INFORMATION SHEET

OBSERVED RATE OF VACCINE REACTIONS

Global Vaccine Safety,
Immunization, Vaccines and Biologicals
RABIES VACCINE
20, avenue Appia, Ch-1211 Geneva 27 June 2012

The Vaccines
There are three main types of rabies vaccine, the outdated nerve tissue vaccines, cell culture vaccines, and embryonated egg
vaccines.
Cell culture vaccines and embryonated egg vaccines have replaced nerve tissue vaccines in industrialized countries and are the
ones recommended for use by WHO. They are considered safe and well tolerated (Briggs et al., 2000, WHO, 2010 B). In
comparison, nerve tissue vaccines can induce severe adverse reactions including a potential risk of rabies from incomplete virus
inactivation (Plotkin, 2008) and are less immunogenic. They are still used in a limited and decreasing number of developing
countries.

Nerve tissue vaccines

 Semple rabies vaccine contains a phenol or ß-propiolactone-inactivated homogenate of rabies virus-infected goat or sheep
brain tissue. The vaccine contains myelin basic protein and is used in an ever decreasing number of countries in Asia and
Africa.
 Fuenzalida rabies vaccine is prepared from suckling mouse brain tissue and has decreased myelin content (Nogueira, 1988).
This vaccine is used in a small number of Latin American countries.

Cell Culture Vaccines and Embryonated egg-based vaccines (CCEEV)

Cell Culture Vaccines (CCV)
 Human diploid cell vaccine (HDCV) contains the Pitman-Moore L503 or Flury strain of rabies virus grown on MRC-5 human
diploid cell culture, concentrated by ultrafiltration and inactivated with ß-propiolactone (Wiktor et al., 1980). This vaccine is
licensed for intra-muscular use. It contains no preservative or stabilizer.
 Purified chick embryo cell vaccine (PCECV) is a sterile lyophilized vaccine obtained by growing the fixed rabies virus strain
Flury LEP-25 in primary cultures of chick fibroblasts. The virus is inactivated with ß-propiolactone, purified and
concentrated by zonal centrifugation (CDC, 1998; Dreesen, 1997).
 Purified Vero cell rabies vaccine (PVRV) contains inactivated and lyophilized Wistar strain of rabies virus grown on Vero
cell cultures in fermenters allowing mass cultivation. These are inactivated by ß-propriolactone and purified by
ultracentrifugation (Jaiiaroensup et al., 1998).
 Primary Hamster Kidney Cell vaccine (PHKCV) uses the Beijing strain and is inactivated with formalin and adsorbed to
aluminum hydroxide. It also contains 0.01% thiomersal and 10 mg human albumin.

Embryonated egg-based vaccines (EEV)

 Purified duck embryo vaccine (PDEV) uses duck embryo cells as substrate. These are inactivated by ß-propiolactone and
purified by ultracentrifugation. PDEV contains thiomersal.

Adverse events
Mild adverse events
Local adverse events
Nerve Tissue Vaccines
Pain, swelling, tenderness, itching, erythematous patches may develop after the beginning of the anti-rabies treatment, fading in 6-8
hours and reappearing after the next dose.

Cell Culture Vaccines and Embryonated egg-based vaccines

 HDCV – Mild, transient local reactions (e.g., pain at the injection site, redness, swelling, and induration) occurred among 60
to 89.5 per 100 vaccinees. Most frequently reported was pain at the injection site occurring in 21—77 per 100 vaccinees
(CDC 2008).
 PCECV – Similar, but less frequent local reactions than HDCV have been noted at a frequency of 4 per 100 vaccinees
(Dutta JK, 1994; WHO, 2010 B)
 PVRV – Similar, but less frequent local reactions than HDCV have been noted among 7 per 100 vaccinees in an evaluation
of safety of PVRV following post-exposure immunization (Wang, 2000; WHO, 2010 B).
Intradermal versus Intramuscular vaccination - Following post-exposure immunization adverse reactions were observed more
frequent in patients receiving intradermal immunization of PCECV (48 per 100 vaccinees) or PVRV (51 per 100 vaccinees), as
compared to patients who received intramuscular injections of this vaccine (33 per 100 vaccinees). All reactions were mild and
resolved without treatment. In decreasing order of frequency, adverse reactions included erythema, pain and or swelling at the site
of injection, and fever. (Briggs et al., 2000; Charanasri et al., 1992; Tanterdtham et al., 1991, Suntharasamai et al., 1994; Quiambao
et al., 2005).
Systemic adverse events
Systemic reactions occur less frequent compared to local reactions.
Nerve Tissue Vaccines
Systemic adverse events may include fever, headache, insomnia, palpitations and diarrhea (Wiktor, 1980).

Cell Culture Vaccines and Embryonated egg-based vaccines

 HDCV – Mild, transient systemic reactions include fever, headache, dizziness, and gastrointestinal symptoms that have
been reported among 7-55.6 per 100 HDCV vaccinees (CDC 2008, Dreesen et al., 1997).
 PCECV - Fifteen per 100 vaccinees reported general symptoms.
 PVRV - Among PVRV vaccinees, mild and moderate reactions were infrequent, but similar after i.d. and i.m. vaccinations.
Fever was seen in less than 6 per 100 vaccinees. Reactions after booster immunization were not different from those
following immunization.

Severe adverse events

Severe adverse events are rare. They occur more common with nerve tissue vaccines than with CCEEV.

Nerve Tissue Vaccines

Neurological - Severe adverse events have been mainly neurological and resulted from an immune response to the myelin basic
protein contained in the vaccine (Piyasirisilp et al., 1999). The incidence of these reactions varies widely from 0.0017 per 100 to 0.44
per 100 and is definitely lower in people receiving Cell Culture Vaccines and Embryonated egg-based vaccines and in people
receiving properly manufactured vaccine of suckling mouse brain (Plotkin S et al., 2008). The reactions are neuro-paralytic and
occur approximately 2 weeks after vaccination. They include:
 Meningo-encephalomyelitis
 Mono-neuritis multiplex – which may affect facial, oculomotor, glossopharyngeal, vagus or the optic nerve.
 Dorsolumbar transverse myelitis – which results in lower limb paralysis, decreased sensation and sphincter disturbance.
 Ascending paralysis of the Landry type (i.e. sudden onset of flaccid paralysis of the legs, followed by paralysis of the arms,
usually developing between one to two weeks after the first injection).

Following administration of the Semple vaccine, the incidence of cases of neurological complications reported in the literature varies
greatly, ranging from 0.14 per 1,000 to 7 per 1,000 cases per treatments. In the best surveys conducted among large numbers of
patients in one institution in charge of post-exposure treatment, complications varied from 0.1 per 1,000 to 7 per 1,000 vaccinees
with a case fatality rate of up to 10%. In case of Landry paralysis, the case fatality rate could reach 30% (Bahri et al., 1996). The
Fuenzalida-type vaccine was associated with neurological complications in about 0.12 per 1,000 to 0.037 per 1000 courses
including post-vaccination neuroparalytic syndromes resembling Guillain-Barré syndrome (Noguiera, 1998, Meslin et al., 1996) with
a case fatality rate of 22% (Meslin et al., quoting Held et al., 1971).

Cell Culture Vaccines and Embryonated egg-based vaccines

Neurological – At least five cases of central nervous system disease, including transient neuroparalytic illness of Guillain–Barré type,
have been reported among the millions of individuals given HDCV (Bernard et al., 1982; Boe & Nyland, 1980; Knittel et al., 1989;
Tornatore & Richert, 1990; Moulignier et al., 1991). This rate may not be an increase above the background rate of about 1 per
100,000 per year (Plotkin et al., 2008). This low incidence after HDCV compares with a neurological complication rate of 0.625 per
1000 after nerve tissue vaccines, 0.125 per 1000 after suckling mouse brain vaccine and 0.031 per 1000 for PDEV (Plotkin et al.,
2008).

Other adverse events - To corroborate the safety of Cell Culture Vaccines, the U.S. Food and Drug Administration (FDA) and CDC
commented on rabies vaccine safety, reported through the Vaccine Adverse Event Reporting System (VAERS), to review 336
reports of adverse events following vaccination with PCECV in the U.S. (Dobardzic et al., 2007). Of the reported incidents 93% were
non-serious and consistent with pre-licensure safety data. There were no reported deaths or serious events. Among the 7% of
reports describing serious events were 20 hospitalizations and 13 neurological events. There was no pattern among the 13
neurological events beyond temporal relationship to vaccination. A total of 20 events, 3 serious, were classified as possible
anaphylaxis.

Immunological - A rarer immune complex-like reaction (characterized by urticaria and sometimes including arthralgia, angioedema,
nausea, vomiting, fever and malaise) has been noted in approximately 6 per 100 vaccinees receiving booster doses of HDCV.
This reaction was less common in persons undergoing primary immunization (WHO 2002; Dreesen, 1986). In no case have these
reactions been life-threatening. The reactions have been attributed to antigenicity conferred on the stabilizer – human albumin – by
the beta-propiolactone used to inactivate the virus. The beta-propiolactone increases the capacity of albumin to form immune
complexes (CDC, 1984; Anderson et al., 1987; Swanson et al., 1987).
Respiratory symptoms are mild. Epinephrine, antihistamines and occasionally steroids have been used in successful treatment of
these reactions, which have resolved in 2 to 3 days (Plotkin et al., 2008).
Allergic reactions have been noted after administration of PDEV (Dreesen, 1997).
Summary of mild and severe adverse events
Nature of Description Rate/doses
Adverse event
Mild

Nerve tissue Local reactions

vaccines Pain, swelling, tenderness, itching and
erythematous patches

Systemic reactions
fever, headache, insomnia, palpitations and
diarrhoea

Cell Culture and Local reactions

Embryonated HDCV (e.g. fever, headache, dizziness, and 21-74 per 100
egg-based gastrointestinal symptoms
vaccines PCECV 4 per 100
PVRV (e.g. pruritus, erythematous rash, and pain) 7 per 100

Systemic
HDCV
- Transient fever, headache, dizziness, and 7 – 55.6 per 100
gastrointestinal symptoms
- Immune complex-like reaction, 1st dose 1.1 per 1000
- Immune complex-like reaction, booster dose 6 per 100
Severe
Neurological events
Nerve tissue Meningo-encephalomyelitis, mono-neuritis
reported but no
vaccines multiplex, dorsolumbar transverse myelitis and
evidence of a
ascending paralysis of the Landry type.
pattern of neurologic
events plausibly
Cell Culture and Neurological disease
related to
Embryonated
vaccination
egg-based
vaccines

This information sheet has been developed in close collaboration with the Global Advisory Committee on Vaccine Safety
(GACVS). GACVS experts are independent and have declared no interests related to the expertise displayed in this product.
Information displayed has been developed using primary sources such (Plotkin et al., 2008, Institute of Medicine of the National
Academies 2011) and from data derived from a literature search on Pubmed in 2008 using key words “vaccine antigen”, “Safety”
and “adverse events”. An independent expert provided a first draft which was reviewed by nominated experts and the GACVS.
Data of different vaccines that may be found in this product should only be compared if there is indication that a comparative
randomized controlled trial has been undertaken. The information sheets will be updated as new information may become
available at the following web link: http://www.who.int/vaccine_safety/vaccrates/en/index.html

Immunization, Vaccines and Biologicals Department

Geneva, 12 March 2012
Quality, Safety & Standards
Global Vaccine Safety
[email protected]
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