-exposure response plan, which is developed as part of the medical surveillance program. More information on the post-exposure response plan can be found in the Canadian Biosafety Handbook.

Immunization

A live attenuated YF vaccine (YF-VAX^® or YF 17D vaccine) is available in Canada^{Footnote 51}. One dose of YF vaccine is recommended for immunocompetent individuals who are 9 months of age and older and travelling to countries with risk of YF transmission. Infants less than 6 months of age are at greater risk for YF vaccine-associated neurotropic disease following YF vaccination and should not receive the YF vaccine. In general, infants under the age of 9 months should not be vaccinated against YF. However, the Advisory Committee on Immunization Practices (ACIP) in the United States recommends that for infants 6 to 8 months of age travelling to an endemic or transitional area, when travel is unavoidable, the decision to vaccinate needs to balance the risks of YF virus exposure with the risk of adverse events (AE) following immunization^{Footnote 51}. Laboratory personnel who work with YFV and those working in endemic YFV areas should receive the YFV vaccine^{Footnote 51}.

YF-VAX^® is contraindicated for those who have hypersensitivity reactions to the vaccine components, including eggs, as well as for children under 9 months of age, lactating individuals with babies under 9 months of age, and for those 60 years and older, as these groups are at a much higher risk of developing vaccine-associated neurotropic disease and viscerotropic disease^{Footnote 51}, although these serious adverse effects are very rare^{Footnote 52}.

Note: More information on the medical surveillance program can be found in the Canadian Biosafety Handbook, and by consulting the Canadian Immunization Guide.

Prophylaxis

There is no approved post-exposure prophylaxis, although there is limited evidence to suggest that administration of passive immunotherapy, interferons, or interferon inducers may be effective if given before or within hours after YFV infection in an individual with known exposure (e.g., laboratory worker)^{Footnote 53}.

Note: More information on prophylaxis as part of the medical surveillance program can be found in the Canadian Biosafety Handbook.

Section VI – Laboratory hazard

Laboratory-acquired infections

Over 30 cases of laboratory-acquired YFV infection were reported during the pre-vaccine era and were associated with contact with blood or tissues of infected patients or laboratory animals, or handling of experimentally infected animals^{Footnote 34}. One case occurred in a hospital technician in 1930 who analyzed a blood sample from a YF patient in London, United Kingdom; the individual died, although the route of transmission was unclear^{Footnote 54}. One case of laboratory transmission was associated with a bite from an infected mosquito^{Footnote 48}.

Note: Please consult the Canadian Biosafety Standard and Canadian Biosafety Handbook for additional details on requirements for reporting exposure incidents.

Sources/specimens

YFV can be detected in blood, serum, organ tissues (liver, spleen, kidneys, heart, lung, and brain)^{Footnote 40}, urine, and semen^{Footnote 55}.

Primary hazards

Autoinoculation with infectious material, bites from infected mosquitoes, and exposure of mucous membranes or damaged skin are primary hazards associated with exposure to YFV.

Special hazards

Direct or indirect exposure to aerosols of concentrated YF 17D vaccine and work with experimentally infected animals can present a special hazard^{Footnote 34Footnote 56}.

Section VII – Exposure controls/personal protection

Risk group classification

YFV is a Risk Group 3 Human Pathogen and Risk Group 3 Animal Pathogen, and is a Security Sensitive Biological Agent (SSBA)^{Footnote 57Footnote 58}.

Containment requirements

Containment Level 3 facilities, equipment, and operational practices outlined in the Canadian Biosafety Standard for work involving infectious or potentially infectious materials, animals, or cultures.

Note that there are additional security requirements, such as obtaining a Human Pathogens and Toxins Act Security Clearance, for work involving SSBAs.

Protective clothing

The applicable Containment Level 3 requirements for personal protective equipment and clothing outlined in the Canadian Biosafety Standard are to be followed. At minimum, use of full body coverage dedicated protective clothing, dedicated protective footwear and/or additional protective footwear, gloves when handling infectious materials or animals, face protection when there is a known or potential risk of exposure to splashes or flying objects, respirators when there is a risk of exposure to infectious aerosols, and an additional layer of protective clothing prior to work with infectious materials or animals.

Note: A local risk assessment will identify the appropriate hand, foot, head, body, eye/face, and respiratory protection, and the personal protective equipment requirements for the containment zone must be documented.

Other precautions

All activities involving open vessels of pathogens are to be performed in a certified biological safety cabinet (BSC) or other appropriate primary containment device. The use of needles, syringes, and other sharp objects are to be strictly limited. Additional precautions must be considered with work involving animals or large scale activities.

Proper precautions should be considered when working with infected arthropods. This may include implementing a program to prevent escapes and monitor any escaped arthropods, as well as using suitable personal protective equipment (PPE), among other measures^{Footnote 59Footnote 60}.

Section VIII – Handling and storage

Spills

Allow aerosols to settle. Wearing personal protective equipment, gently cover the spill with absorbent paper towel and apply suitable disinfectant, starting at the perimeter and working towards the centre. Allow sufficient contact time with the disinfectant before clean-up (Canadian Biosafety Handbook).

Disposal

Regulated materials, as well as all items and waste to be decontaminated at the containment barrier prior to removal from the containment zone, animal room, animal cubicle, or post mortem room. This can be achieved by using decontamination technologies and processes that have been demonstrated to be effective against the infectious material, such as chemical disinfectants, autoclaving, irradiation, incineration, an effluent treatment system, or gaseous decontamination (Canadian Biosafety Handbook).

Storage

The applicable Containment Level 3 requirements for storage outlined in the Canadian Biosafety Standard are to be followed. Primary containers of regulated materials removed from the containment zone to be stored in a labelled, leak-proof, impact-resistant secondary container, and kept either in locked storage equipment or within an area with limited access.

Containers of security sensitive biological agents (SSBAs) stored outside the containment zone must be labelled, leakproof, impact resistant, and kept in locked storage equipment that is fixed in place (i.e., non-movable) and within an area with limited access.

An inventory of RG3 and RG4 pathogens, and SSBA toxins in long-term storage, to be maintained and to include:

• specific identification of the regulated materials
• a mechanism that allows for the detection of a missing or stolen sample in a timely manner

Section IX – Regulatory and other information

Canadian regulatory information

Controlled activities with YFV require a Pathogen and Toxin licence issued by the Public Health Agency of Canada (PHAC). YFV is a terrestrial animal pathogen in Canada; therefore, importation of YFV requires an import permit under the authority of the Health of Animals Regulations (HAR). The PHAC issues a Pathogen and Toxin Licence, which includes a Human Pathogen and Toxin Licence and an HAR importation permit.

Note that there are additional security requirements, such as obtaining a Human Pathogens and Toxins Act Security Clearance, for work involving SSBAs.

The following is a non-exhaustive list of applicable designations, regulations, or legislations:

• Human Pathogens and Toxins Act and Human Pathogens and Toxins Regulations
• Quarantine Act
• Health of Animals Act and Health of Animals Regulations
• National notifiable disease (human)
• Transportation of Dangerous Goods Act and Transportation of Dangerous Goods Regulations

Last file update

June 2024

Prepared by

Centre for Biosecurity, Public Health Agency of Canada.

Disclaimer

The scientific information, opinions, and recommendations contained in this Pathogen Safety Data Sheet have been developed based on or compiled from trusted sources available at the time of publication. Newly discovered hazards are frequent and this information may not be completely up to date. The Government of Canada accepts no responsibility for the accuracy, sufficiency, or reliability or for any loss or injury resulting from the use of the information.

Persons in Canada are responsible for complying with the relevant laws, including regulations, directives and standards applicable to the import, transport, and use of pathogens and toxines in Canada set by relevant regulatory authorities, including the Public Health Agency of Canada, Health Canada, Canadian Food Inspection Agency, Environment and Climate Change Canada, and Transport Canada. The risk classification and related regulatory requirements referenced in this Pathogen Safety Data Sheet, such as those found in the Canadian Biosafety Standard, may be incomplete and are specific to the Canadian context. Other jurisdictions will have their own requirements.

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