Rabies and other lyssaviruses

What

Rabies is a zoonotic disease caused by exposure to saliva or neural tissue from an animal infected with rabies virus or other lyssaviruses. Human exposure can occur through an animal scratch or bite that has broken the skin, or by direct contact of the virus with the mucosal surface of a person, such as nose, eye or mouth.

Who

Pre-exposure rabies vaccine is recommended for:

• people who have contact with bats
• people who travel to rabies-enzootic regions, based on a risk assessment
• laboratory workers who work with live lyssaviruses

Post-exposure rabies vaccine and, in some cases, human rabies immunoglobulin are recommended for anyone who has potentially been exposed to rabies virus or other lyssaviruses.

How

There are 4 options for administering pre-exposure prophylaxis, varying by schedule length, number of doses and route of administration. There is no preferential recommendation for choosing a schedule and route of administration. Consideration should include a person’s circumstance and personal preferences.

Post-exposure prophylaxis includes prompt wound management, and administration of rabies vaccine and, in some cases, human rabies immunoglobulin. The appropriate combination of these interventions and the number of vaccine doses depend on a risk assessment that takes into account the:

• extent of the exposure
• animal source of the exposure
• person’s immune status
• person’s previous vaccination history

Why

Rabies is almost always fatal. Australia is not a rabies-enzootic country. Exposure to classical rabies virus can occur from terrestrial animals and other mammals in rabies-enzootic countries. Bats anywhere in the world are a potential source of lyssaviruses and a potential risk for acquiring rabies, depending on how a person is exposed. Evidence of Australian bat lyssavirus infection has been identified in all 4 species of Australian fruit bats (flying foxes) and in several species of Australian insectivorous bats.

Tables & figures

See also Table. Lyssavirus exposure categories.

Rabies vaccines available in Australia

The Therapeutic Goods Administration website provides product information for each vaccine.

See also Vaccine information and Variations from product information for more details.

Dose and route

The dose of rabies vaccine for pre- and post-exposure prophylaxis is 1.0 mL for Rabipur inactivated rabies virus vaccine and 0.5mL for Verorab inactivated rabies virus vaccine when given by intramuscular injection. This dose is the same for infants, children and adults.

The dose of all rabies vaccines for pre-exposure prophylaxis is 0.1 mL given by intradermal injection. This dose is the same for infants, children and adults. The intradermal route should only be used by suitably qualified and experienced providers. If giving rabies vaccine by the intradermal route, the total dose can be used for more than one person during a single vaccination session. Any remaining vaccine should be discarded at the end of the session. See Administration of vaccines.

Rabies vaccine should be given in the deltoid area, because VNAb (rabies virus neutralising antibody) titres may be lower if given in other sites. Infants <12 months of age are recommended to receive the rabies vaccine in the anterolateral aspect of the thigh. The ventrogluteal site is an acceptable alternative for infants. See Administration of vaccines.

Do not give rabies vaccine in the buttock, because post-exposure prophylaxis can fail when vaccine is given in this area.²⁵

Co-administration with other vaccines

Rabies vaccines can be co-administered with other vaccines, using separate injection sites.

The dose of HRIG (human rabies immunoglobulin) is 20 IU per kilogram of body mass. This is the same for infants, children and adults.

People who need HRIG should receive it at the same time as the 1st dose (day 0) of rabies vaccine. Give HRIG in a different limb to the vaccine.

Do not give HRIG if it has been more than 7 days (168 hours) since the 1st dose of rabies vaccine. This is because HRIG may interfere with the immune response to the vaccine. For more details, see Recommendations.

In exceptional circumstances, such as during product shortages, other HRIG products may be available for use in Australia.

State and territory public health authorities can advise on using HRIG products. See also Public health management.

Infiltrating wounds with HRIG

HRIG must be infiltrated in and around all wounds using as much of the calculated dose as possible. 

Any remaining HRIG that cannot safely be infiltrated in and around the wound should be given intramuscularly at a site away from the rabies vaccine injection site. Depending on the volume, this could be in the alternative deltoid, lateral thigh or gluteal muscle. 

The HRIG dose should all be given intramuscularly if there is no obvious wound or site to infiltrate — for example, for mucous membrane exposures.

If the wounds are severe and the calculated volume of HRIG is not enough to completely infiltrate all wounds (such as extensive dog bites in a young child), dilute the HRIG in saline to make up an adequate volume to carefully infiltrate all wounds.

Wounds to fingers and hands may be small, especially if the wounds are from bats. Infiltrating these wounds with HRIG is likely to be both technically difficult and painful for the recipient.⁴⁰ However, because fingers and hands have extensive nerve supply,^41-43 it is important to infiltrate as much of the calculated dose of HRIG as possible using either a 25 or 26 gauge needle.

To avoid compartment syndrome, infiltrate the HRIG very gently. It should not cause the adjacent finger tissue to go pale or white. It may be necessary to give a ring block using a local anaesthetic.⁴⁰

Interchangeability of rabies vaccines

It is preferable to use the same brand of vaccine for the entire course. However, a course of pre- or post-exposure prophylaxis can be completed with an alternative rabies cell culture–derived vaccine if necessary, if the vaccine is endorsed by the World Health Organization (also known as ‘pre-qualified’). If a person received a chick embryo–derived or cell culture–derived vaccine overseas, they are recommended to continue the standard post-exposure prophylaxis regimen in Australia with a registered Australian vaccine.

Various international vaccine advisory groups state that rabies cell culture–derived vaccines are interchangeable. This is supported by similarities in:

• tissue culture vaccine production methods
• antibody responses 
• adverse reactions after vaccination 

A study specifically assessed the interchangeability of human diploid cell vaccine and purified chick embryo cell vaccine. 165 people were randomised to receive rabies pre-exposure prophylaxis (days 0, 7 and 21–28) using either human diploid cell vaccine or purified chick embryo cell vaccine.⁴⁴ Each group received 1 or 2 booster doses of purified chick embryo cell vaccine 1 year after the pre-exposure prophylaxis doses. The booster dose resulted in an anamnestic response (geometric mean titre several orders of magnitude >0.5 IU per mL) in all participants by day 7. This happened regardless of the vaccine that was used for the primary course. It is expected that this response would be similar with other rabies cell culture–derived vaccines.

Contraindications

There are no absolute contraindications to use of either rabies vaccine or human rabies immunoglobulin as post-exposure prophylaxis in people who have potentially been exposed to rabies virus or other lyssaviruses. This is because rabies is almost always lethal.

Precautions

People with egg allergy

People with a history of anaphylaxis or severe allergic reaction to eggs or egg proteins should not receive purified chick embryo cell vaccine. They should receive human diploid cell vaccine or purified Vero cell vaccine instead.

See also Adverse events.

Cell culture–derived vaccines are generally well tolerated. A large study reported the following adverse events after human diploid cell vaccine was administered to adults:⁴⁵

• sore arm (in 15–25% of vaccine recipients)
• headache (in 5–8%)
• malaise or nausea, or both (in 2–5%)
• allergic oedema (in 0.1%) 

Similar adverse event profiles have been reported for the purified chick embryo cell vaccine and the purified Vero cell rabies vaccine.^46,47 

These reactions occur at the same rates in children.^48-54

Anaphylaxis and allergic reactions

Although anaphylaxis after receiving human diploid cell vaccine is rare (approximately 1 per 10,000 vaccinations), around 6% of people may have an allergic reaction after a booster dose. The reactions typically occur 2–21 days after the booster dose, and may include:⁴⁵

• generalised urticaria
• arthralgia
• arthritis
• oedema
• nausea
• vomiting
• fever 
• malaise 

These reactions are not life-threatening. They have been attributed to the β-propiolactone-altered human albumin in the vaccines.

Managing adverse events

Once started, do not delay or stop rabies post-exposure prophylaxis because of local reactions or mild systemic reactions. Simple analgesics can help manage these reactions.

Because rabies is almost always fatal, the recommended vaccination regimens, especially the post-exposure prophylaxis regimen, should be continued even if the person has a significant allergic reaction after a dose of rabies vaccine. Antihistamines can lessen the symptoms of any subsequent reactions. 

Carefully consider the person’s risk of developing either lyssavirus infection or rabies before deciding to stop the vaccination regimen.

Adverse events following human rabies immunoglobulin

Human rabies immunoglobulin has an excellent safety profile, and generally no chance of immediate hypersensitivity reactions. Hypersensitivity reactions are more common with some equine rabies immunoglobulins used overseas.

Lyssaviruses are single-stranded RNA viruses in the family Rhabdoviridae, genus Lyssavirus. There are 12 known species in the genus Lyssavirus, including classical rabies virus and closely related lyssaviruses such as ABLV (Australian bat lyssavirus) and European bat lyssaviruses.⁵⁵

Rabies is a zoonotic disease caused by exposure to saliva or neural tissue of an animal infected with rabies virus or other lyssaviruses.

The clinical diseases caused by classical rabies virus and other lyssaviruses are indistinguishable. The term ‘rabies’ refers to disease caused by any of the known lyssavirus species.

Rabies is almost always fatal.

Transmission of rabies and lyssaviruses

Humans can be exposed by:⁵⁶

• an animal scratch or bite that has broken the skin
• direct contact of the virus with the mucosal surface of a person, such as nose, eye or mouth 
• tissue or organ transplantation from donors who died with undiagnosed rabies

It is rare for people to acquire rabies if:

• an animal scratches them
• an animal licks an open wound 
• animal saliva contacts intact mucous membranes 

Aerosol transmission has never been well documented in the natural environment.⁵⁷

Transmission of rabies virus to humans through unpasteurised milk may be possible. However, rare reports of transmission by this route have not been confirmed.⁵⁸

Incubation period

Once a person is infected, the incubation period of rabies is usually 3–8 weeks. This can range from as short as 1 week to, on rare occasions, several years. 

The risk of rabies is higher, and the incubation period is shorter: 

• after severe and multiple wounds near the central nervous system (such as on the head and neck)
• in richly innervated sites (such as the fingers)

Initial symptoms of rabies

The rabies prodromal phase lasts up to 10 days. During this phase, the person may experience non-specific symptoms such as:⁴¹

• anorexia
• cough
• fever
• headache
• myalgia and fatigue 
• nausea and vomiting
• sore throat

The person may have abnormal sensations (paraesthesiae) or muscle twitches (fasciculations) at or near the site of the wound. They may also experience anxiety, agitation and apprehension. 

Death from rabies

Most people with rabies present with the furious (also called encephalitic) form.⁴²

In the encephalitic phase, objective signs of nervous system involvement include:⁴²

• aerophobia
• hydrophobia
• bizarre behaviour
• disorientation 
• hyperactivity
• hypersalivation, hyperthermia and hyperventilation (signs of autonomic instability) 

The person’s neurological status deteriorates over a period of up to 12 days. Death occurs either abruptly from cardiac or respiratory arrest, or following coma. 

Rabies epidemiology varies depending on the lyssavirus species and the animal host. Lyssaviruses have been found on all continents except Antarctica.

Australian state or territory health authorities can advise about potential lyssavirus exposures and their management. See Public health management.

International authorities can provide information about the global occurrence of rabies.

Classical rabies virus in terrestrial animals

Rabies that is due to classical rabies virus and occurs in terrestrial mammals is present throughout much of Africa, Asia and the Americas, and parts of Europe. In these regions, the virus is maintained in certain species of mammals, particularly dogs.²⁷

In countries where rabies vaccination of domestic animals is widespread (North America and Europe), wild animals such as raccoons and foxes are important reservoirs. The continual maintenance of rabies in animal populations in these countries is referred to as enzootic rabies.

A country’s status can change at any time. For example, in 2008 on the island of Bali, Indonesia, rabies was reported in dogs, and cases were later reported in humans.⁵⁹ Before this, Bali had been considered free from rabies, although rabies was known to occur in other areas of Indonesia.⁶⁰ Public Health England maintains a list of rabies risk from terrestrial animals by country.

Australian bat lyssavirus

In some parts of the world, bats are important reservoirs of classical rabies virus as well as other lyssaviruses. Bat lyssaviruses are found in some areas that are considered to be free from terrestrial rabies, including Australia. 

ABLV (Australian bat lyssavirus) was first reported in bats in 1996. Since then, 3 cases of fatal encephalitis caused by ABLV have been reported in Australians, in 1996, 1998 and 2013.^61-63 All 3 patients had been either bitten or scratched by bats.

Evidence of ABLV infection has been identified in all 4 species of Australian fruit bats (flying foxes) and in several species of Australian insectivorous bats. It should therefore be assumed that all Australian bats can be infected with ABLV.

The first confirmed cases of ABLV in terrestrial mammals in Australia occurred in 2 horses in Queensland in 2013.⁶⁴

Bat lyssavirus infections in terrestrial animals are extremely rare in areas where rabies is not enzootic, such as Australia. There is no evidence of transmission from an infected terrestrial animal to humans. However, this is theoretically possible. 

Lyssaviruses in bats worldwide

Bats anywhere in the world are a potential source of lyssaviruses and a potential risk for acquiring rabies, depending on how a person is exposed. 

ABLV has not been isolated from bats outside Australia.

However, bats in other countries have closely related lyssaviruses. For example, bats in some parts of Europe can have European bat lyssavirus 1 and European bat lyssavirus 2. At least 4 people have died from European bat lyssavirus variants. None of them had a record of prophylactic rabies immunisation.^65,66

There are rare reports of bat lyssavirus infections in other animals^67-69 (such as ABLV in horses).

3 inactivated rabies cell culture–derived vaccines are available in Australia.

Rabies vaccine is effective when used for pre- or post-exposure prophylaxis for rabies.^27,48,70,51 Although data on the effectiveness of rabies vaccine as prophylaxis against other lyssaviruses are limited, the available animal data and clinical experience support its use.^33,35,71-75

A 3-dose intramuscular (IM) pre-exposure prophylaxis regimen has superior performance to a 3-dose intradermal (ID) regimen with respect to the magnitude of primary antibody response.^76-79 However, studies demonstrate that short-term and long-term anamnestic response following standard ID pre-exposure prophylaxis is similar to that following IM exposure, provided that the ID doses are delivered correctly. A booster dose administered up to 1 year following an accelerated pre-exposure schedule (1, 2 or 3 doses, IM or ID) will also produce an effective anamnestic response by day 7–14.¹⁰

The immunogenicity of the 2 rabies vaccines registered and marketed in Australia — Rabipur (purified chick embryo cell vaccine) and Verorab (purified Vero cell rabies vaccine) — have been assessed in individuals who have potentially been exposed to rabies and in healthy volunteers.^70,80,81 In the majority of studies, 100% of study participants had geometric mean titres (GMTs) above 0.5 IU/mL by day 14. In all studies that assessed antibody response at day 30, after receiving 4 doses of the rabies vaccine, 100% of participants had GMTs >0.5 IU/mL.^{29,30,70,80-83}

In people who are severely immunocompromised, the immune response to rabies vaccination may be suboptimal.¹ People who are mildly immunocompromised and have been previously primed with rabies vaccine can mount an immune response after only 2 doses of post-exposure prophylaxis. However, people who are more severely immunocompromised may mount a lower immune response.⁸⁴

Numerous clinical studies of both IM and ID pre- and post-exposure prophylaxis regimens have shown VNAb (virus neutralising antibody) titres >0.5 IU per mL on days 28 and 90, and VNAb levels did not fall below 0.5 IU per mL until day 180. These data demonstrate that people who receive a rabies pre- or post-exposure prophylaxis regimen do not require revaccination if they are exposed again within 3 months.⁸⁴

2-visit pre-exposure prophylaxis (PrEP) schedules

Studies of HDCV and PCECV rabies vaccines show that a 2 dose PrEP schedule produces an immune response that is comparable to a 3 dose PrEP schedule, particularly in the 7-28 days after vaccination.   

Three clinical trials showed that the 2 dose PrEP schedule produced a rabies VNAb seroconversion rate (96.7 – 100%), a measure of whether the immune system has responded to the vaccine, that was comparable to the 3 dose PrEP schedule (100%) in the 7–28 days after vaccination.^70,86,87 Similar results were also produced in observational studies at this time point.^7,88,89   

A clinical trial showed that the 2 dose PrEP schedule produced a rabies VNAb seroconversion rate that was slightly reduced (46%) compared to the 3 dose PrEP schedule (55%) at 180 days after vaccination.⁷⁰  

There is limited and uncertain evidence on the long-term duration of 2 doses of PrEP verses 3 doses of PrEP. Three clinical trials showed that the 2 dose PrEP schedule produced a rabies VNAb seroconversion rate that was reduced (7–60%) compared to the 3 dose PrEP schedule (35–64%) at 365 days or more after vaccination.^70,86,87 Similar results were also shown in observational studies.^7,88,89 The clinical significance of this difference in seroconversion rates between 2 PrEP doses versus 3 PrEP doses, is unknown.  

Studies of PVRV rabies vaccines show that a 2 dose PrEP schedule produces an immune response that is comparable to a 3 dose PrEP schedule, particularly in the 14-28 days after vaccination. These studies compared either 2 doses or 3 doses of Verorab in a PrEP schedule to the same number of doses of HDCV or PCECV rabies vaccines and found Verorab to be non-inferior in terms of immunogenicity and equivalent for safety.^{46,47,70,88,90}

Rabies vaccine

Transport according to National vaccine storage guidelines: Strive for 5.⁹¹ Store at +2°C to +8°C. Do not freeze.

All rabies vaccines must be reconstituted. Add the entire contents of the diluent container to the vial and shake until the powder completely dissolves. Use the reconstituted vaccine immediately. 

Human rabies immunoglobulin

Transport according to National vaccine storage guidelines: Strive for 5.⁹¹ Store at +2°C to +8°C. Do not freeze. Protect from light.

Use immediately after opening the vial.

Classical rabies virus and ABLV (Australian bat lyssavirus) infections in humans are notifiable diseases in all states and territories in Australia.

Other lyssavirus cases that do not meet the case definition for ABLV or rabies virus infection are also notifiable in all states and territories in Australia.

The Communicable Diseases Network Australia national guidelines for rabies virus and other lyssavirus exposures and infections have details about the management of rabies and other lyssavirus infections, including ABLV.

State and territory public health authorities can provide further advice about the public health management of rabies and other lyssavirus infections.

Both human rabies immunoglobulin and rabies vaccine are available for post-exposure prophylaxis from state and territory public health authorities.

Use in pre- and post-exposure prophylaxis

The product information for the 3 vaccines available in Australia states that they can be used for both pre- and post-exposure prophylaxis for ABLV (Australian bat lyssavirus) exposures. 

ATAGI (the Australian Technical Advisory Group on Immunisation) recommends that, where indicated, any of the available rabies vaccines can be used as pre- or post-exposure prophylaxis for ABLV exposures, as well as exposure to classical rabies virus and other lyssaviruses — see Recommendations.

Human diploid cell vaccine and pre-exposure boosters

The product information for human diploid cell vaccine states that it should not be administered intravenously or intradermally.

ATAGI recommends that the intradermal route is an acceptable alternative to the intramuscular route for pre-exposure prophylaxis.

The product information for human diploid cell vaccine recommends serological testing to determine when the antibody titre is below an acceptable level and a pre-exposure booster is needed.

ATAGI recommends boosters between 6 months and 3 years for people at continuing occupational risk. See People with ongoing occupational exposure to lyssaviruses are recommended to receive booster doses of rabies vaccine in Recommendations.

Human diploid cell vaccine for post-exposure prophylaxis

The product information for human diploid cell vaccine recommends a routine 6th dose at 90 days in a post-exposure prophylaxis regimen.

ATAGI recommends that people who are immunocompromised can receive a 5th dose at day 28.

ATAGI recommends that people who are immunocompromised and have a VNAb (rabies virus neutralising antibody) titre <0.5 IU per mL after the 5th dose of post-exposure prophylaxis can receive further doses.

Purified chick embryo cell vaccine for pre-exposure prophylaxis

The product information for purified chick embryo cell vaccine states that it is for intramuscular injection only.

ATAGI recommends that the intradermal route is an acceptable alternative to the intramuscular route for pre-exposure prophylaxis.

The product information for purified chick embryo cell vaccine recommends that, for people who are considered to be at ongoing risk of exposure to rabies (eg veterinarians and their assistants, wildlife workers, hunters), a serological test should usually be performed at least every 2 years, with shorter intervals if appropriate to the perceived degree of risk.

ATAGI recommends boosters every 3 years for people at ongoing occupational risk. See People with ongoing occupational exposure to lyssaviruses are recommended to receive booster doses of rabies vaccine in Recommendations.

Purified chick embryo cell vaccine for post-exposure prophylaxis

The product information for purified chick embryo cell vaccine recommends a routine 5th dose at 28 days for post-exposure prophylaxis.

ATAGI recommends that immunocompetent people can receive a 4-dose schedule with either cell culture–derived vaccine for post-exposure prophylaxis.

ATAGI recommends that people who are immunocompromised can receive a 5th dose at day 28.

ATAGI recommends that people who are immunocompromised and have a rabies VNAb titre <0.5 IU per mL after the 5th dose of post-exposure prophylaxis can receive further doses.

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