Vaccine Information: RabAvert

RABAVERT- rabies vaccine
GlaxoSmithKline Biologicals SA

Rabies Vaccine for Human Use

DESCRIPTION

RabAvert Rabies Vaccine produced by GlaxoSmithKline GmbH is a sterile, freeze-dried vaccine obtained by growing the fixed-virus strain Flury Low Egg Passage (LEP) in primary cultures of chicken fibroblasts. The strain Flury LEP was obtained from American Type Culture Collection as the 59th egg passage. The growth medium for propagation of the virus is a synthetic cell culture medium with the addition of human albumin, polygeline (processed bovine gelatin), and antibiotics. The virus is inactivated with β-propiolactone and further processed by zonal centrifugation in a sucrose density gradient. The vaccine is lyophilized after addition of a stabilizer solution that consists of buffered polygeline and potassium glutamate. One dose of reconstituted vaccine contains ≤12 mg polygeline (processed bovine gelatin), ≤0.3 mg human serum albumin, 1 mg potassium glutamate, and 0.3 mg sodium EDTA. Small quantities of bovine serum are used in the cell culture process. Bovine components originate only from the United States, Australia, and New Zealand. Minimal amounts of chicken protein may be present in the final product; ovalbumin content is ≤3 ng/dose (1 mL), based on ELISA. Antibiotics (neomycin, chlortetracycline, amphotericin B) added during cell and virus propagation are largely removed during subsequent steps in the manufacturing process. In the final vaccine, neomycin is present at ≤10 mcg, chlortetracycline at ≤200 ng, and amphotericin B at ≤20 ng per dose. RabAvert is intended for intramuscular (IM) injection. The vaccine contains no preservative and should be used immediately after reconstitution with the supplied Sterile Diluent for RabAvert (Water for Injection). The potency of the final product is determined by the National Institutes of Health (NIH) mouse potency test using the United States (US) reference standard. The potency of 1 dose (1.0 mL) of RabAvert is at least 2.5 IU of rabies antigen. RabAvert is a white, freeze-dried vaccine for reconstitution with the diluent prior to use; the reconstituted vaccine is a clear to slightly opalescent, colorless to slightly pink suspension.

CLINICAL PHARMACOLOGY

Rabies in the United States: Over the last 100 years, the epidemiology of rabies in animals in the US has changed dramatically. More than 90% of all animal rabies cases reported annually to the Centers for Disease Control and Prevention (CDC) now occur in wildlife, whereas before 1960 the majority was in domestic animals. The principal rabies hosts today are wild terrestrial carnivores and bats. Annual human deaths have fallen from more than a hundred at the turn of the century to 1 to 2 per year despite major epizootics of animal rabies in several geographic areas. Within the US, only Hawaii has remained rabies free. Although rabies among humans is rare in the US, every year tens of thousands of people receive rabies vaccine for postexposure prophylaxis.

Rabies is a viral infection transmitted via the saliva of infected mammals. The virus enters the central nervous system of the host, causing an encephalomyelitis that is almost invariably fatal. The incubation period varies between 5 days and several years, but is usually between 20 and 60 days. Clinical rabies presents either in a furious or in a paralytic form. Clinical illness most often starts with prodromal complaints of malaise, anorexia, fatigue, headache, and fever followed by pain or paresthesia at the site of exposure. Anxiety, agitation, and irritability may be prominent during this period, followed by hyperactivity; disorientation; seizures; aerophobia and hydrophobia; hypersalivation; and eventually paralysis, coma, and death.

Modern day prophylaxis has proven nearly 100% successful; most human fatalities now occur in people who fail to seek medical treatment, usually because they do not recognize a risk in the animal contact leading to the infection. Inappropriate postexposure prophylaxis may also result in clinical rabies. Survival after clinical rabies is extremely rare, and is associated with severe brain damage and permanent disability.

RabAvert (in combination with passive immunization with Human Rabies Immune Globulin [HRIG] and local wound treatment) in postexposure treatment against rabies has been shown to protect patients of all age groups from rabies, when the vaccine was administered according to CDC’s Advisory Committee on Immunization Practices (ACIP) or World Health Organization (WHO) guidelines and as soon as possible after rabid animal contact. Anti-rabies antibody titers after immunization have been shown to reach levels well above the minimum antibody titer accepted as seroconversion (protective titer) within 14 days after initiating the postexposure treatment series. The minimum antibody titer accepted as seroconversion is a 1:5 titer (complete inhibition in the rapid fluorescent focus inhibition test [RFFIT] at 1:5 dilution) as specified by CDC1 or ≥0.5 IU/mL as specified by WHO.2,3

Clinical Studies:

Preexposure Vaccination: The immunogenicity of RabAvert was demonstrated in clinical trials conducted in different countries such as the US,4,5 the United Kingdom (UK),6 Croatia,7 and Thailand.8-10 When administered according to the recommended immunization schedule (Days 0, 7, and 21 or 0, 7, and 28), 100% of subjects attained a protective titer. In 2 studies carried out in the US in 101 subjects, antibody titers >0.5 IU/mL were obtained by Day 28 in all subjects. In studies carried out in Thailand in 22 subjects and in Croatia in 25 subjects, antibody titers of >0.5 IU/mL were obtained by Day 14 (injections on Days 0, 7, and 21) in all subjects.

The ability of RabAvert to boost previously immunized subjects was evaluated in 3 clinical trials. In the Thailand study, preexposure booster doses were administered to 10 individuals. Antibody titers of >0.5 IU/mL were present at baseline on Day 0 in all subjects.9 Titers after a booster dose were enhanced from geometric mean titers (GMTs) of 1.91 to 23.66 IU/mL on Day 30. In an additional booster study, individuals known to have been immunized with Human Diploid Cell Vaccine (HDCV) were boosted with RabAvert. In this study, a booster response was observed on Day 14 for all individuals (22/22).11 In a trial carried out in the US,4 an IM booster dose of RabAvert resulted in a significant increase in titers in all subjects (35/35), regardless of whether they had received RabAvert or HDCV as the primary vaccine.

Persistence of antibody after immunization with RabAvert was evaluated. In a trial performed in the UK, neutralizing antibody titers >0.5 IU/mL were present 2 years after immunization in all sera (6/6) tested.

Preexposure Vaccination in Children: Preexposure administration of RabAvert in 11 Thai children aged 2 years and older resulted in antibody levels higher than 0.5 IU/mL on Day 14 in all children.12

Postexposure Treatment: RabAvert, when used in the recommended postexposure WHO program of 5 to 6 IM injections of 1 mL (Days 0, 3, 7, 14, and 30 and optionally on Day 90) provided protective titers of neutralizing antibody (>0.5 IU/mL) in 158/160 patients8,9,13-16 within 14 days and in 215/216 patients by Days 28 to 38.

Of these, 203 were followed for at least 10 months. No case of rabies was observed.8,9,13-20 Some patients received HRIG, 20 to 30 IU/kg body weight, or Equine Rabies Immune Globulin (ERIG), 40 IU/kg body weight, at the time of the first dose. In most studies,8,9,13,17 the addition of either HRIG or ERIG caused a slight decrease in GMTs which was neither clinically relevant nor statistically significant. In one study,16 patients receiving HRIG had significantly lower (P <0.05) GMTs on Day 14; however, this was not clinically relevant. After Day 14 there was no statistical significance.

The results of several studies of normal volunteers receiving the postexposure WHO regimen, i.e., “simulated” postexposure, showed that with sampling by Days 28 to 30, 205/208 vaccinees had protective titers >0.5 IU/mL.

No postexposure vaccine failures have occurred in the US since cell culture vaccines have been routinely used.1 Failures have occurred abroad, almost always after deviation from the recommended postexposure treatment protocol.21-24 In 2 cases with bites to the face, treatment failed although no deviation from the recommended postexposure treatment protocol appeared to have occurred.25

Postexposure Treatment in Children: In a 10-year serosurveillance study, RabAvert was administered to 91 children aged 1 to 5 years and 436 children and adolescents aged 6 to 20 years.19 The vaccine was effective in both age groups. None of these patients developed rabies.

One newborn received RabAvert on an immunization schedule of Days 0, 3, 7, 14, and 30; the antibody concentration on Day 37 was 2.34 IU/mL. There were no clinically significant adverse events.26

INDICATIONS AND USAGE

RabAvert is indicated for preexposure vaccination, in both primary series and booster dose, and for postexposure prophylaxis against rabies in all age groups.

Usually an immunization series is initiated and completed with 1 vaccine product. No clinical studies have been conducted that document a change in efficacy or the frequency of adverse reactions when the series is completed with a second vaccine product. However, for booster immunization, RabAvert was shown to elicit protective antibody level responses in persons tested who received a primary series with HDCV.4,11

Preexposure Vaccination: See Table 1 and DOSAGE AND ADMINISTRATION.

Preexposure vaccination consists of 3 doses of RabAvert 1.0 mL given intramuscularly (deltoid region), 1 each on Days 0, 7, and 21 or 281 (see also Table 1 for criteria for preexposure vaccination).

Preexposure vaccination does not eliminate the need for additional therapy after a known rabies exposure (see DOSAGE AND ADMINISTRATION: Postexposure Prophylaxis of Previously Immunized Persons).

Preexposure vaccination should be offered to persons in high-risk groups, such as veterinarians, animal handlers, wildlife officers in areas where animal rabies is enzootic, certain laboratory workers, and persons spending time in foreign countries where rabies is endemic. Persons whose activities bring them into contact with potentially rabid dogs, cats, foxes, skunks, bats, or other species at risk of having rabies should also be considered for preexposure vaccination. International travelers might be candidates for preexposure vaccination if they are likely to come in contact with animals in areas where dog rabies is enzootic and immediate access to appropriate medical care, including biologics, might be limited.27,28

Preexposure vaccination is given for several reasons. First, it may provide protection to persons with inapparent exposure to rabies. Second, it may protect persons whose postexposure therapy might be expected to be delayed. Finally, although it does not eliminate the need for prompt therapy after a rabies exposure, it simplifies therapy by eliminating the need for globulin and decreasing the number of doses of vaccine needed. This is of particular importance for persons at high risk of being exposed in countries where the available rabies-immunizing products may carry a higher risk of adverse reactions.

In some instances, booster doses of vaccine should be administered to maintain a serum titer corresponding to at least complete neutralization at a 1:5 serum dilution by the RFFIT (Table 1); each booster immunization consists of a single dose. See CLINICAL PHARMACOLOGY. Serum antibody determinations to decide upon the need for a booster dose is suggested by ACIP and is considered cost effective.

Table 1. Rabies Preexposure Prophylaxis Guide – United States, 1999a
a Adapted from the Recommendations of the Advisory Committee on Immunization Practices: Human Rabies Prevention – United States, 1999.1
b Judgment of relative risk and extra monitoring of vaccination status of laboratory workers is the responsibility of the laboratory supervisor.29
c Minimum acceptable antibody level is complete virus neutralization at a 1:5 serum dilution by rapid fluorescent focus inhibition test. A booster dose should be administered if the titer falls below this level.

Risk Category and Nature of Risk

Typical Populations

Preexposure Prophylaxis Recommendations

Continuous. Virus present continuously, often in high concentrations. Specific exposures likely to go unrecognized. Bite, non-bite, or aerosol exposure.

Rabies research lab workers,b rabies biologics production workers.

Primary course. Serologic testing every 6 months; booster vaccination if antibody titer is below acceptable level.b

Frequent. Exposure usually episodic, with source recognized, but exposure might be unrecognized. Bite, non-bite, or aerosol exposure.

Rabies diagnostic lab workers,b spelunkers, veterinarians and staff, and animal-control and wildlife workers in rabies enzootic areas.

Primary course. Serologic testing every 2 years; booster vaccination if antibody titer is below acceptable level.c

Infrequent (greater than population-at-large). Exposure nearly always episodic with source recognized. Bite or non-bite exposure.

Veterinarians and animal-control and wildlife workers in areas with low rabies rates. Veterinary students. Travelers visiting areas where rabies is enzootic and immediate access to appropriate medical care including biologics is limited.

Primary course. No serologic testing or booster vaccination.c

Rare (population-at-large). Exposures always episodic with source recognized. Bite or non-bite exposure.

US population-at-large, including persons in rabies-epizootic areas.

No vaccination necessary.

Postexposure Treatment: See Table 2 and DOSAGE AND ADMINISTRATION.

The following recommendations are only a guide. In applying them, take into account the animal species involved, the circumstances of the bite or other exposure, the immunization status of the animal, and presence of rabies in the region (as outlined below). Local or state public health officials should be consulted if questions arise about the need for rabies prophylaxis.1

Table 2. Rabies Postexposure Prophylaxis Guide – United States, 1999a
a Adapted from the Recommendations of the Advisory Committee on Immunization Practices: Human Rabies Prevention – United States, 1999.1
b During the 10-day observation period, begin postexposure prophylaxis at the first sign of rabies in a dog, cat, or ferret that has bitten someone. If the animal exhibits clinical signs of rabies, it should be euthanized immediately and tested.
c The animal should be euthanized and tested as soon as possible. Holding for observation is not recommended. Discontinue vaccine if immunofluorescence test results of the animal are negative.

Animal Type

Evaluation and Disposition
of Animal

Postexposure Prophylaxis Recommendations

Dogs, cats, and ferrets

Healthy and available for 10 days’ observation

Rabid or suspected rabid

Unknown (e.g., escaped)

Should not begin prophylaxis unless animal develops clinical signs of rabiesb

Immediately vaccinate

Consult public health officials

Skunks, raccoons, bats, foxes, and most other carnivores

Regarded as rabid unless animal proven negative by laboratory testsc

Consider immediate vaccination

Livestock, small rodents, lagomorphs (rabbits and hares), large rodents (woodchucks and beavers), and other mammals

Consider individually

Consult public health officials. Bites of squirrels, hamsters, guinea pigs, gerbils, chipmunks, rats, mice, other small rodents, rabbits, and hares almost never require antirabies postexposure prophylaxis.

In the US, the following factors should be considered before antirabies treatment is initiated.

Species of Biting Animal: Wild terrestrial animals (especially skunks, raccoons, foxes, and coyotes) and bats are the animals most commonly infected with rabies and are the most important potential source of infection for both humans and domestic animals. Unless a wild animal is tested and shown not to be rabid, postexposure prophylaxis should be initiated upon bite or non-bite exposure to the animals (see definition in “Type of Exposure” below). If treatment has been initiated and subsequent testing in a qualified laboratory shows the exposing animal is not rabid, postexposure prophylaxis can be discontinued.1

The likelihood of rabies in a domestic animal varies from region to region; hence, the need for postexposure prophylaxis also varies.1

Small rodents (such as squirrels, hamsters, guinea pigs, gerbils, chipmunks, rats, and mice) and lagomorphs (including rabbits and hares) are almost never found to be infected with rabies and have not been known to transmit rabies to humans in the US. Bites from large rodents such as woodchucks (including groundhogs) and beavers should be considered as possible rabies exposures, especially in regions where rabies is enzootic in raccoons.30 In all cases involving rodents, the state or local health department should be consulted before a decision is made to initiate antirabies postexposure prophylaxis.1

Circumstances of Biting Incident: An UNPROVOKED attack is more likely than a provoked attack to indicate the animal is rabid. Bites inflicted on a person attempting to feed or handle an apparently healthy animal should generally be regarded as PROVOKED. A currently vaccinated dog, cat, or ferret is unlikely to become infected with rabies.1

Type of Exposure: Rabies is transmitted by introducing the virus into open cuts or wounds in skin or via mucous membranes. The likelihood of rabies infection varies with the nature and extent of exposure. Two categories of exposure should be considered:

Bite: Any penetration of the skin by teeth. Bites to highly innervated areas such as the face and hands carry the highest risk, but the site of the bite should not influence the decision to begin treatment. Recent epidemiologic data suggest that even the very limited injury inflicted by a bat bite (compared with lesions caused by terrestrial carnivores) should prompt consideration of postexposure prophylaxis unless the bat is available for testing and is negative for evidence of rabies.1

Non-bite: The contamination of open wounds, abrasions, mucous membranes, or theoretically, scratches with saliva or other potentially infectious material (such as neural tissue) from a rabid animal constitutes a non-bite exposure. In all instances of potential human exposures involving bats, and the bat is not available for testing, postexposure prophylaxis might be appropriate even if a bite, scratch, or mucous membrane exposure is not apparent when there is reasonable probability that such exposure might have occurred. Postexposure prophylaxis can be considered for persons who were in the same room as the bat and who might be unaware that a bite or direct contact had occurred (e.g., a sleeping person awakens to find a bat in the room or an adult witnesses a bat in the room with a previously unattended child, mentally disabled person, or intoxicated person) and rabies cannot be ruled out by testing the bat. Other contact by itself, such as petting a rabid animal and contact with blood, urine, or feces (e.g., guano) of a rabid animal, does not constitute an exposure and is not an indication for prophylaxis. Because the rabies virus is inactivated by desiccation and ultraviolet irradiation, in general, if the material containing the virus is dry, the virus can be considered noninfectious. Two cases of rabies have been attributed to probable aerosol exposures in laboratories, and 2 cases of rabies in Texas could possibly have been due to airborne exposures in caves containing millions of bats.1

The only documented cases for rabies from human-to-human transmission occurred in 8 patients, including 2 in the US, who received corneas transplanted from persons who died of rabies undiagnosed at the time of death.1 Stringent guidelines for acceptance of donor corneas have been implemented to reduce this risk.

Bite and non-bite exposure from humans with rabies theoretically could transmit rabies, but no laboratory-diagnosed cases occurring under such situations have been documented. Each potential exposure to human rabies should be carefully evaluated to minimize unnecessary rabies prophylaxis.1

Postexposure Treatment Schedule: See also DOSAGE AND ADMINISTRATION.

The essential components of rabies postexposure prophylaxis are prompt local treatment of wounds and administration of both HRIG and vaccine.

A complete course of postexposure treatment for previously unvaccinated adults and children consists of a total of 5 doses of vaccine, each 1.0 mL: one IM injection (deltoid) on each of Days 0, 3, 7, 14, and 28. For previously immunized adults and children, a total of 2 doses of vaccine, each 1.0 mL: one IM injection (deltoid) on each of Days 0 and 3. No HRIG should be administered to previously vaccinated persons as it may blunt their rapid memory response to rabies antigen.

Local Treatment of Wounds: Immediate and thorough washing of all bite wounds and scratches with soap and water is an important measure for preventing rabies. In animal studies, thorough local wound cleansing alone has been shown to reduce markedly the likelihood of rabies. Whenever possible, bite injuries should not be sutured to avoid further and/or deeper contamination. Tetanus prophylaxis and measures to control bacterial infection should be given as indicated.1

Postexposure Prophylaxis of Rabies: The regimen for postexposure prophylaxis depends on whether or not the patient has been previously immunized against rabies (see below). For persons who have not previously been immunized against rabies, the schedule consists of an initial IM injection of HRIG exactly 20 IU/kg body weight in total. If anatomically feasible, the FULL DOSE of HRIG should be thoroughly infiltrated in the area around and into the wounds. Any remaining volume of HRIG should be injected intramuscularly at a site distant from rabies vaccine administration. HRIG should never be administered in the same syringe or in the same anatomical site as the rabies vaccine. HRIG is administered only once (for specific instructions for HRIG use, see the product package insert). The HRIG injection is followed by a series of 5 individual injections of RabAvert (1.0 mL each) given intramuscularly on Days 0, 3, 7, 14, and 28. Postexposure rabies prophylaxis should begin the same day exposure occurred or as soon after exposure as possible. The combined use of HRIG and RabAvert is recommended by the CDC for both bite and non-bite exposures, regardless of the interval between exposure and initiation of treatment.

In the event that HRIG is not readily available for the initiation of treatment, it can be given through the seventh day after administration of the first dose of vaccine. HRIG is not indicated beyond the seventh day because an antibody response to RabAvert is presumed to have begun by that time.1

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