Medicine:Rabies vaccine

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Short description: Vaccines to prevent rabies in humans and animals
Rabies vaccine
Rabies vaccine.png
Vaccine description
Target diseaseRabies
TypeKilled/Inactivated
Clinical data
Trade namesRabAvert, Rabipur, Rabivax, others
AHFS/Drugs.comMonograph
MedlinePlusa607023
License data
Pregnancy
category
Routes of
administration		Intramuscular, intradermal
ATC code
Legal status
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The rabies vaccine is a vaccine used to prevent rabies.[11] There are several rabies vaccines available that are both safe and effective.[11] Vaccinations must be administered prior to rabies virus exposure or within the latent period after exposure to prevent the disease.[12] Transmission of rabies virus to humans typically occurs through a bite or scratch from an infectious animal, but exposure can occur through indirect contact with the saliva from an infectious individual.[12]

Doses are usually given by injection into the skin or muscle.[11] After exposure, the vaccination is typically used along with rabies immunoglobulin.[11] It is recommended that those who are at high risk of exposure be vaccinated before potential exposure.[11] Rabies vaccines are effective in humans and other animals, and vaccinating dogs is very effective in preventing the spread of rabies to humans.[11] A long-lasting immunity to the virus develops after a full course of treatment.[11]

Rabies vaccines may be used safely by all age groups.[11] About 35 to 45 percent of people develop a brief period of redness and pain at the injection site, and 5 to 15 percent of people may experience fever, headaches, or nausea.[11] After exposure to rabies, there is no contraindication to its use, because the untreated virus is virtually 100% fatal.[11][13]

The first rabies vaccine was introduced in 1885 and was followed by an improved version in 1908.[14] Millions of people globally are vaccinated against the virus.[11] It is on the World Health Organization's List of Essential Medicines.[15][16]

Medical uses

Before exposure

The World Health Organization (WHO) recommends vaccinating those who are at high risk of the disease, such as children who live in areas where it is common.[11] Other groups may include veterinarians, researchers, or people planning to travel to regions where rabies is common.[17] Three doses of the vaccine are given over a one-month period on days zero, seven, and either twenty-one or twenty-eight.[11][17]

After exposure

For individuals who have been potentially exposed to the virus, four doses over two weeks are recommended, as well as an injection of rabies immunoglobulin with the first dose.[18] This is known as post-exposure vaccination.[19] For people who have previously been vaccinated, only a single dose of the rabies vaccine is required.[19] However, vaccination after exposure is neither a treatment nor a cure for rabies; it can only prevent the development of rabies in a person if given before the virus reaches the brain.[19] Because the rabies virus has a relatively long incubation period, post-exposure vaccinations are typically highly effective.[11]

Additional doses

Immunity following a course of doses is typically long lasting, and additional doses are usually not needed unless the person has a high risk of contracting the virus.[11] Those at risk may have tests done to measure the amount of rabies antibodies in the blood, and then get rabies boosters as needed.[17] Following administration of a booster dose, one study found 97% of immunocompetent individuals demonstrated protective levels of neutralizing antibodies after ten years.[20]

Safety

Rabies vaccines are safe in all age groups.[11][21] About 35 to 45 percent of people develop a brief period of redness and pain at the injection site, and 5 to 15 percent of people may experience fever, headaches, or nausea.[11] Because of the certain fatality of the virus, receiving the vaccine is always advisable.[11]

Vaccines made from nerve tissue are used in a few countries, mainly in Asia and Latin America, but are less effective and have greater side effects.[11] Their use is thus not recommended by the World Health Organization.[11]

Types

The human diploid cell rabies vaccine (HDCV) was started in 1967. Human diploid cell rabies vaccines are inactivated vaccines made using the attenuated Pitman-Moore L503 strain of the virus.[22]

In addition to these developments, newer and less expensive purified chicken embryo cell vaccines (CCEEV) and purified Vero cell rabies vaccines are now available and are recommended for use by the WHO.[11] The purified Vero cell rabies vaccine uses the attenuated Wistar strain of the rabies virus, and uses the Vero cell line as its host. CCEEVs can be used in both pre- and post-exposure vaccinations. CCEEVs use inactivated rabies virus grown from either embryonated eggs or in cell cultures and are safe for use in humans and animals.[11][23]

The vaccine was attenuated and prepared in the H.D.C. strain WI-38 which was gifted to Hilary Koprowski at the Wistar Institute by Leonard Hayflick, an Associate Member, who developed this normal human diploid cell strain.[24][25]

Verorab, developed by Sanofi-Aventis and Speeda, developed by Liaoning Chengda are purified vero cell rabies vaccine (PVRV).[26][27] The first is approved by the World Health Organization.[28] Verorab is approved for medical use in Australia and the European Union and is indicated for both pre-exposure and post-exposure prophylaxis against rabies.[4][10]

History

Early-20th-century rabies vaccination in Santa Catarina, Brazil

Virtually all infections with rabies resulted in death until two French scientists, Louis Pasteur and Émile Roux, developed the first rabies vaccination in 1885. Nine-year-old Joseph Meister (1876–1940), who had been mauled by a rabid dog, was the first human to receive this vaccine.[29] The treatment started with a subcutaneous injection on 6 July 1885, at 8:00 pm, which was followed with 12 additional doses administered over the following 10 days. The first injection was derived from the spinal cord of an inoculated rabbit which had died of rabies 15 days earlier. All the doses were obtained by attenuation, but later ones were progressively more virulent.[30]

The Pasteur-Roux vaccine attenuated the harvested virus samples by allowing them to dry for five to ten days. Similar nerve tissue-derived vaccines are still used in some countries, and while they are much cheaper than modern cell culture vaccines, they are not as effective.[31] Neural tissue vaccines also carry a certain risk of neurological complications.[32]

Society and culture

Economics

When the modern cell-culture rabies vaccine was first introduced in the early 1980s, it cost $45 per dose, and was considered to be too expensive. The cost of the rabies vaccine continues to be a limitation to acquiring pre-exposure rabies immunization for travelers from developed countries. In 2015, in the United States, a course of three doses could cost over US$1,000, while in Europe a course costs around €100. It is possible and more cost-effective to split one intramuscular dose of the vaccine into several intradermal doses. This method is recommended by the World Health Organization (WHO) in areas that are constrained by cost or with supply issues. The route is as safe and effective as intramuscular according to the WHO.[33]

Veterinary use

Baits with vaccine for oral vaccination
Machine for distribution of baits from airplane

Pre-exposure immunization has been used on domesticated and wild populations. In many jurisdictions, domestic dogs, cats, ferrets, and rabbits are required to be vaccinated.[34]

There are two main types of vaccines used for domesticated animals and pets (including pets from wildlife species):

  • Inactivated rabies virus (similar technology to that given to humans) administered by injection
  • Modified live viruses administered orally (by mouth): Live rabies virus from attenuated strains. Attenuated means strains that have developed mutations that cause them to be weaker and do not cause disease.[35]

Imrab is an example of a veterinary rabies vaccine containing the Pasteur strain of killed rabies virus. Several different types of Imrab exist, including Imrab, Imrab 3, and Imrab Large Animal. Imrab 3 has been approved for ferrets and, in some areas, pet skunks.[36]

Dogs

Aside from vaccinating humans, another approach was also developed by vaccinating dogs to prevent the spread of the virus. In 1979, the Van Houweling Research Laboratory of the Silliman University Medical Center in Dumaguete in the Philippines [37] developed and produced a dog vaccine that gave a three-year immunity from rabies. The development of the vaccine resulted in the elimination of rabies in many parts of the Visayas and Mindanao Islands. The successful program in the Philippines was later used as a model by other countries, such as Ecuador and the Mexican state of Yucatán, in their fight against rabies conducted in collaboration with the World Health Organization.[38]

In Tunisia, a rabies control program was initiated to give dog owners free vaccination to promote mass vaccination which was sponsored by their government. The vaccine is known as Rabisin (Mérial), which is a cell based rabies vaccine only used countrywide. Vaccinations are often administered when owners take in their dogs for check-ups and visits at the vet.[39]

Oral rabies vaccines (see below for details) have been trialled on feral/stray dogs in some areas with high rabies incidence, as it could potentially be more efficient than catching and injecting them. However these have not been deployed for dogs at large scale yet.[40]

Wild animals

Wildlife species, primarily bats, raccoons, skunks, and foxes, act as reservoir species for different variants of the rabies virus in distinct geographic regions of the United States.[41][42] This results in the general occurrence of rabies as well as outbreaks in animal populations.[41] Approximately 90% of all reported rabies cases in the US are from wildlife.[41]

Oral rabies vaccine

Oral rabies vaccines are distributed across the landscape, targeting reservoir species, in an effort to produce a herd immunity effect.[43] The idea of wildlife vaccination was conceived during the 1960s, and modified-live rabies viruses were used for the experimental oral vaccination of carnivores by the 1970s.[44] Development of an oral immunization for wildlife began in the United States with laboratory trials using the live, attenuated Evelyn-Rokitnicki-Abselseth (ERA) vaccine, derived from the Street Alabama Dufferin (SAD) strain.[45] The first ORV field trial using the live attenuated vaccine to immunize foxes occurred in Switzerland in during 1978.[46][47]

There are currently three different types of oral wildlife rabies vaccine in use:

  • Modified live virus: Attenuated vaccine strains of rabies virus such as SAG2 and SAD B19 [48]
  • Recombinant vaccinia virus expressing rabies glycoprotein (V-RG): This is a strain of the vaccinia virus (originally a smallpox vaccine) that has been engineered to encode the gene for the rabies glycoprotein.
    • V-RG has been proven safe in over 60 animal species including cats and dogs.[49][45] The idea of wildlife vaccination was conceived during the 1960s, and modified-live rabies viruses were used for the experimental oral vaccination of carnivores by the 1970s.
  • ONRAB: an experimental live recombinant adenovirus vaccine [50][51]

Other oral rabies experimental vaccines in development include recombinant adenovirus vaccines.[52]

Oral rabies vaccination (ORV) programs have been used in many countries in an effort to control the spread of rabies and limit the risk of human contact with the rabies virus.[41] ORV programs were initiated in Europe in the 1980s, Canada in 1985, and in the United States in 1990.[53] ORV is a preventive measure to eliminate rabies in wild animal vectors of disease, mainly foxes, raccoons, raccoon dogs, coyotes and jackals, but also can be used for dogs in developing countries.[54] ORV programs typically attractive baits to deliver the vaccine to targeted animals. In the United States, RABORAL V-RG (Boehringer Ingelheim, Duluth, GA, USA) has been the only licensed ORV for rabies virus management since 1997.[45] However, ONRAB "Ultralite" (Artemis Technologies Inc., Guelph, Ontario, Canada) baits have been distributed by the United States Department of Agriculture (USDA) in select areas of the eastern United States under an experimental permit to target raccoons since 2011.[55] RABORAL V-RG baits consist of a small packet containing the oral vaccine which is then either coated in a fishmeal paste or encased in a fishmeal-polymer block.[41] ONRAB "Ultralite" baits consist of a blister pack with a coating matrix of vanilla flavor, green food coloring, vegetable oil and hydrogenated vegetable fat.[51] When an animal bites into the bait, the packets burst and the vaccine is administered.[53] Current research suggests that if adequate amounts of the vaccine is ingested, immunity to the virus should last for upwards of one year.[56] By immunizing wild or stray animals, ORV programs work to create a buffer zone between the rabies virus and potential contact with humans, pets, or livestock.[53] Landscape features such as large bodies of water and mountains are often used to enhance the effectiveness of the buffer.[57] The effectiveness of ORV campaigns in specific areas is determined through trap-and-release methods.[58] Titer tests are performed on the blood drawn from the sample animals in order to measure rabies antibody levels in the blood.[58] Baits are usually distributed by aircraft to more efficiently cover large, rural regions. In order to place baits more precisely and to minimize human and pet contact with baits, they are distributed by hand in suburban or urban regions.[53] The standard bait distribution density is 75 baits/km2 in rural areas and 150 baits/km2 in urban and developed areas.[45]

Implementation of ORV programs in the United States has led to the elimination of the coyote rabies virus variant in 2003 and gray fox variant during 2013.[59][60] Furthermore, ORV has been successful in preventing the westward expansion of the raccoon rabies enzootic front beyond Alabama.[43]

References

  1. ↑ 1.0 1.1 "Verorab". 28 October 2022. https://www.tga.gov.au/resources/auspmd/verorab. 
  2. ↑ "Rabies vaccine, human diploid cell (Imovax Rabies) Use During Pregnancy". 22 November 2019. https://www.drugs.com/pregnancy/rabies-vaccine-human-diploid-cell.html. 
  3. ↑ "Updates to the Prescribing Medicines in Pregnancy database". 21 December 2022. https://www.tga.gov.au/resources/resource/guidance/updates-prescribing-medicines-pregnancy-database. 
  4. ↑ 4.0 4.1 "Verorab". Therapeutic Goods Administration (TGA). 28 October 2022. https://www.tga.gov.au/resources/prescription-medicines-registrations/verorab-sanofi-aventis-australia-pty-ltd. 
  5. ↑ "VERORAB (Sanofi-Aventis Australia Pty Ltd)". 6 October 2022. https://www.tga.gov.au/resources/prescription-medicines-registrations/verorab-sanofi-aventis-australia-pty-ltd. 
  6. ↑ "Rabies Vaccine BP - Summary of Product Characteristics (SmPC)". 28 June 2020. https://www.medicines.org.uk/emc/product/1527/smpc. 
  7. ↑ "Rabipur pre-filled syringe - Summary of Product Characteristics (SmPC)". https://www.medicines.org.uk/emc/product/2502/smpc. 
  8. ↑ "Imovax Rabies (rabies virus strain pm-1503-3m antigen- propiolactone inactivated and water kit". 21 October 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ba8d4e72-f452-4859-ae6f-3644b4b0a78c. 
  9. ↑ "Rabavert- rabies vaccine kit". 18 September 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bd32ad4a-21b9-4890-9c37-4a6d1eff3145. 
  10. ↑ 10.0 10.1 "List of nationally authorised medicinal products, Active substance: rabies vaccine, Procedure no.: PSUSA/00009277/202103". European Medicines Agency (EMA). 21 October 2021. https://www.ema.europa.eu/en/documents/psusa/rabies-vaccine-list-nationally-authorised-medicinal-products-psusa/00009277/202103_en.pdf. 
  11. ↑ 11.00 11.01 11.02 11.03 11.04 11.05 11.06 11.07 11.08 11.09 11.10 11.11 11.12 11.13 11.14 11.15 11.16 11.17 11.18 11.19 11.20 11.21 "Rabies vaccines: WHO position paper – April 2018". Weekly Epidemiological Record 93 (16): 201–19. 2018. https://apps.who.int/iris/bitstream/handle/10665/272372/WER9316-201-219.pdf. Retrieved 28 August 2022. 
  12. ↑ 12.0 12.1 "Rabies re-examined". The Lancet. Infectious Diseases 2 (6): 327–343. June 2002. doi:10.1016/S1473-3099(02)00287-6. PMID 12144896. 
  13. ↑ "Rabies 99.9% fatal, but highly preventable —PCP" (in en). 2023-10-10. https://www.gmanetwork.com/news/topstories/nation/884767/rabies-99-9-fatal-but-highly-preventable-pcp/story/. 
  14. ↑ Vaccine Analysis: Strategies, Principles, and Control. Springer. 2014. p. 63. ISBN 9783662450246. https://books.google.com/books?id=vJKeBQAAQBAJ&pg=PA63. 
  15. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  16. ↑ World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. 2021. WHO/MHP/HPS/EML/2021.02. 
  17. ↑ 17.0 17.1 17.2 "Preexposure Vaccinations". 22 April 2011. https://www.cdc.gov/rabies/specific_groups/travelers/pre-exposure_vaccinations.html. 
  18. ↑ "Rabies Vaccine Information Statement". June 2022. https://www.cdc.gov/vaccines/hcp/vis/vis-statements/rabies.html. 
  19. ↑ 19.0 19.1 19.2 "Rabies Postexposure Prophylaxis (PEP)". 16 November 2019. https://www.cdc.gov/rabies/medical_care/index.html. 
  20. ↑ "An Advisory Committee Statement (ACS). Committee to Advise on Tropical Medicine and Travel (CATMAT). Statement on travellers and rabies vaccine". Canada Communicable Disease Report = Releve des Maladies Transmissibles Au Canada 28 (ACS-4): 1–12. March 2002. PMID 11889905. http://publications.gc.ca/collections/Collection/H12-21-2-28-4.pdf. Retrieved 7 January 2020. 
  21. ↑ "National Rabies Management Program Overview". https://www.aphis.usda.gov/aphis/ourfocus/wildlifedamage/programs/nrmp/ct_national_rabies_management_program_overview. 
  22. ↑ "Rabies - Human Vaccines". World Health Organization (WHO). https://www.who.int/rabies/vaccines/human_vaccines/en/index.html. 
  23. ↑ "Rabies". https://www.who.int/ith/vaccines/rabies/en/. 
  24. ↑ "The serial cultivation of human diploid cell strains". Experimental Cell Research 25 (3): 585–621. December 1961. doi:10.1016/0014-4827(61)90192-6. PMID 13905658. 
  25. ↑ "The limited in vitro lifetime of human diploid cell strains". Experimental Cell Research 37 (3): 614–636. March 1965. doi:10.1016/0014-4827(65)90211-9. PMID 14315085. 
  26. ↑ "Preventing rabies with the Verorab vaccine: 1985-2005 Twenty years of clinical experience". Travel Medicine and Infectious Disease 5 (6): 327–348. November 2007. doi:10.1016/j.tmaid.2007.07.004. PMID 17983973. 
  27. ↑ "Production and evaluation of a chromatographically purified Vero cell rabies vaccine (PVRV) in China using microcarrier technology". Human Vaccines & Immunotherapeutics 8 (9): 1230–1235. September 2012. doi:10.4161/hv.20985. PMID 22894963. 
  28. ↑ "Verorab". 22 June 2005. https://extranet.who.int/pqweb/content/verorab. 
  29. ↑ "Pasteur's work on rabies: reexamining the ethical issues". The Hastings Center Report (The Hastings Center) 8 (2): 26–33. April 1978. doi:10.2307/3560403. PMID 348641. 
  30. ↑ "Four Thousand Years of Concepts Relating to Rabies in Animals and Humans, Its Prevention and Its Cure". Tropical Medicine and Infectious Disease 2 (2): 5. March 2017. doi:10.3390/tropicalmed2020005. PMID 30270864. 
  31. ↑ "Rabies vaccine prepared in human cell cultures: progress and perspectives". Reviews of Infectious Diseases 2 (3): 433–448. 1980. doi:10.1093/clinids/2.3.433. PMID 6158081. 
  32. ↑ "Diagnostic dilemma in flaccid paralysis following anti-rabies vaccine". Neurology India 52 (1): 132–133. March 2004. PMID 15069272. http://www.neurologyindia.com/article.asp?issn=0028-3886;year=2004;volume=52;issue=1;spage=132;epage=133;aulast=Srivastava. 
  33. ↑ "Vaccinations and immunization Rabies". https://www.who.int/teams/control-of-neglected-tropical-diseases/rabies/vaccinations-and-immunization. 
  34. ↑ "State Rabies Vaccination Laws for Domestic Dogs, Cats, and Ferrets in the United States". http://lawatlas.org/datasets/rabies-vaccination-laws. 
  35. ↑ "3.1.17 Rabies (Infection with Rabies Virus and Other Lyssaviruses)". OIE Terrestrial Manual. World Organisation for Animal Health. 2018. https://www.oie.int/fileadmin/Home/eng/Health_standards/tahm/3.01.17_RABIES.pdf. Retrieved 22 July 2021. 
  36. ↑ "Imrab 3". Merial. http://us.merial.com/equine/products/equine_imrab3.asp. 
  37. ↑ "Dr. George W. Beran's Biography". World Rabies Day. http://www.worldrabiesday.org/EN/Media_Center/Perspectives.html. 
  38. ↑ "One World, One Health Rabies". http://www.onehealthinitiative.com/publications/RabiesPresentationWithNotes1.pdf. 
  39. ↑ "Evaluation of mass vaccination campaign coverage against rabies in dogs in Tunisia". Zoonoses and Public Health (Institut Pasteur de Tunis and Blackwell Verlag GmbH) 58 (2): 110–118. March 2011. doi:10.1111/j.1863-2378.2009.01306.x. PMID 20042063. 
  40. ↑ Organization, World Health (2007). "Oral vaccination of dogs against rabies: guidance for research on oral rabies vaccines and Field application of oral vaccination of dogs against rabies". Geneva, Switzerland: World Health Organization. https://apps.who.int/iris/handle/10665/331036. 
  41. ↑ 41.0 41.1 41.2 41.3 41.4 "Oral Rabies Vaccination". https://www.aphis.usda.gov/aphis/ourfocus/wildlifedamage/programs/nwrc/research-areas/SA_Rabies/CT_Orv_vaccination. 
  42. ↑ "Rabies virus vectors and reservoir species". Revue Scientifique et Technique 37 (2): 371–384. August 2018. doi:10.20506/rst.37.2.2808. PMID 30747141. 
  43. ↑ 43.0 43.1 "Wildlife Rabies Management in the New World: Prevention, Control and Elimination in Mesocarnivores" (in en). History of Rabies in the Americas: From the Pre-Columbian to the Present, Volume I. Fascinating Life Sciences. Cham: Springer International Publishing. 2023. pp. 143–198. doi:10.1007/978-3-031-25052-1_7. ISBN 978-3-031-25051-4. 
  44. ↑ "Rabies--an historical perspective". Infectious Agents and Disease 3 (4): 168–180. August 1994. PMID 7827785. https://pubmed.ncbi.nlm.nih.gov/7827785/. 
  45. ↑ 45.0 45.1 45.2 45.3 "Oral vaccination of wildlife using a vaccinia-rabies-glycoprotein recombinant virus vaccine (RABORAL V-RG®): a global review". Veterinary Research 48 (1): 57. September 2017. doi:10.1186/s13567-017-0459-9. PMID 28938920. 
  46. ↑ "Oral vaccination of wildlife against rabies: opportunities and challenges in prevention and control". Developments in Biologicals 119: 173–184. 2004. PMID 15742629. 
  47. ↑ "Control of rabies in wildlife". Scientific American 266 (6): 86–92. June 1992. doi:10.1038/scientificamerican0692-86. PMID 1585150. Bibcode: 1992SciAm.266f..86W. 
  48. ↑ "Field application of oral rabies vaccines for dogs". Report of a WHO Consultation organized in collaboration with the Office International des Epizooties (OIE). Geneva, Switzerland: World Health Organization. July 1998. https://www.who.int/rabies/en/Field_application_for_oral_rabies_vaccines_for_dogs.pdf. 
  49. ↑ "Frequently Asked Questions". 12 November 2019. https://www.aphis.usda.gov/aphis/ourfocus/wildlifedamage/programs/nrmp/ct_rabies_faqs. 
  50. ↑ "Canine adenovirus based rabies vaccines". Developments in Biologicals 131: 467–476. 2008. PMID 18634509. https://pubmed.ncbi.nlm.nih.gov/18634509/. Retrieved 2023-01-29. 
  51. ↑ 51.0 51.1 "Comparing ONRAB® AND RABORAL V-RG® oral rabies vaccine field performance in raccoons and striped skunks, New Brunswick, Canada, and Maine, USA". Journal of Wildlife Diseases 48 (1): 157–167. January 2012. doi:10.7589/0090-3558-48.1.157. PMID 22247384. 
  52. ↑ "Canine adenovirus based rabies vaccines". Developments in Biologicals 131: 467–476. 2008. PMID 18634509. https://pubmed.ncbi.nlm.nih.gov/18634509/. Retrieved 2023-01-29. 
  53. ↑ 53.0 53.1 53.2 53.3 "Oral Rabies Vaccine Information". 12 November 2019. https://www.aphis.usda.gov/aphis/ourfocus/wildlifedamage/programs/nrmp/ct_rabies_vaccine_info. 
  54. ↑ "Oral rabies vaccination". http://www.rabies-vaccination.com/oral-vaccination.asp. 
  55. ↑ "Efficacy of Ontario Rabies Vaccine Baits (ONRAB) against rabies infection in raccoons". Vaccine 36 (32 Pt B): 4919–4926. August 2018. doi:10.1016/j.vaccine.2018.06.052. PMID 30037482. 
  56. ↑ "Frequently Asked Questions". 12 November 2019. https://www.aphis.usda.gov/aphis/ourfocus/wildlifedamage/programs/nrmp/ct_rabies_faqs. 
  57. ↑ "Modeling Raccoon (Procyon lotor) Habitat Connectivity to Identify Potential Corridors for Rabies Spread". Tropical Medicine and Infectious Disease 2 (3): 44. August 2017. doi:10.3390/tropicalmed2030044. PMID 30270901. 
  58. ↑ 58.0 58.1 "Oral Rabies Vaccination Program in the East". January 2011. https://www.aphis.usda.gov/publications/wildlife_damage/content/printable_version/fs_oral_rabies_2011.pdf. 
  59. ↑ "Evaluation of oral rabies vaccination programs for control of rabies epizootics in coyotes and gray foxes: 1995-2003". Journal of the American Veterinary Medical Association 227 (5): 785–792. September 2005. doi:10.2460/javma.2005.227.785. PMID 16178403. 
  60. ↑ "Rabies surveillance in the United States during 2006". Journal of the American Veterinary Medical Association 231 (4): 540–556. August 2007. doi:10.2460/javma.231.4.540. PMID 17696853. 

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