Human rabies is an acute, progressive encephalomyelitis that is nearly always fatal
once symptoms begin. Several measures have been implemented to prevent human rabies
in the United States, including vaccination of targeted domesticated and wild animals,
avoidance of behaviors that might precipitate an exposure (e.g., provoking high-risk
animals), awareness of the types of animal contact that require postexposure prophylaxis
(PEP), and use of proper personal protective equipment when handling animals or laboratory
specimens. PEP is widely available in the United States and highly effective if administered
after an exposure occurs. A small subset of persons has a higher level of risk for
being exposed to rabies virus than does the general U.S. population; these persons
are recommended to receive preexposure prophylaxis (PrEP), a series of human rabies
vaccine doses administered before an exposure occurs, in addition to PEP after an
exposure. PrEP does not eliminate the need for PEP; however, it does simplify the
rabies PEP schedule (i.e., eliminates the need for rabies immunoglobulin and decreases
the number of vaccine doses required for PEP). As rabies epidemiology has evolved
and vaccine safety and efficacy have improved, Advisory Committee on Immunization
Practices (ACIP) recommendations to prevent human rabies have changed. During September
2019–November 2021, the ACIP Rabies Work Group considered updates to the 2008 ACIP
recommendations by evaluating newly published data, reviewing frequently asked questions,
and identifying barriers to adherence to previous ACIP rabies vaccination recommendations.
Topics were presented and discussed during six ACIP meetings. The following modifications
to PrEP are summarized in this report: 1) redefined risk categories; 2) fewer vaccine
doses in the primary vaccination schedule; 3) flexible options for ensuring long-term
protection, or immunogenicity; 4) less frequent or no antibody titer checks for some
risk groups; 5) a new minimum rabies antibody titer (0.5 international units [IUs])
per mL); and 6) clinical guidance, including for ensuring effective vaccination of
certain special populations.
Background
Transmission of rabies virus occurs when saliva or neural tissue from an infected
mammal is introduced into a person or another animal through, for example, a bite
or contact with mucous membranes (
1
). Worldwide, approximately 59,000 human rabies deaths occur each year (
2
). The canine rabies virus variant (CRVV) is the most common source of human rabies
infections, accounting for approximately 98% of cases, including some cases among
U.S. travelers (
3
). In the United States, CRVV has been eliminated (
3
), but wildlife rabies remains endemic, accounting for approximately 5,000 reported
rabid animals each year (
4
). Specific wildlife rabies virus variants (RVVs) associated with mesocarnivores (small
to midsized animals whose diet includes 50%–70% meat) are endemic in distinct geographically
confined locations in 42 U.S. states and Puerto Rico (
4
). In contrast, bat RVVs are widely distributed throughout the United States, with
only Hawaii being rabies-free (
3
). During January 2000–December 2020, 52 cases of human rabies were diagnosed in the
United States, 38 of which were indigenously acquired (i.e., from rabies exposures
that occurred in the United States) (
4
); none were in persons who had previously received PrEP.
In the United States, two modern cell culture vaccines are licensed for rabies PrEP
and PEP: human diploid cell vaccine (HDCV; Imovax/Sanofi Pasteur)* and purified chick
embryo cell vaccine (PCECV; RabAvert/Bavarian Nordic),
†
respectively; both are packaged for intramuscular (IM) administration (
1
). Each IM dose of vaccine consists of 1 mL and should be administered in the deltoid
for adults, and in either the deltoid or anterolateral aspect of the thigh for children.
Reasons for Revisions of Recommendations
ACIP has recommended rabies PrEP since 1969 (
5
). As safe and effective modern cell culture vaccines have replaced those derived
from nerve tissue and duck embryo, and as rabies epidemiology has continued to evolve
(e.g., elimination of CRVV, emergence and spread of the racoon RVV, and host shifts
of bat RVV to mesocarnivores in the southern United States), changes have been made
to ACIP recommendations. Since 2008, when the last ACIP rabies PrEP recommendations
were published, barriers affecting adherence to the recommendations have been identified,
including out-of-pocket costs of rabies biologics (3-dose PrEP vaccination series
is currently estimated at ≥$1,100
§
), confusion about which activities fall within different risk categories, and noncompliance
with recommendations for repeated titer checks (
6
). In addition, travel medicine providers have indicated that the largest group for
which PrEP is recommended (travelers to regions with endemic CRVV) might often be
unable to complete the 3-dose series described in the 2008 ACIP recommendations (
1
) because at least 21 days are required to complete the series before initiation of
travel (
7
).
During September 2019–November 2021, the ACIP Rabies Work Group participated in monthly
or bimonthly teleconferences and considered evidence-based updates to the 2008 ACIP
recommendations. The Work Group comprised experts in diverse disciplines including
laboratory, public health, and clinical specialties. Data collected, analyzed, and
prepared by the Work Group were deliberated by ACIP during six public meetings. With
publication of this report, the recommendations become final and are the official
CDC recommendations for rabies PrEP.
Redefined Risk Categories
Recommendations for PrEP depend on the level of a person’s risk for being exposed
to rabies. The Work Group redefined risk categories into five groups, with level 1
involving activities with the highest risk and level 5 involving those with the lowest
risk (Table). The highest risk categories (levels 1 and 2) include exposures that
might be unrecognized (i.e., not perceived by the exposed person); for example, a
small scratch to the skin during an inconspicuous personal protective equipment breach
might not be noticed by persons testing neural tissue from a rabid animal or conducting
ecologic studies on bats in the field. For persons with risk for unrecognized exposures,
checking serial titers has historically been advised to ensure maintenance of persistently
elevated rabies antibody titers; in its recent discussions, ACIP upheld this guidance
because the assumption is that high titers might provide some protection when PEP
is not sought for an unrecognized exposure. Recognized exposures, as defined by ACIP,
are those bites, scratches, and splashes for which PEP would be sought because the
exposures are usually registered by a person as unusual (e.g., contact with a bat)
or painful (e.g., bite or scratch from a raccoon). The Work Group concluded that most
high-risk activities involving live animals (e.g., providing veterinary health care
or participating in outdoor activities in countries with endemic CRVV) are associated
with only recognized exposures (risk categories 3 and 4); ACIP concluded that checking
serial titers for these persons is unnecessary because recognized exposures should
always prompt evaluation for PEP. Rabies vaccination recommendations for each of the
redefined risk categories is summarized under Recommendations.
TABLE
Rabies preexposure prophylaxis recommendations — United States, 2022
Risk category
Nature of exposure
Typical population*
Relevant disease biogeography†
Recommendations
Primary PrEP§ immunogenicity
Long-term immunogenicity¶
1. Elevated risk for unrecognized** and recognized†† exposures including unusual or
high-risk exposures
Exposure, often in high concentrations, might be recognized or unrecognized, might
be unusual (e.g., aerosolized virus)
Persons working with live rabies virus in research or vaccine production facilities
or performing testing for rabies in diagnostic laboratories
Laboratory
IM rabies vaccine on days 0 and 7
Check titers every 6 months; booster if titer <0.5 IU/mL§§
2. Elevated risk for unrecognized** and recognized†† exposures
Exposure typically recognized but could be unrecognized; unusual exposures unlikely
Persons who frequently 1) handle bats, 2) have contact with bats, 3) enter high-density
bat environments, or 4) perform animal necropsies (e.g., biologists who frequently
enter bat roosts or who collect suspected rabies samples)
All geographic regions where any rabies reservoir is present, both domestic and international
IM rabies vaccine on days 0 and 7
Check titers every 2 years; booster if titer <0.5 IU/mL§§
3. Elevated risk for recognized†† exposures, sustained risk¶¶
Exposure nearly always recognized; risk for recognized exposures higher than that
for the general population and duration exceeds 3 years after the primary vaccination
Persons who interact with animals that could be rabid***; occupational or recreational
activities that typically involve contact with animals include 1) veterinarians, technicians,
animal control officers, and their students or trainees; 2) persons who handle wildlife
reservoir species (e.g., wildlife biologists, rehabilitators, and trappers); and 3)
spelunkers
All domestic and international geographic regions where any rabies reservoir is present
IM rabies vaccine on days 0 and 7
1) One-time titer check during years 1–3 after 2-dose primary series; booster if titer
<0.5 IU/mL,§§ or 2) booster no sooner than day 21 and no later than year 3 after 2-dose
primary series†††
Selected travelers. PrEP considerations include whether the travelers 1) will be performing
occupational or recreational activities that increase risk for exposure to potentially
rabid animals (particularly dogs) and 2) might have difficulty getting prompt access
to safe PEP (e.g., rural part of a country or far from closest PEP clinic)
International geographic regions with rabies virus reservoirs, particularly where
rabies virus is endemic in dog populations
4. Elevated risk for recognized†† exposures, risk not sustained¶¶
Exposure nearly always recognized; risk for exposure higher than for general population
but expected to be time-limited (≤3 years from the 2-dose primary PrEP vaccination
series)
Same as for risk category 3 (above), but risk duration ≤3 years (e.g., short-term
volunteer providing hands-on animal care or infrequent traveler with no expected high-risk
travel >3 years after PrEP administration)
Same as for risk category 3 (above)
IM rabies vaccine on days 0 and 7
None
5. Low risk for exposure
Exposure uncommon
Typical person living in the United States
Not applicable
None
None
Abbreviations: IM = intramuscular; IU = international units; PEP = postexposure prophylaxis;
PrEP = preexposure prophylaxis.
* Nature of exposure and type of work performed are the most important variables to
consider when determining a person’s risk category. The examples provided are intended
to be a guide, but ultimately categorizations should be done on a case-by-case basis
with nature of exposure considered. Some persons might be categorized into a different
risk group from those suggested by the provided examples. For example, most veterinarians
are in risk category 3 because they are at risk for recognized exposures after direct
contact with animals. However, a veterinary pathologist who often performs necropsies
on mammals suspected to have had rabies might have risk for rabies virus exposure
that is more consistent with risk category 2 than risk category 3; such persons should
follow the recommendations for the risk category with which their activities best
fit. Similarly, most spelunkers do not often enter high-density bat caves; those who
do may follow the recommendations for risk category 2 rather than risk category 3.
Persons involved in the diagnosis of rabies virus, but for whom the frequency of handling
rabies virus–infected tissues is low, or the procedures performed do not involve contact
with neural tissue or opening of a suspected rabid animal’s calvarium could consider
following the recommendations for risk category 2 rather than those for risk category
1.
† Local or state health departments should be consulted for questions about local
disease biogeography.
§ Primary immunogenicity refers to immunogenicity that peaks 2–4 weeks after completing
the recommended primary vaccination schedule. Persons without altered immunity are
expected to mount appropriate responses, and checking titers is not routinely recommended.
Persons with altered immunity are advised to confirm, through laboratory testing,
a rabies antibody titer ≥0.5 IU/mL ≥1 week after booster vaccination (but ideally,
2–4 weeks after completing the recommended schedule) and before participating in high-risk
activities. Individual laboratories set facility-specific rules about whether acceptable
antibody titers should be laboratory-confirmed for all personnel, regardless of whether
personnel have altered immunity.
¶ Long-term immunogenicity refers to the ability to mount an anamnestic response to
rabies virus >3 years after completion of the primary rabies vaccination series.
** Unrecognized exposures are those that recipients might not know occurred; for example,
a small scratch during an inconspicuous personal protective equipment breach might
not be noticed by persons testing neural tissue from a rabid animal or persons conducting
ecologic studies on bats in the field.
†† Recognized exposures are bites, scratches, and splashes that are usually registered
by a person because the exposure is unusual (e.g., contact with a bat) or painful
(e.g., bite or scratch from a raccoon).
§§ When rabies antibody titers are <0.5 IU/mL, a booster vaccination should be provided.
Antibody titers to verify booster response need not be checked after these boosters
are administered to persons who are immunocompetent. For persons who are immunocompromised,
the indicated antibody titer should be verified ≥1 week (ideally, 2–4 weeks) after
administration of every booster vaccination.
¶¶ Sustained risk is elevated risk for rabies >3 years after the completion of the
primary rabies PrEP vaccination schedule.
*** Rabies virus is unlikely to persist outside a deceased animal’s body for an extended
time because of virus inactivation by desiccation, ultraviolet irradiation, and other
factors. Risk from transmission to persons handling animal products (e.g., hunters
and taxidermists) is unknown but presumed to be low (risk category 5); direct skin
contact with saliva and neural tissue of mammals should be avoided regardless of profession.
††† Checking titers after recommended booster doses is not indicated unless the recipient
has altered immunity.
Risk categories might change over a person’s lifetime. Some persons for whom PrEP
is indicated might have elevated risk for a limited period (e.g., during a summer
internship working with wildlife or a month-long vacation to a rural village where
CRVV is enzootic [risk category 4]). After the event has passed, risk level and associated
recommendations for such persons will change. Shifts in risk categories are explained
in the management of deviations from the recommendations section under Clinical Guidance.
Minimum Acceptable Rabies Antibody Titer Level
A correlate of protection for rabies antibody titers has not been defined. The minimum
antibody level historically recommended by ACIP is one that results in complete neutralization
of rabies virus at a 1:5 serum dilution by the rapid fluorescent focus inhibition
test. This is approximately equivalent to a titer of 0.1–0.3 IU/mL. Stakeholders have
advocated for a specific titer value in IU/mL units of measure (rather than a range)
and, ideally, one that aligns with current global guidance (i.e., that of the World
Health Organization) (
8
). Although no infections among vaccinated persons occurred with the previous ACIP
cut-off titer, most published studies use 0.5 IU/mL as a correlate of protection.
This level is now endorsed by ACIP and replaces the previous minimum acceptable rabies
antibody titer. The higher value provides a more conservative limit for indicating
inadequate response to rabies vaccination and the need for booster doses (
9
).
Evidence for Updated Vaccine Schedule and Recommendations for Booster Doses and Titer
Checks
Although there is no established correlate of protection for rabies, induction of
a peak antibody response at or above the minimum acceptable antibody titer level (≥0.5
IU/mL) in response to rabies vaccine is an indirect measure of protection (i.e., immunogenicity).
Primary immunogenicity refers to immunogenicity that peaks 2–4 weeks after completing
the recommended vaccination or vaccinations and elicits an anamnestic response to
rabies virus exposures. Since publication of the 2008 ACIP recommendations (
1
), scientists have been evaluating data concerning the efficacy of shorter rabies
PrEP dosing regimens.
Subject matter experts performed a systematic review of scientific evidence published
during 1965–2019 for a 2-dose primary vaccination series (doses administered on days
0 and 7) compared with the 3-dose series (doses administered on days 0, 7, and 21
or 28), which is indicated in the 2008 ACIP recommendations (
1
). Data showed that an anamnestic response after the 2-dose series occurs at 3 years
(
10
); however, an anamnestic response >3 years after the 2-dose series has not been evaluated.
In the absence of data confirming an anamnestic response, the Work Group evaluated
methods of inferring long-term immunogenicity (i.e., an anamnestic response >3 years
after the 2-dose primary vaccination series). Checking a titer or titers was considered
one way of inferring long-term immunogenicity as described in the PrEP schedule and
long-term immunogenicity section that follows. As an alternative to a titer check,
a second systematic review was conducted to evaluate a booster dose after the 2-dose
series compared with no booster dose. The Work Group used an adapted Grading of Recommendations
Assessment, Development and Evaluation (GRADE) approach to determine the certainty
of evidence for immunogenicity rated on a scale of 1 (high certainty) to 4 (very low
certainty). Within the evidence to recommendations (EtR) framework, ACIP considered
the importance of rabies as a public health problem; the benefits and harms (including
GRADE-assessed evidence); the target populations’ values and preferences; and issues
of resource use, acceptability to stakeholders, feasibility of implementation, and
anticipated impact on health equity.
PrEP schedule and primary immunogenicity. The systematic review identified 12 studies
that enrolled a combined total of 1,401 subjects. Studies evaluating both IM and intradermal
vaccination were included because primary immunogenicity is similar for both routes
of administration (
11
). Using the GRADE approach, the Work Group concluded with moderate (level 2) certainty
that the primary immunogenicity of the 2-dose (days 0 and 7) IM schedule is comparable
to that of the 3-dose (days 0, 7, and 21 or 28) IM schedule (risk ratio = 1.00 [95%
CI = 0.99–1.01]).
¶
ACIP deliberated whether the 2-dose (days 0 and 7) IM PrEP schedule should replace
the 3-dose schedule for all persons for whom rabies PrEP is indicated based on this
finding and other findings within the EtR framework**: the target population’s acceptability
of the 2-dose series, feasibility of implementing the 2-dose series, minimal resource
use, and anticipated increase in health equity because the 2-dose series is less expensive
than the 3-dose series.
PrEP schedule and long-term immunogenicity. Serial antibody titer checks are recommended
for persons at elevated risk for unrecognized exposures. During recent discussions,
ACIP upheld this recommendation advising that rabies antibody titers be checked every
6 months for persons in risk category 1 and every 2 years for persons in risk category
2. As previously noted, the main reason to maintain high titers is to provide some
protection from unrecognized exposures; however, high titers also ensure an anamnestic
response after an exposure (i.e., long-term immunogenicity).
For persons at sustained risk for only recognized exposures (risk category 3), checking
serial antibody titers (as recommended for risk groups 1 and 2) was determined unnecessary;
a one-time check of rabies antibody titer during years 1–3 after the 2-dose primary
series was deemed appropriate assurance of long-term immunogenicity for persons with
this risk. The rationale for this conclusion is that data indicate that an antibody
titer ≥0.5 IU/mL 1 year after a rabies PrEP schedule is a marker for long-term immunogenicity
(
12
,
13
), and the 2-dose series is known to be protective for at least 3 years (
10
).
As an alternative to the one-time titer check for risk category 3, the systematic
review identified observational data from two studies that showed a booster dose triggered
an anamnestic response up to 3 years after the 2-dose series. Because the third dose
of the PrEP series recommended in the 2008 ACIP recommendations is given as early
as day 21 and is known to provide long-term immunogenicity, a booster dose administered
from day 21 to year 3 after the primary series was considered. Using the GRADE methodology,
the Work Group concluded with low (level 3) certainty that a one-time booster dose
of rabies vaccine during day 21–year 3 after the primary vaccination series provides
better long-term immunogenicity than no booster dose; low certainty was determined
because the data were not from randomized controlled trials comparing the booster
with no booster.
††
After evaluating these data, ACIP considered an IM booster dose of rabies vaccine
during day 21–year 3 after completing the 2-dose series as an alternative to a titer
check, for persons with sustained and elevated risk for recognized rabies exposures
(i.e., those in risk category 3) from day 21 to year 3 after completing the 2-dose
series. The rationale for the recommendation
§§
within the EtR framework included the public health importance of rabies, moderately
substantial desirable anticipated effect from administering a booster dose, minimal
anticipated undesirable effects, acceptability to stakeholders, and feasibility of
implementing the booster dose.
Recommendations
After considering the evidence, ACIP recommended all persons for whom rabies PrEP
is indicated receive 2 IM doses of HDCV or PCECV on days 0 and 7. In addition, persons
in the newly defined risk category 1 should have rabies antibody titers checked every
6 months, and those in the newly defined risk category 2 should have rabies antibody
titers checked every 2 years; a booster dose should be administered if titers are
<0.5 IU/mL at the time of these title checks (Table). ACIP recommended persons in
risk category 3 either have rabies antibody titers checked during years 1–3 after
completion of the 2-dose primary series (and a booster dose if the titer is <0.5 IU/mL)
or preemptively receive a one-time IM booster dose of rabies vaccine during day 21–year
3 after completion of the 2-dose primary series (Figure). These recommendations apply
both to immunocompetent and immunocompromised persons; however, PrEP administered
to immunocompromised persons requires additional considerations as described in the
approach to PrEP section under the following Clinical Guidance.
FIGURE. Management of long-term immunogenicity* for hypothetical patients (A–E)†,§,¶
who received the Advisory Committee on Immunization Practices recommended 2-dose rabies
preexposure prophylaxis schedule** and have sustained risk for recognized exposures
(risk category 3) — Advisory Committee on Immunization Practices, United States, 2022
Abbreviations: ACIP = Advisory Committee on Immunization Practices; IM = intramuscular
injection; IU = international units; PEP = postexposure prophylaxis; PrEP = preexposure
prophylaxis; RIG = rabies immunoglobulin.
* Long-term immunogenicity is considered a successful anamnestic response (i.e., rapid
rise in antibody levels) after an encounter with the rabies virus antigen >3 years
after the primary vaccination series.
† Patient A received the recommended booster dose during day 21–year 3 and patients
B and C received the recommended one-time titer check during years 1–3. Recommended
options for patients A–C include 1) a one-time rabies vaccine booster dose from day
21 to 3 years after the 2-dose primary series (patient A) and 2) a one-time rabies
antibody titer check 1–3 years after the 2-dose primary series (patients B and C).
§ Patient D did not receive the recommended one-time titer or booster dose but was
realigned to the ACIP recommendations before an exposure occurred. Realigning involves
checking a titer. If the titer is ≥0.5 IU/mL, no further action is needed, and the
patient is considered realigned with the ACIP recommendations. If the titer is <0.5
IU/mL, patient D should receive a booster dose followed by an additional titer no
sooner than 1 week later (preferably 2-4 weeks later) to confirm the appropriate response.
¶ Patient E did not receive the recommended one-time titer or booster dose and had
an exposure before they could be realigned to the ACIP recommendations. This patient
should receive RIG and the 4-dose rabies vaccine PEP series indicated for persons
not previously vaccinated.
** An acceptable antibody titer (i.e., ≥0.5 IU/mL) should be confirmed after boosters
are administered to immunocompromised persons.
The figure is a chart showing the management of long-term immunogenicity for five
hypothetical patients who received the Advisory Committee on Immunization Practices
recommended 2-dose rabies preexposure prophylaxis schedule and have sustained risk
for recognized exposures (risk category 3) in the United States, based on updated
recommendations by the Advisory Committee on Immunization Practices in 2022.
Clinical Guidance
The Work Group identified additional considerations that are essential to effective
administration of rabies PrEP. These include coadministration of PrEP and chloroquine
(or drugs related to chloroquine), the approach to PrEP in special populations, and
management of deviations from the ACIP recommendations.
Coadministration of IM rabies PrEP and chloroquine or drugs related to chloroquine.
Recent data show that although concomitant administration of chloroquine and IM rabies
PrEP is associated with a significant reduction in rabies antibody titer, the reduced
levels remain >0.5 IU/mL (
14
). This finding is of uncertain clinical significance because immunocompetent persons
who receive chloroquine and rabies vaccines would presumably mount rabies antibody
titer levels ≥0.5 IU/mL and therefore not require management that differs from that
for persons who did not receive concomitant rabies vaccine. However, out of an abundance
of caution and because rabies is nearly always fatal, clinicians might consider avoiding
chloroquine when rabies vaccine is being administered. If avoidance is not possible,
ensuring that a patient’s rabies antibody titer is ≥0.5 IU/mL no sooner than 1 week
(preferably 2–4 weeks) after completion of the series will confirm that vaccination
was effective. No impact on efficacy was observed in the same study when other antimalarials
(i.e., Malarone [atovaquone plus proguanil] and doxycycline) were administered with
IM rabies PrEP. Limited anecdotal reports suggest mefloquine does not impair rabies
vaccine effectiveness (
15
); however, large-scale trials are needed to evaluate this hypothesis.
Approach to PrEP in special populations, including persons suspected or confirmed
to be immunocompromised. Modern rabies vaccines are inactivated and have been safely
administered to persons of all ages, including pregnant women and immunocompromised
persons. An adequate immune response is anticipated among all immunocompetent persons
(including elderly immunocompetent persons) who receive rabies vaccines in accordance
with the ACIP recommendations. For this reason, proof of primary immunogenicity through
laboratory confirmation is not advised for immunocompetent persons after the following
actions: completion of the 2-dose primary series; administration of booster doses
for serial titers <0.5 IU/mL (risk categories 1 and 2) or the one-time titer <0.5
IU/mL (risk category 3); and administration of a one-time booster dose (risk category
3).
However, among persons with primary or secondary immunodeficiencies, the immune response
to vaccines, including rabies vaccines, can be suboptimal. ACIP recommends that, when
possible, vaccination be delayed until a temporary immunocompromising condition has
resolved or immunosuppressive medications can be withheld.
¶¶
If an immunocompromising condition cannot be temporarily reversed, rabies vaccines
can be administered, but antibody titer should be checked no sooner than 1 week (preferably
2–4 weeks) (
10
) after completion of the 2-dose PrEP series and all booster doses (including those
administered within 3 years of the primary series and in response to a low titer during
the serial titer checks recommended for risk categories 1 and 2). If the titer is
<0.5 IU/mL, a booster dose should be administered, followed by a subsequent titer
check. If two such booster doses fail to elicit an acceptable antibody titer, local
or state public health authorities should be consulted for case-specific guidance.
Participation in high-risk activities by persons confirmed or suspected to be immunocompromised
should be avoided until the laboratory-confirmed minimum acceptable antibody titer
is achieved or until public health authorities provide alternative guidance. Of note,
if deviations in the ACIP recommendations occur as described in management of deviation
section below, a titer check is recommended regardless of immune status.
Management of deviations from the recommendations. Unavoidable delays of a few days
from the recommended date of the second dose of the 2-dose primary series are clinically
inconsequential. The effect of longer lapses of 2 weeks or more is unknown. When substantial
delays occur, local and state public health authorities should be consulted for guidance.
The second dose of the primary series should not be administered before the recommended
interval between doses has elapsed; if it is inadvertently administered earlier, local
and state public health authorities should be consulted for guidance.
Persons who have not previously received rabies PrEP should identify the risk category
based on their activities. If their activities change over time, the recommendations
of the new risk category should be followed to ensure long-term immunogenicity. Persons
in risk category 3 who do not obtain the titer check or booster dose recommended by
ACIP within the specified interval can be realigned with the ACIP recommendations
(i.e., they should first have a random titer checked regardless of their immune status);
for some, titers remain ≥0.5 IU/mL (
16
) and a booster dose is not required. However, for those whose titer is <0.5 IU/mL,
a booster should be administered and then titers checked no sooner than 1 week (preferably
2–4 weeks) later. Once a titer of 0.5 IU/mL is achieved, these persons should be managed
the same as persons who, consistent with the ACIP recommendations, had the recommended
titer or booster within 3 years of the 2-dose primary vaccination series vaccine (Figure).
Persons who have not realigned with the ACIP recommendations and have a rabies exposure
require the same PEP that is recommended for persons who did not receive PrEP (i.e.,
rabies immunoglobulin and 4 IM doses of rabies vaccine on days 0, 3, 7, and 14) (
17
). After this, they are considered to have been previously vaccinated, and in response
to any subsequent exposure, only require 2 doses of rabies vaccine on days 0 and 3.
Similarly, persons whose risk was categorized as category 4 (e.g., because of short-term
animal care work), might later in life shift to risk category 3 (e.g., because they
are pursuing a veterinary career). Shifts from risk category 3 to risk category 4
should be managed through realignment with the ACIP recommendations described; if
realignment is not done, in response to an exposure to rabies virus should be managed
with rabies immunoglobulin and the 4-dose rabies vaccine series (doses administered
on days 0, 3, 7, and 14)
Implications of These Updates
More persons who are recommended to receive rabies PrEP might be vaccinated because
the 2-dose series recommended in these updates is associated with lower out-of-pocket
costs and takes less time to complete. Persons with only short-term (≤3 years) risk
for rabies (risk category 4) require no additional titer or booster doses, and last-minute
travelers who previously were not vaccinated because the 3-dose series required ≥21
days might now be vaccinated because only 1 week is needed to complete the 2-dose
primary series.
The updates might also facilitate improved adherence to evidence-based ACIP recommendations.
As previously mentioned, in the past, some persons recommended to have serial titers
checked did not adhere to those recommendations; with this update, many such persons
now have the option of a one-time titer check or a one-time booster dose (i.e., a
one-time action with two options for accomplishing it). As described in the EtR framework,
some persons might prefer the titer option because of the potentially lower cost if
a booster is not indicated (i.e., titer is ≥0.5 IU/mL); others might prefer the convenience
of proceeding directly to a booster dose. The wide interval during which the titer
or booster options can be taken might defray up-front costs and allow persons more
time to determine whether they expect risk for rabies >3 years. Appointments for the
titer check or booster dose can be scheduled at the time of the 2-dose primary series
to ensure adherence to the recommendations.
Persons who received the 3-dose PrEP schedule recommended by ACIP in the past and
whose activities place them within risk category 3 require no further titer checks
or booster doses; the last vaccine dose they receive as part of the 3-dose series
is equivalent to the option provided in these updates for a booster dose during day
21 to year 3. However, frequency of serial titer checks (risk categories 1 and 2)
is unchanged, regardless of whether the 2-dose or 3-dose primary series was received
by a person.
A consequence of the updated minimum acceptable rabies antibody titer (0.5 IU/mL)
is that when titers are checked, more persons might require a booster dose than with
the previous minimum acceptable rabies antibody titer level. ACIP concluded that the
benefits of the new acceptable titer outweighed this theoretical concern.
Future Research
Ongoing studies are needed to confirm long-term immunogenicity of the 2-dose PrEP
series >3 years after the primary series. Studies are also needed to evaluate the
frequency of and need for titer checks for persons in risk categories 1 and 2 and
to examine efficacy of PrEP among immunocompromised persons.
Summary
What is already known about this topic?
Rabies is a zoonotic infection that is nearly always fatal. Preexposure prophylaxis
(PrEP) is recommended for certain persons at high risk for exposure.
What is added by this report?
During 2019–2021, the Advisory Committee on Immunization Practices made multiple updates
to the rabies PrEP recommendations, including the following: a 2-dose (days 0 and
7) intramuscular rabies vaccination series replaced the 3-dose schedule, a one-time
titer or booster dose was advised for persons with risk for only recognized rabies
exposures, risk categories were redefined, and the minimum acceptable rabies antibody
titer was changed to 0.5 IU/mL.
What are the implications for public health practice?
The updates are as efficacious as previous recommendations and might facilitate improved
adherence to vaccination recommendations.