Recommendations of the A dvisory Committee on Immunization Practices d e p a r t m e n t o f h e a l t h a n d h u m a n s e r v i c e s c e n t e r s f o r D i s e a s e C o n t r o l a n d P r e v e n t i o n MMWR T h e M M W R series o f p u b lic a tio n s is p u b lis h e d b y S u rv eillan ce, E pid em io lo g y , a n d L ab o rato ry Services, C e n te rs fo r D isease C o n tro l a n d P re v en tio n ( C D C ) , U .S . D e p a r tm e n t o f H e a lth a n d H u m a n Services, A tlan ta, G A 3 0 3 3 3 . Suggested C itation: C e n te rs fo r D isease C o n tro l a n d P revention.# Su m m a ry

# This report summarizes new recommendation and updates previous recommendations o f the Advisory Committee on Immunization Practices (ACIP) for postexposure prophylaxis (PEP) to prevent human rabies (CDC. Human rabies prevention-United States, 2008: recommendations o f the Advisory Committee on Immunization Practices. M M W R 2008;57). Previously, ACIP recommended a 5-dose rabies vaccination regimen with human diploid cell vaccine (HDCV) or purified chick embryo cell vaccine (PCECV)
. These new recommendations reduce the number o f vaccine doses to four. The reduction in doses recommended for PEP was based in part on evidence from rabies virus pathogenesis data, experimental animal work, clinical studies, and epidemiologic surveillance. These studies indicated that 4 vaccine doses in combination with rabies immune globulin (RIG) elicited adequate immune responses and that a fifth dose o f vaccine did not contribute to more favorable outcomes. For persons previously unvac cinated with rabies vaccine, the reduced regimen o f 4 1-mL doses o f H D C V or PCECV should be administered intramuscularly. The first dose o f the 4-dose course should be administered as soon as possible after exposure (day 0). Additional doses then should be administered on days 3, 7, and 14 after the first vaccination. ACIP recommendations for the use o f RIG remain unchanged. For persons who previously received a complete vaccination series (pre-or postexposure prophylaxis) with a cell-culture vaccine or who previously had a documented adequate rabies virus-neutralizing antibody titer following vaccination with noncell-culture vaccine, the recommendation for a 2-dose PEP vaccination series has not changed. Similarly, the number o f doses recommended for persons with altered immunocompetence has not changed; for such persons, PEP should continue to comprise a 5-dose vaccina tion regimen with 1 dose o f RIG. Recommendations for pre-exposure prophylaxis also remain unchanged, with 3 doses o f vaccine administered on days 0, 7, and 21 or 28. Prompt rabies PEP combining wound care, infiltration o f RIG into and around the wound, and multiple doses o f rabies cell-culture vaccine continue to be highly effective in preventing human rabies.

# Introduction
Rabies is a zoonotic disease caused by RNA viruses in the family Rhabdoviridae, genus Lyssavirus (1). Virus is transmitted in the saliva of rabid mammals via a bite. After entry to the central nervous system, these viruses cause an acute, progres sive encephalomyelitis. The incubation period usually ranges from 1 to 3 months after exposure, but can range from days to years. Rabies can be prevented by avoidance of viral exposure and initiation of prompt medical intervention when exposure does occur. In the United States, animal rabies is common. In a recent study, approximately 23,000 persons per year were estimated to have been exposed to potentially rabid animals and received rabies postexposure prophylaxis (PEP) (2). W ith the elimination of canine rabies virus variants and enzootic transmission among dogs, human rabies is now rare in the United States, with an average of one or two cases occurring annually since 1960 (3).
Prompt wound care and the administration of rabies immune globulin (RIG) and vaccine are highly effective in prevent ing human rabies following exposure. A variety of empirical schedules and vaccine doses have been recommended over time, based in part on immunogenicity and clinical experience in areas of the world with enzootic canine or wildlife rabies (4). As more potent vaccines were developed, the number of vaccine doses recommended for PEP has decreased, and studies aimed at further revision and reduction of PEP schedules and doses in humans have been encouraged. By the latter half of the 20th century, a 4-to 6-dose, intramuscular regimen using human diploid cell vaccine (HDCV) or purified chick embryo cell vac cine (PCECV) was being recommended (5-8). In the United States, a 5-dose PEP vaccine regimen was adopted during the 1980s (9-12). In 2007, when human rabies vaccine was in limited supply, an ad hoc National Rabies Working Group was formed to reassess the recommendations for rabies prevention and control in humans and other animals. In 2008, a smaller Advisory Committee on Immunization Practices (ACIP) Rabies Workgroup was formed to review rabies vaccine regimen options. This report provides updated ACIP recommendations regarding the use of a 4-dose vaccination regimen, replacing the previously recommended 5-dose regimen, for rabies PEP in previously unvaccinated persons.

# M ethods
The ACIP Rabies Workgroup- was formed in October 2008 to review 1) previous recommendations; 2) published and unpublished data from both national and global sources regard ing rabies PEP; and 3) the immunogenicity, effectiveness, and safety of a 4-dose PEP rabies vaccination regimen. The ACIP Rabies Workgroup used an evidence-based process for consid eration of a reduced vaccination regimen in human rabies PEP This approach consisted of a review of information available from basic and applied studies of rabies prevention. Because rabies is almost always fatal among immunologically naive - A list o f th e m em bership appears o n page 9 o f this report. persons once clinical symptoms of rabies occur, randomized, placebo-controlled efficacy studies of vaccine in humans cannot be conducted. The ACIP Rabies Workgroup reviewed six areas: 1) rabies virus pathogenesis, 2) experimental animal models, 3) human immunogenicity studies, 4) prophylaxis effectiveness in humans, 5) documented failures of prophylaxis in humans, and 6) vaccine safety. Studies for review were identified by searching the PubMed database and other relevant references and by consulting subject-matter experts. W hen definitive research evidence was lacking, the recommendations incor porated the expert opinion of the ACIP Rabies Workgroup members. The ACIP Rabies Workgroup also sought advice and comment from representatives of the vaccine industry, the National Association of State Public Health Veterinarians, the Council of State and Territorial Epidemiologists, state and local public health officials, additional national stakeholder groups, and other national and international experts. The proposed revised recommendations and a draft statement from the ACIP Rabies Workgroup were presented to the full ACIP during February 2009. After review and comment by ACIP, a revised draft, recommending a reduced regimen of 4 1-mL doses of rabies vaccine for PEP in previously unvaccinated persons, was prepared for consideration. These recommenda tions were discussed and accepted by ACIP at the June 2009 meeting (13).

# R a tio n ale fo r Reduced D o ses of H u m an R a b ies V accine
A detailed review of the evidence in support of a reduced, 4-dose schedule for human PEP has been published (14). The totality of the evidence, obtained from the available peerreviewed literature, unpublished data sources, epidemiologic reviews, and expert opinion strongly supports a reduced vac cination schedule (Table 1). Since the 19 th century, prophy lactic interventions against rabies have recognized the highly neurotropic characteristics of lyssaviruses and have aimed at neutralizing the virus at the site of infection before it can enter the human central nervous system (Figure 1) (4,15,16). To accomplish this, immunologic interventions must be prompt and must be directed toward local virus neutralization, such as local infiltration with RIG and vaccination. Modern recom mended rabies PEP regimens emphasize early wound care and passive immunization (i.e., infiltration of RIG in and around the wound) combined with active immunization (i.e., serial doses of rabies vaccine). Accumulated scientific evidence indi cates that, following rabies virus exposure, successful neutral ization and clearance of rabies virus mediated via appropriate PEP generally ensures patient survival (8).   The induction of a rabies virus-specific antibody response is one important immunologic component of response to vac cination (4). Development of detectable rabies virus-specific neutralizing antibodies is a surrogate for an adequate immune response to vaccination. Clinical trials of human rabies vaccina tion indicate that all healthy persons develop detectable rabies virus-neutralizing antibody titer rapidly after initiation of PEP For example, in a literature review conducted by the ACIP Rabies Workgroup of at least 12 published rabies vaccination studies during 1976-2008 representing approximately1,000 human subjects, all subjects developed rabies virus-neutralizing antibodies by day 14 (14).
Observational studies indicate that PEP is universally effec tive in preventing human rabies when administered promptly and appropriately. O f the >55,000 persons who die annually of rabies worldwide, the majority either did not receive any PEP, received some form of PEP (usually without RIG) after sub stantial delays, or were administered PEP according to sched ules that deviated substantially from current ACIP or World Health Organization recommendations (17). For example, a review of a series of 21 fatal human cases in which patients received some form of PEP indicated that 20 patients devel oped signs of illness, and most died before day 28 (Figure 2). In such cases, in which widespread infection of the central nervous system occurs before the due date (i.e., day 28) of the fifth vaccine dose, the utility of that dose must be nil. In the United States, of the 27 human rabies cases reported during 2000-2008, none of the patients had a history of receiving any PEP before illness, and this is the most common situation for human rabies deaths in both developed and developing coun tries (3,8). In India, an analysis from two animal bite centers during 2001-2002 demonstrated that in 192 human rabies cases, all deaths could be attributed to failure to seek timely and appropriate PEP, and none of them could be attributed to a failure to receive the fifth (day 28) vaccine dose (18). Even when PEP is administered imperfectly or not according to established scheduled dose recommendations, it might be generally effective. Several studies have reported cases involving persons who were exposed to potentially rabid animals and who received less than 5, 4, or even 3 doses of rabies vaccine but who nevertheless did not acquire rabies (Table 2). For example, in one series from New York, 147 (13%) of 1,132 patients had no report of receiving the complete 5-dose vaccine regimen. O f these patients, 26 (18%) received only 4 doses of vaccine, and two of these patients were exposed to animals with laboratoryconfirmed rabies. However, no documented cases of human rabies occurred (CDC, unpublished data, 2003). The ACIP Rabies Working Group estimates that >1,000 persons in the United States receive rabies prophylaxis annually of only 3 or 4 doses, with no resulting documented cases of human rabies, even though >30% of these persons likely have exposure to confirmed rabid animals (14). In addition, no case of human rabies in the United States has been reported in which failure of PEP was attributable to receiving less than the 5-dose vac cine course. Worldwide, although human PEP failures have been reported very rarely, even in cases in which intervention appeared both prompt and appropriate (8), no cases have been attributed to the lack of receipt of the fifth human rabies vac cine dose on day 28 (4,17).
In vivo laboratory animal studies using multiple animal mod els from rodents to nonhuman primates have underscored the importance of timely PEP using RIG and vaccine, regardless of the absolute number of vaccine doses used or the schedule (14,19). For example, in a study in which 1, 2, 3, 4, or 5 doses of rabies vaccine were used in a Syrian hamster model in combination with human rabies immune globulin (HRIG), no statistically significant differences in elicited protection and consequent survivorship were observed among groups receiving different doses (20). In the same study, using a murine model, no differences were detected in immunogenicity and efficacy of PEP with 2, 3, or 4 vaccine doses. In another study using a nonhuman primate model, 1 dose of cell-culture vaccine, in combination with RIG administered 6 hours postexposure, provided substantial protection (21). In another study, a 3-dose regime was evaluated in a canine model and determined to be effective in preventing rabies (22).
Compared with older, nerve tissue-based products, adverse reactions associated with modern human rabies vaccination are uncommon (4). A review by the Workgroup of published and unpublished human rabies vaccine clinical trials and Vaccine Adverse Event Reporting System data identified no adverse events that were correlated to a failure to receive the fifth vac cine dose. As some adverse reactions might be independent clinical events with each vaccine administration, the omission of the vaccine dose on day 28 might have some positive health benefits. Otherwise, the overall safety of human rabies PEP is expected to be unchanged from the evidence provided in the 2008 ACIP report (12).
Preliminary economic assessments support the cost savings associated with a reduced schedule of vaccination (23,24). The ACIP Rabies Workgroup has estimated that, assuming 100% compliance with a recommended vaccine regimen, a change in recommendation from a 5-dose schedule to a 4-dose schedule would save approximately $16.6 million in costs to the U.S. health-care system. Persons who receive rabies vaccination might see some savings related to deletion of the fifth recommended dose of vaccine, measured in both the cost of the vaccine and the costs associated with the additional medical visit.

# R evised R a b ies P o ste x p o su re P ro p h y la x is R eco m m endatio n s
This report presents revised recommendations for human rabies PEP (Table 3). Rabies PEP includes wound care and administration of both RIG and vaccine.

# Postexposure Prophylaxis for Unvaccinated Persons
For unvaccinated persons, the combination of RIG and vaccine is recommended for both bite and nonbite exposures, regardless of the time interval between exposure and initiation   of PEP. If PEP has been initiated and appropriate laboratory diagnostic testing (i.e., the direct fluorescent antibody test) indicates that the animal that caused the exposure was not rabid, PEP may be discontinued.

# Vaccine Use
A regimen of 4 1-mL vaccine doses of H D CV or PCECV should be administered intramuscularly to previously unvac cinated persons (Table 3). The first dose of the 4-dose regimen should be administered as soon as possible after exposure. The date of the first dose is considered to be day 0 of the PEP series. Additional doses then should be administered on days 3, 7, and 14 after the first vaccination. Recommendations for the site of the intramuscular vaccination remain unchanged (e.g., for adults, the deltoid area; for children, the anterolateral aspect of the thigh also is acceptable). The gluteal area should not be used because administration of vaccine in this area might result in a diminished immunologic response. Children should receive the same vaccine dose (i.e., vaccine volume) as recommended for adults.

# HRIG Use
The recommendations for use of immune globulin in rabies prophylaxis remain unchanged by the revised recommendation of a reduced rabies vaccine schedule. HRIG is administered once to previously unvaccinated persons to provide rabies virusneutralizing antibody coverage until the patient responds to vaccination by actively producing virus-neutralizing antibodies. HRIG is administered once on day 0 at the time PEP is initi ated, in conjunction with human rabies vaccines available for use in the United States. If HRIG was not administered when vaccination was begun on day 0, it can be administered up to and including day 7 of the PEP series (12,25). If anatomically feasible, the full dose of HRIG is infiltrated around and into any wounds. Any remaining volume is injected intramuscu larly at a site distant from vaccine administration. HRIG is not administered in the same syringe or at the same anatomic site as the first vaccine dose. However, subsequent doses (i.e., on days 3, 7, and 14) of vaccine in the 4-dose vaccine series can be administered in the same anatomic location in which HRIG was administered.

# Postexposure Prophylaxis for Previously Vaccinated Persons
Recommendations for PEP have not changed for persons who were vaccinated previously. Previously vaccinated persons are those who have received one of the ACIP-recommended pre-or postexposure prophylaxis regimens (with cell-culture vaccines) or those who received another vaccine regimen (or vaccines other than cell-culture vaccine) and had a docu mented adequate rabies virus-neutralizing antibody response. Previously vaccinated persons, as defined above, should receive 2 vaccine doses (1.0 mL each in the deltoid), the first dose immediately and the second dose 3 days later. Administration of HRIG is unnecessary, and HRIG should not be administered to previously vaccinated persons to avoid possible inhibition of the relative strength or rapidity of an expected anamnestic response (26). Local wound care remains an important part of rabies PEP for any previously vaccinated persons.

# V accin atio n a n d Serologic Testing Postvaccination Serologic testing
All healthy persons tested in accordance with ACIP guide lines after completion of at least a 4-dose regimen of rabies PEP should demonstrate an adequate antibody response against rabies virus (14). Therefore, no routine testing of healthy patients completing PEP is necessary to document serocon version (12). W hen titers are obtained, serum specimens col lected 1-2 weeks after prophylaxis (after last dose of vaccine) should completely neutralize challenge virus at least at a 1:5 serum dilution by the rapid fluorescent focus inhibition test (RFFIT). The rabies virus-neutralizing antibody titers will decline gradually since the last vaccination. Minimal differ ences (i.e., within one dilution of sera) in the reported values of rabies virus-neutralizing antibody results might occur between laboratories that provide antibody determination using the recommended RFFIT. Commercial rabies virus antibody titer determination kits that are not approved by the Food and Drug Administration are not appropriate for use as a substitute for the RFFIT. Discrepant results might occur after the use of such tests, and actual virus-neutralizing activity in clinical specimens cannot be measured.

# M a n a g e m e n t of A d v e rse R eactio n s, P recau tio n s, a n d C o n train d icatio n s M anagement of Adverse Reactions
Recommendations for management and reporting of vaccine adverse events have not changed. These recommendations have been described in detail previously (12).

# Immunosuppression
Recommendations for rabies pre-and postexposure pro phylaxis for persons with immunosuppression have not changed. General recommendations for active and passive immunization in persons with altered immunocompetence have been summarized previously (27,28). This updated report discusses specific recommendations for patients with altered immunocompetence who require rabies pre-and postexposure prophylaxis. All rabies vaccines licensed in the United States are inactivated cell-culture vaccines that can be administered safely to persons with altered immunocompetence. Because corticosteroids, other immunosuppressive agents, antimalarials, and immunosuppressive illnesses might reduce immune responses to rabies vaccines substantially, for persons with immunosuppression, rabies PEP should be administered using a 5-dose vaccine regimen (i.e., 1 dose of vaccine on days 0, 3, 7, 14, and 28), with the understanding that the immune response still might be inadequate. Immunosuppressive agents should not be administered during rabies PEP unless essential for the treatment of other conditions. If possible, immunosuppressed patients should postpone rabies preexposure prophylaxis until the immunocompromising condition is resolved. W hen post ponement is not possible, immunosuppressed persons who are at risk for rabies should have their virus-neutralizing antibody responses checked after completing the preexposure series. Postvaccination rabies virus-neutralizing antibody values might be less than adequate among immunosuppressed persons with HIV or other infections (29,30). W hen rabies pre-or postex posure prophylaxis is administered to an immunosuppressed person, one or more serum samples should be tested for rabies virus-neutralizing antibody by the RFFIT to ensure that an acceptable antibody response has developed after completing the series. If no acceptable antibody response is detected after the final dose in the pre-or postexposure prophylaxis series, the patient should be managed in consultation with their physician and appropriate public health officials.

# V a ria tio n from H u m an R ab ies V accin e P a c k a g e In serts
These new ACIP recommendations differ from current rabies vaccine label instructions, which still list the 5-dose series for PEP. Historically, ACIP review and subsequent public health recommendations for the use of various biologics has occurred after vaccine licensure and generally are in agreement with product labels. However, differences between ACIP recom mendations and product labels are not unprecedented. For example, during the early 1980s, ACIP review and recom mendations concerning the intradermal use of rabies vaccines occurred well in advance of actual label claims and licensing (9). O n the basis of discussions with industry representatives, alterations of current product labels for H D CV and PCEC are not anticipated by the producers of human rabies vaccines licensed for use in the United States. Rev In fec t D is 1 9 8 8 ;1 0 (S u p p l 4 ):S 7 3 9 -5 0 . 20. F ran k a R, W u X , Jack so n RF, e t al. Rabies virus pathog en esis in re latio n sh ip to in te rv e n tio n w ith inactiv ated a n d a tte n u a te d rabies vaccines.
V accine 2 0 0 9 ;2 7 :7 1 4 9 -5 5 . 21. Sikes R K , C leary W F, K oprow ski H , W ik to r T J,