Rabies pre-exposure prophylaxis

INTRODUCTION — Pre-exposure prophylaxis is the use of rabies vaccine to induce at least partial immunity in individuals who are at elevated risk for exposure to rabies. This topic will review the benefits, indications, and regimens for rabies pre-exposure prophylaxis.

Management of rabies exposures, including post-exposure prophylaxis, is discussed separately. (See "Rabies immune globulin and vaccine", section on 'Post-exposure prophylaxis'.)

BENEFITS, HARMS, AND BARRIERS

●Benefits – Rabies is almost uniformly fatal once illness develops but disease can be prevented through vaccination. Pre-exposure prophylaxis is thought to be effective at preventing rabies; this is particularly important for individuals who are at risk for unrecognized exposures and thus would not seek post-exposure prophylaxis.

Pre-exposure prophylaxis does not eliminate the need for prophylaxis after a rabies exposure, but it eliminates the need for rabies immunoglobulin and decreases the recommended number of vaccine doses following an exposure [1,2]. Pre-exposure prophylaxis can be especially important in resource-limited settings where vaccine and rabies immunoglobulin may be unavailable and significant delays in administration can occur.

There are no human studies evaluating the effectiveness of rabies pre-exposure prophylaxis in individuals with known or suspected exposure to rabies. Effectiveness is inferred based on two lines of evidence:

•Vaccine studies show that rabies vaccines elicit neutralizing antibody responses at levels expected to protect against infection [3-7].

•Regional data suggest lower rabies rates when pre-exposure prophylaxis is regularly administered. For example, in 2011, pre-exposure prophylaxis was administered in nearly 300 localities (13, 986 people) in the Amazon Region [8]. In these areas, the number of rabies deaths dropped from 13 in 2010 and 20 in 2011 to zero child deaths and only two adult deaths (both had refused vaccination) in 2012.

●Harms – Side effects of rabies vaccination (including rabies pre-exposure prophylaxis) are typically limited to localized transient pain at the site of injection. Modern rabies vaccines have been safely administered to persons of all ages, including pregnant people and immunocompromised persons. (See "Rabies immune globulin and vaccine", section on 'Adverse reactions from rabies vaccine'.)

●Barriers – Significant barriers to adherence to pre-exposure prophylaxis recommendation for at-risk individuals have limited its use. Identified barriers include high out-of-pocket costs, uncertainty about who qualifies for prophylaxis, unavailability in high-risk areas, follow-up vaccines and titers, and inability of high-risk travelers to complete the full course prior to departure [2].

In 2022, the United States Centers for Disease Control and Prevention's (CDC) Advisory Committee on Immunization Practices (ACIP) issued new recommendations for pre-exposure prophylaxis intended to address barriers while still maintaining maximal effectiveness of rabies pre-exposure prophylaxis [2].

DETERMINING WHICH PATIENTS QUALIFY — In general, rabies pre-exposure prophylaxis is indicated for individuals who have elevated risk of exposure to rabies, and patients are stratified based on their level of risk to determine whether they qualify.

Identifying risk factors — A thorough history is necessary to identify patients' risk factors for rabies exposure. Primary risk factors usually involve an occupational risk (eg, veterinarian, worker in a rabies laboratory), a recreational risk (eg, spelunking), or travel to a rabies enzootic area where post-exposure prophylaxis may not be readily available. While obtaining histories, providers should delve into details of patients' activities, the likelihood that patients would notice an exposure should one occur, and the length of time during which patients' risk will persist. Patients should specifically be asked whether they anticipate the risk for exposure to persist (either continuously or intermittently) for more than three years. (See 'Risk-stratification and indications' below.)

Exposures that are unrecognized are the riskiest exposures because they are not noticed by the exposed person and, consequently, post-exposure prophylaxis is never sought. For example, although this has not been reported in the United States, a person performing a necropsy on a rabid animal or a field-study of bats could theoretically receive a small scratch to the skin without noticing the injury and subsequently develop rabies.

Risk-stratification and indications — Once risk factors for exposure to rabies have been identified, patients should be stratified into one of five levels of risk created by the United States Centers for Disease Control and Prevention (CDC). The categories are based on an individual's risk of being exposed, likelihood of noticing the exposure, and duration of time at risk [2]. (See 'Identifying risk factors' above.)

Patients whose risk category falls into Levels 1 through 4 qualify for a primary vaccine series, and those in Levels 1 through 3 also qualify for post-vaccination boosters and/or titers (table 1). Regimen details are described below. (See 'Vaccination schedule (regimens)' below.)

The CDC's five risk categories for adults and children are as follows, and details are provided in the table (table 1):

●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 recognized exposures but exposures could be unrecognized (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, and the duration at risk extends beyond three years after 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 the primary vaccine series (eg, same as Level 3 but duration at risk lasts 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 and Africa) usually fall into Levels 3 or 4, depending on whether travel plans extend three or more years beyond the start of their vaccine series (table 1) (see "Clinical manifestations and diagnosis of rabies", section on 'Geographic distribution'). Specific country-level recommendations for pre-travel rabies vaccination is available on the CDC Travelers' Health website. If pre-exposure prophylaxis is administered to travelers, every effort should be made to complete the series prior to travel. Additionally, all travelers to rabies enzootic regions should receive specific pre-travel counseling about avoidance and management of exposures during travel. (See "Indications for post-exposure rabies prophylaxis", section on 'Pretravel counseling' and "Rabies immune globulin and vaccine", section on 'Wound care'.)

Children should be closely supervised when traveling, since they are more likely to inadvertently provoke animals and be injured; they are also less likely to report exposures [9,10]. 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 [11-13]. 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).

VACCINE FORMULATIONS AND ADMINISTRATION — The same vaccine formulations used for post-exposure prophylaxis are used for pre-exposure prophylaxis, and the injection technique is also the same. However, the vaccine schedules (ie, regimens) for pre- and post-exposure prophylaxis are different.

Details regarding the vaccine formulations, injection technique, and post-exposure vaccination schedules are found elsewhere. (See "Rabies immune globulin and vaccine", section on 'Rabies vaccines'.)

VACCINATION SCHEDULE (REGIMENS) — All patients receive a primary vaccination series, and some receive follow-up serology or boosters (table 1 and table 2)

Regimens for primary vaccination series — Suggested regimens for pre-exposure prophylaxis vary depending on the jurisdiction where the vaccines will be provided. Healthcare providers in the United States should follow recommendations from the United States Centers for Disease Control and Prevention (CDC) [2]. Outside of the United States, others may follow the World Health Organization (WHO) [1] or local guidelines.

●United States Centers for Disease Control and Prevention (CDC) 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 [2]. In select cases, follow-up titers and/or boosters are recommended. The dosing schedule is described in the tables (table 1 and table 2).

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 [2]. 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 [2,4]. After a two-dose series, anamnestic responses (rises in titers from undetectable to adequate levels after an exposure) last for at least three years [2]. These findings do not vary between the two types of cell-culture vaccine preparations used in the United States [5,14].

●World Health Organization (WHO) recommendations – The World Health Organization (WHO) also recommends the use of a two-dose pre-exposure prophylaxis series administered on day 0 and day 7 [1,15]. 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 on day 7).

Intradermal two-dose regimens for pre-exposure prophylaxis have been shown to be immunogenic [3,6]. 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) [3].

Post-vaccination titers and boosters — For certain patients, the CDC recommends post-vaccination serologic testing to determine whether a booster should be given [2]. When serology reveals a titer <0.5 international units [IU]/mL, a booster is typically recommended (table 1 and table 2) [1,2]. Groups who qualify for post-vaccination serology and boosters are detailed below. (See 'Ongoing risk of exposure' below and 'Immunocompromised patients' below and 'Concomitant chloroquine administration' below.)

Serologic testing should be performed using the rapid fluorescent focus inhibition test (RFFIT), and a titer ≥0.5 IU/mL is felt to represent adequate response to vaccination [1,2]. 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 do not specifically detect neutralizing antibodies and should not be used.

Serologic testing is recommended for patients with ongoing risk of exposure, an immunocompromising condition, or treatment with concomitant chloroquine.

Ongoing risk of exposure — Because the immunogenicity of a two-dose series has not been thoroughly evaluated beyond three years, patients who are expected to be exposed for longer than three years typically receive follow-up titers or a booster, the frequency of which depends on their level of risk. (See 'Risk-stratification and indications' above.)

Specifically, individuals who have ongoing risk of exposure (ie, Levels 1 and 2) are recommended to have periodic serologic testing after completion of the primary vaccine series. If the titer is low (<0.5 IU/mL), a booster is recommended. Patients who have a Level 3 risk should have either a one-time serologic test or an appropriately timed booster. Following a booster, confirmatory serologic testing is not recommended.

Specific timing and intervals for serologic testing are outlined in the tables (table 1 and table 2).

Immunocompromised patients — If pre-exposure prophylaxis is provided to an immunocompromised individual, follow-up titers are recommended and should be performed no sooner than one week (preferably two to four weeks) after completing the primary vaccine series and after every booster (table 1). If a follow-up titer is low (<0.5 IU/mL), a booster should be given and 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 and patients should be advised to avoid high-risk activity until immunogenicity can be confirmed (elsewhere, local experts or public health authorities can be consulted).

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, and high-risk activities should be avoided until serologic tests confirm sufficient antibody response.

Concomitant chloroquine administration — Randomized trials suggest that patients on chloroquine have reduced antibody responses to rabies vaccine, although the antibody levels are still within the acceptable range [16,17]. The clinical significance of these findings is unclear. However, as a precaution, the CDC suggests that clinicians consider avoiding chloroquine for malaria prophylaxis when using rabies vaccine. If avoidance is not possible, the CDC suggests checking titers no sooner than one week (preferably two to four weeks) after completion of a rabies vaccine series in patients on chloroquine to confirm that vaccination was effective.

Studies suggest that decreased antibody titers do not occur with atovaquone-proguanil or doxycycline, both of which are other commonly prescribed antimalarial agents [17]. Anecdotal reports suggest that mefloquine (another antimalarial agent) does not impair rabies vaccine response, although large-scale trials are necessary for confirmation [2].

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 administration — For the primary vaccination series, delays of the second dose by a few days are generally considered to be 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 more significantly 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). The authors consider that delays of greater than four days should trigger consultation with public health.

If a booster is late, pre-booster titers are recommended, as discussed below. (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 earlier than recommended – Interpreting titers that were drawn earlier than recommended depends on the titer results and the timing relative to vaccination.

•Interpreting low results (<0.5 IU/mL) – The interpretation of low results in patients whose titer was drawn earlier than recommended may be due to insufficient time for antibody response. This situation may occur in immunocompromised patients or patients on chloroquine because they are individuals for whom follow-up titers are recommended to document initial response to vaccination (ie, primary immunogenicity).

Patients whose titer was drawn during this "window period" should have a titer repeated two to four weeks from the date of their latest vaccine dose. If titers remain low, consultation with local or state public health authorities is suggested, and patients should be advised to avoid high-risk activity until immunogenicity can be confirmed, as discussed elsewhere. (See 'Immunocompromised patients' above.)

Patients whose titers are low well after the window period should receive a booster and then be realigned with their risk-based vaccination schedule from the date of their booster (table 1).

•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 1).

●Titers drawn later than recommended – When titers are drawn later than recommended, 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 1).

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 administration' 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 post-vaccination 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 [18,19].

VACCINE SHORTAGES — Shortages of rabies vaccine due to supply issues among licensed manufacturers have occurred and most likely will recur. In these cases, vaccines 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 the vaccine is not readily available, local or state public health authorities should be consulted (elsewhere, local experts or public health authorities may be consulted). The United States Centers for Disease Control and Prevention (CDC) maintains updated information on vaccine availability on their rabies website.

RABIES EXPOSURE AFTER RECEIVING PRE-EXPOSURE PROPHYLAXIS — For individuals exposed to rabies who have a history of receiving pre-exposure prophylaxis, fewer post-exposure vaccinations may be necessary and rabies immunoglobulin is not recommended, depending upon whether certain criteria are met. Details for management of these patients is found elsewhere. (See "Rabies immune globulin and vaccine", section on 'Regimens for previously vaccinated individuals'.)

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 5^th to 6^th 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 10^th to 12^th 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 e-mail 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

●Definition – Pre-exposure prophylaxis is the use of rabies vaccine to induce at least partial immunity in individuals who are at elevated risk for exposure to rabies. (See 'Introduction' above.)

●Benefits – Pre-exposure prophylaxis does not eliminate the need for prophylaxis after a rabies exposure. However, it usually eliminates the need for rabies immunoglobulin and decreases the recommended number of injections following an exposure. (See 'Benefits, harms, and barriers' above.)

●Risk stratification of patients – To determine the need for pre-exposure prophylaxis, patients are classified into one of five levels of risk based on United States Centers for Disease Control and Prevention (CDC) criteria (table 1). (See 'Risk-stratification and indications' above.)

●Indications for pre-exposure prophylaxis – For patients in risk Levels 1 through and 4, we suggest pre-exposure prophylaxis (Grade 2C). Pre-exposure prophylaxis is particularly important for individuals at high risk of unrecognized exposures. Our suggestions are in accordance with the CDC. (See 'Determining which patients qualify' above.)

●Pre-exposure vaccination schedule – All patients who receive pre-exposure prophylaxis receive a primary vaccination series, and some receive follow-up serology or boosters based on their level of risk (table 1 and table 2). (See 'Vaccination schedule (regimens)' above.)

•Primary vaccination series – The primary series recommended by the CDC is two doses of rabies vaccine administered intramuscularly (IM): the first dose is on day 0 and the second dose is on day 7. The World Health Organization (WHO) recommendations are similar but also include an option for intradermal dosing. (See 'Regimens for primary vaccination series' above.)

•Serologic testing and boosters – For patients in Levels 1 and 2, the CDC recommends post-vaccination serologic testing to determine the need for a booster. Patients in Level 3 should have either a one-time serologic test or an appropriately timed booster. Specific timing and intervals for serologic testing are based on the risk-level (table 1). (See 'Post-vaccination titers and boosters' above.)

Due to reduced immune response to vaccination, the CDC recommends that immunocompromised patients and patients on concomitant chloroquine have follow-up titers shortly after completing their primary vaccine series. Immunocompromised patients should also have titers checked after every booster (table 1). (See 'Immunocompromised patients' above and 'Concomitant chloroquine administration' above.)

●Rabies exposures after pre-exposure prophylaxis – Exposed individuals who have received pre-exposure prophylaxis still need to receive timely post-exposure prophylaxis. (See 'Rabies exposure after receiving pre-exposure prophylaxis' above.)