Rabies and Intradermal Rabies Vaccination

Alan C. Jackson, MDProfessor of Medicine (Neurology)

and of Medical MicrobiologyHead, Section of Neurology

University of ManitobaWinnipeg, Manitoba, Canada

Rabies virus structure

EnvelopeMatrix protein

Source: http://www.cdc.gov

Glycoprotein

Nucleocapsid protein

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 - Barré 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

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

DALY (disability-adjusted life year) scores =years of life lost + years of life with a disability

Human rabies prevention United States

Recommendations of the CDC’sAdvisory Committee on Immunization Practices

MMWR Recommendations and ReportsJanuary 8, 1999

http://www.cdc.gov/mmwr

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.

Rabies postexposure guide: exposure to dogs, cats, and ferrets

Recommended prophylaxis in exposed individuals not previously vaccinated against rabies

Immediate thorough cleansing of all wounds with soap and water.

Tetanus prophylaxis; antibiotics

Wound site(s)

MMWR 48: RR-1, 1999

IM (1 mL) in the deltoid area on days 0, 3, 7, 14, and 28

Rabies Vaccine

20 IU/kg body weight Human RabiesImmune Globulin(RIG)

• 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

Rabies Vaccines Available in Canada

MMWR;48:RR-1, January 8, 1999Product package inserts, 2006

Novartis

(Merck Frosst)

primary chick embryo

fibroblasts

PCECV

Sanofi Pasteur

MRC-5 human lung cell line

HDCV

RabAvert® Imovax ®

Manufacturer

Cell culture

Common designation

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

Day 0 7 21 28

Pre-exposure rabies prophylaxis

Tissue culture vaccine: 1 dose IM or 0.1 ml ID

• 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 post-

exposure boosters – no deaths reported

If no previous vaccine: optimal post-exposure 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