RabAvert / Rabies Vaccine

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

Purified chick embryo cell (PCEC) vaccine (RabAvert®) | Human Rabies Immune globulin (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

Overview of Evidence | Overview of Evidence | Overview of Evidence | Overview of Evidence

Author, year | Design/ sample size | Intervention & Comparison | Outcome | Outcome

Dreesen, 19894 | 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 | Both vaccines had comparable immunogenicity and reactogenicity after an initial three dose series and PCEC was produced at ½ cost

Rupprecht, 20105 | 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 | 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, 20156 | 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. | 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, 20187 | 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 HRG for post-exposure prophylaxis | 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 HRG for post-exposure prophylaxis

Endy, 20198 | 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 | 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

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.

Pharmacology | Pharmacology | Pharmacology

Purified chick embryo cell (PCEC) vaccine (RabAvert®) | Human Rabies Immune globulin (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

Overview of Evidence | Overview of Evidence | Overview of Evidence | Overview of Evidence

Author, year | Design/ sample size | Intervention & Comparison | Outcome | Outcome

Dreesen, 19894 | 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 | Both vaccines had comparable immunogenicity and reactogenicity after an initial three dose series and PCEC was produced at ½ cost

Rupprecht, 20105 | 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 | 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, 20156 | 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. | 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, 20187 | 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 HRG for post-exposure prophylaxis | 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 HRG for post-exposure prophylaxis

Endy, 20198 | 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 | 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

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

Overview of Evidence | Overview of Evidence | Overview of Evidence | Overview of Evidence

Author, year | Design/ sample size | Intervention & Comparison | Outcome | Outcome

Dreesen, 19894 | 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 | Both vaccines had comparable immunogenicity and reactogenicity after an initial three dose series and PCEC was produced at ½ cost

Rupprecht, 20105 | 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 | 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, 20156 | 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. | 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, 20187 | 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 HRG for post-exposure prophylaxis | 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 HRG for post-exposure prophylaxis

Endy, 20198 | 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 | 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

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.

Pharmacology | Pharmacology | Pharmacology

Purified chick embryo cell (PCEC) vaccine (RabAvert®) | Human Rabies Immune globulin (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

Overview of Evidence | Overview of Evidence | Overview of Evidence | Overview of Evidence

Author, year | Design/ sample size | Intervention & Comparison | Outcome | Outcome

Dreesen, 19894 | 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 | Both vaccines had comparable immunogenicity and reactogenicity after an initial three dose series and PCEC was produced at ½ cost

Rupprecht, 20105 | 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 | 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, 20156 | 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. | 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, 20187 | 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 HRG for post-exposure prophylaxis | 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 HRG for post-exposure prophylaxis

Endy, 20198 | 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 | 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