The Australian Immunisation Handbook 10th Edition
- 4.16.1 - Virology
- 4.16.2 - Clinical features
- 4.16.3 - Epidemiology
- 4.16.4 - Rabies vaccines
- 4.16.5 - Rabies immunoglobulin
- 4.16.6 - Transport, storage and handling
- 4.16.7 - Dosage and administration
- 4.16.8 - Recommendations
- 4.16.9 - Pregnancy and breastfeeding
- 4.16.10 - Contraindications
- 4.16.11 - Adverse events
- 4.16.12 - Public health management of lyssavirus
- 4.16.13 - Variations from product information
Lyssaviruses are single-stranded RNA viruses in the family Rhabdoviridae, genus Lyssavirus. There are 12 known species within the genus Lyssavirus, including the classical rabies virus and other closely related lyssaviruses such as the Australian bat lyssavirus (ABLV) and European bat lyssaviruses.1
4.16.2 Clinical features
Rabies is a zoonotic disease caused by human exposure to saliva or nerve tissue of an animal infected with rabies virus or other lyssaviruses. As the clinical disease caused by classical rabies virus and other lyssaviruses is indistinguishable, the term ‘rabies’ refers to disease caused by any of the known lyssavirus species.2-5 Human exposure can occur via a scratch or bite that has broken the skin, or via direct contact with the mucosal surface of a person, such as nose, eye or mouth. Most human cases of rabies occur after animal bites – cases after animal scratches, the licking by animals of open wounds or contact of animal saliva with intact mucous membranes are very rare. Aerosol transmission has never been well documented in the natural environment.6 There has been transmission of rabies virus reported following tissue or organ transplantation from donors who died with undiagnosed rabies.7 Transmission of rabies virus to humans through unpasteurised milk may be possible; however, rare reports of transmission via this route have not been confirmed.8
Once a person is infected, the incubation period of rabies is usually 3 to 8 weeks, but can range from as short as a week to, on rare occasions, several years. The risk of rabies is higher, and the incubation period shorter, after severe and multiple wounds proximate to the central nervous system (such as on the head and neck) and in richly innervated sites (such as the fingers).
Rabies is almost invariably fatal. Typically, in the prodromal phase of rabies, which lasts up to 10 days, the patient may experience non-specific symptoms such as anorexia, cough, fever, headache, myalgia, nausea, sore throat, tiredness and vomiting.9 Paraesthesiae and/or fasciculations at or near the site of the wound may be present at this stage. Anxiety, agitation and apprehension may also occur. Most rabies patients present with the furious or encephalitic form.10 In the encephalitic phase, objective signs of nervous system involvement include aerophobia, hydrophobia, bizarre behaviour, disorientation and hyperactivity. Signs of autonomic instability such as hypersalivation, hyperthermia and hyperventilation may occur.10 The neurological status of the patient deteriorates over a period of up to 12 days, and the patient either dies abruptly from cardiac or respiratory arrest, or lapses into a coma.
The epidemiology of rabies varies depending on the lyssavirus species and the animal host. Lyssaviruses have been found in all continents, except Antarctica.11 Rabies that is due to the classical rabies virus and occurs in land dwelling (terrestrial) mammals is present throughout much of Africa, Asia, the Americas and Europe, where the virus is maintained in certain species of mammals, particularly dogs. 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. Australia, New Zealand, Japan, Papua New Guinea and Pacific island nations are currently free of rabies in terrestrial mammals. However, a country’s status can change at any time. For example, in 2008 on the island of Bali, Indonesia, rabies was reported in dogs, with cases later reported in humans.12 Prior to this, Bali had been considered free of rabies, although rabies was known to occur in other areas of Indonesia.13
In some parts of the world, bats are important reservoirs of classical rabies as well as other lyssaviruses, with bat lyssaviruses found in areas that are considered free from terrestrial rabies. ABLV was first reported in bats in 1996; since then, three cases of fatal encephalitis caused by ABLV have been reported in Australians, in 1996,1998 and 2013.2,14,15 All three patients had been either bitten or scratched by bats. Evidence of ABLV infection has been identified in all four species of Australian fruit bats (flying foxes) and in several species of Australian insectivorous bats.4,16-18 It should therefore be assumed that all Australian bats have the potential to be infected with ABLV. Different regions in Australia have reported higher risk of potential ABLV exposures.19,20 ABLV has not been isolated from bats outside Australia. However, closely related lyssaviruses are found in bats in other countries. For example, European bat lyssavirus 1 and European bat lyssavirus 2 have been isolated in bats in some parts of Europe. Four human deaths from European bat lyssavirus variants have been reported in Europe, all with no record of prophylactic rabies immunisation.3,5 As such, bats anywhere in the world should be considered a potential source of lyssaviruses and a potential risk for acquiring rabies, depending on the exposure. There are rare reports of bat lyssavirus infections in other animals.21-23 The first confirmed cases of ABLV in terrestrial mammals in Australia occurred in two horses in Queensland in 2013.24
Information on the global occurrence of rabies can be obtained from reputable international authorities.11,25,26 In addition, advice on potential lyssavirus exposures and their management should be obtained by contacting the relevant Australian state/territory health authorities (refer to 4.16.12 Public health management of lyssavirus infections below).
4.16.4 Rabies vaccines
- Mérieux Inactivated Rabies Vaccine – Sanofi Pasteur Pty Ltd (human diploid cell vaccine [HDCV]). Lyophilised powder in a monodose vial with 1.0 mL distilled water as diluent. Each 1.0 mL reconstituted dose contains ≥2.5 IU inactivated rabies virus; 100–150 µg neomycin; ≤70 mg human serum albumin; trace of phenol red (indicator). May contain trace amounts of bovine gelatin and β-propiolactone.
- Rabipur Inactivated Rabies Virus Vaccine – CSL Limited/Novartis Vaccines and Diagnostics Pty Ltd (purified chick embryo cell vaccine [PCECV]). Lyophilised powder in a monodose vial with 1.0 mL distilled water as diluent. Each 1.0 mL reconstituted dose contains ≥2.5 IU inactivated rabies virus; trace amounts of neomycin, chlortetracycline, trometamol, β-propiolactone, monopotassium glutamate and amphotericin B. May contain trace amounts of bovine gelatin and egg protein.
There are two inactivated rabies cell culture-derived vaccines available in Australia.
The Mérieux vaccine is a lyophilised, stabilised suspension of inactivated Wistar rabies virus that has been cultured on human diploid cells and then inactivated by β-propiolactone. This human diploid cell vaccine (HDCV) is coloured off-white, but after reconstitution with the diluent it turns a pinkish colour due to the presence of phenol red. The vaccine does not contain a preservative.
Rabipur is a lyophilised, stabilised suspension of inactivated Flury LEP rabies virus that has been cultured on purified chick embryo cells and then inactivated by β-propiolactone. This purified chick embryo cell vaccine (PCECV) does not contain a preservative.
Rabies vaccine is effective and safe when used for pre-exposure prophylaxis (PreP) and post-exposure prophylaxis (PEP) for rabies virus.27,28 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.20,29-34
4.16.5 Rabies immunoglobulin
- Imogam Rabies Pasteurized – Sanofi Pasteur Pty Ltd (human rabies immunoglobulin [HRIG]). Each 1.0 mL contains IgG class human rabies antibodies with a minimum titre of 150 IU; 22.5 mg glycine; 1 mg sodium chloride. Supplied in 2 mL vials.
Human rabies immunoglobulin (HRIG) is prepared by cold ethanol fractionation from the plasma of hyperimmunised human donors.
In exceptional circumstances, such as product shortages, other HRIG products may be made available for use in Australia. For example, KamRAB Rabies Immune Globulin (Kamada, Israel), although not registered by the TGA, has been made available under the Special Access Scheme due to a critical shortage of alternative products. Advice on the use of HRIG products will be provided by state and territory health authorities (refer also to 4.16.12 Public health management of lyssavirus infections above).
4.16.6 Transport, storage and handling
Transport according to National vaccine storage guidelines: Strive for 5.35 Store at +2°C to +8°C. Do not freeze.
Both rabies vaccines must be reconstituted by adding the entire contents of the diluent container to the vial and shaking until the powder is completely dissolved. Reconstituted vaccine should be used immediately.
Human rabies immunoglobulin
Transport according to National vaccine storage guidelines: Strive for 5.35 Store at +2°C to +8°C. Do not freeze. Protect from light.
HRIG should be used immediately once the vial is opened.
4.16.7 Dosage and administration
The dose of rabies vaccine for use in PreP and PEP is 1.0 mL, to be given by IM injection and is the same for infants, children and adults.
HDCV can also be given by SC injection; however, if PCECV is inadvertently given via the SC route, the dose should be repeated.
Note: Rabies vaccination administered via the intradermal (ID) route is not routinely used in Australia and is not recommended. The use of the ID route for rabies vaccination is the practitioner’s own responsibility, as rabies vaccines are not registered for use via this route in Australia. ID administration should be particularly discouraged for post-exposure prophylaxis. For detailed information on the restrictions that apply to the use of ID vaccination, if undertaken for PreP, refer to ‘Pre-exposure prophylaxis administered via the intradermal route’ below.
Rabies vaccine should be given in the deltoid area, as rabies virus neutralising antibody (VNAb) titres may be reduced after administration in other sites. In particular, vaccine should never be given in the buttock, as failure of pre-exposure prophylaxis has been reported when given by this route.36 In infants <12 months of age, administration into the anterolateral aspect of the thigh is recommended.
Pre-exposure prophylaxis (PreP)
The recommended schedule for pre-exposure prophylaxis (PreP) for rabies or other lyssavirus infection consists of a total of 3 doses of vaccine; the 1st dose of vaccine is given on day 0, and subsequent doses on days 7 and 21–28. Although the 3rd dose can be given as early as 21 days, there are no data to support the use of an even more accelerated schedule for those with limited time before travel to a rabies-enzootic area.
Post-exposure prophylaxis (PEP)
In persons previously unvaccinated, the recommended schedule for post-exposure prophylaxis (PEP) for immunocompetent persons consists of 4 doses of vaccine. The 1st dose of vaccine is given as soon as practicable (day 0), and subsequent doses are given on days 3, 7 and 14; deviations of a few days from this schedule are probably unimportant.27
The recommended schedule for PEP for previously unvaccinated immunocompromised persons consists of 5 doses of vaccine. The 1st dose of vaccine is given as soon as practicable (day 0), and subsequent doses are given on days 3, 7, 14 and 28; deviations of a few days from this schedule are probably unimportant.
For more detailed information refer to 4.16.8 Recommendations below.
Human rabies immunoglobulin
When HRIG is indicated, the dose is 20 IU per kilogram of body mass and is the same for infants, children and adults. HRIG should be administered at the same time as the 1st dose (day 0) of rabies vaccine. Do not administer HRIG if more than 7 days have elapsed since the 1st dose of vaccine, as the HRIG may interfere with the immune response to the vaccine. For more detailed information refer to 4.16.8 Recommendations below.
HRIG must be infiltrated in and around all wounds using as much of the calculated dose as possible. The remainder of HRIG that cannot safely be infiltrated in and around the wound, or in situations where there is no wound (such as for mucous membrane exposures), HRIG should be administered intramuscularly at a site away from the rabies vaccine injection site (e.g. the alternative deltoid, lateral thigh or gluteal muscle, depending on volume). If the wounds are severe and the calculated volume of HRIG is inadequate for complete infiltration of all wounds (e.g. extensive dog bites in a young child), the HRIG should be diluted in saline to make up an adequate volume for the careful infiltration of all wounds.
Wounds to fingers and hands may be small, particularly following exposures to bats, and infiltration of HRIG into these wounds is likely to be both technically difficult and painful for the recipient.37 However, due to the extensive nerve supply to these sites9,10,38 it is important that as much of the calculated dose of HRIG as possible should be infiltrated into finger and hand wounds using either a 25 or 26 gauge needle. To avoid the development of a compartment syndrome, the HRIG should be infiltrated very gently, and should not cause the adjacent finger tissue to go frankly pale or white. It may be necessary to give a ring-block using a local anaesthetic.37
Interchangeability of rabies vaccines
The World Health Organization (WHO) does not recommend interchanging rabies cell culture-derived vaccines (CCV), but states that, in situations where it is unavoidable, a PreP or PEP course can be completed with an alternative rabies CCV, providing the vaccine is WHO-endorsed (also termed ‘pre-qualified’).27 Various international vaccine advisory groups state that rabies CCV are interchangeable. This is supported by the similarities in tissue culture vaccine production methods as well as antibody responses and adverse reactions following vaccination. In one study that specifically assessed the interchangeability of HDCV and PCECV, 165 subjects were randomised to receive rabies PreP (days 0, 7 and 21–28) using either HDCV or PCECV.39 One year following PreP, each group received 1 or 2 booster doses of PCECV. The booster dose resulted in an anamnestic response (geometric mean titre several orders of magnitude >0.5 IU/mL) in all subjects by day 7, independent of the vaccine that was used to deliver the primary course. It is expected that this response would be similar with other rabies CCV.
Measures to avoid potential rabies virus and other lyssavirus (including ABLV) exposures
Travellers to rabies-enzootic regions should be advised to avoid close contact with either wild or domestic animals; this is particularly important for children.40-42 They should be advised about pre-travel (i.e. pre-exposure) rabies vaccination (or, if appropriate, booster doses), and on what to do should they be either bitten or scratched by an animal while abroad.42-46 It is recommended that prior to travel, travellers be educated regarding first aid treatment for rabies exposures, irrespective of prior vaccination.
Recommendations to decrease the risk of exposure to rabies include:
- Do not allow young children to feed, pat or play with animals. The height of young children makes bites to the face and head more likely.
- Avoid contact with stray dogs or cats. Remain vigilant when walking, running or cycling.
- Do not carry food, and do not feed or pat monkeys, even in popular areas around temples or markets where travellers may be encouraged to interact with the monkeys. In particular, avoid focusing attention on monkeys carrying their young, as they may feel threatened and bite suddenly.
In addition, contact with bats should be avoided anywhere in the world, including Australia. Only appropriately vaccinated and trained persons should handle bats. If bats must be handled, safety precautions, such as wearing protective gloves and clothing, should be observed.
Pre-exposure prophylaxis for rabies virus and other lyssaviruses (including ABLV)
PreP with rabies vaccine is recommended for:
- persons liable to receive bites or scratches from bats (this includes bat handlers, veterinarians, wildlife officers and others who come into direct contact with bats) in any country, including Australia
- travellers and expatriates who will be spending time in rabies-enzootic areas; PreP should occur following a risk assessment that takes into consideration the likelihood of interaction with animals and access to emergency medical attention
- persons working with terrestrial animals in rabies-enzootic areas
- research laboratory personnel working with any live lyssaviruses.
Parents travelling with children to rabies-enzootic areas should consider PreP for younger children, as many children, if bitten by dogs, are often bitten on the face and hands because they are at an optimal height for such contact.
Serological testing to confirm seroconversion is only necessary in certain circumstances (refer to ‘Serological testing following rabies vaccination’ below).27
PreP simplifies the management of a subsequent exposure because fewer doses of vaccine are needed and because rabies immunoglobulin (RIG) is not required (refer to ‘Post-exposure prophylaxis for rabies virus and other lyssavirus (including ABLV) exposures’ below). This is particularly important as RIG (human or equine) is often difficult to obtain in many developing countries and its safety may not be guaranteed.
Pre-exposure prophylaxis administered via the intradermal route
Intradermal PreP is not recommended because, although initial antibody titres may be higher, titres at 14 days are lower and wane more rapidly after ID administration of rabies vaccine than after either IM or SC administration. There may also be a slow initial immune response following exposure to rabies virus in those given ID rabies vaccine.47-49 For these reasons, it is strongly recommended that the IM route (IM or SC if HDCV is used) be used for pre-exposure prophylaxis. (Refer also to 4.16.7 Dosage and administration above.)
However, if ID rabies PreP is considered (using a dose of 0.1 mL on days 0, 7 and 28) it is essential that:
- it is given by vaccine providers with not only expertise in, but also regular practice of, the ID technique
- it is not administered to anyone who is immunocompromised
- it is not administered to persons taking either chloroquine or other antimalarials structurally related to chloroquine (e.g. mefloquine), at either the time of, or within a month following, vaccination50
- any remaining vaccine is discarded at the end of the session during which the vial is opened (8 hours)
- the rabies VNAb level is checked 14 to 21 days following completion of the pre-exposure course of ID vaccine (refer to ‘Serological testing following rabies vaccination’ below)
- it is only used for PreP for classical rabies exposures (there are no data on the protection provided by ID rabies vaccination for the prevention of infection with other lyssaviruses, including ABLV).
Post-exposure prophylaxis for rabies virus and other lyssavirus (including ABLV) exposures
PEP for rabies virus and other lyssavirus exposures consists of prompt wound management, vaccination and HRIG administration. The appropriate combination of these components depends on a detailed risk assessment, including determining the extent of the exposure, the animal source of the exposure, the person’s immune status and their previous vaccination history. The different PEP pathways are described in more detail below and PEP management algorithms are outlined in Figures 4.16.1and 4.16.2.
Types of potential rabies virus and other lyssavirus (including ABLV) exposures
Three different categories of lyssavirus exposure are outlined in Table 4.16.1, based on those already described by the World Health Organization (WHO).27 The appropriate PEP pathway following each of the different exposure categories depends on whether the source of exposure was a terrestrial animal or a bat. Different PEP pathways are required following potential bat exposures compared with terrestrial animal exposures because the risk from wounds from bats is often hard to determine due to the limited injury inflicted, and there is evidence that superficial bat exposures are more likely to result in human infection compared to superficial bites from terrestrial animals.36
Risk assessment should be conducted for exposures to both live and dead animals. An in-vivo study of mice inoculated with a laboratory strain of rabies demonstrated that rabies virus remained viable for up to 3 days post-mortem in brain tissue extracted from whole carcasses decomposing at 25°C to 35°C and for up to 18 days at lower temperatures.51 Every effort should be made following a potential exposure to have the animal tested so that unnecessary treatment is avoided (refer to ‘ Wound management in post-exposure prophylaxis’ below).
An algorithm detailing the appropriate PEP pathway following potential lyssavirus exposure from a terrestrial animal is provided in Figure 4.16.1; an algorithm for use following potential lyssavirus exposure from a bat is provided in Figure 4.16.2
|Type of exposure||Description|
|Category I||Touching or feeding animals, licks on intact skin, as well as exposure to blood, urine or faeces|
|Category II||Nibbling of uncovered skin, minor scratches or abrasions without bleeding|
|Category III||Single or multiple transdermal bites or scratches, contamination of mucous membrane with saliva from licks, licks on broken skin|
Source: Modified from WHO 201027
The relevant state/territory health authority should be contacted about any of the following potential exposures, in order to conduct a detailed risk assessment and advise on management. (Refer also to 4.16.12 Public health management of lyssavirus infections below.)
- Potential exposure sustained from a terrestrial animal in a rabies-enzootic area, or any potential exposure sustained from a bat anywhere in the world. Dogs and monkeys are the usual exposures in Asia, Africa and Central and South America, but exposures to other terrestrial mammals and bats must also be assessed for potential classical rabies virus transmission. If a traveller presents >10 days after being bitten or scratched by either a domestic dog, cat or ferret in a rabies-enzootic country, and it can be reliably ascertained that the animal has remained healthy (>10 days after the exposure), PEP is not required. Otherwise, PEP appropriate for the category and source of exposure (refer to Figure 4.16.1 or 4.16.2) should be administered, even if there has been a considerable delay in reporting the incident.
- Potential exposure to Australian bats: This includes situations where the exposure may be difficult to categorise because a person is unaware or unable to communicate that an exposure has occurred when in close proximity to a bat (e.g. a person with an intellectual disability, an intoxicated person, a child, or a person who has been sleeping in a confined space with a bat present). If possible, and without placing others at risk of exposure, the bat should be kept and arrangements promptly made for testing the bat for ABLV. Following wound management (refer below), the administration of HRIG and rabies vaccine can be withheld if the bat’s ABLV status will be available within 48 hours of the exposure. If the result will not be available within 48 hours, the appropriate post-exposure prophylaxis should begin as soon as is practicable, following the bat exposure algorithm as outlined in Figure 4.16.2. Where a bat is tested at a reference laboratory and later found to be negative for ABLV, then PEP for the person exposed to that bat can be discontinued.
- Potential exposure to a terrestrial animal with a laboratory-confirmed lyssavirus infection in an area where rabies is not enzootic, such as Australia. Reports of bat lyssavirus infections in terrestrial animals are extremely rare and there is no evidence of transmission from an infected terrestrial animal to humans; however, there is a theoretical possibility that transmission could occur.
Wound management in post-exposure prophylaxis
One of the most vital steps following a potential rabies virus or other lyssavirus exposure is wound management. Immediate and thorough washing of all bite wounds and scratches with soap and water, and the application of a virucidal preparation such as povidone-iodine solution after the washing, are important measures in the prevention of rabies. Consideration should also be given to the possibility of tetanus and other wound infections, and appropriate measures taken. Primary suture of a bite from a potentially rabid animal should be avoided. Bites should be cleaned, debrided and infiltrated well with HRIG, when indicated (refer to Figure 4.16.1 or 4.16.2).
Post-exposure prophylaxis of persons who are previously unvaccinated
After performing wound management, rabies vaccine should be administered with or without HRIG (refer to ‘Human rabies immunoglobulin’ below), depending on the category and source of exposure, as outlined in Figure 4.16.1 or 4.16.2 and described below.
Persons who have not previously received a complete rabies vaccine course, and are immunocompetent, should receive a total of 4 doses of rabies vaccine ( refer to 4.16.7 Dosage and administration above). Although no clinical trial has assessed the efficacy of rabies vaccine, the rationale supporting the use of a 4-dose schedule in immunocompetent persons is based on 11 studies where the immunogenicity of either cell culture-derived vaccine was consistently >0.5 IU/mL by day 30 (after 4 doses) and, in a majority of participants, was >0.5 IU/mL by day 14 (after 3 doses). Antibody responses observed after the 4th and 5th doses were both several orders of magnitude larger than the WHO cut-off of 0.5 IU/mL and were similar in value. As the additional immune boosting following a 5th dose is minimal, a 5th dose is not required in immunocompetent persons.52-62
Persons who have not previously received a complete rabies vaccine course and who have either an immunocompromising illness, or are taking immunosuppressant medications, should receive a 5-dose vaccine schedule ( refer to 4.16.7Dosage and administration above).63-65 The rabies VNAb titre should be measured 14 to 21 days after the 5th dose and a further dose given if the titre is reported as inadequate (i.e. <0.5 IU/mL). Serological testing should be repeated following the 6th dose, and, if titres remain <0.5 IU/mL, infectious disease specialist advice should be sought (refer to ‘Serological testing following rabies vaccination’ below).
Corticosteroids and immunosuppressive therapy can interfere with the development of active immunity and, therefore, if possible, should not be administered during the period of post-exposure prophylaxis.66
Human rabies immunoglobulin
The administration of a single dose of HRIG ( refer to 4.16.7 Dosage and administration above), in addition to vaccination, in previously unvaccinated persons is only indicated in certain circumstances as outlined in Figure 4.16.1 or Figure 4.16.2, and as described below. HRIG is given to provide localised anti-rabies antibody protection while the person responds to the rabies vaccine. This should follow adequate wound care (refer to ‘Wound management in post-exposure prophylaxis’ above).
HRIG is not recommended in persons who:
- received the 1st dose (day 0) of vaccine more than 7 days prior to presenting for HRIG (i.e. more than 7 days have elapsed since the 1st dose of vaccine was given)
- have a documented history of previous completed recommended PreP or PEP ( refer to 4.16.7 Dosage and administration above)
- have documented evidence of adequate VNAb titres (refer to ‘Serological testing following rabies vaccination’ below).
Such persons should receive rabies vaccine only (refer to ‘Post-exposure prophylaxis of persons who have been previously vaccinated’ below).
Although data are limited on the effectiveness of rabies vaccine and HRIG as PEP against infection with lyssaviruses other than classical rabies virus, the available animal data and clinical experience support their use.20,29-34
Post-exposure prophylaxis of persons who have been previously vaccinated
Wound management must still be carried out irrespective of prior rabies vaccination.
Persons who have evidence of a previous completed recommended PreP or PEP regimen, or who have a previously documented adequate VNAb titre, require a total of 2 doses of rabies vaccine (refer to Figure 4.16.1 or 4.16.2). This includes immunocompromised individuals; however, VNAb levels should be checked after the 2nd dose to ensure they are adequate (refer to ‘Serological testing following rabies vaccination’ below).
Note: PreP or PEP vaccine administered via the ID route is not considered appropriate previous vaccination unless documentation of an adequate VNAb titre is available (refer to ‘Serological testing following rabies vaccination’ below).
HRIG is not required and should not be administered, as its use may suppress the level of anamnestic response and circulating VNAb.
In cases where a person’s vaccination status is uncertain because the documentation of a full course of rabies vaccine is not available, the full PEP regimen should be administered.
Post-exposure prophylaxis commenced overseas
Australians travelling overseas who are exposed to a potentially rabid animal (including bats from any country) may be given PEP using vaccines and schedules not used in Australia. In very rare circumstances, if an older nerve tissue-derived rabies vaccine has been administered, any doses given should be disregarded (refer to Table 4.16.2). However, it is most likely that a person vaccinated overseas will have received a cell culture-derived vaccine (refer to ‘Interchangeability of rabies vaccines’ in 4.16.7 Dosage and administration above).27,39 If a person has received a cell culture-derived vaccine abroad, it is recommended that the standard post-exposure prophylaxis regimen be continued in Australia with either HDCV or PCECV.
WHO-approved post-exposure rabies vaccination regimens include:
- Zagreb (2 doses on day 0, doses on days 7 and 21: annotated as 2-0-1-1)
- Essen (doses given on days 0, 3, 7, 14 and 28 (or 30): annotated as 1-1-1-1-1)
- Modified Essen (doses given on days 0, 3, 7 and 14: annotated as 1-1-1-1).
If the PEP was started overseas but HRIG or equine RIG was not given, and the person presents in Australia within 7 days of commencing PEP, HRIG should be given as soon as is practicable (and within 7 days of the 1st rabies vaccine dose).
If the person presents in Australia more than 7 days after commencing PEP, then HRIG should not be administered and the appropriate number of remaining doses of rabies vaccine administered.
For these and other scenarios that may arise, Table 4.16.2 outlines the most common PEP regimens that may be commenced overseas and the recommended schedule to complete PEP in Australia.
In the case of PEP commenced overseas, every traveller should be advised to request a PEP certificate from the vaccination centre and to obtain or record the following information (preferably in English):
- the contact details for the clinic attended (telephone and email address)
- the batch and source of RIG used (Note: equine RIG rather than human RIG may be used in some countries)
- the volume of RIG administered
- the type of cell culture vaccine used
- the vaccine batch number
- the number of vials used
- the route of vaccine administration
- the date of RIG and/or vaccine administration.
These details help inform decisions about PEP on return home.
|Vaccine type/route administered overseas/rabies immunoglobulin (RIG)||Rabies vaccine schedule in Australia|| HRIG
Category III terrestrial animal exposures and Category II and III bat exposures only*
|Nerve tissue vaccine||Recommence schedule starting from day 0|| Administer HRIG if no RIG already given
Do not give HRIG if more than 7 days since 1st dose of vaccine (day 0)
|Unsure/unknown/poor documentation||Recommence schedule starting from day 0|| Administer HRIG if no RIG already given
Do not give HRIG if more than 7 days since 1st dose of vaccine (day 0)
|Well documented, RIG (equine or human) given, plus vaccine given either IM or ID||Align with nearest due dose and resume schedule administering vaccine IM (IM or SC if HDCV used)||No HRIG needed|
| 2 vaccine doses given IM on day 0
Irrespective of whether RIG (equine or human) was administered at same time as the 1st doses of vaccine
|Give a further 2 doses; the 1st dose on day 7 and the 2nd dose on day 14|| Administer HRIG if no RIG already given
Do not give HRIG if more than 7 days since 1st doses of vaccine (day 0)
|Immunocompromised with vaccines administered ID||Irrespective of number of previous doses, administer a 5-dose schedule IM (IM or SC if HDCV used) and check serology (refer to ‘Serological testing following rabies vaccination’ below)|| Administer HRIG if no RIG already given
Do not give HRIG if more than 7 days since 1st dose of vaccine (day 0)
* Refer to Table 4.16.1 Lyssavirus exposure categories and Figures 4.16.1 and 4.16.2 for further information of PEP pathways, including HRIG administration following either a terrestrial animal or bat exposure.
Figure 4.16.1: Post-exposure prophylaxis algorithm for potential exposure to lyssavirus from a terrestrial animal in a rabies-enzootic area
This algorithm is represented as a flow chart. The first box notes that potential exposure from a terrestrial animal in a rabies-enzootic area can fall into one of three categories.
Category 1 exposure involves touching or feeding animals, animal licks on intact skin, or exposure to blood, urine or faeces or to an animal that has been dead for more than 4 hours. The chart indicates that, for Category 1 exposure, no prophylaxis is required if the contact history is reliable. Category 2 exposure involves the nibbling of uncovered skin, minor scratches or abrasions without bleeding. If this category of exposure takes place in a non-immune‡, immunocompetent person, they should be vaccinated§, with 4 doses administered intramuscularly on days 0, 3, 7 and 14. Human rabies immunoglobulin is not indicated. If the person is subjected to further exposures in the future, they should be treated as a person who has been previously immunised*†, and follow the procedure for the appropriate category of previously immunised exposures. If the non-immune,‡ immunocompetent person with a category 2 exposure who is then vaccinated§ suffers ongoing occupational exposure risk, refer to the booster algorithm in Figure 4.16.3.
If a person suffering a category 2 exposure has been previously immunised*†, they should be vaccinated§§ again after exposure; both immunocompetent and immunocompromised persons should receive 2 doses delivered intramuscularly on days 0 and 3. Human rabies immunoglobulin is not indicated. If that person is subjected to further exposures in the future, the category of their exposure should be considered and they should be treated as a previously immunised person.
Category 3 exposure involves a single or multiple transdermal bites or scratches, the contamination of mucous membrane with saliva from licks, or licks on broken skin. If a person suffering a category 3 exposure has been previously immunised*†, they should be vaccinated§§ again after exposure; both immunocompetent and immunocompromised persons should receive 2 doses delivered intramuscularly on days 0 and 3. Human rabies immunoglobulin is not indicated. If that person is subjected to further exposures in the future, the category of their exposure should be considered and they should be treated as previously immunised†. If category 3 exposure occurs in a non-immune‡ and immunocompetent person, they should be vaccinated§ and human rabies immunoglobulin (HRIG) should be administered. HRIG is administered only once, and as soon as possible after the initiation of post-exposure prophylaxis. (HRIG is not indicated beyond the 7th day after the first dose of vaccine at day 0). Rabies vaccination is 4 doses, administered intramuscularly on days 0, 3, 7 and 14. If the non-immune,‡ immunocompetent person is subjected to further exposures in the future, the category of their exposure should be considered and they should be treated as a previously immunised† person. If the non-immune, ‡ immunocompetent person with a category 3 exposure who is then vaccinated§ suffers ongoing occupational exposure risk, refer to the booster algorithm in Figure 4.16.3.
Note: This algorithm is also suitable for potential exposure to a terrestrial animal with a laboratory-confirmed lyssavirus infection in an area where rabies is not enzootic, such as Australia.
* If in doubt, treat as non-immune.
† Previously immunised – documentation of a completed recommended PreP or PEP rabies vaccine regimen. This is irrespective of the time period since the last dose was administered. This may either be a completed primary pre-exposure course or post-exposure course and includes those where subsequent boosting has occurred, or documented rabies antibody (VNAb) titres of ≥0.5 IU/mL.
‡ Non-immune – person who has never received pre- or post-exposure immunisation with rabies vaccine, has had incomplete/inadequate primary vaccination course.
§ Immunocompromised persons, not previously vaccinated, should receive 5 doses of vaccine on days 0, 3, 7, 14 and 28. Serology should be checked 14 to 21 days post dose 5 and a further dose offered if the result is <0.5 IU/mL. In immunocompromised persons, HRIG should be administered if a Category II or III exposure.
¶ Immunocompromised persons, previously immunised, should have serological testing 14 to 21 days after the 2nd dose to confirm acceptable VNAb levels. If the result is <0.5 IU/mL, expert advice should be sought regarding the total number of doses required for PEP.
Figure 4.16.2: Post-exposure prophylaxis algorithm for potential exposure to lyssaviruses from bats in Australia or overseas
This algorithm is represented as a flow chart. Potential exposure to lyssaviruses from a bat (either in Australia or overseas) can be separated into one of three categories. Category 1 exposures involve touching or feeding of bats, licks on intact skin, or exposure to blood, urine or faeces. These do not require any prophylaxis if the contact history is reliable.
Category 2 and 3 exposures are both treated using the same protocol. Exposures in these categories include nibbling of uncovered skin, any scratches or abrasions with or without bleeding, single or multiple transdermal bites or scratches, contamination of mucous membrane with saliva from licks, or licks on broken skin. If a person suffering a category 2 or 3 exposure has been previously immunised*†, they should be vaccinated§§ again after exposure; both immunocompetent and immunocompromised persons should receive 2 doses delivered intramuscularly on days 0 and 3. Human rabies immunoglobulin is not indicated. If the person is at risk of ongoing occupational exposure, serology should be performed, either every 6 months for laboratory staff who are at risk, or every 2 years for veterinary workers, bat handlers or any other workers who are likely to handle bats. If the person has a viral neutralising antibody titre of less than 0.5 international units per millilitre, they should be given a single booster dose of vaccine. If that person is subjected to further exposure, they should be given post-exposure prophylaxis relevant to their category of exposure, and be treated as if they have been previously immunised*†.
If a previously immunised*† person suffers a category 2 or 3 exposure, is vaccinated§§ but is at risk of ongoing occupational exposure, and records a viral neutralising antibody titre of greater than or equal to 0.5 international units per millilitre, no further action should be taken, until either they are exposed again (in which case, post-exposure prophylaxis should be undertaken relevant to their category of exposure and treating them as previously immunised), or until 6 months has elapsed if they are laboratory staff, or 2 years has elapsed if they are a veterinary worker, bat handler or a worker who is likely to need to handle bats. After this time period has elapsed, rabies antibody serology should be retested. If this person remains at risk of ongoing occupational exposure, their levels of viral neutralising antibody should continue to be monitored and boosters given according to their antibody titre, or re-exposure to lyssavirus occurs.
For category 2 or 3 exposure of a person who is non-immune‡ and immunocompetent, they should be vaccinated§ and human rabies immunoglobulin (HRIG)§ should be administered. HRIG§ is administered only once, and as soon as possible after the initiation of post-exposure prophylaxis. (HRIG is not indicated beyond the 7th day after the first dose of vaccine at day 0). Rabies vaccination is 4 doses, administered intramuscularly on days 0, 3, 7 and 14. If the person is at risk of ongoing exposure, serology should be performed, either every 6 months for laboratory staff, or every 2 years for veterinary workers, bat handlers or any other workers who are likely to handle bats. If the person has a viral neutralising antibody titre of less than 0.5 international units per millilitre, they should be given a single booster dose of vaccine. If that person suffers further exposure, they should be given post-exposure prophylaxis relevant to their category of exposure, and be treated as if they have been previously immunised *†. If the person records a viral neutralising antibody titre of greater than or equal to 0.5 international units per millilitre, no further action should be taken, until either they are exposed again (in which case, post-exposure prophylaxis should be undertaken relevant to their category of exposure and treating them as previously immunised), or until 6 months has elapsed if they are laboratory staff, or 2 years has elapsed if they are a veterinary worker, bat handler or a worker who is likely to need to handle bats. After this time period has elapsed, rabies antibody serology should be retested. If this person remains at risk of ongoing occupational exposure, their levels of viral neutralising antibody should continue to be monitored and boosters given according to their antibody titre, or re-exposure to lyssavirus occurs.
* If in doubt, treat as non-immune.
† Includes situations where the exposure may be difficult to categorise because a person is unaware or unable to communicate that an exposure has occurred when in close proximity to a bat. ‡ Previously immunised – documentation of a completed recommended PreP or PEP rabies vaccine regimen. This is irrespective of the time period since the last dose was administered. This may either be a completed primary pre-exposure course or post-exposure course and includes those where subsequent boosting has occurred, or documented rabies antibody (VNAb) titres of ≥0.5 IU/mL.
§ Non-immune – person who has never received pre- or post-exposure immunisation with rabies vaccine or has had incomplete/inadequate primary vaccination course.
¶ Immunocompromised persons, previously immunised, should have serological testing 14 to 21 days after the 2nd dose to confirm acceptable VNAb levels. If the result is <0.5 IU/mL, expert advice should be sought regarding the total number of doses required for PEP.
# Immunocompromised persons, not previously vaccinated, should receive 5 doses of vaccine on days 0, 3, 7, 14 and 28. Serology should be checked 14 to 21 days post dose 5 and a further dose offered if the result is <0.5 IU/mL. In immunocompromised persons, HRIG should be administered if a Category II or III exposure.
A recent WHO position paper applied a quality assessment of a moderate level of scientific evidence to support that cell culture-derived rabies vaccines induce long-term immunity of at least 10 years.27
The WHO states that booster doses are not required for persons who are travelling to, or living in, an area of high rabies risk and who have completed a primary course, either pre- or post-exposure, using either of the currently available cell culture-derived vaccines.27
Booster doses of rabies vaccine are recommended for immunised persons who have ongoing occupational exposure to lyssaviruses in Australia or overseas67 (refer to Figure 4.16.3).
- Persons who work with live lyssaviruses in research laboratories who should have rabies neutralising antibody titres measured every 6 months. If the titre is reported as inadequate (<0.5 IU/mL), they should have a booster dose.
- Others with exposures to bats in Australia or overseas, and those who are likely to be exposed to potentially rabid terrestrial mammals overseas, who should have rabies antibody titres measured every 2 years. If the titre is reported as inadequate (<0.5 IU/mL), they should have a booster dose. Alternatively, a booster dose may be offered every 2 years without determining the antibody titre.
Points that should be considered as to whether a person should receive a booster dose of rabies vaccine because their antibody level falls below 0.5 IU/mL are:
- anticipated risk of exposure (i.e. routinely handling sick animals or rabies reservoir species in enzootic areas)
- length of time until the next antibody measurement
- individual health status (consider immunocompromising conditions or a history of poor vaccine response)
- timely access to vaccine and administration should a potential exposure occur.
Figure 4.16.3: Booster algorithm for persons at ongoing risk of exposure to either rabies or other lyssaviruses, including Australian bat lyssavirus (ABLV)
This flow chart describes the booster algorithm for rabies or bat lyssavirus (including Australian bat lyssavirus). Where people are at risk of ongoing occupational exposure, serology should be performed either every 6 months for laboratory staff at risk, or every 2 years for veterinary workers, bat handlers of any other workers who are likely to need to handle bats. If the serology indicates that the person's viral neutralising antibody titre is less than 0.5 international units per millilitre, a single booster dose* should be given. If the person is immunocompromised, their serology should be checked 14 to 21 days after the booster dose, and a further dose offered if the result remains less than 0.5 international units per millilitre. If the person who received a booster dose is subjected to further exposure to rabies or bat lyssavirus, it should be managed using the appropriate post-exposure prophylaxis algorithm (Figure 4.16.1 for rabies, Figure 4.16.2 for bat lyssaviruses).
If the person's serology indicates levels of viral neutralising antibodies of greater than or equal to 0.5 international units per millilitre, no further action should be taken, until one of two situations occurs. First, if the person suffers further exposure, the appropriate post-exposure prophylaxis algorithm should be referred to (Figure 4.16.1 for rabies, Figure 4.16.2 for bat lyssaviruses). Second, if the indicated time has elapsed since serology was last performed (6 months for laboratory staff at risk, 2 years for veterinary workers or anyone handling bats), viral neutralising antibody serology should be tested again.
* Immunocompromised patients’ serology should be checked 14 to 21 days post booster dose and a further dose offered if the result remains <0.5 IU/mL.
Serological testing following rabies vaccination
The WHO defines adequate immunity to rabies virus as the presence of a VNAb titre ≥0.5 IU/mL.68
Routine serological testing for rabies following PreP or PEP vaccination is not usually necessary. However, persons who are immunocompromised should have their VNAb titres determined 14 to 21 days after the 3rd dose of vaccine in a PreP schedule or after the 5th dose of vaccine in a PEP schedule; a further dose should be given if the titre is reported as inadequate (i.e. <0.5 IU/mL). Serological testing should then be repeated and, if titres remain <0.5 IU/mL, infectious disease specialist advice should be sought.27
If PreP was administered via the ID route, the rabies antibody level should be checked 14 to 21 days following completion of the pre-exposure course to ensure VNAb levels are adequate. If inadequate, expert advice should be sought.
Persons who are at risk of repeated exposure to rabies or other lyssaviruses, including ABLV, should have their VNAb titre determined every 6 months to 2 years, depending on the risk of exposure, to assess the need for booster vaccination (refer to ‘Booster doses’ above).
4.16.9 Pregnancy and breastfeeding
Rabies vaccine and HRIG are recommended in pregnant or breastfeeding women following a potential exposure to rabies virus, ABLV or another bat lyssavirus69,70 (refer to 4.16.8 Recommendations above and 3.3 Groups with special vaccination requirements, Table 3.3.1 Recommendations for vaccination in pregnancy).
There are no absolute contraindications to use of either rabies vaccine or HRIG as post-exposure prophylaxis in persons with a potential exposure to rabies or other lyssaviruses, including ABLV. This is because rabies disease is almost always lethal.
Persons with an anaphylactic sensitivity to eggs, or to egg proteins, should not receive PCECV. HDCV should be used instead.
Refer also to 4.16.11 Adverse events below.
4.16.11 Adverse events
Cell culture-derived vaccines are generally well tolerated. In a large study, the following adverse events were reported after administration of HDCV to adults: sore arm (in 15 to 25% of vaccine recipients), headache (in 5 to 8%), malaise, nausea or both (in 2 to 5%), and allergic oedema (in 0.1%).71 Similar adverse event profiles have been reported for the PCECV; these reactions occur at the same rates in children.27,28,72-77
Although anaphylactic reactions are rare (approximately 1 per 10 000 vaccinations) following administration of HDCV, approximately 6% of persons receiving booster doses may experience allergic reactions. The reactions typically occur 2 to 21 days after a booster dose, and are characterised by generalised urticaria, sometimes with arthralgia, arthritis, oedema, nausea, vomiting, fever and malaise.71 These reactions are not life-threatening; they have been attributed to the presence of β-propiolactone-altered human albumin in the implicated vaccines.71
HRIG has an excellent safety profile and, in general, no chance of immediate hypersensitivity reactions as is more often the case with some equine sources of rabies immunoglobulin.27
Management of adverse events
Once initiated, rabies post-exposure prophylaxis should not be interrupted or discontinued because of local reactions or mild systemic reactions. Such reactions can usually be managed with simple analgesics.
Because rabies disease is almost always lethal, the recommended vaccination regimens, in particular the PEP regimen, should be continued even if a significant allergic reaction occurs following a dose of rabies vaccine. Antihistamines can be administered in an attempt to ameliorate any subsequent reactions.
A patient’s risk of developing either lyssavirus infection or rabies must be carefully considered before deciding to discontinue vaccination.
4.16.12 Public health management of lyssavirus infections
Classical rabies virus and ABLV virus 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.
Detailed information regarding the management of disease from rabies and other lyssaviruses, including ABLV, can be found in the national guidelines for public health units78 (www.health.gov.au/cdnasongs).
Both HRIG and rabies vaccine are available for PEP from the relevant state/territory health authorities (refer to Appendix 1 Contact details for Australian, state and territory government health authorities and communicable disease control).
4.16.13 Variations from product information
Neither of the product information sheets for the two vaccines available in Australia mentions that they can be used for both PreP and PEP for ABLV exposures. The ATAGI instead recommends that, where indicated, either of the available rabies vaccines can be used as PreP or PEP as per 4.16.8Recommendations above.
The product information for HDCV recommends a routine 6th dose at 90 days in a PEP regimen. The ATAGI recommends instead that a 4-dose schedule be used for PEP in immunocompetent persons. Further doses should be offered to a person who is immunocompromised and who has an inadequate antibody level following the 5-dose PEP regimen.
The product information for HDCV also recommends a pre-exposure booster after a year. The ATAGI instead recommends boosters between 6 months and 2 years for persons at continuing occupational risk (refer to ‘Booster doses’ in 4.16.8 Recommendations above).
The product information for PCECV recommends a routine 5th dose at 28 days in a PEP regimen and the product information for HDCV recommends a routine 5th and 6th dose at days 30 and 90, respectively, in a PEP regimen. The ATAGI recommends instead that a 4-dose schedule with either cell culture-derived vaccine be used for PEP in immunocompetent persons. A 5th dose at day 28 should be offered to persons who are immunocompromised. Further doses should be offered to persons who are immunocompromised and have an inadequate antibody level following the 5th dose of PEP.
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