Introduction
Rabies is a fatal, yet preventable, viral disease spread through direct contact with saliva from rabid animals such as, bats, skunks, raccoons, and foxes.
Between 30,000 – 60,000 people receive rabies postexposure prophylaxis yearly in the United States. Twenty-five cases of human rabies have been reported from 2009 – 2018, with seven of those acquired outside of the U.S, with the majority of exposures from bats.
Exposure results in acute, progressive encephalomyelitis caused by viruses in the Rhabdoviridae family
Clinical presentation:
Incubation period of 1 to 3 months, but this period may vary depending on various factors
An initial prodromal phase with non-specific symptoms such as, malaise, anorexia, fatigue, headache, and fever with pain at site of exposure
A neurologic phase characterized by paralysis, anxiety, delirium, convulsions, death
Clinical Detail
Pharmacology and dosing of the two agents used in rabies post-exposure prophylaxis — purified chick embryo cell (PCEC) rabies vaccine (RabAvert®) and human rabies immune globulin (HRIG, HyperRAB®).
| Parameter | RabAvert® (PCEC vaccine) | HRIG (HyperRAB®) |
|---|---|---|
| Dose | Pre-exposure: Total of 3 doses on Days 0, 7, and 21 or 28 Post-exposure: Immunocompetent: 4 doses on Days 0, 3, 7, 14 Immunocompromised: 5 doses on Days 0, 3, 7, 14, 28 In patients who have previously received post-exposure prophylaxis with the rabies vaccine, recommended IM pre-exposure series, or previously documented antibodies, two doses of RabAvert® is appropriate on Days 0 and 3 | 20 units/kg (actual body weight) as a single dose on Day 0 |
| Administration | Intramuscular (IM) into the deltoid | Infiltrated at/around the site of the wound, with the remainder administered IM |
| Formulation | 2.5 units/mL, 1 mL syringe | 300 units/1 mL, 1500 units/5 mL |
| PK/PD | Onset: ~7 – 10 days Peak effect: ~30 – 60 days Duration: > 1 year | – |
| Adverse Effects | Hypersensitivity reactions | Headache, pain at injection site, myalgia |
| Drug Interactions | No known drug interactions | Live vaccines |
| Compatibility | Do not mix with IVIG in same syringe or same anatomical site | Do not mix with other agents |
| Comments | Prolonging the interval between doses does not interfere with immunity after the concluding dose of the basic series. Intradermal administration has been studied for use when vaccine and/or cost is an issue, particularly in rural areas | Recommended to round to the nearest vial size. Not recommended after 7 days following exposure |
Evidence
| Author, Year | Design / Sample Size | Intervention & Comparison | Outcome |
|---|---|---|---|
| Dreesen, 1989 | RCT N = 78 | Comparison of human diploid cell rabies vaccine (HDCV) (Imovax) vs purified chick embryo cell (PCEC) (RabAvert) rabies vaccine for pre-exposure vaccination | Both vaccines had comparable immunogenicity and reactogenicity after an initial three dose series and PCEC was produced at ½ cost |
| Rupprecht, 2010 | Systematic review | 4-dose IM series versus 5-dose IM series of the rabies vaccine plus rabies immune globulin | 4-dose series is equally effective to the 5-dose series in immunocompetent patients for prevention of rabies after exposure, when given in combination with HRIG |
| Ren, 2015 | Minireview including 7 studies | 4-dose IM administration via the 2-1-1 method on days 0, 7, and 21 “Zagreb regimen” versus a 5-dose IM administration on days 0, 3, 7, 14, and 28 “Essen method” | Compliance: (97.16% vs 87.99%, p < 0.01). Zagreb method could induce earlier 7-day seroconversion, but there is concern co-administration with HRIG may reduce this early conversion and further study is needed to confirm. Use of the Zagreb method reduced direct medical costs and resulted in increased compliance, compared with the Essen method. |
| Gogtay, 2018 | Phase 2/3 randomized, single blind, non-inferiority study N = 200 | Patients received either SII RMab or HRIG (1:1 ratio) in wounds and IM (if required) on days 0, 3, 7, 14, and 28. Primary endpoint: 14-day geometric mean concentration (GMC) of rabies neutralizing activity (RVNA) | Day 14 GMC ratio (96.9% vs 95%) for SII RMab vs HRIG. Majority of local injection site reactions were mild-moderate in both groups. SII RMab demonstrated non-inferiority to HRIG for post-exposure prophylaxis |
| Endy, 2019 | Randomized, open label, single center trial N = 54 | Assigned to 1 of 6 treatment/control groups to receive either intradermal (ID) or IM rabies vaccine for 2 vs 3 doses | Day 365, protective titer levels were reached: – 70% in 3-dose IM group – 60% in 3-dose ID group – 50% in 2-dose IM group – 40% in 2-dose ID group ID pre-exposure vaccination induced acceptable antibody titers at 1 year |
Conclusions
Rabies is a fatal but preventable viral disease, and timely post-exposure prophylaxis is essential. Prophylaxis combines the rabies vaccine (RabAvert®) with human rabies immune globulin (HRIG) in previously unvaccinated patients.
For immunocompetent patients, a 4-dose IM vaccine series (Days 0, 3, 7, 14) is recommended, with a 5th dose (Day 28) reserved for immunocompromised patients. HRIG is given once as 20 units/kg (actual body weight) on Day 0, infiltrated at/around the wound with any remainder administered IM, and is not recommended after 7 days following exposure.
Evidence supports the 4-dose schedule as equally effective to the older 5-dose series in immunocompetent patients when combined with HRIG, and emerging data on monoclonal antibody alternatives and abbreviated regimens continue to refine prophylaxis practice.
References
RabAvert. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed April 28, 2020
Rabies Immune Globulin (Human). Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed April 28, 2020
CDC Yellow Book 2020: Health Information for International Travel. New York: Oxford University Press; 2017.
Dreesen DW, Fishbein DB, Kemp DT, Brown J. Two-year comparative trial on the immunogenicity and adverse effects of purified chick embryo cell rabies vaccine for pre-exposure immunization. Vaccine. 1989;7(5):397-400.
Rupprecht CE, Briggs D, Brown CM, et al. Evidence for a 4-dose vaccine schedule for human rabies post-exposure prophylaxis in previously non-vaccinated individuals. Vaccine. 2009;27(51):7141-7148.
Ren J, Yao L, Sun J, Gong Z. Zagreb regimen, an abbreviated intramuscular schedule for rabies vaccination. Clin Vaccine Immunol. 2015;22(1):1-5.
Gogtay NJ, Munshi R, Ashwath Narayana DH, et al. Comparison of a Novel Human Rabies Monoclonal Antibody to Human Rabies Immunoglobulin for Postexposure Prophylaxis: A Phase 2/3, Randomized, Single-Blind, Noninferiority, Controlled Study. Clin Infect Dis. 2018;66(3):387-395.
Endy TP, Keiser PB, Wang D, et al. Serologic Response of 2 Versus 3 Doses and Intradermal Versus Intramuscular Administration of a Licensed Rabies Vaccine for Preexposure Prophylaxis. J Infect Dis. 2020;221(9):1494-1498.
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