Rabies

Content

Available Vaccines

In this chapter:

WHO Recommends 2 Key Human Immunisation Strategies for the Prevention of RABV Infection
Vaccines Available in Malaysia
Mode of Administration of Rabies Vaccines
Additional Notes On Rabies Vaccine Administration
Rabies Immunoglobulin (RIG) and Rabies Monoclonal Antibody (mAb) Available In Malaysia#
Mode of Administration of RIG and Rabies mAb
Co-administration with Other Vaccines
Contraindications and Adverse Effects
Target Groups in Malaysia
Evidence for Effectiveness

Introduction

Rabies is an acute progressive and almost always lethal zoonotic neurological infection. It is caused by rabies lyssa virus (formerly known as rabies virus) and family Rhabdoviridae. The enveloped RNA virus is ubiquitous worldwide except in Antarctica and some islands. Each year approximately 60,000 people die from rabies infection; more than 80% of the deaths occur in Asia and Africa. A further 15 million people receive post-exposure prophylaxis (PEP) against rabies every year.

Dogs are the most important animal reservoir for RABV. In rabies endemic areas virtually all human rabies cases are caused by infected dogs. RABV, which is found in saliva of an infected host, is predominantly transmitted through the bites, licks and scratches of rabid animals to new susceptible hosts. Direct person-to-person transmission of rabies has not been confirmed, except through organ transplantations that involved rabies-infected donors. The incubation period of the dreadful zoonotic infection is remarkably variable, although most of the infected humans become symptomatic between 2 and 3 months after exposure.

Human and animal rabies cases were first documented in Peninsular Malaysia in 1924 and 1925, respectively. Sporadic human cases have been reported in Peninsular Malaysia with the last case occurring in 1998. Between 2015 and 2018, several animal rabies clusters affecting the canine population were observed in several localities in Perlis, Kedah, Penang and Perak.

An on-going rabies outbreak affecting humans, dogs and cats was first detected in the southern region of Sarawak in July 2017. As of 9 September 2020, a total of 25 human rabies cases have been reported in Sarawak.

There is no effective antiviral treatment once the rabies symptoms appear. Whilst the case fatality rate of human rabies exceeds 99% for those previously unvaccinated and did not receive any PEP, rabies is preventable through the use of safe, highly effective and well-tolerated modern, concentrated, purified cell culture and embryonated egg-based rabies vaccines (CCEEVs).

WHO Recommends 2 Key Human Immunisation Strategies for the Prevention of RABV Infection:

After exposure (Post-Exposure Prophylaxis, PEP) (Refer to Table 14.1):
- - It involves the institution of three timely life-saving steps following a potential exposure to RABV. The 3 steps encompass prompt and meticulous wound care (viz. thorough washing and irrigation of wounds, scratches or RABV-exposure sites with running water and soap or detergent for at least 15 minutes followed by wound dressing with iodine, alcohol or anti-septic), administration of CCEEVs, and local wound infiltration with rabies immunoglobulins (RIG) or monoclonal antibody (if indicated).
  - WHO recommends PEP for category II and III exposure, according to the following definitions
    - 1. Category I (no exposure): Touching or feeding animals, licks on intact skin
      2. Category II (exposure): Nibbling of uncovered skin, minor scratches or abrasions without bleeding
      3. Category III (severe exposure): Single or multiple transdermal bites or scratches, contamination of mucous membrane with saliva from licks, licks on broken skin, exposure to bat bites or scratches

Figure 14.1 Post-exposure Prophylaxis (PEP) Based on Category of Exposure and Rabies-Immune Status (Adapted from WHO Position Paper April 2018)

Footnote:
ID: intradermal injection; IM: intramuscular injection; RIG: rabies immunoglobulins.
^# One-week, 2-site ID regimen (Institut Pasteur du Cambodge regimen); duration of entire PEP course: 7 days.
^$ Two-week, 1-site IM regimen (4-dose modified Essen regimen); duration of entire PEP course: between 14 and 28 days.

*Individuals with documented evidence of previous PrEP, or at least 2 previous administrations of rabies vaccine as PEP, are considered previously immunised and benefit from an abridged PEP without RIG in case of exposure.
In the case of HIV-infected individuals who are not on ART or on ART but CD4 count <200cells/mm³ and other potentially immunocompromised individuals, a full course of rabies vaccine with RIG is indicated, even if they are previously immunised. All immunocompromised cases that need PEP should be referred to infectious disease specialist.

2. Before exposure (Pre-Exposure Prophylaxis, PrEP)

- - It aims to prime the immune system before there is an exposure to RABV so that a strong anamnestic immune response could be elicited effectively, even many years after, when there is a re-exposure to RABV and following post-exposure booster.
  - The schedules are:
    1. 1. 2-site ID vaccine administered on Day 0 and 7
      2. 1-site IM vaccine administration on Day 0 and 7
        
        In the case of immunocompromised individuals, a 3-visit regimen consists of either 2-site ID or 1-site IM vaccine administration on Day 0, 7 and between Days 21-28 should be used. They should be managed with full PEP in the event of potential RABV exposure.
        HIV-infected individuals receiving antiretroviral therapy with CD4 count > 200cells/µL are considered not to be immunocompromised; they have been shown to respond to rabies and other vaccines in the same way as healthy individuals. Nonetheless, in the event of exposure, a complete PEP course, including RIG, is recommended.

- - PrEP is recommended for individuals at high risk of RABV exposure:

1. 1. 1. 1. Individuals at occupational risk; such as those involved in rabies research, biologics production and diagnostic laboratories, those involved in animal disease control and wildlife management at settings where rabies may be enzootic, those involved in bat handling or caving activities that may have direct contact with bats, those working in remote rabies-enzootic areas where timely and adequate access to PEP is uncertain e.g. dog vaccination campaign workers, peace keeping, military or religious missions.
      2. Travelers who may be at risk of RABV exposure.
      3. Populations living in highly endemic areas, where annual dog bite incidence is >5%, with limited access to timely and adequate PEP

Vaccines Available in Malaysia

1. Verorab® (inactivated purified vero cell, PVRV)
Sanofi-Aventis (Malaysia) Sdn Bhd/Sanofi Pasteur, France

2. Rabipur® (inactivated, purified chick embryo cell, PCEC)
Glaxo-Smith-kline Pharmaceutical Sdn Bhd/Chiron Behring Vaccine Private Ltd, India

Mode of Administration of Rabies Vaccines

ID route
- - It is the preferred administration because it is cost, dose and time saving when compared to the IM route
  - Use insulin syringe (30G X 5/16”, 0.3mm X 8mm) and needle for ID administration
  - An ID dose is 0.1 mL of vaccine
  - Injection site: deltoid, anterolateral thigh or suprascapular regions
IM route
1. - An IM dose is the entire content of the vial i,e. either 0.5 or 1.0 mL depending on the vaccine brand.
  - Injection site: deltoid region for adults and children aged >2 years. Rabies vaccine should not be administered IM in the gluteal area.

Additional Notes On Rabies Vaccine Administration

If any doses are delayed, vaccination should be resumed, NOT restarted.
A change in the administration route or vaccine product during a PEP course is acceptable if such a change is unavoidable.

Rabies Immunoglobulin (RIG) and Rabies Monoclonal Antibody (mAb) Available In Malaysia^#

RIG types
- - There are 2 types of RIG available for passive immunisation: human rabies immunoglobulin (hRIG) and equine rabies immunoglobulin (eRIG)
  - Both hRIG and eRIG are equally effective and safe.
  - There are a number of RIG products and manufacturers globally but none has received WHO pre-qualification.
Rabies monoclonal antibody
1. - There is only a single mAb product against RABV (Rabishield®, Serum Institute of India) licensed for use in human to date.

^# RIG and Mab are not readily available in Malaysia but may be imported upon special request from the Ministry of Health. The import permits of the biologics may be applied by using Borang Bpf/213-1: Borang Permohonan Mengimport/ Mengilang Keluaran Tidak Berdaftar Bagi Tujuan Merawat Penyakit Yang Mengancam Nyawa (http://www.pharmacy.gov.my/v2/sites/default/ files/document-upload/bpf213-1_1.pdf). Further detailed information may be obtained from Application Guidance Notes (http://www.pharmacy.gov.my/v2/sites/default/files/ document-upload/panduan-syarat-mengisi-borang-lampiran-bpf213-1-pindaan-1.pdf). The completed forms should be submitted to:

Pengarah Kanan Perkhidmatan Farmasi,
Bahagian Perkhidmatan Farmasi,
Kementerian Kesihatan Malaysia,
Lot 36, Jalan Universiti,
46350 Petaling Jaya,
(U/P: Cawangan Perundangan, Bahagian Penguatkuasaan Farmasi)
No. Tel: 03-78413200
No. Faks: 03-79682251

Mode of Administration of RIG and Rabies mAb

The principle and rationale
- - RIG neutralises RABV in-situ within a few hours of its infiltration into and around the local wound before the adaptive immune system can respond to the rabies vaccine by the production of vaccine-induced neutralising antibodies.
  - The rabies biologics (RIG and mAB) should be administered only once, preferably at, or as soon as possible after, the initiation of PEP. It is no longer indicated beyond Day 7 following the first rabies vaccine dose as active humoral antibody response to rabies vaccine has already started. Administration of RIG beyond this time may result in interference in adaptive immune response to active rabies immunisation.
  - Regardless of the size, all wounds should be identified and infiltrated with RIG.
  - Suturing of wounds should be delayed for 6-8 hours after RIG infiltration, or if unavoidable, sutures should be loose to allow optimal RIG diffusion around the wound.
  - Modern purification techniques have made the current eRIGs highly purified and refined preparations. The risk of serious adverse reaction is minimal. Skin testing before eRIG administration is not recommended because it does not predict the occurrence of adverse effects.
Dosage of RIG and mAb
- - The maximum dose of
    1. 1. hRIG: 20 iu/kg body weight
      2. eRIG: 40 iu/kg body weight
      3. mAb (Rabishield®): 3.33 iu/kg body weight
  - There is no minimum dose of RIG. The rabies biologics should be infiltrated as much as possible into and around the wound only. The remainder amount of the calculated rabies biologics does not need to be injected intramuscularly at a distance from the wound. Instead it may be fractionated in aseptic manner into smaller, individual syringes and stored at 2-8ºC for other patients’ use. Unused rabies biologics should be discarded at the end of the clinic day.
  - Caution should be practiced to avoid the occurrence of compartment syndrome when a large volume of rabies biologics is injected into anatomical restricted areas e.g. finger and ear pinna.
  - In the event that there are large & multiple bite wounds, rabies biologics may be diluted with 0.9% normal saline (up to 2-3 times of the calculated volume) so that all wounds could be adequately infiltrated.
  - Rabies vaccination should never be withheld, regardless of the availability of RIG or mAB. The importance of prompt meticulous wound care, together with immediate administration of the first vaccine dose, and followed by a complete course of rabies vaccine is highly effective in prevention of human rabies and could be not overemphasized.
  - If RIG or mAb is of limited supply, its allocation should be prioritised for RABV-exposed patients based on the following criteria:
    - 1. the biting animal is a laboratory-confirmed or probable rabies case,
      2. multiple bites,
      3. deep wounds,
      4. bites to highly innervated body parts (e.g. head, neck and hands),
      5. severe immunodeficiency,
      6. bites, scratches or exposures of mucous membranes caused by a bat.

Co-administration with Other Vaccines

Rabies vaccines can be co-administered with other inactivated and live vaccines, using separate syringes and different injection sites.

Contraindications and Adverse Effects

Individuals with a history of severe hypersensitivity to any of the components or to excipients listed by the vaccine manufacturer should receive an alternative rabies vaccine product for PrEP.
There is no contraindication to PEP and PrEP, including for infants, pregnant and lactating women, HIV-infected and other immunocompromised individuals and those receiving with chloroquine or hydroxychloroquine treatment. Where possible, PrEP should be completed before chloroquine or hydroxychloroquine treatment is initiated.
Reported adverse events include transient minor local erythema (0.5-1%), induration (3-11%), and tenderness (14-29%).

To date, the most frequently reported adverse event for rabies received by the National Pharmaceutical Regulatory Agency (NPRA) is pruritus, headache and fever.

Unlike nerve-tissue derived rabies vaccines that can induce severe adverse reactions and is no longer recommended by WHO, CCEEVs are safe and well-tolerated. Minor and transient local adverse reaction such as erythema, pain and/or swelling may occur at the site of injection in 35-45% of recipients. Mild systemic adverse events such as transient fever, headache, dizziness and gastrointestinal symptoms, have been reported in 5–15% of recipients.

Target Groups in Malaysia

Travelers to rabies endemic areas
Veterinarians and animal handlers

Evidence for Effectiveness

Modern CCEEVs are highly immunogenic. They induce a prompt and strong vaccine-induced neutralising antibody response to the G protein of RABV. A minimum serum antibody concentration of 0.5 IU/mL is widely used and recommended by WHO as a measure of adequate seroconversion following vaccination. The antibody titer is reached by day 7–14 of a PEP regimen, with or without simultaneous administration of RIG in most individuals, regardless of their age or nutritional status.

Whilst PEP using modern CCEEVs is known to be highly effective, it does not necessarily confer 100% protection against the development of human rabies infection. Delay in seeking PEP, inadequate wound care, unnoticed wounds, direct neural inoculation, use of ineffective rabies vaccine, improper vaccine administration (e.g. subcutaneous injection) or non-adherence to vaccination schedule and poor quality vaccine (non-WHO prequalified or cold-chain quality issue) are several important reasons for PEP failure in humans.

References

Abela-Ridder, D. (2018). WHO Expert Consultation on Rabies: WHO TRS N°1012.
Begeman, L., Geurtsvankessel, C., Finke, S., Freuling, C. M., Koopmans, M., Müller, T., . . . Kuiken, T. (2018). Comparative pathogenesis of rabies in bats and carnivores, and implications for spillover to humans. The Lancet Infectious Diseases, 18(4). doi:10.1016/s1473-3099(17)30574-1
National Pharmaceutical Regulatory Agency (NPRA), Ministry of Health Malaysia. Senarai Produk Vaksin Berdaftar Dengan Pihak Berkuasa Kawalan Dadah. Updated September 5, 2019
The Malaysian National Centre of Adverse Drug Reactions Database. Accessed October 10, 2019
World Health Organization Rabies vaccines: WHO position paper, April 2018 – Recommendations. Vaccine (2018), https://doi.org/10.1016/j.vaccine.2018.06.061
World Health Organization Rabies vaccines: WHO position paper – April 2018 Weekly epidemiological record No 16, 2018, 93, 201–220

Guidelines for Adult Immunisation