Vaccine Information: RabAvert

RABAVERT- rabies vaccine
Novartis Vaccines and Diagnostics GmbH

Rabies Vaccine for Human Use

Description

RabAvert, Rabies Vaccine, produced by Novartis Vaccines and Diagnostics GmbH is a sterile freeze-dried vaccine obtained by growing the fixed-virus strain Flury 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 which consists of buffered polygeline and potassium glutamate. One dose of reconstituted vaccine contains less than 12 mg polygeline (processed bovine gelatin), less than 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 less than 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 < 1 μg, chlortetracycline at < 20 ng, and amphotericin B at < 2 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 NIH mouse potency test using the US reference standard. The potency of one dose (1.0 mL) 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 opaque, colorless suspension.

Clinical Pharmacology

Rabies in the United States

Over the last 100 years, the epidemiology of rabies in animals in the United States 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 were 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 one to two per year despite major epizootics of animal rabies in several geographic areas. Within the United States, only Hawaii has remained rabies free. Although rabies among humans is rare in the United States, 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, irritability may be prominent during this period, followed by hyperactivity, disorientation, seizures, aero- 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 the 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 the CDC (1), or ≥ 0.5 IU per milliliter (mL) as specified by the WHO (2,3).

Clinical Studies

Preexposure Vaccination

The immunogenicity of RabAvert has been demonstrated in clinical trials conducted in different countries such as the USA (4,5), UK (6), Croatia (7), and Thailand (8-10). When administered according to the recommended immunization schedule (days 0, 7, 21 or 0, 7, 28), 100% of subjects attained a protective titer. In two studies carried out in the USA 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, 21) in all subjects.

The ability of RabAvert to boost previously immunized subjects was evaluated in three 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 (GMT) of 1.91 IU/mL 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 (22/22) individuals (11). In a trial carried out in the USA (4), a RabAvert IM booster dose resulted in a significant increase in titers in all (35/35) subjects, regardless of whether they had received RabAvert or HDCV as the primary vaccine.

Persistence of antibody after immunization with RabAvert has been 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 from the age of 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, 30, and one optionally on day 90) provided protective titers of neutralizing antibody (> 0.5 IU/mL) in 158/160 patients (8, 9, 13-16) within 14 days and in 215/216 patients by day 28 — 38.

Of these, 203 were followed for at least 10 months. No case of rabies was observed (8, 9, 13-20). Some patients received Human Rabies Immune Globulin (HRIG), 20 — 30 IU per kg body weight, or Equine Rabies Immune Globulin (ERIG), 40 IU per 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, again 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, show that with sampling by day 28 — 30, 205/208 vaccinees had protective titers > 0.5 IU/mL.

No postexposure vaccine failures have occurred in the United States 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 two 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 has been 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 has 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 one 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).

A. Preexposure Vaccination — See Table 1

(see also Dosage and Administration section below)

Preexposure vaccination consists of three doses of RabAvert 1.0 mL, intramuscularly (deltoid region), one each on days 0, 7, and 21 or 28 (1) (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 also Dosage and Administration section, subsection C).

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 (see 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 the ACIP and is considered cost-effective.

Table 1: Rabies Preexposure prophylaxis guide – United States, 1999

Adapted from the Recommendations of the Advisory Committee on Immunization Practices: Human Rabies Prevention – United States, 1999. (1)

* Judgment of relative risk and extra monitoring of vaccination status of laboratory workers is the responsibility of the laboratory supervisor (29).

** Minimum acceptable antibody level is complete virus neutralization at a 1:5 serum dilution by RFFIT. A booster dose should be administered if the titer falls below this level.

Risk Category and Nature of Risk Typical Populations Preexposure Recommendations
Continuous. Virus present continuously, often in high concentrations. Specific exposures likely to go unrecognized. Bite, nonbite or aerosol exposure. Rabies research lab workers,* rabies biologics production workers. Primary course. Serologic testing every 6 months; booster vaccination if antibody titer is below acceptable level.*
Frequent. Exposure usually episodic, with source recognized, but exposure might be unrecognized. Bite, nonbite or aerosol exposure. Rabies diagnostic lab workers,* 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.**
Infrequent (greater than population-at-large). Exposure nearly always episodic with source recognized. Bite or nonbite exposure. Veterinarians and animal- control and wildlife workers in areas with low rabies rates. Veterinary students. Travelers visiting areas where rabies in enzootic and immediate access to appropriate medical care including biologics is limited. Primary course. No serologic testing or booster vaccination.**
Rare (population-at-large). Exposures always episodic. with source recognized. Bite or nonbite exposure. US population-at-large, including persons in rabies-epizootic areas. No vaccination necessary.

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