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

CategoryPurified chick embryo cell (PCEC) vaccine (RabAvert®)Human Rabies Immune globulin (HRIG), HyperRAB®
DosePre-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
AdministrationIntramuscular (IM) into the deltoidInfiltrated at/around the site of the wound, with the remainder administered IM
Formulation2.5 units/mL, 1 mL syringe300 units/1 mL, 1500 units/5 mL
PK/PDOnset: ~7 - 10 days
Peak effect: ~30 - 60 days
Duration: > 1 year		-
Adverse EffectsHypersensitivity reactionsHeadache, pain at injection site, myalgia
Drug InteractionsNo known drug interactionsLive vaccines
CompatibilityDo not mix with IVIG in same syringe or same anatomical siteDo not mix with other agents
CommentsProlonging 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, yearDesign/sample sizeIntervention & ComparisonOutcome
Dreesen, 19894RCT
N = 78		Comparison of human diploid cell rabies vaccine (HDCV) (Imovax) vs purified chick embryo cell (PCEC) (RabAvert) rabies vaccine for pre-exposure vaccinationBoth vaccines had comparable immunogenicity and reactogenicity after an initial three dose series and PCEC was produced at ½ cost
Rupprecht, 20105Systematic review4 dose IM series versus 5-dose IM series of the rabies vaccine plus rabies immune globulin4 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, 20156Minireview including 7 studies4 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, 20187Phase 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, 20198Randomized, 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 dosesDay 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

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.
    • Tags: rabies RabAvert postexposure prophylaxis vaccine

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