Junin virus: Infectious substances pathogen safety data sheet 

Section I – Infectious agent

Name

Junin virus

Agent type

Virus

Taxonomy

Family

Arenaviridae

Genus

Mammarenavirus

Species

Mammarenavirus juninense

Synonym or cross-reference

Junin virus (JUNV) causes Argentine haemorrhagic fever (AHF)^{Footnote 1}.

Characteristics

Brief description

Junin virus is a member of the family Arenaviridae, genus Mammarenavirus, and belongs to the New World complex^{Footnote 2}. Like all other arenaviruses, it is an enveloped, pleomorphic virion, measuring from 40 to more than 200 nm in diameter with a negative-stranded bi-segmented RNA genome^{Footnote 3}. The segments of the genome consist of the small segment (S) and the large segment (L) which are 3.5 kb and 7.3 kb in size respectively^{Footnote 2Footnote 3}. An ambisense coding strategy is used by both to allow for synthesis of two polypeptides in opposite orientation^{Footnote 3}. The L segment encodes the zinc-binding Z protein matrix and the RNA-dependent RNA polymerase, while the S segment encodes for the glycoprotein precursor, GPC, and the nucleocapsid protein, N^{Footnote 2}. GPC is post-translationally cleaved to yield mature virion glycoproteins G1, G2, and stable signal peptide, SSP. The G1/G2/SSP trimer form the spikes on the virion surface that are integral in receptor recognition and viral entry^{Footnote 1Footnote 2}. The virion interior contains host cell ribosomes that resemble grains of sand, which are characteristic of the family Arenaviridae^{Footnote 4}.

Properties

Similar to other New World arenaviruses, JUNV uses transferrin receptor 1 (TfR1) to infect cells^{Footnote 1Footnote 3}. JUNV enters the cell via clathrin-mediated endocytosis. This requires acidification of the endosome to allow for a pH-dependent conformational change of the spike protein to reveal G2^{Footnote 3}. This glycoprotein facilitates fusion of the virion with the host cell membrane and release of virus ribonucleoprotein (RNP) core into the cytoplasm where replication and transcription take place^{Footnote 2Footnote 3}. Z protein plays an important role in the assembly of nucleocapsid and glycoproteins and in virus particle budding, but it may also be involved in evading the host immune response by binding to RIG-I, resulting in interferon β (IFNβ) response down-regulation^{Footnote 2Footnote 3}.

Section II – Hazard identification

Pathogenicity and toxicity

80% of JUNV infections result in clinical disease, which is commonly known as Argentine hemorrhagic fever (AHF)^{Footnote 5}. The disease course consists of three phases: prodromal, neurological-haemorrhagic (illness), and convalescence^{Footnote 5Footnote 6}.

Prodromal phase: This phase typically lasts for 6 days after the onset of symptoms^{Footnote 6} with flu-like symptoms such as chills, malaise, anorexia, headache, myalgia, vomiting, joint pain, slow heart rate, conjunctivitis and fever (38 to 39°C)^{Footnote 1Footnote 5Footnote 7 Footnote 8Footnote 9}. Other common symptoms include retro-orbital pain, nausea or vomiting, epigastric pain, photophobia, dizziness, constipation, or mild diarrhoea^{Footnote 5Footnote 7}. An early indicator, in some cases, is tongue tremor and pneumonitis^{Footnote 8}. Upon physical examination, redness of the face, neck, and upper chest, as well as conjunctival congestion, and periorbital oedema may be present^{Footnote 5}. Initial signs of vascular damage may appear during this phase^{Footnote 7}. In females, non-menstrual uterine bleeding is common^{Footnote 5}. The first week of illness results in progressive leucopenia and thrombocytopenia^{Footnote 5}. Around 75% of patients will show signs of improvement after this phase as a result of a robust neutralizing antibody response^{Footnote 6Footnote 8Footnote 9}.

Neurological-haemorrhagic phase: Around 20 to 30% of AHF cases develop neurological and haemorrhagic symptoms, or secondary bacterial infections, usually during the second week of illness^{Footnote 5Footnote 7}. Haemorrhagic signs include bleeding from mucous membranes, blood in vomit, petechia in the oral mucosa, blood in urine, collection of blood outside of blood vessels in a tissue or organ, gingival bleeding, coughing up blood, bleeding of nostrils, and ecchymosis at needle puncture sites^{Footnote 7Footnote 8}. Neurological manifestations include mental confusion, marked ataxia, irritability, seizures, convulsions, tremor of hands and tongue, and less frequently, delirium, coma, encephalitis, and meningoencephalitis^{Footnote 5Footnote 7}. Secondary bacterial infections presenting as pneumonia and septicaemia may complicate the disease at this phase^{Footnote 5}.

Convalescence phase: Surviving cases experience a prolonged, protracted convalescence that may last for 3 months^{Footnote 5Footnote 6}. Patients experience fatigue, dizziness, asthenia, irritability, memory loss, and hair loss^{Footnote 5Footnote 6Footnote 7}.

The common cause of death in AHF patients is due to hypovolaemic shock and typically occurs 7 – 12 days after disease onset^{Footnote 7Footnote 8}. When untreated, the case fatality for AHF is 15 to 30%, which is lowered to less than 1% when patients are treated with convalescent serum/plasma within 8 days of symptom onset^{Footnote 6Footnote 8}. However, 10% of patients who receive convalescent serum develop Late Neurologic Syndrome with transient symptoms such as dizziness, headache, fever, and nausea^{Footnote 6Footnote 9}.

Epidemiology

JUNV is endemic to the Pampa region of Argentina^{Footnote 9}. Cases outside of Argentina are linked to travel to the endemic area^{Footnote 5}. The emergence of AHF in the 1950s is hypothesised to have occurred due to alterations of the habitat by agricultural practices which favoured rodent population growth and ultimately increased human exposure to rodent reservoirs^{Footnote 5Footnote 8}. Since the identification of AHF, annual outbreaks have been recognised without interruption; however, since the development of a vaccine, the incidence of the disease has decreased from around 1,000 cases per year to 30-50 cases^{Footnote 9}. Most cases of human infection occur during the harvesting season in Argentina and reach peak incidence in May^{Footnote 1}. The disease is four times as prevalent in males than females based on occupational trends in Argentina and is 90% more widespread in rural populations than urban^{Footnote 1Footnote 8}. AHF during pregnancy is infrequent, but it presents as a more severe disease with a mortality rate of over 50% when in the last trimester due to diagnosis delays and failure to administer specific treatment^{Footnote 1Footnote 9}.

Host range

Natural host(s)

Rodents are natural hosts, mainly Calomys musculinus and Calomys laucha, but JUNV infection is also possible in Akodon azarae, Mus musculus, and Orizomys flavescens^{Footnote 1Footnote 2Footnote 8Footnote 9}. JUNV also infects humans^{Footnote 1}.

Other host(s)

Mice, rats, guinea pigs, and non-human primates are experimentally infected hosts^{Footnote 2Footnote 8Footnote 9}.

Infectious dose

Unknown.

Incubation period

The incubation period is typically 6 – 14 days^{Footnote 6Footnote 7}.

Communicability

Transmission from one rodent to another occurs via bites and scratches, and during pregnancy from mother to offspring^{Footnote 1Footnote 8}. Horizontal transmission is thought to be the main form of dissemination^{Footnote 1}. C. musculinus shed JUNV in their saliva, urine, blood, and feces^{Footnote 1Footnote 8}.

Humans usually become infected through contact with infected rodents (cuts or bites) or via inhalation of infectious aerosolized rodent excreta or secreta^{Footnote 6}. Transmission from human-to-human is rare; however, nosocomial outbreaks can occur via spread from highly viraemic patients or through direct contact with infected bodily fluids and blood of a viraemic patient^{Footnote 1Footnote 8Footnote 9}.

Section III – Dissemination

Reservoir

The principal reservoirs of JUNV are Calomys musculinus, and Calomys laucha^{Footnote 1Footnote 8}.

Zoonosis

Infected rodents spread the virus to humans via their secretions and excretions or through bites and scratches^{Footnote 8Footnote 9}.

Vectors

None.

Section IV – Stability and viability

Drug susceptibility/resistance

JUNV is susceptible to ribavirin, favipiravir, trifluoperazine, and chlorpromazine in vitro^{Footnote 6Footnote 9Footnote 10}. Psoralens, diathanes, and disulfide-based compounds are capable of inactivating arenaviruses^{Footnote 11}. NSC2065, an aromatic disulfide, is effective in inactivating JUNV due to the presence of zinc finger motifs within viral proteins. Arbidol, a clinically used anti-influenza virus drug, is effective in vitro against arenaviruses, and there is synergistic inhibition of JUNV when arbidol is combined with either aripiprazole or sertraline^{Footnote 12}. Fusion inhibitors, ARN‐75039 and ARN‐75041, also exhibit potent activity against JUNV^{Footnote 13}.

Susceptibility to disinfectants

Sodium hypochlorite is the most readily available disinfectant capable of inactivating arenaviruses; a 1% solution is effective for disinfection of medical equipment, patient bedding, and reusable protective clothing before laundering, while a 10% bleach solution should be used to disinfect excreta, corpses or items to be discarded^{Footnote 14}. Arenaviruses are also inactivated by 4% formaldehyde, guanidinium thiocyanate, formalin, 100% methanol, 100% acetone, 1% Triton X-100 and SDS buffer^{Footnote 15}. Common to other enveloped viruses, JUNV may be inactivated by 0.5% accelerated hydrogen peroxide-based (AHP) disinfectants for one minute, 13% hydrogen peroxide for 5 minutes, 60-70% ethyl alcohol for one minute, 60% isopropyl alcohol for one minute, solutions containing 7.5-10% iodophor, which inactivate virus within one minute, quaternary ammonium compounds, and non-ionic surfactants (Tween-20 and Tween-80)^{Footnote 16}.

Physical inactivation

Arenaviruses are inactivated by heating to 60°C for 1 hour, at pH below 5.5 or above 8.5, ultraviolet radiation, and gamma irradiation^{Footnote 11Footnote 15Footnote 17Footnote 18}. 90 000 µW/cm² of UV-A radiation and 4’-aminomethyl-trioxsalen (a psoralen) are required to inactivate JUNV; a dose-dependent relationship was observed between the amount of UV-A exposure and the proportion of inactivated virus particles^{Footnote 19}. A gamma irradiation dose of 8 Mrads, which includes a 2x safety factor, is necessary for inactivation of 1 × 10⁶ TCID₅₀ of Lassa virus (member of the Arenaviridae family) in a liquid medium containing protein^{Footnote 20}.

Survival outside host

The viability of arenaviruses in the environment is not well characterized^{Footnote 14}. Lassa virus strains, Josiah and Sauerwald, were found to have similar decay rates on high-density polyethylene (Josiah, k = 4.3 days; Sauerwald, k = 2.3 days) and stainless steel (Josiah, k = 5.3 days; Sauerwald, k = 2.7 days)^{Footnote 21}.

Section V – First aid/medical

Surveillance

Reverse transcription polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and cell culture can be used to diagnose AHF from blood, serum or tissue samples^{Footnote 6Footnote 8Footnote 14}. RT-PCR is considered the most efficient method for diagnosis of AHF and is used to detect etiological agents before the production of antibodies^{Footnote 1Footnote 8}. RT-PCR offers greater sensitivity for the low viremia encountered during the early phase of disease, which allows a faster response to infection^{Footnote 1}. ELISA can also be used to detect antibodies (mainly IgG or IgM) that are usually present after day 12 of infection^{Footnote 2Footnote 8Footnote 14}.

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

Supportive therapy is important in the management of patients with AHF^{Footnote 6}. Pain relief with conservative doses of opiates, acetaminophen, tramadol, or other analgesics is recommended^{Footnote 14}. The administration of convalescent serum is the treatment of choice and has been shown to be highly effective if administered within 8 days of symptom onset^{Footnote 1Footnote 5Footnote 6}. Antiviral treatment with ribavirin and favipiravir may be effective, provided that it is administered early in the course of the illness^{Footnote 3Footnote 6Footnote 9Footnote 22}. Anemia and teratogenicity are side effects of ribavirin if taken while pregnant^{Footnote 6}. Favipiravir should be used with caution in pregnant women due to potential teratogenicity and embryotoxicity^{Footnote 6}. These antivirals are not approved for use in the United States and the efficacy of ribavirin for treatment of JUNV has yet to be determined^{Footnote 6}. Ibavyr (ribavirin tablets) is approved in Canada for the treatment of chronic hepatitis C (CHC) in adults, and it must be used in combination with other therapeutic agents^{Footnote 23}. Favipiravir has been authorized for use in two clinical trials to treat COVID-19 in Canada^{Footnote 24}.

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

No vaccine currently available in Canada; however, Candid #1, a live attenuated Junin virus vaccine, has been developed and is in use in Argentina^{Footnote 1}. The vaccine is offered to nonpregnant individuals 15-65 years of age who live in endemic areas in Argentina^{Footnote 6}.

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

Prophylaxis

Post-exposure prophylaxis involves the administration of convalescent serum within 8 days of symptom onset^{Footnote 6Footnote 8}. Antivirals, such as ribavirin or favipiravir, have also been proven effective in in vitro studies and have been used in a clinical setting^{Footnote 1Footnote 6Footnote 8Footnote 9Footnote 14Footnote 22}.

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

Between 1958 and 1980, 38 clinical cases of AHF were recorded among laboratory personnel in Argentina who worked directly with virulent strains of JUNV^{Footnote 25}. Three of the cases resulted in death. Since then, there have been no documented laboratory-acquired infections.

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

Sources/specimens

Blood, urine, saliva, feces, and infected tissues from animals and humans are likely to contain the infectious agent^{Footnote 2Footnote 8}.

Primary hazards

Inhalation of aerosolized infectious material, exposure of mucous membranes to infectious material, and bites/scratches of an infected animal represent the primary hazards associated with exposure to Junin virus^{Footnote 1Footnote 8}.

Special hazards

Since communicability of JUNV involves aerosolization, a major concern when working with the virus in a laboratory setting is the generation of aerosols when using a high-energy equipment like centrifuges or homogenisers^{Footnote 17}.

Section VII – Exposure controls/personal protection

Risk group classification

Junin virus is a Risk Group 4 Human Pathogen, Risk Group 4 Animal Pathogen, and a Security Sensitive Biological Agent (SSBA)^{Footnote 26Footnote 27}.

Containment requirements

Containment Level 4 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 4 requirements for personal protective equipment and clothing outlined in the Canadian Biosafety Standard are to be followed. The use of a positive-pressure suit or use of a Class III biological safety cabinet (BSC) line is required for all work with RG4 pathogens.

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 regulated materials to be performed in a certified biological safety cabinet (BSC) or other appropriate primary containment device. Centrifugation of infected materials must be carried out in closed containers placed in sealed safety cups, or in rotors that are unloaded in a biological safety cabinet. The integrity of positive pressure suits must be routinely checked for leaks. The use of needles, syringes, and other sharp objects are to be strictly limited. Open wounds, cuts, scratches, and grazes are to be covered with waterproof dressings. Additional precautions must be considered with work involving animal activities.

Section VIII – Handling and storage

Spills

The spill area is to be evacuated and secured. Aerosols must be allowed to settle for a minimum of 30 minutes. For spills outside of a BSC, air supply to positive-pressure suits must be ensured. Positive-pressure suits that have been in contact with the regulated materials must be completely decontaminated by following procedures for gross decontamination of a positive-pressure suit. Plastics to be transferred to a dishpan, which should be moved to the BSC. Spills of potentially contaminated material to be covered with absorbent paper-based material (e.g., paper towels), liberally covered with an effective disinfectant (e.g., 5% MicroChem), and left to soak for at least 5 minutes before being wiped up. Following the removal of the initial material, the disinfection process are to be repeated. After disinfection, inform the appropriate internal authority (e.g., containment zone supervisor, BSO) of the incident. 

Disposal

All materials/substances that have come in contact with the regulated materials must be completely decontaminated before they are removed from the containment zone. This can be achieved by using decontamination technologies and processes that have been demonstrated to be effective against the regulated materials, such as chemical disinfectants, autoclaving, irradiation, incineration, an effluent treatment system, or gaseous decontamination (Canadian Biosafety Handbook).

Storage

The applicable Containment Level 4 requirements for storage outlined in the Canadian Biosafety Standard are to be followed. Pathogens, toxins, and other regulated materials to be stored inside the containment zone.

An inventory of 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 Junin virus require a Pathogen and Toxin licence issued by the Public Health Agency of Canada. Junin virus is a non-indigenous terrestrial animal pathogen in Canada; therefore, importation of Junin virus requires an import permit under the authority of the Health of Animals Regulations (HAR), issued by the Canadian Food Inspection Agency.

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
• Health of Animals Act and Health of Animals Regulations
• Quarantine Act
• Non-Indigenous Animal Pathogen or WOAH (OIE)-listed disease (please contact the Canadian Food Inspection Agency)

Last file update

July, 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 toxins 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.

Copyright © Public Health Agency of Canada, 2024, Canada

References