Rabies Issues for Travel Kevin C. Kain MD Professor of Medicine, University of Toronto Director, Center for Travel and Tropical Medicine
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BLUF: Bottom Line Up Front Everyone who travels internationally on expeditions should be offered/receive a 3 dose preexposure series of a modern cell based rabies vaccine Be aware of bites and other exposures and implement immediate first aid
Objectives Advise: Should most adventure/international travelers should consider (get!) pre-exposure vaccination? Update: Post bite management With and w/o pre-exposure prophylaxis Inform: Product specific issues HRIG Worldwide availability of vaccines
Rabies Acute viral encephalomyelitis Transmission Animal to animal Animal to human Dramatic symptoms Colorful history 100% fatal infection
Rabies: Historical Perspective Louis Pasteur 1822-1895 6 July 1885, Pasteur inoculated Joseph Meister, a 9 yr old boy bitten 14 times by a rabid dog, 13 times over 10 days Vaccine was a suspension of dried rabbit spinal cord
Lyssaviruses Genotype Virus Name Geographic Distribution 1 Rabies bats in Americas; terrestrial mammals globally Description Classic rabies Protection with RAB vaccine Yes 2 Lagos bat Sub-Saharan Africa Fruit Bats; never in humans 3 Mokola Sub-Saharan Africa Shrew; lethal infection in rabies vaccinated dogs; cats; 2 human deaths 4 Duvenhage Sub-Saharan Africa Rabies like illness / deaths in humans; bats no no Yes 5 European bat lyssavirus type 1 Europe Bats; human case in Russia Yes 6 European bat lyssavirus type 2 Europe Bats, human case in Finland Yes 7 Australian bat lyssavirus Australia bats Yes
The Rabies Virus Family Rhabdoviridae Genus Lyssavirus Enveloped viruses Single negative strand RNA Bullet shaped 5 structural proteins G glycoprotein elicits virus-neutralizing antibodies or VNA
Neurologic Clinics 2008 26:717-726 Rabies Pathogenesis Days to weeks to reach CNS from bite site Virus attaches to nicotininc acetylcholine receptors at neuromuscular junction Travels 12-24 mm per day in rodents Encephalitis is widespread but neuronal destruction is not Once in CNS, virus travels back down axon of peripheral nerves, esp. to salivary glands
Rabies: Clinical Disease Incubation period 20-60 days (range, 5 days - 7 years) < 1% cases with incubation period > 6 months Shorter when bite is on head / face / fingers Non-specific prodrome (2-10 days) Fever, malaise, headache, anxiety, agitation Pain and paresthesias at bite site
Rabies: Clinical Disease Acute neurological phase (2-12 days) Furious rabies in 60-80% Hydrophobia, aerophobia, hyperexcitability, autonomic dysfunction Paralytic rabies in 20% - 33% Progressive paresthesias and flaccid paralysis Coma (hours to months) Death is cardiorespiratory
Rabies: Diagnosis Clinical Suspicion Hx of exposure (travel, bite, bat contact) Pain / paresthesia at bite site, hydrophobia, hypersalivation, aerophobia Identification of virus in nerve tissue Ag (FAT), specific inclusions (Negri bodies), RNA, virus isolation (cornea, neck hairline), RT-PCR Serology RFFIT
Rabies virus Negri body Electron micrograph of rabies virus in brain cells at 64,000 x magnification. Courtesy of Dr. F.A. Murphy, UC Davis.
Diagnosis: detection of rabies antigen The fluorescent antibody test (FAT) is considered the gold standard for rabies diagnosis. Specific aggregates of rabies virus antigen are detected by their fluorescence. The FAT is accurate, sensitive and rapid. Results can often be obtained within 1 to 2 hours of receipt of the specimen.
How do you get rabies? Exposure to saliva bites or licks/scratches to mm and broken skin Improperly inactivated vaccine Solid organ transplantation Cornea Aerosols Occupational (lab) Caves (bats) Human to human (all body fluids!) Intercourse, kissing, lactation, skin contamination, bites
Travel and Rabies Rabies in travelers is rare Bites / rabies exposures are common Many rabies cases in developed countries acquired while traveling Bites and exposures are not rare 13 dog bites per 1000 in Thailand Post exposure dilemmas and travelers are common
Bites and Exposures 10% of travellers report a dog bite or lick during an average of 17 days of travel Ann Med Interne (Paris) 145:409, 1994 320 bites in short term travel (85% < 3 months) Dogs in 51%, monkeys in 21%, cats in 8% Vaccine. 2007 Mar 30;25(14):2656-63.
GeoSentinel Data 320 episodes of animal-related injuries were reported to GeoSentinel during the period of January 1998 May 2005, representing 1.4% of the 23,509 ill returned travellers entered into the database during this period. 54.7% female compared to 47.4% male Females more likely to be injured by monkeys Males were more likely to be injured by dogs. Only 66.1% of all patients reported with animalrelated injury received rabies post-exposure prophylaxis
Who is higher risk? Rural travel Cycling dogs hate cyclists! Areas populated with stray dogs Children 4X higher risk More likely to be bitten Less likely to report it More facial and upper extremity bites Boys > girls Spelunkers and other cave activities
Bite Management Pre-exposure Rabies vaccine 3 doses: 0, 7, 28 No pre-exposure Rabies Vaccine Dog bite! Wound Care! Post-exposure Management: 2 doses of vaccine 3 days apart Post-exposure Management: 1) 4 doses of vaccine 0,3,7,14 2) HRIG
Prevention Don t get bitten Presume all dogs have rabies Don t contact or handle bats Don t feed or annoy monkeys (don t carry food in temples) Pre-travel vaccine X 3 Wound care Get cell based vaccine X 2 if bitten
N=10,499 travellers and 4854 expats 2533 environmental illnesses 3.3% of travellers and 1.8% of ex-pats received a bite requiring rabies prophylaxis (#1 = dogs; #2 = monkeys)
Post-exposure Management Vaccine plus passive antibodies (rabies immune globulin) Must give both Fatal human cases documented in those receiving vaccine only JAMA 1982:248;2304-2306. Lancet 1982:2;870.
The Importance of HRIG Exposure: Injection into Masseter muscle of dogs HDCV only HRIG only Combination HRIG + HDCV 0% 20% 50% Exposure: Injection into Femoral muscle of dogs HDCV only HRIG only Combination HRIG + HDCV 0% 50% 100% Can J Vet Res 53:434-437, 1989
Rabies Immune Globulin (RIG) Derived from horses: Equine rabies immune globulin (ERIG) Derived from humans: Human rabies immune globulin (HRIG)
ERIG: Equine Rabies Immune Globulin Multiple products worldwide - India, SE Asia None approved in USA or other Western countries Anaphylaxis Serum sickness Contaminating equine viruses Skin test pre-administration? Intermittent availability Generally lower cost
HRIG: Human Rabies Immune Globulin Two products in NA: HyperRab (Talecris BIotherapeutics) Imogam Rabies - HT (Aventis Pasteur) Not reliably available overseas Expensive Both products 150 IU / ml 2 ml vials = 300 IU = 15 kg person 10 ml vials = 1500 IU = 75 kg person Require cold chain storage (2-8º C) No preservatives Do not freeze
HRIG: Human Rabies Immune Globulin Passive transfer of antibodies to rabies virus Intervention yields low level antibodies lasting for 14-21 days Give 20 IU / kg on Day 0 Full dose given at bite site if anatomically feasible At least half of volume injected at bite site Other half injected IM in gluteal or thigh area (different site than vaccine which is deltoid) Works best when given shortly after bite Not indicated more than 7 days after post-exposure immunization begins May interfere with immune response to vaccine if given > 7 days after vaccine
HRIG / perig Local infiltration is very important Total dose if possible 5 children in Thailand died when local infiltration of perig not performed Clin Infect Dis 22:228-232, 1996
Why should you get pretravel rabies vaccine? If bitten, you don t need HRIG Non-bite exposures Child tropism to animals / dogs Kids face at mouth level of dogs Kids may not report minor bites to caregiver/parents Pre-travel rabies immunization is a form of trip insurance.
Rabies: What Vaccines to Use Approved mammalian cell culture vaccines (CCVs) Human Diploid cell vaccine (HDCV) Purified Vero Cell Vaccine (PVRV) Purified chick embryo vaccine (PCEC) Purified duck embryo vaccine (PDEV) Avoid neurotissue vaccines Derived directly from sheep or mouse brain
Rabies Vaccine Timeline Pasteur - inactivated by drying Semple - phenol inactivated Fuenzalida - myelin free Crude neuro-tissue preparations HDCV licensed by FDA Increasing Purity 1885 1911 1956 1980 2008 Number of Doses
FDA Approved Rabies Vaccines Imovax (Aventis-Pasteur, France) FDA approved 1980 HDCV Rabavert (Chiron Behring Gmbh & Co) Manufactured in Marburg, Germany FDA approved in 1997
Efficacy of Pre-Exposure Vaccine No cases of rabies ever documented in a person who received three 1.0 ml doses IM and appropriate postexposure management.
Immunogenicity of Imovax Post-exposure prophylaxis 45 persons bitten by rabid wolves and dogs in Iran (JAMA 1976. 236:2751-4) All rec d vaccine and anti-rabies globulin Hours to days after exposure All protected
Administration of HDCVs Vaccine failure when given in gluteal area presumably due to sub Q fat Give only in deltoid muscle for adults and children Mid-lateral thigh in infants and very small children NEJM 1987. 316: 1257-58 MMWR 1978. 36: 759-765
Immunogenicity of CCVs 1 Corticosteroids and other immunosuppressive drugs can interfere with the development of rabies antibodies following vaccination. Post anesthesia has been associated with a decrease in protective efficacy
Immunogenicity of CCVs 2 Anti-malarial chemoprophylaxis with chloroquine (? mefloquine?) can decrease antibody response to HDCV NEJM 314:280, 1986 Complete pre-exposure rabies vaccine series before beginning malaria prophylaxis with CQ or MQ
Hypersensitivity Reactions to HDCV? Modern CCVs not associated with systemic reactions following boosters Additional purification steps to remove human albumin HDCVs Pasteur Mérieux Connaught Canada, Berna, and Behring PVRV and PCECV PMC and Chiron
Pre-Exposure Vaccine Schedules: Decreasing Cost in LDCs USA CDC / ACIP FDA approved vaccines ACIP guidelines Three 1.0 ml doses given IM pre-travel: D0, D7, D21-28 No FDA approved or ACIP recommended ID ROA regimen $500-$1000 per three dose series Worldwide WHO Many CCVs WHO guidelines Three 1.0 ml doses given IM pre-travel: D0, D7, D21-28 Three 0.1 ml doses given ID pre-travel: D0, D7, D21-28 Much lower cost = greater use / access
Post-Exposure Vaccine Schedules: Decreasing Cost in LDCs USA CDC / ACIP FDA approved vaccines ACIP guidelines Four 1.0 ml doses given IM pre-travel: D0, D3, D7, D14 No FDA approved or ACIP recommended ID regimen All suspect exposures receive vaccine and HRIG Worldwide WHO Many CCVs WHO guidelines The indication for postexposure prophylaxis depends on the type of contact with the suspected rabid animal Much lower cost = greater use / access
WHO Post-Exposure Prophylaxis ID Administration
Overseas, remote area, you get bitten Clean water, soap, povidone, etc. Who do you see? Where do you go? How do you assess products? Can you trust the products? Can you find RIG? Can you pay for it? You are scared, really Your trip is over
When traveling and you need rabies vaccine, how do you know what to use? Caveat Emptor! Poorly made / manufactured Proper vaccines, improperly stored Proper vaccines, improperly stored Counterfeit vaccines Can t locate CCVs
Caveat Emptor! Substandard Manufacture Illegal Counterfeit / Fakes
Treatment Failures: Rabies Despite Modern Vaccines 28 Cases reviewed 25 / 28 (90%) failed to use HRIG or used HRIG incorrectly No HRIG Poor or no wound cleaning Very late start of HRIG Injection of vaccine into buttocks instead of deltoid Late use of immunization 2 cases of severe facial injury considered true Rx failure Thraenhart O et al. Curr Top Microbiol Immunol 1994: 187; 173-194.
Post-Exposure Management: PCECV w/o HRIG? 15 million doses with 47 failures 100% of failures did not follow accepted WHO guidelines for HRIG International Rabies Meeting; Institute Pasteur, Paris; 1997
Rationale for Pre-Exposure Prophylaxis for Travelers Up side / Benefit Protection from inapparent exposures Protection if post-exposure prophylaxis likely to be delayed Eliminates need for ERIG/HRIG Decreases the number of doses for postexposure (2 vs. 5) Avoids possibility of receiving neurotissue vaccines Avoids possibility of receiving fake / counterfeit vaccines Children at higher risk = greater benefit for pre-exposure Very safe / low reactogenicity risk of modern CCVs Prevent 100% fatal disease Greatly simplifies post-exposure management Cost Down side / Risk
Case CRYPTIC CASES (i.e. No history of exposure) are the #1 cause of rabies deaths in the USA! Genetically BAT origin
Bats and rabies USA MMWR April 13, 2012 42 cases of rabies 1995-2010 26% travel related dogs 71% of USA cases bats
Bats host major viruses Drexler et al. Nature April 27, 2012;766 Bats are the origin of paramyxoviruses mumps, measles, RSV, paraflu Hendra and Nipah fatal encephalitis in Australia/Asia African origin rinderpest, distemper PLUS 67 new ones! Live in large colonies with viral genetic mixing and transmission. Implications: disease emergence & elimination
Monkeys and Rabies Can monkeys get rabies? YES Yes most will give rabies vaccine/rig Only 5 reported human cases from monkeys - Gautret et al. PloS ND May 2014 Why so rare? TOO Fast and TOO smart! (unlike humans!)
Rodents and Rabies KTM reports 30 rat bites/day! Can mice/rats get rabies YES In USA no reported human cases Elsewhere rare but reported e.g. Thailand n=7000 cases 1% Poland n=9998 0.04% Why so rare? usually killed in the initial attack