VA C C INE UPDATE S

Epidemiology of Rabies and Current US Vaccine Guidelines

CHRISTINA LIU, MD; JOHN D. CAHILL, MD

A BST RA C T transmission has never been confirmed except in extremely

Rabies is an acute encephalitis that is caused by rabies rare case reports of transmission from infected tissue/
virus (RABV) infection, which belongs to the Rhabdo- organ transplantation.1 The incubation period on average
viridae family of viruses. It causes about 59,000 human lasts 1–3 months, but has been documented to range from
deaths per year (although this number may be under-re- weeks up to more than a year. Clinical rabies rarely occurs
ported) and is generally fatal, once signs and symptoms after one year from exposure.2 Signs and symptoms include
begin to appear. Rabies is still very prevalent and under- pain/paresthesias at the wound site, fever, paralysis, delir-
reported, particularly in low to middle-income countries ium, convulsions, and hydrophobia. Death is almost always
such as Asia and Africa, where there is lack of access to imminent within 7–10 days once the infection clinically
healthcare and domestic dogs are not widely vaccinated. manifests itself. The rabies vaccine and rabies immunoglob-
Although not commonplace in the USA, rabies is most- ulin (RIG) are very effective in preventing rabies if adminis-
ly transmitted by wild animals such as bats, raccoons, tered during the incubation period. Rabies vaccines activate
skunks and foxes. Domesticated cats and dogs are also at the immune system to produce rabies virus neutralizing
risk of acquiring rabies, if they have not been vaccinat- antibodies (VNAs). Detectable antibodies take about 7–10
ed. Larger carnivores, such as coyotes, bobcats, mountain days to develop and generally last for several years.
lions, wolves, bears, woodchucks, and beavers, should Louis Pasteur and Emile Roux developed and tested the
also be considered rabid (unless proven otherwise) if they first live attenuated injectable rabies vaccine in 1885. It
are involved in an unprovoked attack on a person. The was made from rabbit nerve tissue. Since 1984, the WHO
rabies vaccine can prevent 99% of deaths if administered has recommended discontinuation of production and use of
promptly after exposure. There are two main vaccination nerve tissue vaccines and replacing them with modern, con-
strategies for rabies prevention: pre-exposure prophylaxis centrated, purified cell culture and embryonated egg-based
(PrEP) and post-exposure prophylaxis (PEP). This article rabies vaccines (CCEEVs). Nerve tissue vaccines can cause
reviews background and epidemiology of rabies and cur- severe adverse events and are not as effective. However, they
rent guidelines for rabies PrEP and PEP regimens for the are still being used in some developing countries. Since the
United States. 1960s, CCEEVs have been widely distributed and used in
K E YWORD S: rabies, animal bites, dogs, rabies vaccine, the U.S.2 There are two types of CCEEVs licensed for use
rabies immunoglobulin in the U.S: human diploid cell vaccine (HDCV) and purified
chick embryo cell vaccine (PCECV). Both are formulated for
intramuscular (IM) administration and can be used for pre-
or post-exposure prophylaxis.3 Intradermal injections are
sometimes used off license in the USA, but are not approved
BA C K GRO U N D by the FDA.
Rabies is an acute progressive encephalitis caused by the There are two human RIG, HyperRabTM S/D and Imogam®
rabies virus (RABV), a single stranded RNA virus that’s part Rabies-HT, licensed for use in the U.S. for PEP. They are
of the family Rhabdoviridae, genus Lyssavirus. The virus is IgG preparations made from human donor plasma and for-
most commonly transmitted through the saliva of a rabid mulated for IM administration only.3 RIG provides passive
animal. It can also be transmitted through exposure to urine, immunity that is intended to protect the victim until active
sweat, and nervous tissues. RABV is not considered to be a immunity produced by the administered vaccine kicks in.
bloodborne pathogen. When a human/animal is bitten by a
rabid animal, the virus travels from the bite wound into the
peripheral nervous system and then makes its way to the EP ID EMIOLOGY
brain where the virus replicates and then disseminates back Rabies causes about 59,000 deaths globally per year and
into various tissues, including the salivary glands, where associated loss of 3.7 million disease associated life years
the transmission cycle repeats itself. Human-to-human (DALYs). The majority of deaths occur in Asia and Africa.2

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Children under 15 years account for approximately 40% of veterinarians, wildlife workers in areas where rabies is
deaths.5 Children are more susceptible because of their curi- enzootic) require antibody titer testing every 2 years. If titers
ous nature and their shorter stature, making them more likely fall under the acceptable level of complete neutralization at
to sustain a wound in a higher-risk anatomical location such a serum dilution of 1:5, a single IM booster vaccine should
as the head.1 Transmission by unvaccinated domestic dogs be administered. Routine antibody testing for travelers in
is responsible for the majority of human rabies cases glob- the infrequent risk exposure category is not recommended.
ally. Mass vaccination of domestic dogs has been an effec-
tive strategy at decreasing the prevalence of rabies in many
countries in Africa, Asia, Europe and the Americas. Dog-me- P OSTEXP OSU RE P ROP HY LA XIS ( P EP )
diated rabies has been eliminated from the U.S. (i.e. no cases All persons exposed to rabies should start by thoroughly
of dog-mediated rabies in the last 2 years).2 Rabies in the U.S. washing and cleaning out the wound with soap and water
is rare and is now primarily transmitted through wild ani- or a virucidal agent. This should be followed immediately
mal vectors such as bats, foxes, raccoons, and skunks. Since by passive rabies immunization with RIG in unvaccinated
1980, there has been an average of 2 deaths per year in the patients and vaccination with a cell culture rabies vaccine.
U.S. Between 2000 and 2007, 20 of 25 cases of human rabies HRIG is made from the plasma of hyperimmunized healthy
reported in the United States were acquired domestically. volunteers and is not easily accessible in some resource poor
Among those 20 cases, 17 were associated with bat rabies settings. Equine rabies immunoglobulin may also be used as
virus variants.4 The rate of rabies exposures is about 16 to an alternative if HRIG is not available.
200 per 100,000 travelers.1 Approximately 16,000 to 39,000 After a Rabies Workgroup met in 2008 to review current
patients are exposed to rabies and receive PEP annually in literature and expert opinion, the ACIP published revised
the U.S. Since routine use of cell culture vaccines and HRIG, guidelines in favor of reducing PEP vaccination from 5 doses
no PEP failures have been reported in the United States. to 4 doses.5 Unvaccinated individuals should receive four
1-mL dose vaccines and RIG promptly after being exposed
to the rabies virus. For adults and older children, the only
PREEXP O S U RE P R OP H Y L AX I S (P R E P ) acceptable area to administer the vaccine is in the deltoid
PrEP should be offered to high-risk populations, such as area. In younger children, the outer thigh can be used as
travelers who will spend a long time in a rabies endemic well. Vaccine should never be administered in the gluteal
country, veterinarians and their staff, animal handlers, area because efficacy is decreased.
rabies researchers, certain laboratory workers, and those The first dose of the vaccine should be administered as
with frequent exposures to rabid animals (i.e. cavers, animal soon as possible after the exposure on what is considered
control officers). day 0. It can also be started weeks to months after exposure
In the United States, the Advisory Committee on Immu- within the incubation period if signs and symptoms of rabies
nization Practices (ACIP) recommends a series of three 1-mL have not yet appeared. The next 3 doses should then be
IM injections in the deltoid. Immunizations should be admin- administered on days 3, 7, and 14 after the first vaccination.
istered on days 0, 7, 21 or 28. If exposed to rabies, PrEP does Serum antibody titer testing is not recommended for healthy
not eliminate the need to seek out PEP; however, it reduces patients as the vaccine has been shown to consistently
the number of vaccine injections post-exposure and elim- produce adequate VNAs.
inates the need for RIG. A few studies have demonstrated For immunosuppressed persons, rabies PEP should be
that a two-dose regimen given over the course of a week is administered by using the 5-dose vaccine regimen (ie, 1 dose
just as effective as three doses, and more cost-effective. of vaccine on days 0, 3, 7, 14, and 28). Immunosuppressed
Rabies occurs most often in resource limited settings. A patients should undergo rabies serum antibody testing 1 to
clinical trial of 500 healthy volunteers showed that an intra- 2 weeks after the fifth dose of vaccine. The WHO specified
dermal 2-dose regimen given on days 0 and 7 did not elicit minimum serum antibody concentration of 0.5 IU/mL is
less of an immune response compared with a 3-dose regimen widely used as a measure of adequate seroconversion after
given over the course of a month.6 The WHO recommends vaccination.2
a 2-dose vaccination regimen in resource limited settings RIG should only be administered once on day 0 to exposed
given on days 0 and 7 given either IM or ID. humans who have never previously received a complete
vaccination regimen (pre- or post-exposure). If RIG admin-
istration is delayed, it can be administered at any time up
SER O L O GI C T ES T I NG to day 7.2 HRIG is intended to provide passive rabies VNAs
Rabies virus researchers or those who work in vaccine while the active antibody production is occurring. After day
production are at highest risk for rabies and should get 7, we presume that antibodies have already been produced
virus neutralizing antibody titer testing every 6 months. from vaccine administration. The recommended dose for
Those in the frequent exposure risk category (i.e. cavers, patients of all ages is 20 IU/kg of body weight. RIG should be

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 VA C C INE UPDATE S

infiltrated around the wound(s) as much as possible and any References

remaining volume should be administered IM at an anatom- 1. Centers for Disease Control and Prevention. CDC Yellow Book
2020: Health Information for International Travel. New York:
ical site distant from vaccine administration. RIG should Oxford University Press; 2017.
be administered in a different syringe than the vaccine. No 2. World Health Organization. Weekly epidemiological record, No
more than the recommended dose should be given because 16. 20 April 2018. http://apps.who.int.eresources.mssm.edu/iris/
it may suppress active immunity production.3 bitstream/handle/10665/272371/WER9316.pdf?ua=1 (Accessed
on July 20, 2020).
Persons who have previously received complete vaccina-
3. CDC. Human rabies prevention – United States, 2008: recom-
tion regimens (pre-exposure or postexposure) with a rabies mendations of the Advisory Committee on Immunization Prac-
vaccine and have a documented rabies virus neutralizing tices (ACIP). MMWR. 2008;57(No. RR-3).
antibody titer should receive only 2 vaccine injections 3 days 4. Committee on Infectious Diseases. Rabies-Prevention Policy
Update: New Reduced-Dose Schedule. Pediatrics. 2011;127:785.
apart (i.e. days 0 and 3). RIG should not be administered.
5. Rupprecht CE, Briggs D, Brown CM, et al. Use of a reduced
If an individual has a repeat exposure within 3 months, (4-dose) vaccine schedule for postexposure prophylaxis to pre-
RIG and vaccine are not indicated. However, if the repeat vent human rabies: recommendations of the advisory commit-
exposure occurs >3 months, then the protocol for postexpo- tee on immunization practices [published correction appears
in MMWR Recomm Rep. 2010 Apr 30;59(16):493]. MMWR
sure prophylaxis in a person who has been previously vac- Recomm Rep. 2010;59(RR-2):1-9.
cinated should be followed (i.e. IM injection of vaccine on 6. Preexposure Intradermal Rabies Vaccination: A Noninferiority
days 0 and 3).2 Trial in Healthy Adults on Shortening the Vaccination Schedule
From 28 to 7 Days. Soentjens P, Andries P, Aerssens A, Tsou-
Minor deviations from the schedule by a few days are
manis A, Ravinetto R, Heuninckx W, van Loen H, Brochier B,
inconsequential. The schedule should be resumed with the Van Gucht S, Van Damme P, Van Herrewege Y, Bottieau E. Clin
same intervals between doses. For more substantial devia- Infect Dis. 2019;68(4):607.
tions from the schedule, antibody titers should be checked 7. Chutivongse S, Wilde H, Benjavongkulchai M, Chomchey P,
Punthawong S. Postexposure rabies vaccination during preg-
1–2 weeks after the final dose of the vaccine is administered, nancy: effect on 202 women and their infants. Clin Infect Dis.
as effects have not been properly studied. 1995;20:818–20.
Post exposure prophylaxis can be discontinued if the
Authors
appropriate diagnostic laboratory testing (i.e., the direct flu-
Christina Liu, MD, Icahn School of Medicine at Mount Sinai,
orescent antibody test) concludes that the animal in question Third-Year Emergency Medicine Resident.
was not rabid. John D. Cahill, MD, Assistant Professor of Medicine and
Emergency Medicine, Icahn School of Medicine at Mount
Sinai; Adjunct Assistant Professor of Emergency Medicine,
A DVERS E EFFECT S AND Alpert Medical School of Brown University, Providence, RI.
SPEC I A L C O N S IDE R AT I ONS
Correspondence
Serious hypersensitivity, neurological, and fatal adverse John D. Cahill, MD
events following immunization are extremely rare. Consid- Assistant Professor of Medicine and Emergency Medicine
ering the risk of death from rabies, there are no contraindi- Icahn School of Medicine at Mount Sinai
cations to rabies vaccination. Local symptoms of erythema, 2109 Broadway, NY, NY 10023
pain and swelling at the site of injection commonly occur. 212-523-8672
Mild systemic symptoms such as transient fever, headache, Johndcahill@gmail.com
dizziness, nausea, and abdominal pain can present in about
5–15% of people after receiving the vaccine.2 Prophylaxis
should not be discontinued or interrupted because of minor
or local adverse events.
Rabies vaccines and RIG should be administered normally
to infants and children. Limited data suggests that rabies
vaccines are safe in pregnancy and is not associated with
abortion, premature births, or fetal abnormalities.7
Some studies suggest that antimalarial prophylaxis with
chloroquine may blunt the immune response to rabies
vaccine. According to the WHO, the effect of antimalarial
agents on antibody production is unlikely to be clinically
significant. They previously recommended IM over ID
administration in persons taking antimalarial prophylaxis
but removed this statement from their 2018 position paper.2

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