VET September 2024 The Monthly Magazine of the SOUTH AFRICAN VETERINARY ASSOCIATION Die Maandblad van die SUID-AFRIKAANSE VETERINÊRE VERENIGING Vitreous Humor Biochemical Analysis in Postmortal Diagnostics of Ruminants CPD THEME Rabies, Physical Therapy nuus•news CPD article QR code
Dagboek • Diary Ongoing / Online 2024 SAVETCON: Webinars Info: Corné Engelbrecht, SAVETCON, 071 587 2950, corne@savetcon.co.za / https://app.livestorm.co/svtsos Acupuncture – Certified Mixed Species Course Info: Chi University: https://chiu.edu/courses/cva#aboutsouthafrica@tcvm.com SAVA Johannesburg Branch CPD Events Monthly - please visit the website for more info. Venue: Johannesburg Country Club Info: Vetlink - https://savaevents.co.za/ September 2024 October 2024 November 2024 SAVA Eastern Free State Branch Mini Congress 06-07 September Venue: Protea Hotel, Clarens Info: conference@savetcon.co.za SAVA Eastern Cape and Karoo Branch CPD Day 07 September Venue: Dolphins Leap, Port Elizabeth Info: www.vetlink.co.za 8th World One Health Congress 20-23 September Venue: CTICC, Cape Town, South Africa Info: https://globalohc.org/8WOHC or contact conferences@vetlink.co.za SAVA Northern Natal and Midlands Branch Congress 05-06 October Venue: Lythwood Lodge, Midlands Info: www.vetlink.co.za PARSA Conference 06 – 08 October Venue: Villa Paradiso, Hartbeespoort, Gauteng Info: corne@savetcon.co.za SAAVT 2024 Conference 09 – 10 October Venue: 26 Degrees South, Muldersdrift Info: conference@savetcon.co.za or https://savetcon.co.za/2024-saavt-biennial-congress/ 12th IAVRPT Symposium 30 October – 02 November Venue: Somerset-West, Cape Town, South Africa Info: https://iavrpt2024.co.za/ or contact conferences@vetlink.co.za Poultry Group of SAVA Annual Congress 06-08 November Venue: 26 Degrees South, Muldersdrift, Gauteng Info: conferences@savetcon.co.za https://savetcon.co.za/poultry2024/
Vetnuus | September 2024 1 Contents I Inhoud President: Dr Paul van der Merwe president@sava.co.za Managing Director: Mr Gert Steyn md@sava.co.za/ +27 (0)12 346 1150 Editor VetNews: Ms Andriette van der Merwe vetnews@sava.co.za Bookkeeper: Ms Susan Heine accounts@sava.co.za/+27 (0)12 346 1150 Bookkeeper's Assistant: Ms Sonja Ludik bookkeeper@sava.co.za/+27 (0)12 346 1150 Secretary: Ms Elize Nicholas elize@sava.co.za/ +27 (0)12 346 1150 Reception: Ms Hanlie Swart reception@sava.co.za/ +27 (0)12 346 1150 Marketing & Communications: Ms Sonja van Rooyen marketing@sava.co.za/ +27 (0)12 346 1150 Membership Enquiries: Ms Debbie Breeze debbie@sava.co.za/ +27 (0)12 346 1150 Vaccination booklets: Ms Debbie Breeze debbie@sava.co.za/ +27 (0)12 346 1150 South African Veterinary Foundation: Ms Debbie Breeze savf@sava.co.za/ +27 (0)12 346 1150 Community Veterinary Clinics: Ms Claudia Cloete cvcmanager@sava.co.za/ +27 (0)63 110 7559 SAVETCON: Ms Corné Engelbrecht corne@savetcon.co.za/ +27 (0)71 587 2950 VetNuus is ‘n vertroulike publikasie van die SAVV en mag nie sonder spesifieke geskrewe toestemming vooraf in die openbaar aangehaal word nie. Die tydskrif word aan lede verskaf met die verstandhouding dat nóg die redaksie, nóg die SAVV of sy ampsdraers enige regsaanspreeklikheid aanvaar ten opsigte van enige stelling, feit, advertensie of aanbeveling in hierdie tydskrif vervat. VetNews is a confidential publication for the members of the SAVA and may not be quoted in public or otherwise without prior specific written permission to do so. This magazine is sent to members with the understanding that neither the editorial board nor the SAVA or its office bearers accept any liability whatsoever with regard to any statement, fact, advertisement or recommendation made in this magazine. VetNews is published by the South African Veterinary Association STREET ADDRESS 47 Gemsbok Avenue, Monument Park, Pretoria, 0181, South Africa POSTAL ADDRESS P O Box 25033, Monument Park Pretoria, 0105, South Africa TELEPHONE +27 (0)12 346-1150 FAX General: +27 (0) 86 683 1839 Accounts: +27 (0) 86 509 2015 WEB www.sava.co.za CHANGE OF ADDRESS Please notify the SAVA by email: debbie@sava.co.za or letter: SAVA, P O Box 25033, Monument Park, Pretoria, 0105, South Africa CLASSIFIED ADVERTISEMENTS (Text to a maximum of 80 words) Sonja van Rooyen assistant@sava.co.za +27 (0)12 346 1150 DISPLAY ADVERTISEMENTS Sonja van Rooyen assistant@sava.co.za +27 (0)12 346 1150 DESIGN AND LAYOUT Sonja van Rooyen PRINTED BY Business Print: +27 (0)12 843 7638 VET nuus•news Diary / Dagboek II Dagboek • Diary Regulars / Gereeld 2 From the President 4 Editor’s notes / Redakteurs notas Articles / Artikels 6 Rabies in Cape fur seals: outbreak update report 10 Rabies Vaccine for Prophylaxis and Treatment of Rabies: A Narrative Review 16 Development of mRNA rabies vaccines 24 Long-acting solution for gastric ulceration in equines evaluated 26 The Value of a Veterinary Rehabilitation Practitioner in the Animal Health Team Association / Vereniging 27 SAVA News 28 CVC News 30 In Memoriam 38 Legal Mews Events / Gebeure 32 Onderstepoort residence – houseparents 1952 to 1975 Vet's Health / Gesondheid 43 Life Coaching Technical / Tegnies 40 Ophthalmology Column Relax / Ontspan 15 Knee-jerk reaction or mitigating circumstances 48 Life Plus 25 Marketplace / Markplein 44 Marketplace Jobs / Poste 45 Jobs / Poste 47 Classifieds / Snuffeladvertensies 15 28 24 Scan the QR code for easy access to this month's CPD article «
Vetnews | September 2024 2 « BACK TO CONTENTS I’ve got a coffee mug with an inscription and picture printed on it: “Real doctors treat more than one species”. It is my preferred mug, for my my son-in-law, a medical doctor! You can only imagine the backlash and banter that it evokes. It, however, does raise the question if veterinarians could and should be considered health professionals. Health is defined as a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity. The enjoyment of the highest attainable standard of health is one of the fundamental rights of every human being without distinction of race, religion, political belief, economic or social condition. Nutrition, lifestyle, environment, and genetics are considered the four pillars of health and determinants thereof. When any one or more of these is compromised, health is at risk and some form of health care is required as a support system. Proper nutrition by insurance of safe and wholesome food from secured food sources is a critical part of health and development. Better nutrition is related to improved infant, child and maternal health, stronger immune systems, safer pregnancy and childbirth, lower risk of communicable and non-communicable diseases (such as diabetes and cardiovascular disease), and longevity. During graduation, all veterinarians undertake and sign the veterinary oath stating: I herewith solemnly declare that I will: • practise my profession with honesty and integrity, • maintain and uphold high professional and scientific standards, • treat my patients to the best of my knowledge and ability and never intentionally cause them harm, • use my professional knowledge, skills and resources to protect and promote the health and welfare of animals and humans, (emphasis added) • continue to improve my professional knowledge and strive to further the status and image of the profession. Calvin Schwabe has proposed that “human health provides the most logical unifying or apical cause in veterinary medicine’s hierarchy of values.” Veterinarians thus have the opportunity and the responsibility to protect human health and well-being in all that they do. Their broad, comparative medical training and environmental perspective add critical insights to solving a broad spectrum of health problems, including but not limited to those involving animals directly or indirectly. Today with public awareness of and focus on food safety, concerns over bioterrorism preparedness, the environment, and biodiversity, and the highly visible epidemics, veterinarians play a critical role as a members of a collaborative health effort. The Institute of Medicine has defined public health as “what we, as a society, do collectively to assure the conditions in which people can be healthy.” Veterinarians are making important contributions to public health in the areas of food security and safety, emerging infectious diseases, environmental health, zoonotic and non-zoonotic disease surveillance, prevention, and control, health security, and basic and applied medical research. Veterinarians, through the diverse services they render, do and always will make a considerable impact on the health and welfare of humans, directly or indirectly. It can thus be postulated that veterinarians are indeed health professionals. v Kind regards, Paul van der Merwe From the President Dear members, Family Feud
Vetnuus | September 2024 3 Vetnuus | August 2024 3 To find out more: Building better practice, together. The co.mpanion partnership is a co.llaborative model that gives you the ownership, support and autonomy you need to build your individual practice’s legacy inside a growing network. co.mpanion is not a corporate body, it is a professional owned and led veterinary model that is right for you if: You are looking for a support structure. You are looking for a better way to exit from or sell your practice. You want to become a shareholder. www.companion.partners Download Value Proposition View Video WhatsApp Sr Dale Parrish
Vetnews | September 2024 4 « BACK TO CONTENTS Dear all. I hope that the last revenge of winter did not disrupt you too much. This was the prediction for Hoedspruit for the last week of August: Wednesday Minimum 17 and Maximum 37; Thursday minimum 13, maximum 16; Friday minimum 13, maximum 14; Saturday minimum 12, maximum 20; Sunday minimum 10, maximum 24; Monday minimum 17 and maximum 27; and then people say we never have winter in Hoedspruit. I suspect there will be a distinct mothball aroma over the area towards the end of the week. I follow a psychologist on Facebook (do I detect some rolling eyes) Naomi Holdt. She writes a lot about education and raising children, and I find her credible as she is also a mom and what she says carries some weight for me. In one of her blogs, she says the following: “No matter what behaviour you witness, or what gets said, or done, before you leap in with assumptions, judgement and punishment, bring this phrase to mind: ‘‘I wonder why’. These words have the power to turn judgment into compassion and empathy. The thing to remember about all human behaviour, including everything happening in classrooms, is that there is always another story. There is always another side. Compassion. Have you ever considered being compassionate towards yourself? Selfcompassion is the practice of being kind and understanding towards yourself. Simple as it seems, many people neglect to extend the same compassion and understanding to themselves as they do to other people. It’s especially important to be compassionate towards yourself in difficult times, during periods of stress or unfortunate circumstances, or in situations where we fail or feel inadequate.If something negative happens or you don’t do as well in something as you’d hoped, selfcompassion can be an invaluable tool to help you through it. It means showing yourself the same warmth, understanding and compassion that you would to anyone else in similar circumstances. Ask: “I wonder why” when other people don’t behave well, but also when you do not. Admitting that your behaviour was out of character, is the first introspective step to healing. In the September edition, we pay tribute to Dr Chetty who passed a while ago, we also look into the outbreak of rabies in Cape Fur seals and a couple of other interesting rabies-related articles. There is a short piece written by myself, please find it and respond to me by mail, I would love to hear your thoughts on the topic August is considered the last official month of Winter and September is often seen as Spring Month. I hope that the first of September was not winter’s last revenge day of cold. Enjoy the promise of warmer weather on its way. The Editor v From the Editor Editor’s notes / Redakteurs notas ‘Nine times out of ten the story behind the misbehaviour won’t make you angry, it will break your heart’~ Annette Breaux“.
Vetnuus | September 2024 5 “The South African Veterinary Association aims to serve its members and to further the status and image of the veterinarian. We are committed to upholding the highest professional and scientific standards by utilising the professional knowledge, skill and resources of our members, to foster close ties with the community and thus promote the health and welfare of animals and mankind”. MISSION STATEMENT SAVA-CVC supports vets that provide primary animal health care (vaccinations, deworming as well as tick and flea treatments, sterilisations) Servicing and enhancing the veterinary community since 1920! Tel: 012 346 1150 E-mail: vethouse@sava.co.za www.sava.co.za 24-Hour Toll-Free Helpline: 0800 21 21 21
Vetnews | September 2024 6 « BACK TO CONTENTS 1. Introduction Rabies is endemic in South Africa. It is a zoonotic disease, which means that people can become infected by an infected animal. The rabies virus is transmitted through the saliva of an infected animal when it bites, scratches or licks a person. Rabies affects the brain and is fatal once a person or animal shows clinical signs. Animals infected with rabies show changes in behaviour and neurological signs. They may drool a lot, become paralysed, lose the ability to swallow, continuously vocalise (barking, whining, howling etc.), and become aggressive, or on the contrary, they may appear weak and unresponsive. Any mammal can become infected with rabies, but the biggest threat to human health is infected dogs and cats. South Africa is aiming for the goal of zero cases of dog-mediated human rabies cases by 2030, through the “National Strategy for the Elimination of Canine Mediated Human Rabies in South Africa”, which is available at https://www.dalrrd.gov.za/index.php/publication/425animal-health-information Cape fur seals (Arctocephalus pusillus pusillus), occur along the coast of Africa between southern Angola and Algoa Bay, South Africa. They are a social species that live close together in colonies. They are known to approach people and other animals out of curiosity or if motivated by food. They are predated on by wild carnivores on land, including black-backed jackals and brown hyenas. Cape fur seals can travel extensively in the ocean in search of food or territory, swimming hundreds of kilometres in a matter of days. Reports of Cape fur seals showing aggressive behaviour, especially towards people, have increased since several mass mortality events occurred in South Africa in 2021 and 2022. Initially, seal samples collected during one of these events in 2021 tested negative for rabies. The only known positive case of rabies in seals recorded in literature was of a ringed seal (Phoca hispida) in the Svalbard Islands (Norway) in 1980, which was associated with an outbreak in the arctic fox population. Rabies occurs in a wide range of wild and domesticated mammals, but this is the first detected occurrence in cape fur seals in Southern Africa. It should be emphasized that in South Africa, the vast majority of human rabies cases are caused by exposure to rabid dogs. 2. Background In June 2024, a rabies outbreak was detected in South African Cape fur seals, a species in which rabies has not been recorded previously. The events leading up to this detection started on 20 May 2024, when a three-year-old dog in Cape Town was euthanised at a private veterinary practice after showing signs of severe aggression which triggered a suspicion of rabies. The dog was sampled and its brain subsequently tested positive for rabies with the fluorescent antibody test (FAT). The owner of this dog suspected that the dog had been bitten by a Cape fur seal while walking on the beach two weeks before the onset of clinical signs. Shortly after this incident, there were reports of aggressive Cape fur seals from two Cape Town beaches. Two of these Cape fur seals subsequently tested positive for rabies. This finding triggered retrospective testing of stored samples collected from Cape fur seal mortalities (2021-2024) for rabies. Some of these retrospective samples have tested positive for rabies, indicating that this outbreak is not new. To date, positive samples originated from the South African coast between Yzerfontein and Plettenberg Bay and the earliest positive case so far occurred in August 2022. Rabies in Cape fur seals: outbreak update report 31 July 2024 Report compiled by: Directorate Animal Health Map 1: Reported outbreaks of rabies in Cape fur seals in the Western Cape Province. Note: Dots on the maps that indicate locations in close proximity might appear as single dots
Vetnuus | September 2024 7 3. Diagnostic tests Only the ARC Onderstepoort Veterinary Research (ARC-OVR) Rabies Laboratory and the Allerton Provincial Veterinary Laboratory (PVL) are SANAS accredited and Director Animal Health (DAH) approved to conduct animal rabies diagnostic testing using the fluorescent antibody test (FAT) – This test is conducted on fresh/ glycerosaline brain samples (that include the hippocampus portion). Formalinised seal brain samples (retrospective samples) that were submitted for histopathology were available at the Pathology Section of the Faculty of Veterinary Science, University of Pretoria, Onderstepoort. The DAH allowed rabies testing of these samples using an immunohistochemistry (IHC) test at the Pathology Section, Onderstepoort, as these samples cannot be tested using the FAT. For diagnostic purposes for all suspect rabies cases, fresh/ glycerosaline brain samples should be submitted to either ARC-OVR or Allerton PVL. Any suspected case of rabies must immediately be reported to the responsible state veterinary office. Samples that have tested positive on FAT at the ARC-OVR Rabies Laboratory are being sequenced through the ARC-OVR. Samples that have tested positive on IHC testing at the Pathology Section, Onderstepoort, are being sequenced through the Centre for Viral Zoonosis (CVZ), University of Pretoria. The first FAT positive case was reported to the World Organisation for Animal Health (WOAH) and all additional FAT positive cases are reported to the WOAH as well. IHCpositive cases are not reported to the WOAH, as this method is not SANAS accredited and DAH approved for official diagnostic use in South Africa. The IHC test’s current value is limited to adjunct use in rabies diagnosis for brain tissue that is fixed in formalin (FAT testing cannot be conducted on formalin-fixed brain tissue). 4. Epidemiology Sequencing of positive seal samples (prospective and retrospective) has been initiated to better understand the epidemiology of the disease. Initial sequencing results have revealed that the rabies strain involved is a canid strain, possibly of dog- or jackal-cycle origin, indicating a potential introduction from other canid dog and/or jackal rabies cycles to Cape fur seals. The closest links identified to date are to a canid rabies strain from a black-backed jackal from Namibia, and a separate link to a canid rabies strain from a bat-eared fox from the Western Cape. Some of the sequences that have been obtained to date cluster together and in some cases the sequences are similar, indicating that this rabies virus is very likely circulating within the Cape fur seal population, and may already be established in this population, i.e. representing a canid rabies Cape fur seal cycle. On the other hand, at least one sample seems to have yielded a distinctly separate sequence, thus indicating that there may have been more than one introduction into the Cape fur seal population. Additionally, the dog from Cape Town that tested positive in May 2024 was likely infected by a rabid Cape fur seal, indicating that rabies transmission from seals is possible. Further investigations and comparisons are required to consolidate any theory around the origin of the current Cape fur seal cycle with the note that phylogenetic trees can only be drawn from other available sequences. There are vast areas in Namibia and the Northern Cape Province of South Africa that are sparsely populated and some areas are restricted due to mining activities. Observational surveillance in such areas is limited, and hence samples from these areas for rabies testing in animals will be limited. In addition, it has not been possible to date to obtain and sequence all rabies strains from dog cases in South Africa either, not even in the Western Cape Province in which dog rabies remains a relatively rare occurrence. The table below provides a summary of all reported rabies cases in Cape fur seals. To date, positive Cape fur seal rabies cases have only been reported from the Western Cape Province. Cape fur seals occur along the coast of Africa between southern Angola and Algoa Bay, South Africa. The Eastern Cape and Northern Cape Provinces are aware of the outbreaks and surveillance in Cape fur seals will be enhanced to detect any possible cases. Information has also been extended to the neighbouring countries of Namibia and Angola. >>> 8 Leading Article Sample collection date Areas where the sample was collected FAT or IHC 2022/08/05 Kommetjie IHC + 2023/05/24 Noordhoek Beach IHC + 2023/07/30 Kalk Bay IHC + 2023/08/09 Melkbosstrand FAT + and IHC + 2023/10/12 Fish Hoek IHC + 2024/01/07 Plettenberg Bay FAT + and IHC + 2024/02/23 Pringle Bay IHC + 2024/04/08 Plettenberg Bay FAT + 2024/05/15 Strand IHC + 2024/05/22 Blouberg FAT + and IHC + 2024/05/26 Muizenberg IHC + 2024/06/13 Die Dam (between Gansbaai and Cape Agulhas) FAT + 2024/06/26 Muizenberg FAT + and IHC + 2024/06/27 Glencairn FAT + and IHC + 2024/07/15 Yzerfontein (2 CAPE FUR SEAL) FAT + 2024/07/17 Mossel Bay FAT + Total no. of positive cases = 17 Table 1 Summary of rabies-positive Cape fur seals from Western Cape Province
Vetnews | September 2024 8 « BACK TO CONTENTS • A total of 28 Cape fur seal brain samples (fresh/ gycerosaline) have been submitted to the ARC-OVR Rabies Laboratory, of which 10 have tested positive on FAT. • A total of 140 formalinised Cape fur seal brain samples (that were submitted for histopathology, mainly retrospectively) were available at the Pathology Section, Onderstepoort, of which 12 tested positive on IHC. 5. Control Measures a. Awareness and education The public is urged to avoid interaction with Cape fur seals encountered at the beach, harbours, etc., as they are wild animals and are therefore potentially dangerous. If a person has been bitten, scratched or licked by an animal that is suspected of having rabies, they are advised to wash the wound well with soap and running water for 10 minutes and go to the nearest clinic immediately for treatment. Any abnormal behaviour or aggression observed in Cape fur seals or any other mammal must be reported to the local state veterinary office for investigation. Pet owners should ensure that pets are always on a leash when on the beach and other seal haul-out sites. It is additionally extremely important for pet owners to ensure that their dogs and cats are fully vaccinated against rabies, to protect them, and the community they live in. These messages are continuously emphasized through awareness material. For more information on rabies in humans and in animals, please visit: • https://www.nicd.ac.za/diseases-a-z-index/rabies/ • https://www.dalrrd.gov.za/index.php/publication/204outbreaks-and-diseases For contact details of State Veterinary Services, please visit: • https://www.dalrrd.gov.za/index.php/component/content/ article/451-provincial-veterinary-services-contacts b. Surveillance Surveillance for suspect rabies in Cape fur seals is being enhanced along the Cape coastline. Any suspected incident must be reported to the local state veterinary office for investigation. Suspect rabies in Cape fur seals may present as behavioural abnormalities (including aggression), neurological signs and death, that cannot be attributed to another known cause. Knowledge of normal Cape fur seal behaviour is required in order to ascertain what is abnormal, hence suspect cases should be reported to the authorities for further investigation. Sampling of suspect rabies cases is required to confirm if rabies is, in fact, present. c. Vaccination Due to the novel nature of rabies in Cape fur seals, very little is known about the transfer of the virus in the marine environment, as well as the effectiveness of existing registered rabies vaccines in Cape fur seals. Approved research projects are in the process of being conducted on rabies vaccination of Cape fur seals to generate information. Before any research may be conducted, all relevant permissions must be obtained through the Department of Agriculture and the Department of Forestry, Fisheries and the Environment. Large-scale vaccination of Cape fur seals against rabies is at this point not practical or feasible, but targeted vaccination of specific populations may be considered, depending on the outcome of the research projects. This is also a very important opportunity to emphasise that all dogs and cats are required to be vaccinated against rabies, by law [Animal Disease Act, 1984 (Act No. 35 of 1984)]. Dogs are by far the leading cause of human rabies in South Africa, due to our close association with these animals. 6. One Health response Rabies is a controlled animal disease as per the Animal Diseases Act, 1984 (Act No. 35 of 1984) and a Notifiable Medical Conditions as per the National Health Act, 20023 (Act No. 61 of 2003). A localised Working Group was established within the City of Cape Town and now includes stakeholders from other municipalities within the migration range of Cape fur seals where positive test cases were reported. Under the Working Group, Task Teams were convened and tasked with different aspects of handling the status quo with respect to positive rabies cases. Participating parties include Municipalities, Provincial and National Departments (Human-, Animal- and Environmental Health), relevant NGOs, management agencies, academia, seal rehabilitation facilities, exhibition facilities, veterinarians and marine mammal experts. The Directorate: Animal Health of the National Department of Agriculture together with the national Rabies Action Group, which functions under the Ministerial Technical Committee of Veterinary Services led by the Department of Agriculture, is overseeing this development. The Department of Forestry, Fisheries and the Environment and the Department of Health are closely working with the Department of Agriculture at the national level to ensure smooth handling of the situation, adopting the One Health approach. As several of the Cape fur seals that tested positive for rabies displayed aggressive behaviour and were involved in biting people and animals, efforts are being made by the South African government authorities and several NGOs to trace people and animals who have been in contact with suspect rabid seals in order for them to receive medical or veterinary attention. Any person who has an increased risk of exposure to seals (e.g. some animal handlers, veterinarians, researchers, etc.) is strongly advised to receive pre-exposure prophylaxis (be vaccinated) against rabies. v Leading Article
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Vetnews | September 2024 10 « BACK TO CONTENTS Rabies Vaccine for Prophylaxis and Treatment of Rabies: A Narrative Review Alan D. Kaye1 , Dominique M. Perilloux2 , Elizabeth Field2 , Cody A. Orvin2 , Spencer C. Zaheri2 , William C. Upshaw2 , Raju Behara1 , Tomasina Q. Parker-Actlis1, Adam M. Kaye3 , Shahab Ahmadzadeh1 , Sahar Shekoohi1, Giustino Varrassi4 1. Department of Anesthesiology, Louisiana State University Health Sciences Center, Shreveport, USA 2. School of Medicine, Louisiana State University Health Sciences Center, Shreveport, USA 3. Department of Pharmacy Practice, Thomas J. Long School of Pharmacy and Health Sciences University of the Pacific, Stockton, USA 4. Pain Medicine, Paolo Procacci Foundation, Rome, ITA Corresponding author: Sahar Shekoohi, sahar.shekoohi@lsuhs.edu Abstract Rabies, a millennia-old viral infection transmitted through animal bites, poses a lethal threat to humans, with a historic fatality rate of 100% if left untreated. Louis Pasteur’s introduction of the rabies vaccine in 1885 marked a turning point in the battle against rabies, preventing numerous cases. The purpose of this paper is to review the historical development, current challenges, and future prospects of rabies vaccination and treatment, with emphasis on the importance of continued research and collaborative efforts in the quest to eradicate this deadly infection. Historical vaccine development progressed from inactivated to live attenuated forms, with modern recombinant techniques showing promise. The preventive measures at present primarily involve vaccination, but challenges persist, such as differing safety profiles and immunogenicity among vaccine types. Pre-exposure prophylaxis with a three-dose vaccine series is crucial, especially in high-risk scenarios. Post-exposure prophylaxis combines human rabies immunoglobulin and inactivated rabies virus vaccine. The quest for the next generation of vaccines explores genetically modified and viral vector-based approaches; emerging treatments include gene therapy, virus-like particles, and monoclonal antibodies, offering hope for improved outcomes. Economic barriers to post-exposure prophylaxis, limited education, and awareness challenge rabies control. Cost-effective solutions and comprehensive awareness campaigns are vital for the successful eradication of rabies. More research and collaborative endeavours remain pivotal in the ongoing journey to eradicate rabies, one of the deadliest infectious diseases known to humans, if not met with prophylactic measures. Introduction And Background Rabies is a lethal viral infection often transmitted through animal bites or saliva entering through mucosal membranes or broken skin and has been known for thousands of years. It is caused by the bullet-shaped, single-stranded, negative-sense RNA Rhabdoviridae family of viruses, which are carried by both wild and domesticated animals. A viral envelope and ribonucleocapsid core contribute to viral virulence and cause nervous system infection, leading to severe symptoms like hydrophobia and aerophobia. Hydrophobia is defined as a fear of water, but for patients experiencing this symptom of rabies, it describes the fear of pain upon swallowing fluids. The pain is caused by spasms of the pharynx due to furious rabies infection, which is characteristic of 80% of human rabies infections. The remaining 20% of cases are paralytic. The presenting symptoms include fever, headache, and fatigue that progress to encephalomyelitis characterized by delirium. The five stages of the disease course are incubation, which can last from days to years; prodrome; acute neurologic illness; coma; and death, thought to be due to the massive inflammatory response in the central nervous system (CNS). Historically, rabies infection was 100% fatal, leading to increased suicide rates in individuals who believed they had contracted the disease. Thanks to Louis Pasteur developing the rabies vaccine in 1885, countless cases have been prevented, especially in developed countries [1]. Vaccination remains the foundation for preventing the infection that causes this viral zoonotic disease in exposed individuals. Along with vaccination, post-exposure prophylaxis includes wound cleaning and rabies immunoglobulin administration. Several types of rabies vaccines are available and utilized today. The issue with the numerous rabies vaccines that have been created is the vaccine candidate’s differing safety profiles and immunogenicity. Thus, continued efforts towards rabies vaccine research have focused on improving upon these factors. The limitations of the live-attenuated vaccine include inducing rabies in animals due to mutations in the host and resistant viral capabilities to cause infection [2]. The drawbacks of inactivated vaccines include lower immunogenicity, higher cost, and the requirement of multiple vaccinations during pre- and post-exposure to the rabies virus, which led to the development of adjuvanted vaccines [3]. Research efforts are now geared toward next-generation vaccines, like genetically modified and viral vector-based vaccines, which have limitations, including safety and proper distribution [2]. Preventative measures outside human vaccination include animal vaccination and spreading public awareness [1]. In 2018, the Global Strategic Plan was put in place by international organizations, including the World Health Organization, to eradicate human fatalities due to rabid canines by 2030, highlighting the importance of animal vaccination [2]. Targeted communities for rabies prevention education include high-risk populations like farmers and those who live in areas where rabies is endemic. Additionally, high-risk occupations, such as veterinarians, zookeepers, and forest workers, can receive pre-exposure prophylaxis [4]. This review will discuss the historical development, significance, and challenges surrounding rabies vaccines for prevention and treatment. Review Historical development of rabies vaccines Beginning as early as the first century BC, various techniques to treat rabies were practised [2]. 2024 Kaye et al. Cureus 16(6): e62429. DOI 10.7759/cureus.62429
Vetnuus | September 2024 11 >>> 12 The methods, including cauterization, excision, and amputation, among others, were deemed inconsistent and eventually considered unsuitable as treatment methods. However, this understanding persisted until Louis Pasteur developed the first rabies vaccine in the nineteenth century [2]. The first generation of vaccines began in 1885 with Louis Pasteur, who used an infected rabbit spinal cord that was inactivated via sun drying to develop a vaccine [2]. The vaccine was able to provide success; however, there were many concerns. The consistency of inactivation of the virus in the vaccine was questioned, given that post-vaccine rabies cases were being reported. Given the development method, large-scale production of Pasteur’s vaccine was also challenging. Using Pasteur’s work, other researchers added their advancements, including adding phenol to inactivate the virus, using baby animal brains to create vaccines as they contained less myelin, using embryonated chicken and duck eggs to make a live attenuated vaccine, and using the cell culture system to enhance the production of a vaccine [2,4,5]. In the modern world, the vaccines used are the modified live vaccine, the inactivated rabies vaccine, and the adjuvanted rabies vaccine [2]. With the advancement of recombinant DNA technologies, new vaccination candidates may soon be available. Types of rabies vaccines The first vaccines created to immunize people against the rabies virus contained an inactivated form [6]. These vaccines were initially developed through the isolation of the virus from animals infected with rabies, followed by the inactivation of the virus through the addition of various chemicals [7]. However, this technique led to numerous issues, such as poor antigenicity of the virus and adverse reactions to different components in the vaccine [8]. To overcome these deficiencies, new methods were developed to generate superior vaccines. Improvements in cell culture techniques allowed for the growth of viruses in various cell lines in vitro [9]. After the viruses were cultured, they were extracted from the cells and inactivated via treatment with compounds such as beta-propiolactone and formalin [10]. The inactivated viruses were then administered to people or animals. This stimulates the innate and adaptive immune response, ultimately creating memory B and T cells, providing long-lasting immunological protection against the virus [11]. Vaccines containing the inactivated virus are typically administered via intramuscular injection. The vaccine may be given either pre-exposure or post-exposure, with multiple doses required to achieve maximum immunological protection [12]. Vaccines generated via virus culturing in vitro are safe and efficacious and allow for a high degree of control in growing the virus [9]. Unfortunately, there is a risk that some viruses may not be fully inactivated during development. Additionally, multiple doses of the vaccine are required, which may lead to issues regarding patient compliance [13]. Following the development of vaccines containing inactivated forms of the virus, vaccines for rabies were created containing a live-attenuated form of the rabies virus. These were initially created by passing the rabies virus through numerous cell cultures and selecting nonpathogenic forms of the virus [2]. When vaccines containing this product were administered via intramuscular injection to various animals, a robust immune response was generated, and high levels of antibody titers were recovered in the serum against the rabies virus. However, numerous adverse effects, such as severe tremors and paralysis, were reported [14]. The large number of adverse effects combined with a high sensitivity to fluctuations in temperature resulted in the modified live vaccine no longer being recommended for parenteral administration by the World Health Organization [2,14]. More recently, vaccines containing mutated forms of the rabies virus have been created, greatly reducing virulence [2]. The glycoprotein (g) is crucial for the rabies virus to be pathogenic [15]. Thus, mutations can be induced at sites in the gene that encodes for this protein, rendering the virus no longer pathogenic though still infectious, allowing for a strong immune response to be still generated against it [16]. Vaccines containing mutated forms of the rabies virus may be administered orally and are often given to animals that serve as a reservoir for the rabies virus, such as dogs [2]. The advantages of this vaccination method include the production of a vigorous immune response and few doses required to achieve a high degree of immunological protection. One study showed numerous antibodies against the rabies virus in dogs three years after receiving a single dose of the vaccine [17]. Limitations of the live attenuated vaccine form are a higher cost than other vaccination methods and a risk of reversion back to the pathogenic form of the virus through back mutations [18,19]. A third method of generating vaccines against the rabies virus involves using recombinant techniques to express proteins of the rabies virus in various vectors such as the vaccinia virus, canarypox virus, and the Orf virus [20-22]. This is done by creating attenuated viral vectors that express the rabies virus glycoprotein. This protein is generally chosen to be expressed in the vector because it is expressed on the surface of the rabies virus. This allows for the generation of antibodies that can bind to glycoprotein, thus preventing rabies virions from entering host cells, as this glycoprotein is critical in mediating cell entry [23,24]. Vaccines containing these recombinant virions are typically only used in animals, with most instances of human administration of this vaccine only being done in the context of clinical trials [21]. However, studies involving animals have shown that this vaccine produces a very strong B and T cell response that offers protection for an extended period, even after just a single administration of the vaccine [25]. Additionally, immunological solid reactions have been documented after both intramuscular and oral administration of this vaccine in animals [25]. The drawbacks of this type of vaccine include its high cost of production and a limited number of studies of its use in humans (Table 1) [13]. Article
Vetnews | September 2024 12 « BACK TO CONTENTS Article Prophylactic use of rabies vaccines Rabies is a devastating disease that is fatal in nearly 100% of cases. The primary source of human contraction is through a bite from a rabid animal; in these instances, there are vaccinations available for humans to be taken pre- and/or post-exposure to lower the fatality rate. The effectiveness of the pre-and post-prophylaxis vaccines when taken together is remarkably high, with no reported deaths due to rabies in any individual who has taken both; however, there was one reported death in an individual who had only the preexposure immunization with no post-exposure booster [26]. The pre-exposure prophylaxis (PrEP) vaccination is a safe vaccine that can be co-administered with other vaccines in children or can be given separately. The administration of the PrEP vaccination series involves three intramuscular or intradermal injections to prime the patient’s immune system; these injections are done on a standard schedule, and an injection is administered on days 0, 7, and 28 [27]. The purpose of this vaccine is to allow the immune system to exhibit recall when exposed to the virus in the event of a rabid animal bite [27]. Additionally, PrEP administration would decrease the amount of post-exposure vaccination an individual would have to receive in the event of an exposure [27]. This may not limit the cost of overall care per patient, but it most certainly would benefit patients in varying circumstances, such as in remote communities where post-exposure prophylaxis (PEP) is not readily available, in situations where risk of exposure is high and may not be recognized, in places where controlling rabies in the animal reservoir is difficult and where human exposure risk is high, and in occupations where animal interactions are frequent (i.e. bat handlers or zoologists) [27]. PrEP should also be included in the immunization of children in high-risk areas, followed by a booster after one year. The administration of the PEP treatment is determined via an assessment based on the risk of infection, the severity of infection, the site of the wound, the appearance of the wound, behavior, the fate of the biting animal, and the vaccination status of the biting animal [26]. An unusual contact with a bat, regardless of location, is a sufficient ground for considering rabies exposure [26]. Rabies exposure is considered as contact of the saliva of a rabid animal to broken skin or intact mucous membrane of the patient [26]. Under these circumstances, PEP is indicated in the patient, regardless of how long before the contact with animal saliva occurred, and the patient will undergo wound care, active immunization, and passive immunization. If a patient was previously immunized, a shorter booster regimen is given along with wound care. There are a multitude of vaccine regimens, both intramuscular and intradermal, that involve variable sites of injection and number of injections, requiring multiple clinical follow-ups to maintain a proper injection schedule[26]. Therapeutic applications of rabies vaccines and novel treatment modalities The current standard for PEP involves a combination of human rabies immunoglobulin (HRIG) and rabies vaccine administration [2]. In a prospective study from January 2021 to December 2021 at the Kempegowda Institute of Medical Sciences (KIMS) Hospital and Research Center, 123 category III animal bite victims provided clinical evidence of the safety and efficacy of HRIG in combination with an entire course of antirabies vaccinations for PEP [28]. HRIG provides immediate passive immunity by neutralizing the virus at the site of infection, while the rabies vaccine stimulates the immune system to produce long-lasting active immunity [28]. The most used vaccine in combination with HRIG is the inactivated or killed rabies virus vaccine [12]. Immunization against these inactivated vaccines develops over time due to the activation of helper and cytotoxic T cells, allowing for virus-neutralizing antibodies to be produced for long-lasting active immunity. These vaccines are administered globally [29]. The effectiveness of RIG and vaccine therapy in treating rabies infection is wellestablished, especially when administered promptly after exposure. In an open-label, single-arm study of 12 healthy adult subjects, Hanna et al. found that caprylate/chromatography purified HRIG (RIG-C) produced a rapid increase in rabies-neutralizing antibodies within 24 hours, peaked on day four and maintained through day 21 [30]. However, limitations exist with RIG administration, such as the worldwide availability of RIG, potential allergic reactions, and Vaccine Type Characteristics Route of Administration Target Population Limitations Inactivated rabies vaccine [10-13] Contains rabies virus inactivated via various chemicals Intramuscular injection Humans and animals Many doses required, creating issues with compliance and reduced immune response compared to other methods Live attenuated rabies vaccine [2, 14, 18, 19] Contains less virulent form of rabies virus but still capable of replication in host cells Intramuscular injection or oral administration Primarily animals, though still given to humans in some parts of the world Risk of reversion to pathogenic strain and expensive, especially when administered orally Recombinant-vectored vaccine [13, 20-25] Contains attenuated vectors expressing the rabies virus glycoprotein Intramuscular injection or oral administration Animals with human use restricted to clinical trials Expensive to produce; limited studies involving its use in humans TABLE 1: Characteristics, route of administration, target population, and limitations of different types of rabies vaccines
Vetnuus | September 2024 13 the need for timely administration immediately following exposure. In the same open-label, single-arm study of 12 healthy adult subjects, a total of 15 adverse events (AE) were noted, including gastrointestinal disorders, injection site pain/nodules, dizziness, and extremity pain, all of which were mild except for one subject who experienced moderate oropharyngeal pain [30]. The efficacy of rabies therapy decreases once clinical symptoms manifest, underscoring the importance of early intervention. Recent research has focused on developing novel treatment strategies composed of molecules that target viral replication at different stages of the rabies virus life cycle and molecules that inhibit some pathways of the innate host immune response [31]. In one study on mice, a cocktail regimen of six compounds was selected for use based on the results of previous studies: caspase-1 inhibitor, tumour necrosis factor (TNF)-α inhibitor, mitogenactivated protein (MAP)-kinase inhibitor, mouse interferon (IFN)- α/β, favipiravir, ribavirin and HRIG [31]. Mannitol was utilized as a blood-brain barrier opener [31]. The results of this study report a statistically significant extension of survival of mice treated with the drug cocktail compared to the survival of mice in the virus control group. They found a significant downregulation of proinflammatory molecules (caspase-1 and TNF-α) in the CNS in rhinovirus (RV)-infected mice treated with a combination of drugs, including IFN-α/β [31]. While the traditional combination therapy of RIG and vaccines remains the standard for PEP, ongoing research is uncovering new therapeutic avenues for treating rabies infections. One approach involves enhancing the immune response using adjuvants or novel vaccine formulations. Adjuvants can boost the immune response, potentially improving vaccine efficacy. A separate animal study on mice revealed that the absence of Toll-like receptor 7 (TLR7), an innate receptor sensing single-stranded viral RNA, led to lower antibody production in mice immunized with rabies virus (RABV) [32]. The results showed that TLR7 deficiency affected the recruitment of germinal center (GC) B cells and led to lessened GC formation, resulting in impaired RABV-neutralizing antibodies (VNA) and an inadequate Th1-based immune response [32]. Novel rabies infection treatments targeting the TLR7 signalling pathway for activation are promising strategies for improving the current efficacy of future rabies vaccines. Novel vaccine formulations, such as virus-like particles, are being explored for their ability to induce a more potent and more targeted immune response. Another animal study with rabies viruslike particles (RV-VLPs) in mice was conducted using stable cell lines for producing RV-VLPs via lentiviral-based transduction of human embryonic kidney (HEK)-293 cells [33]. This study developed a G protein-expressing cell line (HEK-G) to produce G-containing viruslike particles, evaluated the immunogenicity of these particles in mice, and found that the RV-VLPs were able to induce specific immune responses against rabies virus G protein [33]. These results encourage the study of new VLPs because these particles produced a specific antibody response. Other advancements in molecular biology and virology have paved the way for potential breakthroughs in more advanced rabies infections. Gene therapy, for example, holds promise for delivering antiviral genes directly to infected neurons by using rAAV-N796, a small interfering RNA (siRNA) that targets the nucleoprotein gene of rabies, preventing the virus from evading the host’s innate immune response [34]. Other forms of gene therapy being studied include clustered regularly interspaced short palindromic repeats (CRISPR) or CRISPR-associated protein (Cas9)-based technologies and induced pluripotent stem cells (iPSCs). The iPSC technique is proposed to target the editing of the rabies virus genome, potentially rendering it non-pathogenic, which is more helpful for disease modelling [35]. A combination therapy of the CRISPR/Cas9 system and iPSC method was found to correct erroneous strings in vitro. Gene delivery tools such as adeno-associated virus (AAV), Sendai virus, and episomes can then deliver corrected genes to target organs [35]. Furthermore, monoclonal antibodies specific to rabies virus proteins are being investigated for their therapeutic potential, offering a more targeted, precise, and time-sensitive approach to rabies treatment than HRIG [36]. From serum polyclonal antibodies to hybridoma monoclonal antibodies (mAbs) and from murine mAbs to human mAbs, considerable progress has been made in the urgent PEP of rabies [36]. RVC20, a broadly neutralizing mAb, was shown to neutralize all 35 tested RABV strains worldwide [36]. The efficiency of neutralizing mAb cocktails has been confirmed in clinical trials [36]. However, developing a neutralizing rabies cocktail binding to the nonoverlapping glycoprotein epitopes is a challenge, indicating the need for subsequent research. Eventually, safe, effective, and affordable rabies mAbs are presumed to replace HRIG in rabies PEP (Figures 1-3). Article FIGURE 1: Comparison of live attenuated and inactivated vaccines in rabies prevention. Live vaccines use weakened virus forms and are temperature sensitive, while inactivated vaccines require multiple doses and are globally used. Both stimulate the immune system against rabies and are used in post-exposure prophylaxis. FIGURE 2: Illustration of the differences and similarities between HRIG and monoclonal antibodies in rabies PEP. HRIG offers immediate immunity but has availability issues; monoclonal antibodies are advanced, broadly neutralizing, and may replace HRIG. Both are used with vaccines for immediate rabies immunity. HRIG: human rabies immunoglobulin; PEP: post-exposure prophylaxis >>> 14
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