RABIES

1. RABIES

2. Rhabdoviruses • Features • Bullet-shaped (75 x 180 nm) • Enveloped • Single stranded RNA genome, 12 kb • Many viruses with broad host ranges • Classification • Family Rhabdoviridae • Genus Lyssavirus (including Rabies virus) • Vertebrates • Invertebrates • Plants • Genus Vesiculovirus (Vesicular stomatitis-like viruses)

3. Rabies Virus • Rabies virus replication • Spike protein mediates attachment (nicotinic acetylcholine receptor) • Viral RNA polymerase transcribes a monocistronic mRNA • Five polypeptides are encoded by the genome • N • L (polymerase) • P (polymerase) • M • G • The N assembles with the polymerase and RNA in progeny virus (spiral configuration) • Virus exits by budding • G protrudes from plasma membrane • M binds to inner PM leaflet

4. Rabies Virus • Animal susceptibility • All warm-blooded animals can be infected with varying susceptibility • High - wolves, coyotes, foxes, dogs • Intermediate - skunks, raccoons, bats • Low - opossums • Virus occurs in saliva, nervous system, urine, lymph, milk • Recovery is rare and only occurs in bats; fatal in nearly all others • Vampire bats can transmit virus for months

5. Rabies Virus • Pathogenesis • Requires several weeks for infection to become apparent • Transmission through bite or scratch from infected animal • Replication in muscle and connective tissues at site of inoculation • Enters peripheral nervous system at neuromuscular junctions • Spreads up the peripheral nerves to the central nervous system • Encephalitis • Virus grows to high titers in the salivary glands • Rabies patients must be restrained • Negri bodies appear in neuron cell bodies • Clinical spectrum • Prodrome - nausea, headaches, fever, sore throat, photophobia • Acute neurologic phase - apprehension, nervousness, hallucinations, behavioral anomalies, salivation, perspiration, hydrophobia, photophobia • Coma - seizures and death (99+%) Negri bodies

6. Rabies Virus • One survival using novel medical treatment • NEJM. 2005. 352:2508-2514 • 15 year old Jeanna Giese bitten by a bat • Presented with clinical rabies after one month • Treatment • Induced coma • Administered high doses of ketamine to suppress brain activity • Required mechanical ventilation • Administered heparin • Administered ribavirin, an antiviral, to protect the heart from rabies-induced cardiomyopathy • Days 8-10 showed improvement in cardiovascular and neurological functions • By day 23 she could sit up in bed, but neurological manifestations persisted • Required prolonged physical therapy, but is continuing to recover • This treatment failed for a Texas boy

7. Rabies Virus • Laboratory diagnosis • PCR • Serology (IFA) • Animal control • Rabid or suspected rabid animals are killed and examined by histopathology for Negri bodies and viral antigen • Vaccination of pets is required by law in most states • Immunity and protection • Vaccines • First one developed by Pasteur by using spinal cords from infected dogs • Today’s principal vaccine is the human diploid cell vaccine (HDCV) made in the WI-38 fibroblast cell line • Virus is inactivated by βPL • Post-exposure prophylaxis • One dose of hyperimmune antiserum • Five immunizations over 28 days

8. Rabies Virus • Epidemiology • Enzootic in wild and domesticated animals • In the U.S., edible vaccines are dispersed to control wild animal rabies • More than 200 people die from rabies in China each month • Reservoirs might be bats • But the slow-growing nature of rabies virus also contributes to its persistence in nature

9. Prion Diseases • Proteinacious infectious agents • Diseases are transmissible spongiform encephalopathies (TSEs) • There are also inherited spongiform encephalopathies • Human • Creutzfeldt-Jakob Disease - sporatic • New Variant CJD - from beef (“mad cow disease”) • Kuru - ritualistic cannibalism (consuming brains of infected dead) • Fatal familial insomnia • Animal • Bovine spongiform encephalopathy (“mad cow” disease) • Scrapie - sheep • Chronic wasting disease - deer, elk, moose

10. Prion Diseases • Pathogenesis • Poorly understood • The prion protein is a normal cellular protein, encoded by the PRPC gene • The gene is found on the short arm of chromosome 20 • It is thought to be involved in ion transport • It is prominently expressed in the CNS • Some mutant alleles occur in familial enecphalopathies • Protein folding • The properly-folded protein is termed PrPc • The misfolded protein is termed PrPSc • It is unknown why the protein misfolds • However, once misfolded, it can cause misfolding of other copies of PrPc • The misfolded protein is highly resistant to heat and protease digestion • TSEs have been transmitted by autoclaved surgical instruments • The misfolded proteins apparently elude the ubiquitin/proteosome system • Cells export the misfolded protein, which then forms extracellular plaques • These plaques interfere with neuronal communication Normal Misfolded

12. Rabies 1

13. Rabies • Defined: Rabies is a preventable viral disease of mammals most often transmitted through the bite of a rabid animal Return To Work PPT- 2

14. Rabies Virus The rabies virus infects the central nervous system, ultimately causing disease in the brain and death PPT- 3

15. General Symptoms • Fever • Headache • Weakness • Discomfort • * Usually exhibited for 2-10 days PPT- 4

16. More Severe Symptoms • Insomnia • Anxiety • Confusion • Slight or Partial Paralysis • Hallucinations PPT- 5

17. More Severe Symptom • Excitation • Agitation • Hypersalivation • Difficulty Swallowing • Hydrophobia • * Death usually occurs within days of the onset of the more severe sym PPT- 6

18. The vast majority of rabies cases reported to the Centers for Disease Control and Prevention (CDC) each year occur in wild animals like raccoons, skunks, bats and foxes Rabies Cases PPT- 7

19. Rabid Animals By Frequency • Raccoons • Skunks • Bats • Foxes • Rodents & Lagomorphs PPT- 8

20. The rabies virus is transmitted through saliva or brain/nervous system tissue. You can only get rabies by coming in contact with these specific bodily excretions and tissues • Rabies is transmitted only when the virus is introduced into a bite wound, open cuts in skin, or onto mucous membranes such as the mouth or eyes Exposure PPT- 9

21. Bite • Any penetration of the skin by teeth constitutes a bite exposure • Nonbite • The contamination of open wounds, abrasions, mucous membranes or, theoretically, scratches (potentially contaminated with infectious material from a rabid animal) constitutes a nonbite exposure Types of Exposure PPT- 10

22. Exposure The following does not constitute exposure: • Petting • Handling an animal • Contact with blood • Contact with urine or feces PPT- 11

23. Incubation Period • This is the period of time from the exposure to rabies virus until the animal finally becomes sick and/or acts differently and is capable of infecting other animals or people • The incubation period can be as short as two weeks or in very rare cases as long as one year PPT- 12

24. During the incubation period, the animal cannot transmit rabies and its behavior remains normal • During the incubation period, there may be time for the vaccine to prevent the animal from developing disease and prevent it from shedding or transmitting virus Step 1: Health Care Incubation Period PPT- 13

25. Wound Care • Wash wounds immediately with soap & water • This is the most effective way to decrease the chance of infection Medical Care PPT- 14

26. Approximately 120,000 animals or more are tested for rabies each year in the United States • Approximately 6% are found to be rabid; the proportion of positive animals depends largely on the species of animal and ranges from <1% in domestic animals to >10% of wildlife species Rabies Facts PPT- 15

27. Visit your veterinarian with your pet on a regular basis and keep rabies vaccinations up-to-date for all cats, ferrets, and dogs • Maintain control of your pets by keeping cats and ferrets indoors and keeping dogs under direct supervision Rabies Prevention PPT-064-01 16

28. Spay or neuter your pets to help reduce the number of unwanted pets that may not be properly cared for or vaccinated regularly • Call animal control to remove all stray animals from your neighborhood since these animals may be unvaccinated or ill Rabies Prevention PPT- 17

29. If traveling to a country where there is an increased incidence in rabies, especially in canine populations, rabies pre-exposure vaccination may be recommended • Rabies vaccination should also be considered if you will be spending lots of time outdoors in rural areas or plan to handle animals Rabies Prevention PPT- 18

30. People who work with rabies in laboratory settings and animal control and wildlife officers are just a few of the people who should consider rabies pre-exposure vaccinations • If you are traveling to a country where rabies is widespread, you should consult your doctor about the possibility of receiving pre-exposure vaccination against rabies Pre-Exposure Vaccination PPT- 19

31. Pre-Exposure Vaccination • Consider pre-exposure vaccination if: • Your planned activity will bring you into contact with wild or domestic animals, for example if you are a biologist, veterinarian, or agriculture specialist working with animals • You will be visiting remote areas where medical care is difficult to obtain or may be delayed, for example, hiking through remote villages where dogs are common • Your stay is longer than 1 month in an area where dog rabies is common; the longer your stay, the greater the chance of an encounter with an animal PPT- 20

32. Pre-Exposure Vaccination Although pre-exposure vaccination does not eliminate the need for additional therapy after a rabies exposure, it simplifies management by eliminating the need for rabies immune globulin and decreasing the number of doses of vaccine needed PPT- 21

33. Primary Vaccinations PPT- 22

34. Primary Vaccination Three 1.0-mL injections of HDCV or PCEC vaccine should be administered intramuscularly (deltoid area) -- one injection per day on days 0, 7, and 21 or 28 Primary Vaccination PPT- 23

35. Continuous Risk • People who work with rabies virus in research laboratories or vaccine production facilities are at the highest risk for unapparent exposures • Such persons should have a serum sample tested for rabies antibody every six months; Intramuscular booster doses of vaccine should be administered to maintain a serum titer corresponding to at least complete neutralization at a 1:5 serum dilution by the RFFIT (Rapid Fluorescent Focus Inhibition Test for rabies) Booster Doses PPT- 24

36. Frequent Risk • This group includes other laboratory workers such as those performing rabies diagnostic testing, spelunkers, veterinarians and staff, and animal-control and wildlife officers in areas where animal rabies is enzootic as well as persons who frequently handle bats, regardless of location in the United States Booster Doses PPT- 25

37. Frequent Risk • Persons in the frequent risk group should have a serum sample tested for rabies antibody every 2 years; if the titer is less than complete neutralization at a 1:5 serum dilution by the RFFIT, the person also should receive a single booster dose of vaccine Booster Doses PPT- 26

38. Infrequent risk • Veterinarians, veterinary students, and terrestrial animal-control and wildlife officers working in areas where rabies is uncommon to rare (infrequent exposure group) and at-risk international travelers fall into this category and do not require pre-exposure booster doses of vaccine after completion of primary pre-exposure vaccination Booster Doses PPT- 27

39. Any animal bitten or scratched by either a wild, carnivorous mammal or a bat that is not available for testing should be regarded as having been exposed to rabies • Unvaccinated dogs, cats, and ferrets exposed to a rabid animal should be euthanized immediately; if the owner is unwilling to have this done, the animal should be placed in strict isolation for 6 months and vaccinated 1 month before being released What is the risk for my pet? PPT- 28

40. Animals with expired vaccinations need to be evaluated on a case-by-case basis; dogs and cats that are currently vaccinated are kept under observation for 45 days • Small mammals such as squirrels, rats, mice, hamsters, guinea pigs, gerbils, chipmunks, rabbits and hares are almost never found to be infected with rabies and have not been known to cause rabies among humans What is the risk for my pet? PPT- 29

41. What is the risk for my pet? • Bites by these animals are usually not considered a risk of rabies unless the animal was sick or behaving in any unusual manner PPT- 30

42. Each state collects specific information about rabies, and is the best source for information on rabies in your area Is rabies prevalent in my area? PPT- 31

43. Is rabies prevalent in my area? • In addition, the CDC publishes rabies surveillance data every year for the United States. • The report, entitled Rabies Surveillance in the United States, contains information about the number of cases of rabies reported to CDC during the year, the animals reported rabid, maps showing where cases were reported for wild and domestic animals, and distribution maps showing outbreaks of rabies associated with specific animals PPT- 32

44. Centers For Disease Control & Prevention (CDC) – www.cdc.gov PA Department of Agriculture - www.agriculture.state.pa.us Resources PPT- 33

45. Questions? PPT- 34