Rabies and Intradermal

Rabies Vaccination
Alan C. Jackson, MD
Professor of Medicine (Neurology)
and of Medical Microbiology
Head, Section of Neurology
University of Manitoba
Winnipeg, Manitoba, Canada

Rabies virus structure

Envelope

Matrix protein

Glycoprotein

Nucleocapsid protein

Source: http://www.cdc.gov

Human rabies

Photo courtesy of David Warrell, UK

Clinical forms of rabies

encephalitic = furious

~ 80%

paralytic = dumb

~ 20%

Encephalitic rabies
prodromal

symptoms
paresthesias/pain/pruritus at site of bite
episodes of generalized arousal or
hyperexcitability separated by lucid
periods
autonomic dysfunction
hydrophobia

Paralytic rabies

paresthesias/pain/pruritus at site of bite

early flaccid muscle weakness

often begins in bitten extremity

progresses to produce quadriparesis
bilateral facial weakness

sensory examination is usually normal

sphincter involvement
fatal outcome
often misdiagnosed as Guillain - Barr syndrome

Geographic distribution of rabies - 2000

No information: DRC, Benin ,Burkina, Sierra Leone, Liberia, Gambia,

Mauritania, Somalia, Yemen, Malaysia, Laos, Myanmar, Vietnam
Cambodia, North Korea

DALY (disability-adjusted life year) scores =

years of life lost + years of life with a disability
Disease

Total DALYs lost (X 1000)

Malaria

42,280

Tuberculosis

36,040

Lymphatic filariasis

5,644

Leishmaniosis

2.357

Schistosomiasis

1,760

Trypanosomiasis

1,598

Rabies

1,160

Onchocerciasis

987

Dengue

653

Chagas

649

Leprosy

177

Emerg Inf Dis 10, 2004

Human rabies prevention

United States

Recommendations of the CDCs

Advisory Committee on Immunization Practices
MMWR Recommendations and Reports
January 8, 1999
http://www.cdc.gov/mmwr

Rabies postexposure guide:

exposure to dogs, cats, and ferrets
Evaluation of Animal

Recommendation

Healthy and available for

10 days observation

No treatment unless
animal develops clinical
signs of rabies

Rabid or suspected rabid

Immediate treatment*

Unknown (e.g., escaped)

Consult local
public health
department

*Discontinue treatment if tests on animal prove negative.

Recommended prophylaxis in exposed individuals

not previously vaccinated against rabies
Wound site(s)

Immediate thorough cleansing of

all wounds with soap and water.
Tetanus prophylaxis; antibiotics

Human Rabies
Immune Globulin
(RIG)

20 IU/kg body weight

Rabies Vaccine

IM (1 mL) in the deltoid area on

days 0, 3, 7, 14, and 28

As much of the RIG as possible

should be infiltrated in wound(s)
The remainder should be given IM
at a site distant from vaccine

MMWR 48: RR-1, 1999

Rabies Vaccines Available in Canada

RabAvert

Imovax

Manufacturer

Novartis
(Merck Frosst)

Sanofi Pasteur

Cell culture

primary chick
embryo
fibroblasts

MRC-5 human
lung cell line

Common
designation

PCECV

HDCV

MMWR;48:RR-1, January 8, 1999

Product package inserts, 2006

Adverse Reactions to Rabies Vaccines

Most common side-effects of rabies vaccines:

Systemic reactions such as headache,

myalgia, malaise (5-40%)

Mild to moderate local reactions at injection

site (30-74%)

Populations at increased risk of

exposure to rabies

Rabies research laboratory workers

Veterinarians, staff, veterinary students

Animal control and wildlife workers

Bat handlers

Spelunkers

Travellers to certain rabies-endemic areas

MMWR 48: (RR-1), 1999

Assessing the Rabies Risk for Travellers

Destination

Duration of travel

Anticipated activities

Access to medical care and

appropriate PEP biologics

Preexposure rabies prophylaxis

3 doses of rabies vaccine (days 0, 7, and 21 or

28)

May check rabies antibody titre periodically

want >0.5 IU/mL

after a rabies exposure:

2 doses of IM rabies vaccine (days 0 and 3)

no HRIG

Pre-exposure rabies prophylaxis

Tissue culture vaccine: 1 dose IM or 0.1 ml ID

Day 0

21

28

If CHLOROQUINE malaria prophylaxis, give IM only

If immunosuppressed check neut. Antibody titre 0.5 IU/ml
HIV positive patients - CD4 counts <300 may be unresponsive
Modified from MJ Warrell, University of Oxford

Photo courtesy of Claudius Malerczyk (Novartis)

Can Comm Dis Rep 31:1, 2005

Intradermal use of rabies vaccine

Gold standard is IM administration of rabies

vaccine

ID regimen is an acceptable alternative

Uses one-tenth the dose

Comparable degree of protection

Economical and widely accepted

Can Comm Dis Rep 31:1, 2005

Intradermal use of rabies vaccine

Pre-exposure = three 0.1 mL doses on days 0,

7, and 21 or 28 intradermally on upper arm

After reconstitution of 1.0 mL dose, may store

at 4 8 degrees C for up to 8 hours with
proper aseptic precautions

PCECV shown to be immunogenic 7 days

after reconstitution with storage in a clinic
refrigerator (Khawplod et al. CID 2002)
Can Comm Dis Rep 31:1, 2005

Intradermal use of rabies vaccine

Neutralization titres after ID vaccination are

lower than after IM, but adequate protective
levels

Briggs found that after 2-2.5 years:

79% of IM vs. 51% of ID had satisfactory titres

ACIP, at 2 years:

93-98% for IM vs. 83-95% for ID

Can Comm Dis Rep 31:1, 2005

Intradermal use of rabies vaccine

Manitoba n=488 in 2005

6-12 mo after 3rd dose:

95% >0.5 IU/mL

Median 2.7 IU/mL

Ontario and Alberta

favourable, but smaller experience

Can Comm Dis Rep 31:1, 2005

Intradermal use of rabies vaccine

Manitoba n=1000 as of 2008

1 year after 3rd dose: 92% >0.5 IU/mL

2 years after 3rd dose: 87% >0.5 IU/mL

3 years after 3rd dose: 80% >0.5 IU/mL

5 years after 3rd dose: 75% >0.5 IU/mL

Preliminary data from Drs. O. Larios and F. Aoki

Importance of maintaining the

antibody level is unknown

The response to booster doses is

predictable and rapid.

In low responders the antibody response

may not be so high (significance unknown).

Detectable antibodies may not be

necessary for protection if booster doses
are given promptly after exposure.
Modified from MJ Warrell, University of Oxford

Approach to immunization of travellers

3 dose pre-exposure course
If risk of exposure continues, then booster dose at
1 2 years
Travellers with access to vaccine: If exposed to
rabies need no further boosters
Travellers to remote areas with no access to
vaccine: Should repeat booster dose before
departure if last dose was > 3 - 5 years
previously (if antibody < 0.5 IU/ml)
Ensure booster doses if rabies exposure ASAP
Modified from MJ Warrell, University of Oxford

Efficacy of prophylaxis

Pre-exposure vaccine followed by postexposure boosters no deaths reported

If no previous vaccine: optimal postexposure treatment highly effective, but

deaths occur with delay or incomplete
treatment
Modified from MJ Warrell, University of Oxford

Rabies prevention - Summary

Rabies is a preventable disease.

Failure to recognize a risk of infection results in
human deaths.
Increased awareness of sources and routes of
virus transmission could save lives.
Pre-exposure vaccination should be used widely.
Post-exposure treatment is urgent.
For previously vaccinated people post -exposure
treatment is simpler, cheaper and more effective.

Modified from MJ Warrell, University of Oxford