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Rabies immune globulin and vaccine

Rabies immune globulin and vaccine
Authors:
Catherine M Brown, DVM, MSc, MPH
Alfred DeMaria, Jr, MD
Section Editors:
Martin S Hirsch, MD
Sheldon L Kaplan, MD
Deputy Editor:
Keri K Hall, MD, MS
Literature review current through: Dec 2022. | This topic last updated: Nov 22, 2022.

INTRODUCTION — More than 3.3 billion people worldwide live in areas where rabies is enzootic. Human mortality from rabies is estimated at 59,000 deaths per year. Most cases occur in Africa and Asia and result primarily from canine reservoirs of rabies virus [1]. In the United States, an average of three fatal human rabies cases have occurred annually since 2000, and almost 25 percent of those were imported cases due to exposures occurring abroad; among the 75 percent acquired within the United States, most have been associated with exposure to bats [2,3].

Rabies is virtually always fatal, but infection can be prevented with proper wound care and prompt post-exposure prophylaxis. Pre-exposure prophylaxis may also prevent rabies but is not a replacement for wound care and post-exposure prophylaxis. In the United States, approximately 16,000 to 39,000 patients with contact to potentially rabid animals receive rabies post-exposure prophylaxis annually [4,5].

The safety, efficacy, and administration of rabies immune globulin and rabies vaccine will be reviewed here. Clinical decision-making regarding the necessity for rabies post-exposure prophylaxis can be complex and is discussed in detail elsewhere. (See "Indications for post-exposure and pre-exposure rabies prophylaxis".)

RABIES BIOLOGICS — Rabies vaccine and rabies immune globulin (RIG) are administered to prevent rabies. Several formulations are available and are described in this section. Additional information on choice of regimen and dosing schedules are discussed in detail below. (See 'Pre-exposure prophylaxis' below and 'Post-exposure prophylaxis' below.)

Rabies vaccines — Rabies vaccine is administered for pre- or post-exposure prophylaxis. The dosing schedule is determined by the intended use and whether the United States Centers for Disease Control and Prevention (CDC) [4,6] or the World Health Organization (WHO) [7] guidelines, or other local guidelines, represent the standard of care in the jurisdiction.

Rabies vaccines should be administered intramuscularly (IM) in doses of 1 mL according to the recommended schedules for pre- or post-exposure prophylaxis (table 1 and table 2). The suggested anatomic sites for vaccine administration depend on the age of the patient [4,8]:

In adults (ie, age ≥19 years), the deltoid muscle of the arm is the only acceptable IM site of vaccine administration.

In children 3 to 18 years old, the deltoid muscle of the arm is preferred, although the anterolateral aspect of the thigh is an acceptable alternative.

In children ≤2 years old, the anterolateral aspect of the thigh is preferred; however, in children aged 12 months to 2 years, the deltoid muscle of the arm is an acceptable alternative if the deltoid muscle mass is adequate.

Vaccine should never be administered in the gluteal area because this may result in lower antibody titers [9].

Two licensed, inactivated virus vaccines are currently available in the United States:

Human diploid cell vaccine (HDCV; Imovax Rabies)

Purified chick embryo cell vaccine (PCECV; RabAvert)

Rabies vaccines available outside the United States include the following: PCECV (Rabipur), HDCV (Rabivac), purified Vero cell rabies vaccine (PVRV; Verorab; Imovax-Rabies Vero, Rabivax-S, TRC Verorab) and purified duck embryo vaccine (Lyssavac N). In resource-limited countries, PVRV and PCECV are most commonly used because they are less expensive and are as safe and effective as HDCV [10]. However, their cost is still too high for many resource-limited countries given the frequency of post-exposure prophylaxis that is needed.

To reduce costs, WHO guidelines include recommendations for a reduced-dose intradermal regimen [11,12]. Intradermal administration is not an approved route of administration for patients receiving a rabies vaccine in the United States. More detailed discussions of intradermal regimens are found elsewhere. (See 'Pre-exposure prophylaxis' below and 'Resource-limited settings' below.)

Some countries have produced vaccine in sheep, goat, or suckling mouse nervous tissue to reduce costs, but these vaccines have unreliable potency and a high incidence of neurologic complications [13]. There is an international effort to eliminate such products [14].

Experimental vaccines are under investigation, such as a rabies messenger RNA vaccine. In a phase I trial that included 101 healthy adults, this vaccine was generally found to be safe and immunogenic when administered with a needle-free device [15]. Recombinant virus-vectored rabies vaccines are available in veterinary medicine but not for human use. Although these novel vaccines may offer a pathway to more robust and durable immune responses and possibly single-dose post-exposure prophylaxis, it will be challenging to conduct studies evaluating their efficacy compared with currently available vaccines that have proven to be highly effective in preventing fatal disease.

Rabies immune globulin — Rabies immune globulin (RIG) is administered as part of a post-exposure prophylaxis regimen. RIG is derived from pooled plasma samples of hyperimmunized human donors (human RIG; HRIG) or from horses (equine RIG; ERIG). Both preparations are considered equally potent and effective; however, only HRIG is recommended for use in the United States [4]. Although these products are derived from human donors or horses, they are treated in ways that eliminate other infectious agents, and no transmission of any infections has been documented from either product.

The recommended dose of HRIG is 20 international units/kg in all age groups (higher doses should be avoided as they may partially suppress antibody response to the vaccine) [16]. Outside the United States, if ERIG is used (including F(ab')2 products), the dose is 40 international units/kg body weight.

As much of the RIG dose as is anatomically feasible should be infiltrated in the area around and in the wound at the same depth as the wound. Any remaining dose should be given intramuscularly and at a different intramuscular site than the vaccine (such as the opposite deltoid).

If there is no obvious wound (eg, suspected bat exposure), the entire volume of RIG should be administered intramuscularly, preferably into the anterolateral thigh or the deltoid muscle contralateral to the vaccine dose. In children with small muscle mass, it may be necessary to administer RIG into more than one anatomic site [17]. Injection into the gluteus muscle should be avoided as it carries the risk for sciatic nerve damage.

Three preparations of HRIG are approved and available for use in the United States (table 3):

HyperRAB 300 international units/mL (1 mL, 5 mL); caprylate/chromatography purified.

Imogam Rabies – HT 150 international units/mL (2 mL, 10 mL); heat treated.

KEDRAB 150 international units/mL (2 mL, 10 mL); solvent/detergent treated [18].

The 150 international units/mL formulations should not require dilution; volumes at the recommended dose are often substantial. The Grifols HyperRab 300 international units/mL product should be diluted with 5 percent dextrose in water (D5W) rather than saline, if necessary, to provide adequate volume for wound infiltration with careful attention to assure the recommended dose is administered.

HRIG is also available outside the United States under a variety of trade names including: BayRab, Berirab P, Imogam, and Imogam Rabies. However, imported HRIG is expensive, and generic products (made in some blood banks outside of the United States) are in scarce supply.

ERIG (ie, equine RIG) is a less expensive but safe and effective alternative for RIG in some resource-limited settings [10,14,19]. Certain ERIG products are available in a more purified form consisting of immunoglobulin cleavage fragments that are more rapidly cleared after administration [7]. Despite the potential advantages of ERIG, during the past two decades several major manufacturers have discontinued ERIG production because of costs, pressures from animal rights activists, and increased requirements of national regulatory authorities [19].

Due to global shortages of HRIG and ERIG and the expense of production, alternative means of prophylaxis are being sought. Human monoclonal antibodies (CR57 and CR4098) have demonstrated in vitro neutralization against rabies virus and have provided a level of protection similar to HRIG against lethal rabies virus in animal models [20]. In the first clinical study among healthy adults in the United States and India, CR57 and CR4098 were safe and well tolerated [21]. All subjects had adequate neutralizing activity against rabies virus from day 14 onward when administered in combination with rabies vaccine.

Another neutralizing monoclonal antibody (SII RMAb) has also shown promise and appears safe and noninferior to HRIG in rabies virus neutralizing antibody activity as measured by the rapid fluorescent focus inhibition test [22,23]. In 2016, the first rabies monoclonal antibody product using SII RMAb was licensed for use in India as the passive antibody component of post-exposure prophylaxis.

PRE-EXPOSURE PROPHYLAXIS — Pre-exposure prophylaxis is the use of rabies vaccine to induce at least partial immunity in individuals who are at elevated risk of acquiring rabies.

Benefits and barriers

Although pre-exposure prophylaxis does not eliminate the need for prophylaxis after a rabies exposure, it often decreases the recommended number of injections following an exposure and sometimes eliminates the need for rabies immunoglobulin (RIG) altogether [6,11]. This can be especially important in resource-limited settings where vaccine and RIG may be unavailable and significant delays in administration can occur. Pre-exposure prophylaxis may also help to prevent rabies infection in individuals who are at frequent risk for unrecognized exposure to rabies and thus would not seek post-exposure prophylaxis.

Significant barriers to initiation or completion of pre-exposure prophylaxis in at-risk individuals have limited its use. Identified barriers include high out-of-pocket costs, uncertainty about who qualifies for prophylaxis, noncompliance with follow-up vaccines and titers, and inability of high-risk travelers to complete the full course prior to departure [6].

In 2022, the United States Centers for Disease Control and Prevention (CDC) issued new recommendations for pre-exposure prophylaxis intended to address barriers while still maintaining maximal effectiveness of the regimens [6].

Indications — The 2022 CDC recommendations modified the indications for pre-exposure prophylaxis by creating five categories of risk based on an individual’s risk of being exposed and likelihood of noticing the exposure [6]. Although uncommon in the United States, unrecognized exposures (ie, not noticed by the exposed person) potentially represent the highest risk exposures because post-exposure prophylaxis is never provided; for example, a person performing a necropsy on a rabid animal or a field study of bats could receive a small scratch to the skin without noticing the injury and subsequently develop rabies.

The CDC's five risk categories for adults and children are as follows, and details are provided in the table (table 4):

Level 1 – Elevated risk for unrecognized or recognized high-risk exposures (eg, persons who work with live rabies virus in a laboratory or vaccine production facility)

Level 2 – Elevated risk for unrecognized exposures but could be recognized (eg, persons who perform animal necroscopies or have frequent contact with or high-density exposures to bats, including spelunkers who enter high-density bat caves)

Level 3 – Elevated risk for exposures that are nearly always recognized extending three years beyond the primary vaccine series (eg, veterinarians or other individuals whose occupation or recreational activities regularly involve contact with potentially rabid animals, including spelunkers who do not enter high-density bat caves; frequent or long-term travelers whose activities increase risk of exposure to animals in areas where rabies [especially canine] is enzootic and post-exposure prophylaxis is not readily available)

Level 4 – Elevated risk for recognized exposures within three years of receiving the primary vaccine series (eg, same as level 3 but lasting less than three years)

Level 5 – Low risk of exposure (eg, typical person living in the United States)

Travelers to rabies enzootic regions of the world (including most of Asia, Africa, the Middle East, Mexico, and Latin America) usually fall into levels 3 or 4, depending on whether travel plans extend three or more years beyond the primary vaccine series (table 4). If pre-exposure prophylaxis is administered to travelers, every effort should be made to complete the series prior to travel. Details regarding pre-travel counseling for travelers are found elsewhere. (See "Indications for post-exposure and pre-exposure rabies prophylaxis", section on 'Pre-travel counseling'.)

Children are at greater risk for bites from canines than adults. If a child is going to be in a canine-rabies enzootic area for an extended period or where access to post-exposure prophylaxis is limited, the child may benefit from pre-exposure prophylaxis even if planned activities do not specifically increase the risk of exposure [24-26]. Local or state public health authorities may be consulted to inform the decision-making process if families or providers are unsure whether to give prophylaxis (elsewhere, local experts or public health authorities can be consulted). Further information regarding rabies and child travelers is available elsewhere. (See "Indications for post-exposure and pre-exposure rabies prophylaxis", section on 'Travelers'.)

In rare situations, a rabies exposure occurs before the pre-exposure prophylaxis primary series is completed. Management of these situation is discussed below. (See 'Regimens for previously vaccinated individuals' below.)

Vaccine schedule — In general, the CDC 2022 guidelines recommend a primary vaccine series for individuals whose risk category falls into levels 1 through 4, and follow-up boosters and/or titers are recommended for individuals in levels 1 through 3. Vaccine schedule details are outlined in the table (table 4). Exceptions due to special circumstances are discussed elsewhere. (See 'Special considerations' below.)

Regimens for primary vaccine series — Suggested regimens for pre-exposure prophylaxis vary depending on the jurisdiction where the vaccines will be provided. Health care providers in the United States should follow recommendations from the United States Centers for Disease Control and Prevention (CDC) [6]. Outside of the United States, others may follow the World Health Organization (WHO) [11] or local guidelines.

United States Centers for Disease Control and Prevention recommendations – The primary series for pre-exposure prophylaxis recommended in the United States is two doses of rabies vaccine administered intramuscularly (IM): the first dose is on day 0 and the second dose is on day 7 [6]. In select cases, follow-up titers and/or boosters are recommended. The dosing schedule and administration is described in the tables and elsewhere (table 1 and table 4). (See 'Rabies vaccines' above and 'Serologic testing and boosters' below.)

The two-dose recommendation was officially endorsed by the CDC in 2022 based on recommendations from the Advisory Committee on Immunization Practices (ACIP) Rabies Work Group. Prior to 2022, CDC recommended a three-dose series for pre-exposure prophylaxis.

A systematic review demonstrated that two-dose and three-dose vaccine series result in comparable levels of neutralizing antibodies within 14 to 28 days of completion of the series [6]. After either series, anamnestic responses (rises in titers from undetectable to adequate levels after a vaccine dose) last for at least three years, and observational data suggest that the anamnestic response may persist for at least 10 to 24 years [6,27]. These findings do not vary between the two types of cell-culture vaccine preparations used in the United States [28,29].

World Health Organization recommendations – The WHO also supports the use of a pre-exposure prophylaxis series administered on days 0 and 7 [11,12]. Per WHO recommendations, one IM dose can be administered on each day (refer to the vaccine label for specific dosing recommendations) or two intradermal doses can be administered on each day (ie, two 0.1 mL doses intradermally in separate anatomic sites on day 0 and day 7).

Intradermal two-dose regimens for pre-exposure prophylaxis have been shown to be immunogenic [30,31]. As an example, in a study of 500 healthy volunteers, a regimen of two doses administered intradermally twice over the course of one week (on days 0 and 7) appeared to be as immunogenic as three individual doses administered intradermally over the course of one month (on days 0, 7, and 28) [30].

Serologic testing and boosters — Antibody responses after the primary series are predictable and relatively long-lived in the vast majority of patients [29,32].

However, in certain circumstances, the CDC recommends postvaccination serologic testing to determine whether a booster should be given [6]. A booster is administered if the titer is <0.5 international units/mL [6,11]. For patients with a moderate level of risk (level 3 risk), a one-time booster can replace a serologic test. Details regarding serologic testing and boosters after pre-exposure prophylaxis are provided in the tables (table 1 and table 4).

Those for whom serologic testing is recommended include the following:

Ongoing risk of exposure – Individuals who have ongoing risk of exposure are recommended to have periodic serologic testing after completion of the primary vaccine series. The timing and intervals for serologic testing are based on the risk level and are outlined in the tables (table 1 and table 4). If the titer is low (<0.5 international units/mL), a booster is typically recommended. Following a booster, confirmatory serologic testing is not recommended.

Immunocompromised patients – If pre-exposure prophylaxis is provided to an immunocompromised individual, follow-up titers should be performed no sooner than one week (preferably two to four weeks) after completing the primary vaccine series and after any boosters (table 4). If a follow-up titer is low (<0.5 international units/mL), a booster with another follow-up titer should be performed. If titers remain inadequate after two sequential boosters, consultation with local or state public health authorities is suggested (elsewhere, local experts or public health authorities can be consulted).

Participation in high-risk activities should be avoided by immunocompromised individuals until serologic tests confirm sufficient antibody response. Further suggestions regarding management of immunocompromised individuals are discussed below. (See 'Immunocompromised patients' below.)

Concomitant chloroquine administration Data suggest that patients on chloroquine have reduced antibody responses to rabies vaccine, although the antibody levels are still within the acceptable range. Nonetheless, the CDC suggests checking titers no sooner than one week (preferably two to four weeks) after completion of a rabies vaccine series to confirm that vaccination was effective. Further details regarding the interaction between rabies vaccination and other antimalarial drugs are discussed elsewhere. (See 'Patients taking antimalarial agents' below.)

Deviation from vaccine schedule – In some cases, deviation from the pre-exposure vaccination schedule warrants serologic testing. For example, testing may be necessary when vaccine doses or titers are mistimed (before or after recommended schedule), mismatched or alternative vaccine formulations are used, or an individual’s risk category changes. Detailed management of these situations is discussed elsewhere. (See 'Deviation from the vaccine schedule' below.)

Serologic testing should be performed using the rapid fluorescent focus inhibition test (RFFIT) and a titer ≥0.5 international units/mL is felt to represent adequate response to vaccination [6,11]. In 2022, the CDC endorsed this cut-off, which matches the WHO cut-off. The CDC’s new cut-off is a more cautious value than the previous one, although no infections occurred among vaccinated individuals using the prior lower cut-off.

Commercially available enzyme-linked immunosorbent assay (ELISA) tests for rabies antibody are not specific to neutralizing antibodies and should not be used for testing for immunity.

Special considerations — Certain situations may lead to alterations in pre-exposure prophylaxis protocols.

Vaccine shortages — Shortages of rabies vaccine due to supply issues among licensed manufacturers have occurred and most likely will recur. In these cases, vaccine for pre-exposure prophylaxis may be restricted or rationed to maintain supplies for post-exposure prophylaxis. In the United States, if pre-exposure vaccination cannot be safely delayed and vaccine is not readily available, the local or state public health authorities should be consulted (elsewhere, local experts or public health authorities may be consulted). The CDC maintains updated information on vaccine availability on their rabies website.

Immunocompromised patients — Immunocompromised patients, including those on disease-modifying agents for autoimmune diseases, should ideally avoid activities that put them at risk for exposure to rabies. If avoiding exposure is not possible, immunocompromising conditions should be remedied (if possible) prior to vaccination to optimize response to the vaccines. Postvaccination serologic testing is recommended for immunocompromised individuals and is discussed in detail elsewhere. (See 'Serologic testing and boosters' above.)

Patients taking antimalarial agents — Randomized trials suggest that coadministration of chloroquine with rabies vaccine reduces postvaccination antibody titers [33,34]. However, in the trials, all participants (including those on chloroquine) developed adequate antibody levels according to past and present CDC criteria, suggesting that the effect of chloroquine is not strong enough to meaningfully limit immunity.

Studies suggest that decreased antibody titers do not occur with atovaquone-proguanil or doxycycline, both of which are common antimalarial agents [34]. Anecdotal reports suggest that mefloquine (another antimalarial agent) does not impair rabies vaccine response, although large-scale trials are necessary for confirmation [6].

The clinical significance of these findings is unclear. However, as a precaution, the CDC suggests that clinicians consider avoiding chloroquine when using rabies vaccine. If avoidance is not possible, they recommend checking postvaccination titers, as described elsewhere. (See 'Serologic testing and boosters' above.)

Deviation from the vaccine schedule — Strict adherence to the vaccine schedule is recommended. In some situations, deviations from the schedule may occur and adjustments may be necessary to achieve realignment.

Delayed or early vaccine doses — Vaccine doses should be given on schedule whenever possible.

For the primary vaccination series, delays of the second dose by three to four days are clinically inconsequential and do not require reinitiation of the vaccine series. However, the effect of lapses beyond a few days during the primary series is unknown. In the United States, if the second dose of the primary series is delayed greater than 4 days or is inadvertently administered early, local or state public health authorities should be consulted for guidance (elsewhere, local experts or public health authorities should be consulted).

If a booster is late, pre-booster titers are recommended, as discussed elsewhere. (See 'Delayed or early titers' below.)

Delayed or early titers — Recommended titer tests should be on schedule whenever possible. In the United States, questions about significant deviations should trigger consultation with the local or state public health authorities if uncertainty regarding management exists (elsewhere, local experts or public health authorities should be consulted).

Titers drawn too early – Interpreting titers that were drawn too early depends on the titer results.

Interpreting low results (<0.5 international units/mL) – The interpretation of low results in patients whose titer was drawn too early depends on whether the titer was drawn during the "window period" (ie, the time it takes for the body to mount an adequate antibody response after vaccination, which is generally one to two weeks).

Patients whose early titers show inadequate results and were not drawn during the window period should receive a booster and then be realigned with their risk-based vaccination schedule from the date of their booster (table 4).

Patients whose follow-up titer was drawn during the "window period" should be realigned with their initial schedule by having a titer repeated at least one week (preferably two to four weeks) from the date of their latest vaccination. This situation generally only occurs in immunocompromised patients or patients on chloroquine because these are the only patients for whom follow-up titers are recommended shortly after receipt of a primary vaccination series.

Interpreting high results – Patients whose early titers reveal an adequate antibody level should be realigned with their risk-based vaccination schedule from the date of the titer (table 4).

Titers drawn too late When titers are drawn too late, results are valid (whether they are high or low), and the patient should be realigned with their risk-based vaccination schedule from the date of the titer (ie, a booster should be given for low results) (table 4).

Patients whose level of risk changes — When an individual’s risk of exposure changes due to a change in activities, the pre-exposure recommendations for the new risk category should be followed. Patients whose boosters or follow-up titers are overdue according to the new schedule should be realigned either by having titers drawn or by receiving a booster depending on their new risk-level. (See 'Delayed or early vaccine doses' above and 'Delayed or early titers' above.)

Use of mismatched or alternative vaccine formulations — The two rabies vaccine formulations available in the United States are interchangeable and can be used in the same individual to adhere to the vaccine schedule. Many, but not all, vaccines available outside the United States are essentially equivalent in immunogenicity to those available in the United States and can be used interchangeably as well. If there is any question about the type of vaccine that was received, patients can typically have postvaccination titers drawn no sooner than one week after the last dose to confirm adequate response. Consultation with local or state public health authorities is recommended in the United States (elsewhere, local experts or public health authorities should be consulted) if uncertainty regarding management exists [4,35].

POST-EXPOSURE PROPHYLAXIS — Post-exposure prophylaxis includes proper wound care and administration of rabies biologics. A detailed discussion of who should receive post-exposure prophylaxis is found elsewhere. (See "Indications for post-exposure and pre-exposure rabies prophylaxis", section on 'Post-exposure prophylaxis'.)

Our approach to post-exposure prophylaxis is based upon guidelines from the United States Centers for Disease Control and Prevention (CDC) [4]. The full set of guidelines can be accessed at www.cdc.gov/mmwr/pdf/rr/rr57e507.pdf (with updated vaccine schedule recommendations from 2010 at www.cdc.gov/mmwr/pdf/rr/rr5902.pdf). These post-exposure guidelines are being reviewed and updated by an Advisory Committee on Immunization Practices (ACIP) workgroup [36].

Special considerations for post-exposure prophylaxis in resource-limited settings are discussed below. (See 'Resource-limited settings' below.)

Wound care — The most important initial step to prevent rabies is wound care. Thorough washing of bite wounds, scratches, and nonbite exposures with soap and water is important. When available, a virucidal agent such as povidone-iodine should also be used. Tetanus prophylaxis, as well as antibiotics, should also be considered, depending on the type of wound. (See "Tetanus-diphtheria toxoid vaccination in adults" and "Animal bites (dogs, cats, and other animals): Evaluation and management".)

In animal studies of rabies, wound cleansing alone reduced the likelihood of rabies by up to 90 percent [37]. However, a survey of international travel medicine providers suggested that many of those presenting with wounds from an animal exposure did not perform adequate wound cleaning [38].

Post-exposure immunization — Post-exposure prophylaxis includes rabies vaccine (active immunization) with or without rabies immune globulin (passive immunization). The use of these agents elicits neutralizing antibodies after rabies exposure and prevents infection.

Rabies vaccine induces the production of protective virus-neutralizing antibodies within approximately 7 to 10 days; measurable antibody generally persists for several years, although individual variability exists [29,32,39].

The administration of rabies immune globulin (RIG) provides immediate virus-neutralizing antibodies until protective antibodies are generated in response to vaccine. Human RIG (HRIG) has a half-life of approximately three weeks [16]. Virus neutralization is most effective when HRIG is infiltrated into and around the wound; circulating neutralizing antibody levels remain low when it is administered intramuscularly at a site distant from the wound [40]. (See 'Rabies immune globulin' above.)

The regimen for post-exposure prophylaxis depends primarily upon the patient's previous immunization history. Immunization schedules, doses, and routes of administration are summarized in the table (table 2) and discussed in greater detail below. (See 'Regimens for unvaccinated individuals' below and 'Regimens for previously vaccinated individuals' below.)

Occasional case reports of rabies in individuals who have received partial rabies post-exposure prophylaxis exist in the literature. (See 'Risk of prophylaxis failure' below.)

Timing of immunization — Once it has been determined that a patient should receive rabies post-exposure prophylaxis, prophylaxis should begin as soon as possible after the exposure [41]. The decision to initiate prophylaxis requires a thorough risk assessment, which depends upon the type of exposure, the local rabies epidemiology, the circumstances of the exposure incident, and the availability of the animal for observation or rabies testing (algorithm 1) [4]. This is discussed in detail elsewhere. (See "Indications for post-exposure and pre-exposure rabies prophylaxis", section on 'When to administer prophylaxis'.)

Post-exposure prophylaxis should be administered following a rabies exposure, even if there is a delay; post-exposure prophylaxis is only too late when signs of clinical rabies develop. The average incubation period is 45 days but is highly variable; latency periods between exposure and onset of disease as long as one to eight years have been reported [42,43]. No post-exposure prophylaxis failures have been reported in the United States despite an average delay to initiation of approximately five days. Nonetheless, every effort should be made to administer post-exposure prophylaxis as soon as possible following a rabies exposure, unless the animal is available for observation or testing.

State and local public health officials are available to assist with risk assessments in the United States, and contacts can be found on the Centers for Disease Control and Prevention website.

Regimens for unvaccinated individuals — For patients who have not been previously vaccinated, post-exposure prophylaxis should always include both passive and active immunization (table 2).

Studies that have evaluated the efficacy of RIG plus vaccine include the following:

The combination of five intramuscular (IM) doses of human diploid cell vaccine (HDCV) and HRIG prophylaxis was evaluated in 90 persons treated after exposure to rabies, 21 of whom were bitten by proven rabid animals [39]. All 87 persons tested developed protective titers of antibody (≥0.5 international units/mL). One year after vaccination, all 33 persons who had follow-up testing had detectable antibodies to rabies virus.

Forty-five persons bitten by rabid dogs and wolves in Iran were treated with HDCV, and all except one also received RIG [44]. None of the exposed persons developed rabies.

In a series of 40 patients with rabies exposure treated with HDCV, all patients seroconverted regardless of whether they received RIG. However, those who received both had significantly higher rabies antibody titers [45].

Another study reported no human rabies cases among 45 patients receiving six intramuscular doses of purified chick embryo cell vaccine (PCECV) and HRIG after being exposed to biopsy-proven rabid animals [46].

A Chinese study of 171 patients with severe rabies exposure who received five IM purified Vero cell rabies vaccine (PVRV) plus equine RIG (ERIG) demonstrated protective neutralizing antibodies of more than 0.5 international units/mL by day 14 in all 171 cases. No one developed rabies up to six months after treatment [47].

Rabies immune globulin administration — Rabies immune globulin should be administered at the same time as the initial dose of vaccine (day 0) to patients who have not received a rabies vaccine series in the past. It is also required for some patients who have received prior rabies vaccination. (See 'Vaccine schedule for unvaccinated persons' below and 'Vaccine schedule for previously vaccinated persons' below.)

RIG should always be given in a different syringe from the vaccine. Additional details regarding administration of RIG are found in the table (table 2) and described above. (See 'Rabies immune globulin' above.)

The use of RIG in patients who have a potential rabies exposure during (ie, before completing) a pre-exposure vaccine series, as well as in those who have initiated a post-exposure vaccination regimen without receiving immediate RIG, is discussed below. (See 'Regimens for previously vaccinated individuals' below and 'Deviations from immunization regimens' below.)

Vaccine schedule for unvaccinated persons — After a rabies exposure, immunocompetent patients should receive rabies vaccine starting promptly after exposure (day 0) and on days 3, 7, and 14 (table 2) [48,49]. Additional information regarding timing and administration of the vaccine is described above. (See 'Timing of immunization' above and 'Rabies vaccines' above.)

For immunocompromised hosts, a fifth dose on day 28 should be administered. In addition, such patients should have an antibody titer checked 7 to 14 days after the final dose to assess their response (see 'Postvaccination serologic testing' below). Although data are limited, corticosteroids, other immunosuppressive drugs and biologic agents, and immunocompromising illnesses may prevent the immune response to rabies vaccination to the point of insufficient neutralizing antibody [50-52].

Earlier guideline recommendations had included a fifth dose of rabies vaccine on day 28 for all patients, which is consistent with the package inserts from both manufacturers that provide vaccine in the United States (Bavarian Nordic and Sanofi Pasteur) [48]. The decision to reduce the regimen to a four-dose series for immunocompetent patients is based upon global epidemiologic studies, which found that rabies did not develop in any patient who received appropriate wound care, HRIG, and four doses of vaccine; in addition, immunologic studies found the fifth dose did not lead to a further increase in antibody titers [48,53,54].

Reducing the number of clinic visits for rabies prophylaxis can help improve completion of post-exposure dosing schedules, especially in areas where access to medical care is limited and requires significant travel. Preliminary results from one study in healthy volunteers suggest that a one-week schedule of prophylaxis increases neutralizing antibody levels compared with standard regimens [55], although this has not been adopted by either the CDC or the World Health Organization (WHO).

Regimens for previously vaccinated individuals — Some previously vaccinated individuals require only two vaccine doses after an exposure, whereas others require a full four-dose series and RIG despite having received prior vaccination.

Criteria for a two-dose post-exposure vaccination series — Patients who report having received a prior three-dose pre-exposure prophylaxis series or a prior post-exposure series of ≥4 doses and were immunocompetent at the time of the prior vaccinations require only two booster doses for post-exposure prophylaxis. If they were immunocompromised at the time of their prior vaccinations, they must also have had at least one titer that showed a result of ≥0.5 international units/mL.

Additional situations for which only two vaccine doses are necessary for post-exposure prophylaxis include the following:

Completion of at least two doses of a pre-exposure prophylaxis series within the three years prior to the exposure. Persons who were immunocompromised at the time of their pre-exposure vaccination series must also have had at least one titer that showed a result of ≥0.5 international units/mL.

Prior partial completion of a pre- or post-exposure vaccination series and at least one titer check that showed a result of ≥0.5 international units/mL.

All prior vaccine doses must have been given after the advent of modern vaccines (PCECV, HDCV, or PVRV), which became available in the United States in the early 1980s.

For certain previously vaccinated patients, we suggest consultation with local or state public health authorities to determine the most appropriate post-exposure regimen:

Patients who became immunocompromised after their last positive titer check

Patients whose exposure occurred in the midst of (or <21 days after) a two-dose pre-exposure prophylaxis series

Patients whose prior vaccines were not derived from cell-culture or chick-embryo

Vaccine schedule for previously vaccinated persons — For individuals who meet the above criteria for a two-dose postvaccination series, the first dose is administered on day 0 as soon after exposure as possible and the second dose is administered three days later (table 2). Both the CDC and the WHO endorse the two-dose post-exposure vaccination series for individuals described above [4,11]. (See 'Criteria for a two-dose post-exposure vaccination series' above.)

RIG is not recommended for individuals who qualify for the two-dose post-exposure series. It is unnecessary in these patients because the anamnestic response to vaccine is sufficiently rapid in persons who were effectively vaccinated previously [4,11].

For all individuals who don’t qualify for a two-dose post-exposure series, prophylaxis is provided using the same regimen recommended for individuals without any history of prior vaccination (four vaccine doses plus RIG for immunocompetent individuals) [6,11]. (See 'Regimens for unvaccinated individuals' above.)

Additional information regarding administration of the vaccine is found above. (See 'Rabies vaccines' above.)

Special considerations

Resource-limited settings — While post-exposure prophylaxis can prevent deaths in patients exposed to rabies, the treatment regimen is expensive, costing up to several thousand dollars per person for biologics alone [56]. The annual expenditure for rabies globally has been estimated at USD $8.6 billion in direct costs and lost productivity, with Asia and Africa accounting for the majority. The cost of post-exposure prophylaxis with rabies immune globulin and vaccine accounts for a significant proportion of this expenditure [1].

To address these cost-related issues in resource-limited settings, the WHO has developed protocols that include the use of intradermal vaccination regimens and the use of RIG only after select exposures and to the extent that it can be infiltrated into and around the wound. The WHO guidelines are summarized in the table (table 5) [11,12]. More detailed information on the WHO recommendations can be accessed at the WHO website.

In areas where vaccine and financial resources are in short supply, intradermal administration of vaccine can reduce costs by up to 80 percent. The effectiveness of current cell culture vaccines given intradermally with or without RIG among rabies-exposed humans has been demonstrated in several studies with different schedules [57-60].

For United States travelers who received post-exposure prophylaxis in a resource-limited setting, receipt of the complete series of vaccine by the intradermal method may be sufficient, and documentation of antibody titer response may be used to assure the expected level of neutralizing antibody. (See 'Postvaccination serologic testing' below.)

A more detailed discussion of the approach to rabies vaccination in returning travelers is presented elsewhere. (See "Indications for post-exposure and pre-exposure rabies prophylaxis", section on 'Returning travelers'.)

Deviations from immunization regimens — Every attempt should be made to administer post-exposure prophylaxis according to the appropriate CDC or WHO schedule, since data on effectiveness are limited to regimens that are administered using the published schedules. (See 'Regimens for unvaccinated individuals' above and 'Regimens for previously vaccinated individuals' above and 'Resource-limited settings' above.)

However, if there is a deviation from standard immunization regimens, the following approach can be used:

Timing of doses – Deviations of a few days from the immunization schedule do not require complete reinitiating vaccination [61]. If a patient misses an injection, the immunization series should be continued until all doses have been administered according to the regular intervals (eg, if day 7 vaccine is given on day 10, the next dose should be on day 17, 7 days later, etc).

For more significant deviations from the schedule, antibody testing using the rapid fluorescent focus inhibition test (RFFIT) should be conducted 7 to 14 days after the final dose is given [4]. Serologic testing is discussed below. (See 'Postvaccination serologic testing' below.)

If different vaccine formulations were used – In returning travelers who need to complete a vaccine series, it is important to determine what vaccine they received abroad and the dosing schedule. Many vaccines available internationally are essentially equivalent in immunogenicity to those available in the United States and the series can be completed on schedule. If there is any question about the type of vaccine that was received, patients can typically complete the immunization series with intramuscularly administered rabies vaccine and have a follow-up titer to document appropriate response [4]. Consultation with local or state public health authorities is recommended (elsewhere, local experts or public health authorities should be consulted). A more detailed discussion of the approach to prophylaxis in returning travelers is found elsewhere. (See "Indications for post-exposure and pre-exposure rabies prophylaxis", section on 'Returning travelers'.)

If RIG was not administered – If a traveler sustained scratches or abrasions, WHO guidelines recommend only vaccine, which differs from CDC guidelines, which recommend both vaccine and RIG for this type of exposure (see 'Resource-limited settings' above). In this setting, RIG can be administered upon return if it is no later than seven days after the start of an immunization series; RIG should not be administered after that because RIG may suppress the immune response to rabies vaccine [62]. (See "Indications for post-exposure and pre-exposure rabies prophylaxis", section on 'Returning travelers'.)

Pregnancy — There is no evidence that rabies vaccination is associated with fetal abnormalities or adverse pregnancy outcomes of any kind [63,64]. Pregnancy is therefore not a contraindication to post-exposure prophylaxis if a rabies exposure has occurred. The danger of rabies after a significant exposure far outweighs any theoretical risk from administration. For patients in a continuous or frequent risk category, pre-exposure prophylaxis might also be necessary during pregnancy.

Antimalarial prophylaxis — Limited data show that antimalarial prophylaxis with chloroquine may blunt the immune response to rabies vaccine. In a randomized controlled study of 51 veterinary students, antibody responses to intradermal HDCV were assessed when chloroquine was administered [33]. Although all participants achieved an adequate vaccine response according to CDC criteria, the mean neutralizing antibody titers were lower in the 26 individuals who also received malaria prophylaxis. Decreased antibody titers have not been documented with other antimalarials (eg, mefloquine); however, this is being studied.

The clinical significance of these findings is unclear. Although the WHO had previously recommended that patients receiving antimalarial prophylaxis be given rabies vaccine intramuscularly rather than intradermally, this recommendation was removed from its 2018 position paper on rabies vaccines [11,12]. According to the WHO, the effect of antimalarial agents on vaccine-induced neutralizing antibody is unlikely to be clinically significant.

Risk of prophylaxis failure — Recommended post-exposure prophylaxis regimens appear uniformly effective.

Occasional case reports of rabies in vaccinated individuals have occurred and have been associated with the following deviations from currently recommended practice [4]:

Improper wound cleaning

Inadequate dosing of RIG

Absence of RIG administration in the wound site

Vaccine administration in the gluteal area

To reduce the risk of failure, an antibody titer should be checked if a post-exposure prophylaxis regimen using unknown or nonstandard biologics was administered. (See 'Deviations from immunization regimens' above and 'Postvaccination serologic testing' below.)

If the serologic response was appropriate, no additional immunization is needed. However, if the response was not adequate, post-exposure prophylaxis should be readministered in consultation with the local or state public health department (elsewhere, local experts or public health authorities should be consulted).

Postvaccination serologic testing — In general, routine postvaccination serologic testing is not necessary following post-exposure prophylaxis. Rabies vaccine induces protective neutralizing antibodies in the vast majority of patients. Questions as to whether a particular patient should have serologic testing after post-exposure prophylaxis should be directed to the local or state public health department (elsewhere, local experts or public health authorities should be consulted).

Immunocompromised patients For immunocompromised patients receiving post-exposure prophylaxis, testing should be performed 7 to 14 days after the final dose is given (table 2).

Patients who may have received inadequate prophylaxis – To assess the response to post-exposure prophylaxis in patients who may have received a regimen that provided suboptimal protection (eg, the prophylaxis regimen did not include human rabies immune globulin [HRIG] or substituted equine RIG [ERIG]; the patient received any part of the post-exposure regimen in a resource-limited setting where vaccine handling and storage may have been compromised or where vaccine production was not well regulated; there were significant deviations from the vaccine schedule), testing should be performed 7 to 14 days after the final dose is given if the first titer is below 0.5 international units/mL as measured by the RFFIT. Additional doses may be needed.

Serologic testing should be performed using the rapid fluorescent focus inhibition test (RFFIT), and a titer ≥0.5 international units/mL is felt to represent an adequate response to vaccination [6,11]. In 2022, the CDC endorsed this cut-off, which matches the WHO cut-off. The CDC’s new cut-off is a more cautious value than the previous one, although no infections occurred among vaccinated individuals using the prior cut-off.

Commercially available enzyme-linked immunosorbent assay (ELISA) tests for rabies antibody are not specific to neutralizing antibodies and should not be used for testing for immunity.

For immunocompromised patients and those who may have received a suboptimal post-exposure regimen, failure to demonstrate an adequate immune response when tested may indicate the need for additional vaccination. Such patients should be managed in consultation with local or state public health authorities.

ADVERSE EVENTS — Modern rabies vaccines are inactivated and have been safely administered to persons of all ages, including pregnant people and immunocompromised persons.

Adverse reactions from rabies vaccine — Patients who receive the rabies vaccine can have a variety of adverse reactions depending upon the type they receive:

Human diploid cell vaccine (HDCV) – Local reactions, including pain at the injection site, redness, swelling, and induration, have been reported in many patients [65,66]. Most are mild and resolve in a few days. Systemic reactions are less common and include mild fever, headache, dizziness, and gastrointestinal symptoms [65,66].

Allergic reactions can occur, and patients who develop a hypersensitivity to this vaccine can receive purified chick embryo cell vaccine (PCECV) formulation if future doses are needed. During surveillance for adverse events following HDCV immunization from 1980 to 1984, the United States Centers for Disease Control and Prevention (CDC) received reports of 108 systemic allergic reactions, ranging from hives to anaphylaxis, for a rate of approximately 11 per 10,000 vaccinees [67]. In addition, systemic hypersensitivity reactions have been reported in up to 6 percent of persons receiving a booster vaccination with HDCV following primary rabies prophylaxis [68].

Purified chick embryo cell vaccine (PCECV) – PCECV is also associated with local reactions at the injection site [69]. A retrospective review of adverse events following immunization with PCECV was conducted using data from the Vaccine Adverse Event Reporting System (VAERS) over an eight-year period [70]. Mild side effects included headache, fever, myalgia, nausea, and weakness. Serious adverse events were uncommon (3 per 100,000 doses distributed). Hypersensitivity to PCECV is less well described [69]; however, HDCV vaccine can replace PCECV if hypersensitivity develops with the use of that product as the initial vaccine.

Purified Vero cell rabies vaccine (PVRV) – Like HDCV and PCECV, PVRV is associated with both local and systemic reactions [71]. In a study of 60 healthy adult volunteers who received a pre-exposure vaccine series of a new PVRV vaccine either intramuscularly or intradermally or received a previously licensed PVRV vaccine intramuscularly, 116 adverse events were reported across all three groups. Twenty-eight local reactions included pain at the injection site, erythema, pruritus, induration, and edema. All local reactions were judged to be relatively mild and resolved rapidly. Eighty-eight systemic reactions were comprised primarily of headache, arthralgia, and myalgia and were self-limited. There were no significant differences in the type of rate of reported local or system reactions between the three groups.

Rare case reports of neurologic adverse events (eg, acute disseminated encephalomyelitis, Guillain-Barré) following rabies vaccination have also been reported; however, causality has not been established [4].

Clinicians in the United States who require assistance in the management of a patient with significant hypersensitivity should contact their state health department rabies consultant or the CDC. All serious vaccine reactions should be reported to VAERS, phone number 800-822-7967 or online at vaers.hhs.gov.

Although severe reactions are rare, one study found that approximately 50 percent of individuals receiving either pre- or post-exposure prophylaxis experienced at least one systemic reaction and that 5 percent of individuals actually discontinued the vaccine series due to their reaction. Individuals who have had a rabies exposure and who experience a systemic reaction may need to be encouraged to complete the post-exposure series [72]. Counseling patients about the possibility of such systemic reactions prior to vaccination may help manage expectations and reduce drop-out rates through the series.

Adverse reactions from rabies immune globulin — Human rabies immune globulin (HRIG) is associated with local reactions including pain and tenderness, erythema, and induration. Headache is the most commonly reported systemic side effect [73]. There has never been evidence of transmission of any known virus or other infectious agent by HRIG approved for use in the United States.

Use of equine rabies immune globulin (ERIG) products can be associated with hypersensitivity reactions and should be administered under close medical supervision. However, most of the available preparations are associated with very few adverse reactions. The purified immunoglobulin cleavage fragment products may be less reactogenic [7].

In a retrospective study at the Thai Red Cross, adverse events to HRIG and ERIG were reviewed in more than 70,000 patients [74]. A higher number of side effects occurred among those who had received ERIG (1.83 versus 0.09 percent). General observations also included a higher risk of hypersensitivity to either product among females and a lower risk of serum sickness in children under 10 years of age. Only one patient developed anaphylaxis associated with ERIG administration.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rabies".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Rabies (The Basics)")

SUMMARY AND RECOMMENDATIONS

Overview – Rabies is virtually always fatal, but infection can be prevented with proper wound care and post-exposure prophylaxis using rabies biologics (rabies vaccine, rabies immune globulin [RIG]). (See 'Introduction' above.)

Rabies biologics – Several rabies vaccine and RIG formulations are available. The proper route and sites of administration are critical to optimize the protective efficacy and prevent vaccine failure. (See 'Rabies biologics' above.)

Vaccine administration – Rabies vaccines should be administered intramuscularly (IM):

-In adults (ie, age ≥19 years), the deltoid muscle of the arm is the only acceptable IM site of vaccine administration.

-In children 3 to 18 years old, the deltoid muscle is preferred, although the anterolateral aspect of the thigh is an acceptable alternative.

-In children ≤2 years old, the anterolateral aspect of the thigh is preferred; however, in children aged 12 months to 2 years, the deltoid muscle is an acceptable alternative if the muscle mass is adequate.

Vaccine should never be administered in the gluteal area because this may result in lower antibody titers. (See 'Rabies vaccines' above.)

Immune globulin administration – If RIG is required, the wound should be infiltrated with RIG; any remaining dose should be given IM and at a different intramuscular site than the vaccine. (See 'Rabies immune globulin' above.)

Pre-exposure prophylaxis – For patients with increased risk of exposure to rabies, we suggest pre-exposure prophylaxis (Grade 2C). Pre-exposure prophylaxis is especially important for patients at high risk of unrecognized exposures.

Risk categorization – Specific pre-exposure prophylaxis regimens depend on a patient’s level of risk for acquisition of rabies over time. (See 'Indications' above.)

Pre-exposure regimens – All patients who receive pre-exposure prophylaxis should receive a two-dose primary vaccine series on day 0 and day 7; in some higher risk groups, especially those at risk for unrecognized exposures, additional follow-up titers or boosters are administered (table 1 and table 4). (See 'Regimens for primary vaccine series' above.)

Our suggested regimens match guidance from the United States Centers for Disease Control and Prevention (CDC). The World Health Organization (WHO) also supports the use of a two-visit series on days 0 and 7 and includes the option of an intradermally administered vaccine that can be used in resource-limited settings. (See 'Regimens for primary vaccine series' above.)

Post-exposure prophylaxis – Post-exposure rabies prophylaxis includes proper wound care and administration of rabies biologics (ie, rabies vaccine with or without RIG) to elicit neutralizing antibodies after a rabies exposure. (See 'Post-exposure prophylaxis' above.)

Indications – Once it has been determined that the patient should receive rabies post-exposure prophylaxis, prophylaxis should begin as soon as possible after the exposure. The decision to initiate prophylaxis requires a careful risk assessment and depends upon the type of exposure, the local rabies epidemiology, the circumstances of the exposure incident, and the availability of the animal for observation or rabies testing (algorithm 1) [4]. A detailed discussion of when to initiate rabies prophylaxis is discussed separately. (See "Indications for post-exposure and pre-exposure rabies prophylaxis", section on 'Risk assessment'.)

Post-exposure regimens – For patients who have had an exposure to rabies, we recommend post-exposure prophylaxis (Grade 1A). Because post-exposure prophylaxis is highly effective and rabies is a fatal infection, we give post-exposure prophylaxis to any patient who is deemed to have had a potential exposure.

The regimen used for post-exposure prophylaxis depends upon the patient's previous immunization history and immune status.

Dosing schedules, doses, and routes of administration are summarized in the table (table 2) but, in certain resource-limited settings, may be modified to maximize the availability of vaccine (table 5). (See 'Regimens for unvaccinated individuals' above and 'Regimens for previously vaccinated individuals' above and 'Resource-limited settings' above.)

Deviations from vaccine schedule – Immunization schedules should be adhered to as closely as possible. However, if a delay of only three to four days occurs, the schedule should simply resume with intervals preserved within the new schedule. By contrast, if the dosing schedule has been significantly violated, antibody titers should be assessed to evaluate efficacy. (See 'Deviations from immunization regimens' above and 'Postvaccination serologic testing' above.)

Adverse events – Both rabies immunoglobulin and rabies vaccines have been associated with local reactions. In the setting of a hypersensitivity reaction to a vaccine, an alternative formulation can be used. (See 'Adverse events' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Wichai Techasathit, MD, MPH, who contributed to earlier versions of this topic review.

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Topic 8303 Version 36.0

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