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What lessons about vaccine development can be learnt from animal coronaviruses?

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There are many types of coronaviruses that infect a wide variety of species other than humans, including livestock, other domesticated animals and wildlife species. The development of veterinary coronavirus vaccines highlights numerous successes, but also two potential hurdles that might be faced in the development of a COVID-19 vaccine. One is that vaccines have to be effective against potential new coronavirus variants. Another is that studies of animal coronaviruses have shown that not all antibodies protect against virus infection; some can be detrimental as they bind the virus and increase its uptake.

Have vaccines been developed for animal coronaviruses?

Coronaviruses infect a wide variety of mammals and birds and are commonly associated with intestinal (enteritis) and respiratory illnesses. Effective veterinary coronavirus vaccines have been developed against several animal coronaviruses that cause economically and clinically important diseases of domestic animals, such as pigs, chickens, dogs and cats. However, some of these vaccines have only short-term effectiveness because of the emergence of new virus variants. Coronaviruses are divided into four groups (see Table) and it might be significant that the majority of veterinary vaccines have been developed for alphacoronaviruses. COVID-19 is caused by a betacoronavirus and might present a greater challenge.

Table: Animal coronaviruses (CoV), those for which vaccines are available (adapted with permission of the European Advisory Board for Cat Diseases)
Host Alpha Beta Gamma Delta
Felids Feline CoV Wild Asian leopard cat CoV
Canines Canine enteric CoV
Ferret CoV
Canine respiratory CoV
Porcines Porcine epidemic diarrhoea virus
Porcine respiratory CoV
Transmissible gastroenteritis virus
Porcine haemagglutinating encephalomyelitis virus Porcine CoV HKU15
Ruminants Bovine CoV
Antelope CoV
Giraffe CoV
Equids Equine CoV
Bat Various bat CoVs Three bat CoVs
Avian Turkey CoV
Infectious bronchitis virus
Nine avian CoVs
Rodents Murine CoV
Rat CoV
Various Hedgehog CoV HKU31
Pangolin CoV
Beluga whale CoV-SW1

Infectious bronchitis virus, which was first reported in the USA in the 1930s, was the first coronavirus to be described; it is a significant respiratory pathogen of commercial poultry that causes high mortality in unvaccinated flocks. Related viruses have been discovered in wild birds and pigs. Outbreaks of infectious bronchitis have declined as a result of the extensive use of vaccines; however, the disease may occur even in vaccinated flocks because new variants of the virus continue to emerge in poultry that are not neutralised by antibodies induced by existing vaccines.[1] Therefore, veterinary vaccine companies must respond by producing new vaccines based on the latest strains.

One way to do this is by replacing the gene for the coronavirus spike protein with the spike gene from the newly emerging variant of the virus. Then a new vaccine is produced that protects birds against the coronavirus containing the new form of the spike.[2] The advantage of this system is that new vaccines can be created relatively quickly in response to the emergence of a novel virus and similar approaches, focusing on vaccines comprising the spike protein, are being explored for human COVID-19 virus.

Other veterinary vaccines for coronaviruses that are commercially available in the UK include vaccines against canine enteric coronavirus infection in dogs, porcine epidemic diarrhoea virus and transmissible gastroenteritis virus infection in pigs, and bovine coronavirus virus infection to prevent shipping fever in young calves (see Table). There is no vaccine yet for the canine betacoronavirus.

Have any coronavirus vaccines been detrimental in animals?

Feline coronavirus infects domestic, feral and some wild cats. Most cats infected with feline coronavirus remain healthy or develop only mild enteritis. However, a small proportion develop feline infectious peritonitis (FIP), a disease with a very poor prognosis; many cats that develop FIP die or are euthanised. The virulence of the virus, the amount of virus and the cat’s immune response determine whether or not FIP will develop.

Many attempts have been made to develop feline coronavirus vaccines, most of which have failed. The role of antibodies in preventing cats from developing FIP is still unclear.[3] However, it has been found that some antibodies neutralise the virus while others bind to the virus and increase viral uptake; this phenomenon, known as antibody-dependent enhancement of infection,[4] apparently amplified rather than prevented disease.[5] Although cats that developed antibodies following vaccination were more likely than unvaccinated cats to develop FIP after being experimentally infected with the virus,[6] antibody-positive cats that were naturally exposed to the virus did not show enhanced disease.[7] This difference could be related to the higher doses of virus to which cats were exposed in experimental infections compared to natural infections. Alternatively, the difference could be related to the virus being administered by injection in experimental infections whereas, in nature, cats are exposed to the virus through the nose, mouth and eyes.

Currently one vaccine is commercially available in the USA and in some European countries. The vaccine is given through the nose (intranasally) and contains an attenuated or weakened form of the virus that multiplies only in the upper respiratory tract; it cannot survive at the higher temperatures in the lower respiratory tract. The vaccine is not recommended for use in antibody-positive cats, because such cats will either already have natural immunity, or will already be incubating FIP.[8] However, intranasal vaccination of antibody-negative kittens has been shown to be safe and effective.[8]

Veterinary research into animal coronaviruses has led to several successful veterinary vaccines, as well as a better understanding of the potential challenges that will inform research efforts to develop a safe, effective vaccine against COVID-19.

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References

  1. Cavanagh D. Severe acute respiratory syndrome vaccine development: experiences of vaccination against avian infectious bronchitis coronavirus. Avian Pathology. 2003 Dec;32(6):567-582. DOI: 10.1080/03079450310001621198.

  2. Armesto M, Evans S, Cavanagh D, et al. A recombinant avian infectious bronchitis virus expressing a heterologous spike gene belonging to the 4/91 serotype. PLoS One. 2011 ;6(8):e24352. DOI: 10.1371/journal.pone.0024352.

  3. Addie D, Belák S, Boucraut-Baralon C, et al. Feline infectious peritonitis. ABCD guidelines on prevention and management. Journal of Feline Medicine and Surgery. 2009 Jul;11(7):594-604. DOI: 10.1016/j.jfms.2009.05.008.

  4. Takano T, Kawakami C, Yamada S, Satoh R, Hohdatsu T. Antibody-dependent enhancement occurs upon re-infection with the identical serotype virus in feline infectious peritonitis virus infection. The Journal of Veterinary Medical Science. 2008 Dec;70(12):1315-1321. DOI: 10.1292/jvms.70.1315.

  5. Vennema H, de Groot RJ, Harbour DA, et al. Early death after feline infectious peritonitis virus challenge due to recombinant vaccinia virus immunization. Journal of Virology. 1990 Mar;64(3):1407-1409.

  6. Olsen CW. A review of feline infectious peritonitis virus: molecular biology, immunopathogenesis, clinical aspects, and vaccination. Veterinary Microbiology. 1993 Jul;36(1-2):1-37. DOI: 10.1016/0378-1135(93)90126-R.

  7. Addie DD, Toth S, Murray GD, Jarrett O. Risk of feline infectious peritonitis in cats naturally infected with feline coronavirus. American Journal of Veterinary Research. 1995 Apr;56(4):429-434.

  8. Fehr D, Holznagel E, Bolla S, et al. Placebo-controlled evaluation of a modified life virus vaccine against feline infectious peritonitis: safety and efficacy under field conditions. Vaccine. 1997 Jul;15(10):1101-1109. DOI: 10.1016/S0264-410X(97)00006-6.

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