CHAPTER 16 RABIES  VACCINE Introduction Rabies  is  an  acute  encephalomyelitis  caused  by  a  rhabdovirus.  It is primarily  an infection  of mammals,  spread by bites of infected animals.  In  many  parts  of  the  world  especially  in  South  East  Asia, dogs are the principal  reservoir of rabies1.  Humans  are  occasionally infected  by  wild  animals,  but  domestic  dogs  and  cats  are  responsible for  the  majority  of  cases2.    In  Sri  Lanka  rabies  has  been  detected  in mongoose,  cattle,  goats,  pigs,  bandicoots,  jackals,  pole  cats,  civet cats,  squirrels,  monkeys,  horses  and  elephants.  House    rats  have  not been  implicated  in  the  transmission  of  rabies  in  Sri  Lanka.  Human  to human transmission also has not been documented2. The  virus  can  penetrate  broken  skin  or  intact  mucous  membranes. Humans  are  usually  infected  when  virus  laden  saliva  is  inoculated through  the  skin  by  the  bite  of  a  rabid  animal.  Saliva  can  also  infect if  the  skin  is  already  broken  e.g.  by  the  claw  of  the  animal.  The  virus has been isolated in an animal’s saliva even up to 14 days before it exhibits  the  first  signs  of  rabies.  Intermittent  excretion  of  the  virus  in the  saliva  continues  throughout  the  illness.  The  incubation  period  in humans  averages  1  to  3  months  but  can  range  from  5  days  to  more than one year3,4,5. Infection with  rabies  virus  characteristically  produces  an  acute  illness with  rapidly  progressive  central  nervous  system  manifestations, including  anxiety,  dysphagia  and  seizures.  Some  patients  may  present with paralysis. Illness almost invariably progresses to death. Types of  Vaccine Inactivated anti rabies cell culture vaccine •  Human diploid cell vaccine (HDCV) •  Purified vero cell rabies vaccine (PVRV) * •  Purified  chick embryo cell vaccine (PCEC)*

Vaccines available in Sri Lanka at present. These freeze dried vaccines have a potency of ≥2.5 IU/IM dose Efficacy 100% seroconversion is achieved with a full course of vaccine. Indications Pre-exposure immunization Pre  exposure  immunization  is  recommended  for  the  following  risk groups •  Veterinary surgeons,students and support staff •  Laboratory staff handling  material contaminated with rabies virus •  Abattoir workers, animal handlers and vaccinators •  Wild life officers •  Employees  in  animal  quarantine  premises  and  zoological establishments Dosage and  Administration Freeze  dried  vaccine  should  be  reconstituted  with  the  diluent  provided. Administration by IM or ID route5. Primary immunization One  full  vial  administered  IM  or  a  single  dose  of  0.1mL  ID  in  the deltoid on days 0, 7, and 28. One booster to be taken 01 year later. Further  boosters  to  be  taken  every  5  years  for  maintenance  of  rabies protective antibody levels.

Management  of  a  person  who  is  on  pre-exposure  anti  rabies vaccine (ARV) If an  exposure  takes  place,  medical  advice  should  be  sought immediately regarding booster doses of vaccine. Following  an  exposure,  irrespective  of  severity,  additional  doses  of ARV  are  recommended.  A  single  IM  dose  /2  site  ID  0.1mL  doses  on day  0  and  day  3  as  boosters  should  be  administered  depending  on the  route  of  pre–exposure  schedule  which  has  been  initiated  in  the primary immunization6.  Administration  of  rabies  immunoglobulin  is  contraindicated  in  persons on pre-exposure therapy. Post exposure immunization It  is  essential  to  screen  the  patient  and  the  animal  before  a  decision is made regarding post-exposure treatment (PET) Choice  of  therapy  depends  on  the  screening  of  the  person  exposed  and also the animal involved in the incident. Screening the patient  - Categorization of the exposure Major exposures: a.  Single  or  multiple  bites  with  bleeding  on  head,  neck,  face,  chest, upper arms, palms, tips of fingers & toes and genitalia b.  Multiple  deep  scratches  with  free  flowing  of  blood      on  the  head, neck & face c.  Single or multiple deep bites on any part of the body d.  Contamination of mucous membranes with saliva e.  Bites of wild animals with  bleeding Minor exposures: a.  Single,  superficial  bite  with  oozing  of  blood  or  scratches  with bleeding on the lower limbs, upper limbs, abdomen and back

b.  Multiple  bites  without  bleeding  or  scratches  with  oozing  of blood on any part of the body c.  Nibbling of  uncovered skin d.  Contamination of open wounds with saliva e.  Drinking of raw milk of rabid cow or goat f.  Superficial  bites  and  scratches  of  wild  animals  without  bleeding Screening the animal Major  exposure to dogs and cats : •  With  a  reliable  history,  if  the  animal  is  healthy,  observable  and has documented proof of  a minimum  of 2  rabies vaccinations given  not  more  than  2  years  apart,  with  the  last  vaccination given  within  1  year  of  the  incident,    PET  can  be  delayed  while observing  the  animal  for  14  days.  If  the  animal  goes  missing, becomes  sick,  is  having  suspicious  behavior  or  dies,  the  patient should be advised to report to the  hospital  immediately to commence PET. •  When  the  animal  is  suspected  to  have  rabies  or  is  sick,  but observable  (irrespective  of  vaccination  status  of  the  animal), initiate  PET  while observing the animal.  Discontinue treatment if the animal is healthy after 14 days. •  If the  animal  is  having  rabies,  confirmed  by  laboratory  diagnosis or  unobservable  (missing,  stray  or  dead)  initiate  PET  and continue the full course of vaccine. In case of  minor  exposure to dogs and cats: •  If  the  animal  is    healthy,  observable  and  has  had  a  minimum  of 1 rabies vaccination with documented evidence :-  within 1 year of the incident-  at an age above 3 months-  incident occurring at least  1 month after the vaccination

PET  can  be  delayed  while  observing  the  animal  for  healthiness  or behavioral changes for 14 days from the day of the exposure. If an animal  concerned  is a dog or cat,  is healthy  and  alive  for 14 days following the bite, the person is not at risk of developing rabies3,4,5. •  PET for superficial  scratches,  under  provocation,  caused  by  healthy observable  domestic  animals  (irrespective  of  vaccination  status  of the  animal)  also  can  be  delayed  while  observing  the  animal  for  14 days6. •  When  the  animal  is  suspected  to  have  rabies  or  is  sick,  but observable,  initiate  PET  while  observing  the  animal.  Discontinue PET if the animal is healthy after 14 days. •  If  the  animal  is  having  rabies,  confirmed  by  laboratory  diagnosis  or unobservable  (missing,  stray  or  dead)  initiate  PET  and  continue  the full course of vaccine. The  patient  must  be  clearly  advised  that  the  animal  should  be  put  in  a cage  or  leashed  during  the  observation  period.  If  the  animal  becomes sick,  develops  any  abnormal  behavior  or  dies;  the  patient  should  be advised  to  report  to  the  hospital  immediately.  In  case  of  death  of  the animal,  patient  should  be  encouraged  to  send  the  head  of  the  animal    to a rabies diagnostic laboratory for  confirmation of rabies7. The following are not considered as exposures: •  Contamination  of  intact  skin  with  saliva  of  a  suspected  rabid/stray animal. •  Petting,  bathing  or  coming  in  contact  with  utensils  of  a  suspected rabid /stray animal. •  Eating  left  overs  which  were  previously  eaten  by  suspected  rabid/ stray animal

Anti Rabies PET  when indicated : 1.  All  patients  in  the  major  category  should  be  given  rabies immunoglobulin  (equine  or  human)  followed  by  a  course  of  anti rabies vaccine (ARV). 2.  Patients  in  the  minor  category  should  be  given  only  a  course  of ARV. Rabies Immunoglobulin (RIG) RIG available in Sri Lanka at present: •  Equine rabies immunoglobulin (ERIG) •  Human rabies immunoglobulin (HRIG) Rabies  immunoglobulin  should  be  given  immediately  after  the incident.  However  if  the  patient  reports  late,  RIG  could  be  given  up  to 3  months  after  exposure  if  he  has  not  taken  more  than  2  doses  of    anti rabies vaccine3,4,8. It  is  necessary  to  test  for  sensitivity  before  administering  ERIG.  HRIG does not require sensitivity testing prior to its administration. Method of sensitivity testing (ST) for  ERIG Control:  Inoculate  0.1mL  of  sterile  N  saline  ID  on  flexor  aspect  of the forearm. Test:  Prepare  a  1:10  dilution  of  rabies  equine  serum  with  sterile  N saline  and  inoculate  0.1ml  ID  on  flexor  aspect  of  the  opposite  forearm. Initial  diameter of the  indurated  area  should be  measured  in  mm  and recorded. Patient  is  kept  under  observation  and  the  ST  should  be  read  after  20 minutes.  Examine  for  itching,  induration  or  urticaria  or  any  systemic 

effects  of  anaphylaxis.  If  the  initial  diameter  of  the  induration  is  less than  6  mm  and  the  induration  after  20  minutes  is  over  10  mm  or  if there  is  any  systemic  reaction,  ST  should  be  considered  as  a  positive8. Separate fixed needle-syringes should be used for each patient. The  drug  of  choice  in  anaphylaxis  is  1:1000  adrenaline  0.5  mL  given IM immediately. (Dosage for children - refer Chapter 27). Mild  sensitivity  reactions  could  be  managed  with  antihistamine therapy.  Oral  or  parenteral  steroids  should  be  best  avoided  as  it could depress the immune response. If  a  patient  with  a  major  exposure  is  ST  positive  for  all  available products of ERIG, HRIG should be considered8. However6, 1.  If the animal is   healthy and observable,  the modified  4     site ID  ARV  schedule could be considered while observing a   healthy  animal for 14 days6. Report to hospital immediately,   if the animal goes missing, falls sick or dies during this period. 2.  If  the  animal  is  suspected  of  having  rabies  or  is  not observable,  in  a  situation  where  HRIG  is  not  available,  the WHO    recommended  method  of  using  ERIG  under  adrenaline and  antihistamine  in  an  emergency  care  facility  (ETU,  PCU,  A &  E  or  ICU)  should  be  considered7.  In  this  situation,  modified  4 site  ID  ARV  should  not  be  considered  as  equivalent  for  RIG  and a course of  ARV. 3.  If  the  patient  reports  after  the  day  7  dose  (3rd  dose)  of  ARV, continue  and  complete  the  modified  4  site  ID  ARV  schedule, RIG  is  not  recommended.  In  such  situations,  additional  doses of  ARV  could be considered after seeking expert opinion. Dosage and  Administration of RIG HRIG 20 IU/kg body weight ERIG 40 IU/kg body weight

Part  of  the  dose  (as  much  as  possible  depending  on  the  site)  should be  infiltrated  in  and  around  all  wounds.  After  infiltration  if  there  is any  remaining  RIG,  it  should  be  given  deep  SC  or  IM  on  the  thighs. Administration  of  RIG  on  the  buttocks  is  not  recommended  as absorption  is  unpredictable.  Deltoids  should  be  spared  for  ARV  when giving  RIG.  Vaccine  should  be  administered  preferably  on  the  same day after RIG, but at a different site. In  situations  with  multiple  bites,  where  the  volume  of  RIG  is insufficient  for  infiltration  of  all  wounds,  RIG  could  be  diluted  with sterile N. Saline up to a maximum of 3 times. Anti rabies vaccines (ARV) Intramuscular  schedule Patients  with  major  exposures  should  be  given  rabies  cell  culture vaccine IM according to the following schedule. One  dose  (1  vial)  to  be  given  in  the  deltoid  on  days  0,  3,  7,  14  and  30 following the administration of RIG. Patients  with  minor  exposures  should  be  given  a  total  of  4  doses  of rabies cell culture vaccine IM on the following days: Day 0 - 2 doses to be given IM , one in each deltoid. Day 7 - 1 dose IM Day 21 - 1 dose IM Intradermal inoculation of rabies cell culture vaccine ID  vaccination  schedule  has  been  recommended  by  the  WHO  to  be used in developing countries where cost is a major limiting factor1,8. Recommended ID dose is 0.1mL per site for both PCEC and PVRV 2 Site ID Schedule  (2-2-2-0-2) Standard schedule used in government hospitals 

One  dose  (0.1mL)  given  ID  at  each  of  2  sites  in  the  deltoids  on  days 0, 3, 7 and 30. 2 site schedule  is routinely  used in all  patients  irrespective  of the  use of rabies immunoglobulins. Example:  Major  exposure  -  rabies  immunoglobulin  +  2  site  ID schedule of anti rabies vaccine. Minor exposure - 2 site ID schedule of anti rabies vaccine only Modified 4  Site ID Schedule  (4-2-2-0-2) Gives  an  early  antibody  response  when  compared  to  the  2  site  ID schedule. The  modified  4  site  schedule  is  helpful  in  patients  with  major  exposure, with  a  reliable  history,  who  are  sensitive  to  ERIG  and  the  animal  is healthy  and  observable  and  for  patients  with  a  minor  exposure  who come late for treatment.  One  dose  of  (0.1mL)  given  ID  at  each  of  4  sites  on  day  0  (both  deltoids and lateral thighs) and 0.1mL  given at 2 sites on days 3, 7 and 30. Please  note:  In  a  patient  with  a  major  exposure,  modified  4  site  ID ARV should  not  be  considered  as  equivalent  for  RIG  and  a  course of ARV. Precautions that should be taken when using ID  ARV  schedules. All  ID  injections  should  be  administered  only  by  trained  staff  under supervision  of  a  medical  officer.  Once  the  vaccine  is  reconstituted  the contents  should  be  used  as  soon  as  possible  (preferably  within  6  hours stored at 20 - 80C).  Separate  disposable  syringes  and  needles  should  be used for each patient to prevent contamination. Sterile  1mL fixed  needle-syringes  should  be  used  for  administration  of ID  ARV  to minimize wastage. Post exposure therapy for  immunocompromised patients

ID  schedules  of  ARV  is  not  recommended  for  these  patients.  Often these  patients  may  require  RIG  even  for  minor  exposures  with  IM schedule of  ARV  after expert advice. In  high  risk  situations,  after  expert  advice  is  obtained  from  the  Dept. of  Rabies,  MRI,  rabies  antibody  assessment  could  be  offered  to  these patients. Management  of  patients  who  have  subsequent  exposure  to  rabies infection A.  With documented evidence of a  full course of  ARV With  a  reliable  history,  irrespective  of  the  vaccination  status  of  the animal,  for  both  major  and  minor  exposures:  If  the  animal  is  healthy and  observable,  PET  could  be  delayed  while  observing  the  animal for 14 days. If the animal  is  proven  rabid,  suspected  of  rabies  or  unobservable: •  for individuals who are not immunocompromised •  who have  been  previously  vaccinated  with  a  full  course  of  a  potent and effective rabies vaccine •  have adequate documentation-  should  receive  2  booster  doses  of  ARV  on  days  0  and  3  (one  IM dose /2 site ID 0.1mL)9-  patient  may  be  offered  a  one  visit  “4  site”  ID  doses  consisting of  4  injections of  0.1mL,  over  left and  right  deltoids and  suprascapular  /  antero-lateral  thigh  areas.  These  patients  do  not require administration of RIG5 In any doubtful or complicated  situations, expert opinion should be sought. B.  After a partial course of  ARV

The  management  will  depend  on  the  time  duration  from  previous course  of  ARV.  Expert  opinion  should  be  sought  from  Dept.  of Rabies, MRI. If  a person develops an allergic reaction to one type of cell  culture rabies  vaccine,  switching  over  to  the  other  type  of  cell  culture    ARV is recommended. Contraindications In  view  of  the  gravity  of  the  disease,  all  contraindications  are  secondary in  cases  of  exposure  to  suspected  rabies  infections.  This  also  pertains to post-exposure rabies prophylaxis in infancy and pregnancy. Adverse effects Local - pain, tenderness, erythema Systemic - malaise, headache, nausea, mild fever, urticaria Storage 20-80  C