Veterinary coronavirus vaccines: successes, challenges & lessons learned for SARS-CoV-2 control
Vaccine Insights 2023; 2(8), 259–277
10.18609/vac.2023.039
Members of the Coronaviridae family infect a large number of animal species, including humans. Coronaviruses of clinical significance in veterinary species include severe and fatal vasculitis in cats caused by feline infectious peritonitis virus (FIPV), and highly contagious and economically devastating diseases in livestock, including porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV) in pigs, bovine coronavirus (BCoV) in dairy and beef cattle, and avian infectious bronchitis virus (IBV) in chickens. Knowledge of the viral replication, pathogenesis, protective immunity, and genomic mutations and evolution has led to the development of a variety of licensed vaccines against these veterinary coronaviruses. Some of the licensed animal coronavirus vaccines have been in commercial use for decades and have demonstrated many of the same challenges in veterinary species that are being faced today with the relatively new SARS-CoV-2 vaccines. Here we review the coronaviruses of high clinical impact in veterinary species, identify common themes regarding the challenges and successes of animal coronavirus vaccines that have been in commercial use for decades, and offer potential insights and lessons learned for SARS-CoV-2 vaccine and vaccination programs.
Since 2002 three novel coronaviruses, Severe Acute respiratory syndrome-associated coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and most recently, SARS-CoV-2, have caused deadly diseases in humans with immense social, economic and health impacts worldwide [1]Cui J, Li F, Shi Z-L. Origin and evolution of pathogenic coronaviruses.Nat. Rev. Microbiol. 2019; 17(3), 181–192. [2]Baker RE, Mahmud AS, Miller IF, et al. Infectious disease in an era of global change. Nat. Rev. Microbiol. 2022; 20(4), 193–205.. The SARS-CoV-2 pandemic introduced key concepts of virology into the consciousness of the world’s populace, providing lessons on the importance of coronavirus vaccine development, ‘herd health’, and biosecurity measures as a means of disease control. In veterinary medicine, these concepts have been put to use for decades in many veterinary species to prevent and control deadly animal coronaviruses that have been the cause of clinically significant disease, increased treatment costs in companion animals and livestock, and led to economic losses across several livestock and poultry industries worldwide.
The Coronaviridae family are enveloped, positive-sense, single-strand RNA viruses which are divided into four distinct genera that infect avian and mammalian species [1]Cui J, Li F, Shi Z-L. Origin and evolution of pathogenic coronaviruses.Nat. Rev. Microbiol. 2019; 17(3), 181–192. [3]Masters PS. The molecular biology of coronaviruses.Adv. Virus Res. 2006; 66, 193–292., including Alpha-, Beta-, Gamma-, and Delta-coronaviruses [4]Woo PC, Lau SK, Lam CS, et al. Discovery of seven novel mammalian and avian coronaviruses in the genus deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus.J. Virol. 2012; 86(7), 3995–4008.Woo PC, Lau SK, Lam CS, et al. Discovery of seven novel mammalian and avian coronaviruses in the genus deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus.J. Virol. 2012; 86(7), 3995–4008.. The Alphacoronavirus genus includes viruses that generally cause gastrointestinal disease in porcine, feline and canine hosts; the Betacoronavirus genus includes several viruses that cause respiratory diseases in humans, including SARS-CoV-1, MERS-CoV, and SARS-CoV-2, as well as the bovine coronavirus, which causes both enteric and respiratory disease [1]Cui J, Li F, Shi Z-L. Origin and evolution of pathogenic coronaviruses.Nat. Rev. Microbiol. 2019; 17(3), 181–192. [4]Woo PC, Lau SK, Lam CS, et al. Discovery of seven novel mammalian and avian coronaviruses in the genus deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus.J. Virol. 2012; 86(7), 3995–4008.Woo PC, Lau SK, Lam CS, et al. Discovery of seven novel mammalian and avian coronaviruses in the genus deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus.J. Virol. 2012; 86(7), 3995–4008.. The Gammacoronavirus genus includes an important virus in avian species, and the genus Deltacoronavirus infects mammalian and avian hosts [4]Woo PC, Lau SK, Lam CS, et al. Discovery of seven novel mammalian and avian coronaviruses in the genus deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus.J. Virol. 2012; 86(7), 3995–4008.Woo PC, Lau SK, Lam CS, et al. Discovery of seven novel mammalian and avian coronaviruses in the genus deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus.J. Virol. 2012; 86(7), 3995–4008..
Veterinarians and producers have been using licensed commercial vaccines for decades to prevent and control coronavirus infection in various animal populations (Table 1). A review of these veterinary coronavirus vaccines demonstrates the importance of understanding the pathogenesis of the virus, elucidates many important aspects of mucosal immunity, and illustrates the challenges faced specific to development of effective coronavirus vaccines. While there are many coronaviruses that infect a wide range of veterinary species, this review focuses only on a few selected animal coronaviruses with significant clinical and/or economic impact, and the efficacy of vaccines in controlling infection caused by these viruses. We hope that the knowledge gained during decades of use of these animal coronavirus vaccines will offer potential insight to the field of SARS-CoV-2 vaccine and vaccination programs.
Table 1. Examples of licensed commercial vaccines in the United States against selected economically important animal coronaviruses in various veterinary species. | |||||
Animal coronavirus | Genus | Clinical diseases | Licensed vaccine | Vaccine type | Recommended vaccination route |
Feline infectious peritonitis (FIPV) | Alphacoronavirus | Phlebitis Peritonitis +/ − effusion Serositis High mortality | Vanguard® FIP/ Felocell® FIP | Modified-live | Intranasal |
Transmissible gastroenteritis virus of swine (TGEV) | Alphacoronavirus | Diarrhea Vomiting Severe disease in neonatal piglets High neonatal mortality | USDA licensed | Modified-live | |
Porcine epidemic diarrhea virus (PEDV) | Alphacoronavirus | Diarrhea Vomiting Anorexia Severe dehydration Severe disease and high mortality in neonatal piglets | PED vaccine (Zoetis) | Killed vaccine | IM Administer 2 doses to pregnant sow/gilt prior to farrowing |
SEQUIVITY (personalized vaccine, Merck) | RNA particle vaccine | ||||
Bovine coronavirus (BCoV) | Betacoronavirus | Calf diarrhea Winter dysentery (adults) Respiratory disease Generally mild disease unless there are comorbidities | Bovilis (Merck) | Modified live | Intranasal Administer to neonatal calves |
Bovilis Guardian (Merck) Scourguard 4KC (Zoetis) | Killed virus vaccine | IM or SQ in pregnant cattle Administer 2 doses prior to calving | |||
Infectious bronchitis virus (IBV) | Gammacoronavirus | Primarily mild upper respiratory disease, complications with co-infections Pneumonia & airsacculitis Nephritis Decreased egg production and quality Stunted growth | Merck Massachusetts serotype Zoetis Massachusetts serotype | Inactivated virus vaccine | IM or SQ vaccination Best used to booster chickens previously immunized with live vaccine of the same strain (Merck) |
Vaccines targeting one or more of the following IBV serotypes: Merck Massachusetts Connecticut Arkansas GA-08 Mildvac-MA5TM MildvacTM Mass+Conn NEWHATCH-C2-M® NEWHATCH-C2-MC® Zoetis Massachusetts Connecticut GA08 GA98 Arkansas Elanco Arkansas Massachusetts Connecticut Boehringer Ingelheim Arkansas Connecticut Massachusetts | Live virus vaccine | Administered in drinking water or as coarse spray Periodic re-vaccinations may be needed | |||
IBV: Infectious bronchitis virus ; IM: Intramuscular ; SQ: Subcutaneous. |
Alphacoronaviruses
Members in the genus Alphacoronavirus cause animal diseases of great economic importance, including porcine epidemic diarrhea virus (PEDV) and transmissible gastroenteritis virus of swine (TGEV). The highly contagious but relatively clinically quiet, feline enteric coronavirus (FeCV) and canine coronavirus (CCoV) also belong to this genus. Feline infectious peritonitis virus (FIPV) is a, unique, randomly mutated FeCV with severe and fatal clinical consequences in cats [4]Woo PC, Lau SK, Lam CS, et al. Discovery of seven novel mammalian and avian coronaviruses in the genus deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus.J. Virol. 2012; 86(7), 3995–4008.. The economic impact of PEDV, TGEV, and the fatal consequences of FIPV, have led to considerable interest in developing vaccines against these animal alphacoronaviruses.
Feline infectious peritonitis virus (FIPV)
Feline coronaviruses (FCoV) consist of two serotypes: type I FCoV and type II FCoV [5]Bálint Á, Farsang A, Szeredi L, et al. Recombinant feline coronaviruses as vaccine candidates confer protection in SPF but not in conventional cats.Vet. Microbiol. 2014; 169(3–4), 154–162.Bálint Á, Farsang A, Szeredi L, et al. Recombinant feline coronaviruses as vaccine candidates confer protection in SPF but not in conventional cats.Vet. Microbiol. 2014; 169(3–4), 154–162.. Either of these types can take one of two different pathotypes, remaining an enteric coronaviruses (FeCV) or mutating into the highly pathogenic and fatal FIPV [5]Bálint Á, Farsang A, Szeredi L, et al. Recombinant feline coronaviruses as vaccine candidates confer protection in SPF but not in conventional cats.Vet. Microbiol. 2014; 169(3–4), 154–162.Bálint Á, Farsang A, Szeredi L, et al. Recombinant feline coronaviruses as vaccine candidates confer protection in SPF but not in conventional cats.Vet. Microbiol. 2014; 169(3–4), 154–162.. The majority of circulating FeCV are type I, which are ubiquitous within feline populations, especially in group-housed settings such as catteries or shelters, and tend to be asymptomatic or cause mild enteric disease [6]Kiss I, Poland AM, Pedersen NC. Disease outcome and cytokine responses in cats immunized with an avirulent feline infectious peritonitis virus (FIPV)-UCD1 and challenge-exposed with virulent FIPV-UCD8.J. Feline Med. Surg. 2004; 6(2), 89–97.. FeCV initially infects enterocytes and can lead to viremia by infecting monocytes [7]Kipar A, Meli ML. Feline infectious peritonitis: still an enigma? Vet. Pathol. 2014; 51(2), 505–526.. A small percentage (5–20%) of FeCV mutate to FIPV by gaining the ability to replicate rapidly within monocytes and macrophages [7]Kipar A, Meli ML. Feline infectious peritonitis: still an enigma? Vet. Pathol. 2014; 51(2), 505–526. [8]Pedersen NC, Allen CE, Lyons LA. Pathogenesis of feline enteric coronavirus infection.J. Feline Med. Surg. 2008; 10(6), 529–541. [9]Vennema H, Poland A, Foley J, et al. Feline infectious peritonitis viruses arise by mutation from endemic feline enteric coronaviruses.Virology 1998; 243(1), 150–157.. The mechanism for this adaptation is not well understood, but mutations in the Spike protein are thought to play at least a partial role in altering cell tropism [10]Chang H-W, Egberink H, Halpin R, et al. Spike protein fusion peptide and feline coronavirus virulence.Emerg. Infect. Dis. 2012; 18(7), 1089. [11]Licitra BN, Millet JK, Regan AD, et al. Mutation in spike protein cleavage site and pathogenesis of feline coronavirus.Emerg. Infect. Dis. 2013;19(7), 1066–1073. . FIPV causes phlebitis, peritonitis, and serositis, as well as granulomatous inflammation in almost any organ system; it can present with (‘wet’, ‘effusive’ form) or without (‘dry’, ‘non-effusive’ form) body effusions, and is almost always fatal [12]Malbon AJ, Fonfara S, Meli ML, et al. Feline infectious peritonitis as a systemic inflammatory disease: contribution of liver and heart to the pathogenesis.Viruses 2019; 11(12), 1144. [13]Tekes G, Thiel HJ. Feline coronaviruses: pathogenesis of feline infectious peritonitis.Adv. Virus Res. 2016; 96, 193–218..
Vaccine development against FIPV has been ongoing since the 1980s and has involved a myriad of vaccine platforms and approaches, with early studies focusing mainly on live-attenuated FIPV [6]Kiss I, Poland AM, Pedersen NC. Disease outcome and cytokine responses in cats immunized with an avirulent feline infectious peritonitis virus (FIPV)-UCD1 and challenge-exposed with virulent FIPV-UCD8.J. Feline Med. Surg. 2004; 6(2), 89–97. [14]Gerber JD, Ingersoll JD, Gast AM, et al. Protection against feline infectious peritonitis by intranasal inoculation of a temperature-sensitive FIPV vaccine.Vaccine 1990; 8(6), 536–542. [15]Reeves NC, Pollock RV, Thurber ET. Long-term follow-up study of cats vaccinated with a temperature-sensitive feline infectious peritonitis vaccine.Cornell Vet. 1992; 82(2), 117–123. [16]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; 15(10), 1101–1109. [17]Haijema BJ, Volders H, Rottier PJ. Live, attenuated coronavirus vaccines through the directed deletion of group-specific genes provide protection against feline infectious peritonitis.J. Virol. 2004; 78(8), 3863–3871. and heterologous live vaccines (canine coronavirus, transmissible gastroenteritis of swine, and human coronavirus 229E) [18]Woods RD, Pedersen NC. Cross-protection studies between feline infectious peritonitis and porcine transmissible gastroenteritis viruses.Vet. Microbiol. 1979; 4(1), 11–16. [19]Stoddart CA, Barlough JE, Baldwin CA, et al. Attempted immunisation of cats against feline infectious peritonitis using canine coronavirus.Res. Vet. Sci. 1988; 45(3), 383–388. [20]Barlough JE, Johnson-Lussenburg CM, Stoddart CA, et al. Experimental inoculation of cats with human coronavirus 229E and subsequent challenge with feline infectious peritonitis virus.Can. J. Comp. Med. 1985; 49(3), 303–307.. A licensed, modified-live, intranasal FIPV vaccine is available in the United States (Vanguard® FIP, formerly: Felocell® FIP; Zoetis). However, vaccination against FIPV proved challenging from the onset, with vaccines unable to protect against disease, and frequent reports of vaccinated cats appearing to develop FIPV infection earlier compared to controls when challenged [6]Kiss I, Poland AM, Pedersen NC. Disease outcome and cytokine responses in cats immunized with an avirulent feline infectious peritonitis virus (FIPV)-UCD1 and challenge-exposed with virulent FIPV-UCD8.J. Feline Med. Surg. 2004; 6(2), 89–97. [19]Stoddart CA, Barlough JE, Baldwin CA, et al. Attempted immunisation of cats against feline infectious peritonitis using canine coronavirus.Res. Vet. Sci. 1988; 45(3), 383–388. [21]Pedersen NC, Black JW. Attempted immunization of cats against feline infectious peritonitis, using avirulent live virus or sublethal amounts of virulent virus.Amer. J. Vet. Res. 1983; 44(2), 229–234. [22]Vennema H, De Groot R, Harbour D, et al. Early death after feline infectious peritonitis virus challenge due to recombinant vaccinia virus immunization.J. Virol. 1990; 64(3), 1407–1409.. These results were caused by antibody-dependent enhancement (ADE) following vaccination, and were mediated by an imbalance between humoral and cell-mediated immune (CMI) responses [22]Vennema H, De Groot R, Harbour D, et al. Early death after feline infectious peritonitis virus challenge due to recombinant vaccinia virus immunization.J. Virol. 1990; 64(3), 1407–1409. [23]Pedersen NC. Animal virus infections that defy vaccination: equine infectious anemia, caprine arthritis-encephalitis, maedi-visna, and feline infectious peritonitis.Adv. Vet. Sci. Comp. Med. 1989; 33, 413–428. [24]Olsen CW, Corapi WV, Ngichabe CK, et al. Monoclonal antibodies to the spike protein of feline infectious peritonitis virus mediate antibody-dependent enhancement of infection of feline macrophages.J. Virol. 1992; 66(2), 956–965. and by antibodies directed against specific regions within the FIPV S protein [24]Olsen CW, Corapi WV, Ngichabe CK, et al. Monoclonal antibodies to the spike protein of feline infectious peritonitis virus mediate antibody-dependent enhancement of infection of feline macrophages.J. Virol. 1992; 66(2), 956–965. [25]Corapi WV, Olsen CW, Scott FW. Monoclonal antibody analysis of neutralization and antibody-dependent enhancement of feline infectious peritonitis virus.J. Virol. 1992; 66(11), 6695–6705.. Subsequent studies developed vaccines that meant to stimulate CMI but not humoral immunity, using recombinant vaccines containing one or both of the FIPV nucleocapsid (N) or membrane (M) proteins [26]Wasmoen TL, Kadakia NP, Unfer RC, et al. Protection of cats from infectious peritonitis by vaccination with a recombinant raccoon poxvirus expressing the nucleocapsid gene of feline infectious peritonitis virus.Adv. Exp. Med. Biol. 1995; 380, 221–228. [27]Vennema H, De Groot RJ, Harbour DA, et al. Primary structure of the membrane and nucleocapsid protein genes of feline infectious peritonitis virus and immunogenicity of recombinant vaccinia viruses in kittens.Virology 1991; 181(1), 327–335.. While these vaccines avoided FIPV S protein-associated ADE, they had varying results in protecting against disease [26]Wasmoen TL, Kadakia NP, Unfer RC, et al. Protection of cats from infectious peritonitis by vaccination with a recombinant raccoon poxvirus expressing the nucleocapsid gene of feline infectious peritonitis virus.Adv. Exp. Med. Biol. 1995; 380, 221–228. [27]Vennema H, De Groot RJ, Harbour DA, et al. Primary structure of the membrane and nucleocapsid protein genes of feline infectious peritonitis virus and immunogenicity of recombinant vaccinia viruses in kittens.Virology 1991; 181(1), 327–335..
The route of transmission for FeCV is fecal-oral and as such, induction of mucosal immunity is an important vaccination strategy to prevent FIPV infection. Several studies utilize either an intranasal or oral route of immunization in attempts to induce a mucosal immune response [14]Gerber JD, Ingersoll JD, Gast AM, et al. Protection against feline infectious peritonitis by intranasal inoculation of a temperature-sensitive FIPV vaccine.Vaccine 1990; 8(6), 536–542.Gerber JD, Ingersoll JD, Gast AM, et al. Protection against feline infectious peritonitis by intranasal inoculation of a temperature-sensitive FIPV vaccine.Vaccine 1990; 8(6), 536–542. [17]Haijema BJ, Volders H, Rottier PJ. Live, attenuated coronavirus vaccines through the directed deletion of group-specific genes provide protection against feline infectious peritonitis.J. Virol. 2004; 78(8), 3863–3871. [19]Stoddart CA, Barlough JE, Baldwin CA, et al. Attempted immunisation of cats against feline infectious peritonitis using canine coronavirus.Res. Vet. Sci. 1988; 45(3), 383–388. [21]Pedersen NC, Black JW. Attempted immunization of cats against feline infectious peritonitis, using avirulent live virus or sublethal amounts of virulent virus.Amer. J. Vet. Res. 1983; 44(2), 229–234.. Two of these studies reported protection against challenge with homologous FIPV and no ADE [14]Gerber JD, Ingersoll JD, Gast AM, et al. Protection against feline infectious peritonitis by intranasal inoculation of a temperature-sensitive FIPV vaccine.Vaccine 1990; 8(6), 536–542.Gerber JD, Ingersoll JD, Gast AM, et al. Protection against feline infectious peritonitis by intranasal inoculation of a temperature-sensitive FIPV vaccine.Vaccine 1990; 8(6), 536–542. [17]Haijema BJ, Volders H, Rottier PJ. Live, attenuated coronavirus vaccines through the directed deletion of group-specific genes provide protection against feline infectious peritonitis.J. Virol. 2004; 78(8), 3863–3871.. One study documented neutralizing mucosal IgA responses and a CMI response in addition to protection [14]Gerber JD, Ingersoll JD, Gast AM, et al. Protection against feline infectious peritonitis by intranasal inoculation of a temperature-sensitive FIPV vaccine.Vaccine 1990; 8(6), 536–542.. This live-attenuated vaccine consisted of a temperature-sensitive FIPV DF2 (type II FIPV) and was successfully licensed for commercial use (Vanguard® FIP, formerly: Felocell® FIP; Zoetis) [14]Gerber JD, Ingersoll JD, Gast AM, et al. Protection against feline infectious peritonitis by intranasal inoculation of a temperature-sensitive FIPV vaccine.Vaccine 1990; 8(6), 536–542. [28]Christianson KK, Ingersoll JD, Landon RM, et al. Characterization of a temperature sensitive feline infectious peritonitis coronavirus.Arch. Virol. 1989; 109(3–4), 185–196.. Several large post-marketing follow-up studies of this commercial vaccine concluded that the vaccine was safe, with no evidence of ADE under field conditions [15]Reeves NC, Pollock RV, Thurber ET. Long-term follow-up study of cats vaccinated with a temperature-sensitive feline infectious peritonitis vaccine.Cornell Vet. 1992; 82(2), 117–123., and can protect cats that have no or low serum FCoV antibodies at the time of first vaccination [16]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; 15(10), 1101–1109.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; 15(10), 1101–1109.. However, in cats that had previous exposure or current infection at the time of vaccination, the vaccine showed no protection against disease [16]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; 15(10), 1101–1109.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; 15(10), 1101–1109.. The absence of ADE following vaccination may be attributed to the low infectious dose in a natural setting compared to high doses of virus during experimental challenge [16]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; 15(10), 1101–1109. [29]Hohdatsu T, Yamato H, Ohkawa T, et al. Vaccine efficacy of a cell lysate with recombinant baculovirus-expressed feline infectious peritonitis (FIP) virus nucleocapsid protein against progression of FIP.Vet. Microbiol. 2003; 97(1–2), 31–44..
As of 2020, the feline vaccination guidelines from the American Animal Hospital Association (AAHA)/American Association of Feline Practitioners (AAFP) do not recommend vaccination for FIPV. The vaccines currently available are labeled for administration at 16 weeks of age, however, it is assumed that most cats have already been exposed and/or infected by the virus before this age [16]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; 15(10), 1101–1109. [30]Stone AE, Brummet GO, Carozza EM, et al. 2020 AAHA/AAFP feline vaccination guidelines.J. Feline Med. Surg. 2020; 22(9), 813–830..
The potential for ADE following natural infection or vaccination with SARS-CoV-2 has also been reported [31]Li D, Edwards RJ, Manne K, et al.In vitro and in vivo functions of SARS-CoV-2 infection-enhancing and neutralizing antibodies.Cell 2021; 184(16), 4203–4219.e4232. [32]Ricke DO. Two different antibody-dependent enhancement (ade) risks for SARS-CoV-2 antibodies.Front. Immunol. 2021; 12, 640093. [33]Zhou Y, Liu Z, Li S, et al. Enhancement versus neutralization by SARS-CoV-2 antibodies from a convalescent donor associates with distinct epitopes on the RBD.Cell Rep. 2021; 34(5), 108699. [34]Shimizu J, Sasaki T, Koketsu R, et al. Reevaluation of antibody-dependent enhancement of infection in anti-SARS-CoV-2 therapeutic antibodies and mRNA-vaccine antisera using FcR- and ACE2-positive cells.Sci. Rep. 2022; 12(1), 15612. [35]Wang S, Wang J, Yu X, et al. Antibody-dependent enhancement (ADE) of SARS-CoV-2 pseudoviral infection requires FcγRIIB and virus-antibody complex with bivalent interaction.Comm. Biol. 2022; 5(1), 262., however, currently this does not seem to be clinically problematic. Certainly, this will need to be monitored for future variants of concern. Regardless, the importance of CMI in the control of viral infection is well-known and is illustrated in the case of FIPV. Strategies targeting non-surface viral proteins for FIPV vaccine development can help guide future coronavirus vaccine designs to augment humoral immune responses and produce a more well-rounded and robust T cell response.
Transmissible gastroenteritis virus of swine (TGEV)
TGEV causes gastrointestinal disease in pigs worldwide [36]Chen F, Knutson TP, Rossow S, et al. Decline of transmissible gastroenteritis virus and its complex evolutionary relationship with porcine respiratory coronavirus in the United States.Sci. Rep. 2019; 9(1), 3953. and disease epidemiology depends on the herd’s immune status. In naïve herds, older pigs exhibit inappetence, mild diarrhea and vomiting, and have a low mortality rate [37]Maxie MG. Jubb, Kennedy, and Palmer’s pathology of domestic animals. Volume 2. 2016 Elsevier: St. Louis, Missouri.. In contrast, neonatal piglets less than 2 weeks of age experience severe disease, including diarrhea, vomiting and dehydration, and mortality rates can be as high as 100% [38]Bohl EH, Gupta RKP, Olquin MVF, et al. Antibody responses in serum, colostrum, and milk of swine after infection or vaccination with transmissible gastroenteritis virus.Infect. Immun. 1972; 6(3), 289–301. [39]Gough PM, Frank CJ, Moore DG, et al. Lactogenic immunity to transmissible gastroenteritis virus induced by a subunit immunogen.Vaccine 1983; 1(1), 37–41. [40]Welter MW, Horstman MP, Welter CJ, et al. An overview of successful TGEV vaccination strategies and discussion on the interrelationship between TGEV and PRCV.Adv. Exp. Med. Biol. 1993; 342, 463–468.. In herds that are persistently infected with TGEV, disease and the highest mortality occurs in piglets of newly introduced, naive animals, and to a lesser extent, in 2–3-week-old piglets as protection from maternal antibodies wanes [37]Maxie MG. Jubb, Kennedy, and Palmer’s pathology of domestic animals. Volume 2. 2016 Elsevier: St. Louis, Missouri. [40]Welter MW, Horstman MP, Welter CJ, et al. An overview of successful TGEV vaccination strategies and discussion on the interrelationship between TGEV and PRCV.Adv. Exp. Med. Biol. 1993; 342, 463–468..
TGEV infects enterocytes that line the surface of the small intestinal villi; infection is initiated by binding between the TGEV spike protein and host cell Aminopeptidase N receptors [41]Garwes D, Lucas M, Higgins D, et al. Antigenicity of structural components from porcine transmissible gastroenteritis virus.Vet. Microbiol. 1979; 3(3), 179–190. [42]Delmas B, Gelfi J, L’Haridon R, et al. Aminopeptidase N is a major receptor for the entero-pathogenic coronavirus TGEV.Nature 1992; 357(6377), 417–420.. A decrease in severity of TGEV-associated disease and mortality is seen in neonatal suckling piglets due to lactogenic immunity from sow to piglet in either colostrum or milk [38]Bohl EH, Gupta RKP, Olquin MVF, et al. Antibody responses in serum, colostrum, and milk of swine after infection or vaccination with transmissible gastroenteritis virus.Infect. Immun. 1972; 6(3), 289–301. [43]Voets MT, Pensaert M, Rondhuis P. Vaccination of pregnant sows against transmissible gastroenteritis with two attenuated virus strains and different inoculation routes.Vet. Q. 1980; 2(4), 211–219.. Effectiveness of passive immunity requires that piglets regularly receive and maintain adequate levels of neutralizing IgA within the small intestine [38]Bohl EH, Gupta RKP, Olquin MVF, et al. Antibody responses in serum, colostrum, and milk of swine after infection or vaccination with transmissible gastroenteritis virus.Infect. Immun. 1972; 6(3), 289–301. [43]Voets MT, Pensaert M, Rondhuis P. Vaccination of pregnant sows against transmissible gastroenteritis with two attenuated virus strains and different inoculation routes.Vet. Q. 1980; 2(4), 211–219. [44]Saif LJ, Bohl EH, Gupta RKP. Isolation of porcine immunoglobulins and determination of the immunoglobulin classes of transmissible gastroenteritis viral antibodies.Infect. Immun. 1972; 6(4), 600–609.. These neutralizing antibodies target the antigenically and immunogenically important spike protein of TGEV [45]De Diego M, Laviada MD, Enjuanes L, et al. Epitope specificity of protective lactogenic immunity against swine transmissible gastroenteritis virus.J. Virol. 1992; 66(11), 6502–6508. [46]De Diego M, Rodriguez F, Alcaraz C, et al. Characterization of the IgA and subclass IgG responses to neutralizing epitopes after infection of pregnant sows with the transmissible gastroenteritis virus or the antigenically related porcine respiratory coronavirus.J. Gen. Virol. 1994; 75(10), 2585–2593.. Therefore, the goal of developing an effective TGEV vaccine is to elicit the production of mucosal, anti-spike IgA antibodies in the small intestine of neonatal pigs. Modified-live TGEV vaccines in combination with other enteric pathogens (rotavirus, Clostridium perfringens Type C, E. coli bacterin-toxoid) are currently licensed in the United States (United States Department of Agriculture (USDA), Current Veterinary Biologics Product Catalog, Feb 2, 2023).
The two most used vaccine platforms for TGEV are live-attenuated and inactivated vaccines, which are administered to pregnant sows by various routes. Whereas natural TGEV infection induces protective IgA antibodies in colostrum and milk, the majority of orally-administered, live-attenuated TGEV vaccine studies report IgG antibody secretion in milk [47]Bohl EH, Saif LJ. Passive immunity in transmissible gastroenteritis of swine: immunoglobulin characteristics of antibodies in milk after inoculating virus by different routes.Infect. Immun. 1975; 11(1), 23–32.Bohl EH, Saif LJ. Passive immunity in transmissible gastroenteritis of swine: immunoglobulin characteristics of antibodies in milk after inoculating virus by different routes.Infect. Immun. 1975; 11(1), 23–32.. Although not as protective as natural infection, these studies do report less severe disease and lower mortality rates in neonatal pigs born to vaccinated sows when challenged with TGEV, compared to unvaccinated controls [47]Bohl EH, Saif LJ. Passive immunity in transmissible gastroenteritis of swine: immunoglobulin characteristics of antibodies in milk after inoculating virus by different routes.Infect. Immun. 1975; 11(1), 23–32.Bohl EH, Saif LJ. Passive immunity in transmissible gastroenteritis of swine: immunoglobulin characteristics of antibodies in milk after inoculating virus by different routes.Infect. Immun. 1975; 11(1), 23–32. [48]Aynaud JM, Bernard S, Bottreau E, et al. Induction of lactogenic immunity to transmissible gastroenteritis virus of swine using an attenuated coronavirus mutant able to survive in the physicochemical environment of the digestive tract.Vet. Microbiol. 1991; 26(3), 227–239.. Interestingly, these vaccines do not seem to produce protective immunity in vaccinated sows, as some developed clinical signs and began secreting IgA in milk when their nursing piglets were experimentally challenged [47]Bohl EH, Saif LJ. Passive immunity in transmissible gastroenteritis of swine: immunoglobulin characteristics of antibodies in milk after inoculating virus by different routes.Infect. Immun. 1975; 11(1), 23–32.Bohl EH, Saif LJ. Passive immunity in transmissible gastroenteritis of swine: immunoglobulin characteristics of antibodies in milk after inoculating virus by different routes.Infect. Immun. 1975; 11(1), 23–32.. The ineffectiveness of oral administration of a live-attenuated TGEV vaccine may be due to several factors, including degradation and loss of replicative ability as the vaccine moves through the stomach [43]Voets MT, Pensaert M, Rondhuis P. Vaccination of pregnant sows against transmissible gastroenteritis with two attenuated virus strains and different inoculation routes.Vet. Q. 1980; 2(4), 211–219.. Other routes of inoculation of live-attenuated TGEV vaccines also report IgG antibodies in milk, decreased severity of disease, and variable levels of protection upon challenge, with a moderate level of protection against mortality by intramammary routes [38]Bohl EH, Gupta RKP, Olquin MVF, et al. Antibody responses in serum, colostrum, and milk of swine after infection or vaccination with transmissible gastroenteritis virus.Infect. Immun. 1972; 6(3), 289–301. [49]Thorsen J, Djurickovic S. Experimental immunization of sows with cell-cultured TGE virus.Can. J. Comp. Med. 1970; 34(3), 177–180., and varying levels of protection by intramuscular (IM) or IM+oral administration [38]Bohl EH, Gupta RKP, Olquin MVF, et al. Antibody responses in serum, colostrum, and milk of swine after infection or vaccination with transmissible gastroenteritis virus.Infect. Immun. 1972; 6(3), 289–301. [48]Aynaud JM, Bernard S, Bottreau E, et al. Induction of lactogenic immunity to transmissible gastroenteritis virus of swine using an attenuated coronavirus mutant able to survive in the physicochemical environment of the digestive tract.Vet. Microbiol. 1991; 26(3), 227–239. [49]Thorsen J, Djurickovic S. Experimental immunization of sows with cell-cultured TGE virus.Can. J. Comp. Med. 1970; 34(3), 177–180.. The most promising finding of the IM vaccines reported high levels of protection comparable to the then-available vaccine [50]Woods RD. Efficacy of a transmissible gastroenteritis coronavirus with an altered ORF-3 gene.Canadian J. Vet. Res. 2001; 65(1), 28.. Inactivated TGEV vaccines have also struggled to replicate the effective lactogenic immunity noted in natural TGEV infection, reporting varying degrees of protection against challenge regardless of administration route, as well as stimulation of IgG (but not IgA) antibodies in colostrum and milk [41]Garwes D, Lucas M, Higgins D, et al. Antigenicity of structural components from porcine transmissible gastroenteritis virus.Vet. Microbiol. 1979; 3(3), 179–190. [51]Bohl EHEEH. Immunology of transmissible gastroenteritis.J. Amer. Vet. Med. Assoc. 1972; 160(4), 543–549. [52]Thorsen J, Djurickovic S. Experimental immunization of sows with inactivated transmissible gastroenteritis (TGE) virus.Can. J. Comp. Med. 1971; 35(2), 99–102..
Although IgA antibodies at the mucosal surface following natural infection elicit the best protective efficacy, high levels of IgG in colostrum and milk after vaccination with either live-attenuated or inactivated TGEV appear to be capable of lowering mortality and severity of disease [38]Bohl EH, Gupta RKP, Olquin MVF, et al. Antibody responses in serum, colostrum, and milk of swine after infection or vaccination with transmissible gastroenteritis virus.Infect. Immun. 1972; 6(3), 289–301.. Licensed live-attenuated TGEV vaccines have historically been available in the United States. However, when post-marketing evaluation was performed on two such vaccines, survival in piglets from sows that received the live-attenuated TGEV vaccine was no different from unvaccinated sows [53]Moxley RA, Olson LD. Clinical evaluation of transmissible gastroenteritis virus vaccines and vaccination procedures for inducing lactogenic immunity in sows.Amer. J. Vet. Res. 1989; 50(1), 111–118..
One development that may have led to natural immunologic protection against TGEV disease came not from TGEV vaccines, but from the emergence of another coronavirus, porcine respiratory coronavirus (PRCV). PRCV, a deletion mutant in the S gene of TGEV, is antigenically and genetically related to TGEV but has altered tropism, infecting tonsillar and respiratory epithelial cells rather than small intestinal enterocytes, and is generally asymptomatic in infected pigs [40]Welter MW, Horstman MP, Welter CJ, et al. An overview of successful TGEV vaccination strategies and discussion on the interrelationship between TGEV and PRCV.Adv. Exp. Med. Biol. 1993; 342, 463–468. [54]Brim TA, VanCott JL, Lunney JK, et al. Cellular immune responses of pigs after primary inoculation with porcine respiratory coronavirus or transmissible gastroenteritis virus and challenge with transmissible gastroenteritis virus.Vet. Immunol. Immunopathol. 1995; 48(1–2), 35–54.. Pigs exposed to PRCV antigen by natural and experimental infection, or immunization, have been shown to shed infectious TGEV for shorter periods of time compared to PRCV seronegative pigs, and these exposures induce varying degrees of protection against challenge with TGEV [40]Welter MW, Horstman MP, Welter CJ, et al. An overview of successful TGEV vaccination strategies and discussion on the interrelationship between TGEV and PRCV.Adv. Exp. Med. Biol. 1993; 342, 463–468. [45]De Diego M, Laviada MD, Enjuanes L, et al. Epitope specificity of protective lactogenic immunity against swine transmissible gastroenteritis virus.J. Virol. 1992; 66(11), 6502–6508. [54]Brim TA, VanCott JL, Lunney JK, et al. Cellular immune responses of pigs after primary inoculation with porcine respiratory coronavirus or transmissible gastroenteritis virus and challenge with transmissible gastroenteritis virus.Vet. Immunol. Immunopathol. 1995; 48(1–2), 35–54. [55]Bernard S, Bottreau E, Aynaud J, et al. Natural infection with the porcine respiratory coronavirus induces protective lactogenic immunity against transmissible gastroenteritis.Vet. Microbiol. 1989; 21(1), 1–8. [56]Cox E, Pensaert M, Callebaut P. Intestinal protection against challenge with transmissible gastroenteritis virus of pigs immune after infection with the porcine respiratory coronavirus.Vaccine 1993; 11(2), 267–272.. The prevalence of TGEV has decreased since the emergence of PRCV and this may be due to partial protection from natural PRCV exposure, increased biosecurity measures, or both [36]Chen F, Knutson TP, Rossow S, et al. Decline of transmissible gastroenteritis virus and its complex evolutionary relationship with porcine respiratory coronavirus in the United States.Sci. Rep. 2019; 9(1), 3953. [45]De Diego M, Laviada MD, Enjuanes L, et al. Epitope specificity of protective lactogenic immunity against swine transmissible gastroenteritis virus.J. Virol. 1992; 66(11), 6502–6508.. This decrease in TGEV prevalence has likewise decreased the demand for a vaccine, although live-attenuated and killed TGEV vaccines are currently licensed by the USDA.
Porcine epidemic diarrhea virus (PEDV)
PEDV is antigenically distinct from TGEV, however, the two cannot be differentiated based on clinical disease or histological lesions in affected pigs [57]Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.. PEDV can infect as many as 50% of small intestinal enterocytes, leading to acute necrosis of infected cells and contributing to malabsorptive diarrhea, severe dehydration, electrolyte imbalances, and death [57]Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.. Disease patterns during PEDV outbreaks also depend on the herd’s immune status. In naïve herds, the clinical picture includes disease in pigs of all age groups, with more severe clinical signs in neonates, in which mortality can reach 95% [57]Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.. Clinical disease on an affected farm experiencing an epidemic typically lasts up to 4 weeks as animals either succumb to disease or develop immunity [57]Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.. In contrast, in facilities with endemic PEDV, diarrhea is more severe in newly introduced and naïve gilts or piglets, while clinical disease is mild to absent in nursing neonatal piglets [57]Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.. Low morbidity and mortality in this latter group is attributed to passive transfer of lactogenic immunity from sows [57]Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143..
PEDV initially was identified in Europe in the 1970s and over the next two decades, spread to many Asian countries [58]Jung K, Saif LJ, Wang Q. Porcine epidemic diarrhea virus (PEDV): an update on etiology, transmission, pathogenesis, and prevention and control.Virus Res. 2020; 286, 198045.. Despite vaccine and vaccination programs in these countries, PEDV epidemics continued to occur, and in 2013, PEDV suddenly emerged for the first time in the United States, where it caused immense economic losses to the swine industry [59]Huang YW, Dickerman AW, Piñeyro P, et al. Origin, evolution, and genotyping of emergent porcine epidemic diarrhea virus strains in the United States.mBio 2013; 4(5), e00737–00713.. Two conditionally licensed vaccines became available within a year of the initial outbreak in the United States [60]Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116. but epidemics continue to occur. As with other coronaviruses, the most important PEDV immunogenic antigen is the S protein, which binds to the host cell aminopeptidase N receptor on small intestinal enterocytes and induces neutralizing antibodies [57]Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143.. There are two genotypes of PEDV: genotype 1 (subtypes G1a and G1b) and genotype 2 (subtypes G2a, G2b, G2c) [61]Kim SJ, Nguyen VG, Huynh TM, et al. Molecular characterization of porcine epidemic diarrhea virus and its new genetic classification based on the nucleocapsid gene.Viruses 2020; 12(8), 790.; the circulating genotypes play a role in vaccine effectiveness and escape, with G2 strains contributing to epidemics [62]Gerdts V, Zakhartchouk A. Vaccines for porcine epidemic diarrhea virus and other swine coronaviruses.Vet. Microbiol. 2017; 206, 45–51..
Like TGEV, the ideal vaccine against PEDV would induce a mucosal immune response targeting the S protein. The majority of early PEDV vaccines in Asia were live-attenuated vaccines administered by various routes, including orally administered to neonatal piglets [63]de Arriba ML, Carvajal A, Pozo J, et al. Mucosal and systemic isotype-specific antibody responses and protection in conventional pigs exposed to virulent or attenuated porcine epidemic diarrhoea virus.Vet. Immunol. Immunopathol. 2002; 85(1–2), 85–97., and oral and/or IM administration to pregnant sows/gilts pre-farrow [62]Gerdts V, Zakhartchouk A. Vaccines for porcine epidemic diarrhea virus and other swine coronaviruses.Vet. Microbiol. 2017; 206, 45–51. [64]Song DS, Oh JS, Kang BK, et al. Oral efficacy of Vero cell attenuated porcine epidemic diarrhea virus DR13 strain.Res. Vet. Sci. 2007; 82(1), 134–140.Song DS, Oh JS, Kang BK, et al. Oral efficacy of Vero cell attenuated porcine epidemic diarrhea virus DR13 strain.Res. Vet. Sci. 2007; 82(1), 134–140. [65]Kweon CH, Kwon BJ, Lee JG, et al. Derivation of attenuated porcine epidemic diarrhea virus (PEDV) as vaccine candidate.Vaccine 1999; 17(20–21), 2546–2553.. While none of these vaccine strategies were completely protective against PEDV infection, piglets born to, and nursing from vaccinated pregnant sows that received an oral vaccine reported the best outcomes, with decreased severity of disease and decreased mortality when challenged with homologous virus [64]Song DS, Oh JS, Kang BK, et al. Oral efficacy of Vero cell attenuated porcine epidemic diarrhea virus DR13 strain.Res. Vet. Sci. 2007; 82(1), 134–140.. PEDV vaccines have been on the market in Asia for many decades, and yet epidemics continue to occur, largely due to recombination between variants and vaccine strains, emergence of mutations leading to vaccine escape, incomplete protection provided by vaccines, and potentially increased virulence in newly emerging variants [57]Jung K, Saif LJ. Porcine epidemic diarrhea virus infection: etiology, epidemiology, pathogenesis and immunoprophylaxis.Vet. J. 2015; 204(2), 134–143. [66]Zhang YH, Li HX, Chen XM, et al. Genetic characteristics and pathogenicity of a novel porcine epidemic diarrhea virus with a naturally occurring truncated ORF3 gene.Viruses 2022; 14(3), 487. [67]Gao Q, Zheng Z, Wang H, et al. The new porcine epidemic diarrhea virus outbreak may mean that existing commercial vaccines are not enough to fully protect against the epidemic strains.Front. Vet. Sci. 2021; 8, 697839. [68]Islam MT, Kubota T, Ujike M, et al. Phylogenetic and antigenic characterization of newly isolated porcine epidemic diarrhea viruses in Japan.Virus Res. 2016; 222, 113–119. [69]Wang H, Zhang L, Shang Y, et al. Emergence and evolution of highly pathogenic porcine epidemic diarrhea virus by natural recombination of a low pathogenic vaccine isolate and a highly pathogenic strain in the spike gene.Virus Evol. 2020; 6(2), veaa049. [70]Li D, Li Y, Liu Y, et al. Isolation and identification of a recombinant porcine epidemic diarrhea virus with a novel insertion in S1 domain.Front. Microbiol. 2021; 12, 667084.. Many of the earlier vaccines targeted G1 strains, which have only partial to no cross protection against G2 epidemic strains [67]Gao Q, Zheng Z, Wang H, et al. The new porcine epidemic diarrhea virus outbreak may mean that existing commercial vaccines are not enough to fully protect against the epidemic strains.Front. Vet. Sci. 2021; 8, 697839. [71]Sato T, Oroku K, Ohshima Y, et al. Efficacy of genogroup 1 based porcine epidemic diarrhea live vaccine against genogroup 2 field strain in Japan.Virol. J. 2018; 15(1), 28..
After the sudden emergence of PEDV in 2013 in the United States, two vaccines were quickly developed and both received conditional licenses from the USDA, including a killed-virus vaccine and an RNA particle vaccine [60]Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116.Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116.Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116.Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116.Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116.. The RNA particle vaccine was composed of the PEDV spike gene in a replication deficient Venezuelan equine encephalitis virus (VEEV) vector, and was tested on neonatal piglets as well as naïve and previously exposed pregnant sows pre-farrow, by both oral and IM administration [60]Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116.Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116.Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116.Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116.Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116.. Decreased disease severity and mortality but incomplete protection against infection were reported [60]Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116.Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116.Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116.Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116.Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116.. The killed vaccine consisted of an inactivated, whole-virus plus adjuvant, and was administered IM to sows pre-farrow and reported higher antibody titers in both the vaccinated sows and their piglets but no mortality data [60]Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116.Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116.Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116.Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116.Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116.. Field studies of each of these two conditionally-licensed vaccines yielded disappointing results, reporting increased IgG antibodies in the colostrum of vaccinated sows (RNA particle vaccine) but no protection against mortality between piglets born to sows vaccinated with either the RNA particle or inactivated vaccine [60]Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116.Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116.Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116.Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116.Crawford K, Lager KM, Kulshreshtha V, et al. Status of vaccines for porcine epidemic diarrhea virus in the United States and Canada.Virus Res. 2016; 226, 108–116..
One strategy for improving the immune response to the currently licensed vaccines is to utilize a prime-boost vaccination schedule. Several studies report increased IgA levels in milk, and colostrum, and protection against disease in piglets from sows that received a pre-farrow IM booster dose of killed PEDV vaccine following either natural infection or priming with an initial live-attenuated PED vaccine [72]Gillespie T, Song Q, Inskeep M, et al. Effect of booster vaccination with inactivated porcine epidemic diarrhea virus on neutralizing antibody response in mammary secretions.Viral Immunol. 2018; 31(1), 62–68. [73]Wen Z, Xu Z, Zhou Q, et al. A heterologous ‘prime-boost’ anti-PEDV immunization for pregnant sows protects neonatal piglets through lactogenic immunity against PEDV.Lett. Appl. Microbiol. 2019; 69(4), 258–263.. Due to the evolving mutations of PEDV, emerging PEDV variants are likely to continue to cause vaccine escape and outbreaks in regions where PEDV remains endemic, including in Asian countries and in the United States. Currently existing vaccines, such as the licensed killed vaccine (Zoetis, Inc.) in the United States, may need to be updated periodically in order to offer better protection against contemporary circulating strains.
Betacoronavirus
Betacoronaviruses are known to cause deadly respiratory diseases in humans, including SARS-CoV-1, MERS-CoV, and SARS-CoV-2. One clinically and economically important betacoronavirus in veterinary species is the bovine coronavirus (BCoV), which causes both enteric and respiratory disease [1]Cui J, Li F, Shi Z-L. Origin and evolution of pathogenic coronaviruses.Nat. Rev. Microbiol. 2019; 17(3), 181–192. [4]Woo PC, Lau SK, Lam CS, et al. Discovery of seven novel mammalian and avian coronaviruses in the genus deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus.J. Virol. 2012; 86(7), 3995–4008..
Bovine coronavirus (BCoV)
BCoV infects both the gastrointestinal and respiratory tracts and causes three distinct clinical syndromes: calf diarrhea, winter dysentery in adults, and respiratory disease at any age [74]Saif LJ. Coronaviruses of domestic livestock and poultry: interspecies transmission, pathogenesis, and immunity, in nidoviruses. Nidoviruses 2007; 18, 279-298.Saif LJ. Coronaviruses of domestic livestock and poultry: interspecies transmission, pathogenesis, and immunity, in nidoviruses. Nidoviruses 2007; 18, 279-298.Saif LJ. Coronaviruses of domestic livestock and poultry: interspecies transmission, pathogenesis, and immunity, in nidoviruses. Nidoviruses 2007; 18, 279-298. [75]Boileau MJ, Kapil S. Bovine coronavirus associated syndromes.
Vet. Clin. North Am. Food Anim. Pract. 2010; 26(1), 123–146.. In calves, enteric BCoV infects the enterocytes throughout the small and large intestine, causing malabsorptive diarrhea [74]Saif LJ. Coronaviruses of domestic livestock and poultry: interspecies transmission, pathogenesis, and immunity, in nidoviruses. Nidoviruses 2007; 18, 279-298.Saif LJ. Coronaviruses of domestic livestock and poultry: interspecies transmission, pathogenesis, and immunity, in nidoviruses. Nidoviruses 2007; 18, 279-298.Saif LJ. Coronaviruses of domestic livestock and poultry: interspecies transmission, pathogenesis, and immunity, in nidoviruses. Nidoviruses 2007; 18, 279-298. [75]Boileau MJ, Kapil S. Bovine coronavirus associated syndromes.
Vet. Clin. North Am. Food Anim. Pract. 2010; 26(1), 123–146.. Disease can be mild but co-infections with other pathogens such as rotavirus and enterotoxigenic E. coli can lead to severe dehydration and mortality [74]Saif LJ. Coronaviruses of domestic livestock and poultry: interspecies transmission, pathogenesis, and immunity, in nidoviruses. Nidoviruses 2007; 18, 279-298.Saif LJ. Coronaviruses of domestic livestock and poultry: interspecies transmission, pathogenesis, and immunity, in nidoviruses. Nidoviruses 2007; 18, 279-298.Saif LJ. Coronaviruses of domestic livestock and poultry: interspecies transmission, pathogenesis, and immunity, in nidoviruses. Nidoviruses 2007; 18, 279-298. [75]Boileau MJ, Kapil S. Bovine coronavirus associated syndromes.
Vet. Clin. North Am. Food Anim. Pract. 2010; 26(1), 123–146.. In adults, enteric BCoV presents clinically as hemorrhagic diarrhea, with lesions mainly in the colon [74]Saif LJ. Coronaviruses of domestic livestock and poultry: interspecies transmission, pathogenesis, and immunity, in nidoviruses. Nidoviruses 2007; 18, 279-298.Saif LJ. Coronaviruses of domestic livestock and poultry: interspecies transmission, pathogenesis, and immunity, in nidoviruses. Nidoviruses 2007; 18, 279-298.. Mortality is low in adults but infection does cause economic loss in the form of a prolonged decrease in milk production [74]Saif LJ. Coronaviruses of domestic livestock and poultry: interspecies transmission, pathogenesis, and immunity, in nidoviruses. Nidoviruses 2007; 18, 279-298.Saif LJ. Coronaviruses of domestic livestock and poultry: interspecies transmission, pathogenesis, and immunity, in nidoviruses. Nidoviruses 2007; 18, 279-298.. Respiratory BCoV mainly infects the epithelium of the upper respiratory tract and can contribute to bovine respiratory disease complex (BRDC), which is a major cause of death and economic loss in feedlot cattle [75]Boileau MJ, Kapil S. Bovine coronavirus associated syndromes.
Vet. Clin. North Am. Food Anim. Pract. 2010; 26(1), 123–146. [76]Vlasova AN, Saif LJ. Bovine coronavirus and the associated diseases.Front. Vet. Sci. 2021; 8, 643220.. Importantly, no antigenic difference has been found between the BCoV causing these three syndromes; different serotypes of BCoV have good cross-protection and any serotype can cause either enteric or respiratory disease [74]Saif LJ. Coronaviruses of domestic livestock and poultry: interspecies transmission, pathogenesis, and immunity, in nidoviruses. Nidoviruses 2007; 18, 279-298. [75]Boileau MJ, Kapil S. Bovine coronavirus associated syndromes.
Vet. Clin. North Am. Food Anim. Pract. 2010; 26(1), 123–146. [76]Vlasova AN, Saif LJ. Bovine coronavirus and the associated diseases.Front. Vet. Sci. 2021; 8, 643220. [77]Hasoksuz M, Lathrop SL, Gadfield KL, et al. Isolation of bovine respiratory coronaviruses from feedlot cattle and comparison of their biological and antigenic properties with bovine enteric coronaviruses.Amer. J. Vet. Res. 1999; 60(10), 1227–1233. [78]Cho KO, Hasoksuz M, Nielsen PR, et al. Cross-protection studies between respiratory and calf diarrhea and winter dysentery coronavirus strains in calves and RT-PCR and nested PCR for their detection.Arch. Virol. 2001; 146(12), 2401–2419.. There are currently two licensed BCoV vaccines in the United States: a modified live vaccine and a killed vaccine (USDA, Current Veterinary Biologics Product Catalog, Feb 2, 2023).
BCoV is unique in that it has two structural proteins involved with attachment to the host cell: the prototypical spike (S) protein and the hemagglutinin-esterase (HE) protein [76]Vlasova AN, Saif LJ. Bovine coronavirus and the associated diseases.Front. Vet. Sci. 2021; 8, 643220.Vlasova AN, Saif LJ. Bovine coronavirus and the associated diseases.Front. Vet. Sci. 2021; 8, 643220. [79]Saif LJ. Bovine respiratory coronavirus.Vet. Clin. North Am. Food Anim. Pract. 2010; 26(2), 349–364.. The S protein is responsible for binding to sialic acid containing receptors on host cells and contains the main neutralizing epitopes, while the HE reverses hemagglutination [76]Vlasova AN, Saif LJ. Bovine coronavirus and the associated diseases.Front. Vet. Sci. 2021; 8, 643220.. Efficient binding to, and release from, host cells is thought to occur through the right balance in the activities of these two proteins [80]Lang Y, Li W, Li Z, et al. Coronavirus hemagglutinin-esterase and spike proteins coevolve for functional balance and optimal virion avidity.Proc. Natl. Acad. Sci. 2020; 117(41), 25759–25770..
BCoV vaccine development has focused mainly on establishing protection against diarrhea in neonatal calves. ‘Scours’ in calves is often caused by mixed infections composed of not only BCoV, but other enteric pathogens as well such as rotavirus, enterotoxigenic E. coli (K99) and C. perfringens Types C and D [74]Saif LJ. Coronaviruses of domestic livestock and poultry: interspecies transmission, pathogenesis, and immunity, in nidoviruses. Nidoviruses 2007; 18, 279-298., and as such, many of the historical and current BCoV vaccines are formulated together with immunogens from these other pathogens [81]Thurber ET, Bass EP, Beckenhauer WH. Field trial evaluation of a reo-coronavirus calf diarrhea vaccine.Can. J. Comp. Med. 1977; 41(2), 131–136. [82]Waltner-Toews D, Martin SW, Meek AH, et al. A field trial to evaluate the efficacy of a combined rotavirus-coronavirus/Escherichia coli vaccine in dairy cattle.Can. J. Comp. Med. 1985; 49(1), 1–9. [83]Crouch CF, Oliver S and Francis MJ. Serological, colostral and milk responses of cows vaccinated with a single dose of a combined vaccine against rotavirus, coronavirus and Escherichia coli F5 (K99).Vet. Rec. 2001; 149(4), 105–108.. Experimental and field studies have reported increased antibody responses in serum, colostrum, and milk of cows and/or heifers that were vaccinated (IM or subcutaneous) with an inactivated vaccine plus adjuvant [84]Chambers GP, Kelton W, Smolenski G, et al. Impact of prepartum administration of a vaccine against infectious calf diarrhea on nonspecific colostral immunoglobulin concentrations of dairy cows.J. Anim. Sci. 2022; 100(8), skac212. [85]Crouch CF, Oliver S, Hearle DC, et al. Lactogenic immunity following vaccination of cattle with bovine coronavirus.Vaccine 2000; 19(2-3), 189–196.Crouch CF, Oliver S, Hearle DC, et al. Lactogenic immunity following vaccination of cattle with bovine coronavirus.Vaccine 2000; 19(2-3), 189–196. [86]Takamura K, Matsumoto Y, Shimizu Y. Field study of bovine coronavirus vaccine enriched with hemagglutinating antigen for winter dysentery in dairy cows.Canadian J. Vet. Res. 2002; 66(4), 278–281., and, in pregnant cows, a corresponding increase in antibody responses in their calves’ serum [85]Crouch CF, Oliver S, Hearle DC, et al. Lactogenic immunity following vaccination of cattle with bovine coronavirus.Vaccine 2000; 19(2-3), 189–196.. Many studies on BCoV vaccination were performed in the field, and few studies report virus challenge results due to the difficulties in assessing clinical disease in the field and in the face of mixed infections. Initial field studies reported little to no protection following vaccination, however, more recent vaccination studies have shown some promise, with increased antibody responses in cows vaccinated with a single dose of inactivated (IM) vaccine prior to calving, and decreased diarrhea after challenge in their calves [87]Pinheiro FA, Decaris N, Parreño V, et al. Efficacy of prepartum vaccination against neonatal calf diarrhea in Nelore dams as a prevention measure.BMC Vet. Res. 2022; 18(1), 323.. Calves have also been directly vaccinated with an orally administered, modified-live BCoV vaccine; after virus challenge, vaccinated calves remained clinically normal, had a faster rate of gain, and had no fecal viral shedding, compared to unvaccinated controls [88]Welter MW. Adaptation and serial passage of bovine coronavirus in an established diploid swine testicular cell line and subsequent development of a modified live vaccine.Adv. Exp. Med. Biol. 1998; 440, 707–711..
There is evidence that respiratory shedding of BCoV may be a source of continual exposure of a herd or to newly mingled animals on feedlots [74]Saif LJ. Coronaviruses of domestic livestock and poultry: interspecies transmission, pathogenesis, and immunity, in nidoviruses. Nidoviruses 2007; 18, 279-298. [89]El-Kanawati ZR, Tsunemitsu H, Smith DR, et al. Infection and cross-protection studies of winter dysentery and calf diarrhea bovine coronavirus strains in colostrum-deprived and gnotobiotic calves.Amer. J. Vet. Res. 1996; 57(1), 48–53.. However, the current vaccines are directed against enteric disease and only a few studies have addressed efficacy in preventing respiratory disease. There is evidence that intranasal vaccination with a modified-live BCoV vaccine upon entry into a feedlot decreases the risk of being treated for respiratory disease [90]Plummer PJ, Rohrbach BW, Daugherty RA, et al. Effect of intranasal vaccination against bovine enteric coronavirus on the occurrence of respiratory tract disease in a commercial backgrounding feedlot.J. Amer. Vet. Med. Assoc. 2004; 225(5), 726–731.. Development of a live-attenuated BCoV vaccine targeting respiratory disease reported a high safety profile and high antibody titers but no virus challenge was performed [91]Decaro N, Campolo M, Mari V, et al. A candidate modified-live bovine coronavirus vaccine: safety and immunogenicity evaluation.New Microbiol. 2009; 32(1), 109–113.. Unfortunately, no experimental virus challenge studies on respiratory protection following vaccination have been reported, and to date there is no licensed vaccine targeting the respiratory disease associated with BCoV infection.
The relative paucity of research on BCoV vaccines is likely due to several challenges, including: (1) the virus has a wide range of cell tropism and establishing mucosal immunity in multiple sites is unlikely to be accomplished with a single vaccine; (2) the benefits of enteric mucosal immunity are well understood due to the extensive research in coronaviruses of pigs, however, passive, lactogenic immunity is more challenging to practically achieve in large beef herds and in dairy herds in general; and (3) both the enteric and respiratory syndromes experienced with BCoV infection are often seen in conjunction with co-infections with one or more other pathogens, further complicating experimental methods and assessment of outcomes associated with the protective efficacy of vaccines. Nonetheless, multiple modified live and killed virus vaccines are licensed and in use in the United States.
Gammacoronavirus
The gammacoronaviruses include an economically important veterinary virus infecting poultry, the infectious bronchitis virus (IBV), and many commercial vaccines have been licensed and are in use.
Avian infectious bronchitis virus (IBV)
IBV is primarily a disease of the upper respiratory tract and infects the ciliated and mucous-secreting epithelial cells, causing clinical signs such as gasping, snicking, sneezing, coughing, and nasal discharge in birds [92]Cavanagh D. Coronavirus avian infectious bronchitis virus.Vet. Res. 2007; 38(2), 281–297.Cavanagh D. Coronavirus avian infectious bronchitis virus.Vet. Res. 2007; 38(2), 281–297.Cavanagh D. Coronavirus avian infectious bronchitis virus.Vet. Res. 2007; 38(2), 281–297. [93]Jackwood MW. Review of Infectious bronchitis virus around the world.Avian Dis. 2012; 56(4), 634–641.. IBV infection compromises mucociliary function, and predisposes animals to secondary infections that are often the actual cause of death [93]Jackwood MW. Review of Infectious bronchitis virus around the world.Avian Dis. 2012; 56(4), 634–641. [94]Hoerr FJ. The pathology of infectious bronchitis.Avian Dis. 2021; 65(4), 600–611.Hoerr FJ. The pathology of infectious bronchitis.Avian Dis. 2021; 65(4), 600–611.. While the upper respiratory tract is the primary site of virus infection, IBV is capable of infecting many other organ systems, including the lower respiratory tract, the gastrointestinal tract, kidneys, and reproductive tract [92]Cavanagh D. Coronavirus avian infectious bronchitis virus.Vet. Res. 2007; 38(2), 281–297.Cavanagh D. Coronavirus avian infectious bronchitis virus.Vet. Res. 2007; 38(2), 281–297.. As a result, IBV can be isolated from both respiratory secretions and feces, and disease can include pneumonia and airsacculitis, decreased egg production and decreased egg quality, including soft and deformed shells [92]Cavanagh D. Coronavirus avian infectious bronchitis virus.Vet. Res. 2007; 38(2), 281–297.Cavanagh D. Coronavirus avian infectious bronchitis virus.Vet. Res. 2007; 38(2), 281–297.. Nephropathogenic strains of IBV target renal tubular epithelial cells and cause severe, acute, necrotizing nephritis, renal failure, and increased mortality in birds [92]Cavanagh D. Coronavirus avian infectious bronchitis virus.Vet. Res. 2007; 38(2), 281–297. [94]Hoerr FJ. The pathology of infectious bronchitis.Avian Dis. 2021; 65(4), 600–611.Hoerr FJ. The pathology of infectious bronchitis.Avian Dis. 2021; 65(4), 600–611.. When exposed at a young age, IBV can cause enteritis, stunted growth, and chronic cystic oviduct that prevents egg formation [94]Hoerr FJ. The pathology of infectious bronchitis.Avian Dis. 2021; 65(4), 600–611.. IBV is extremely contagious: morbidity in an affected flock is typically 100% and mortality is usually low, unless the IBV strain is nephropathogenic or there are coinfections with other pathogens [92]Cavanagh D. Coronavirus avian infectious bronchitis virus.Vet. Res. 2007; 38(2), 281–297.Cavanagh D. Coronavirus avian infectious bronchitis virus.Vet. Res. 2007; 38(2), 281–297.Cavanagh D. Coronavirus avian infectious bronchitis virus.Vet. Res. 2007; 38(2), 281–297. [93]Jackwood MW. Review of Infectious bronchitis virus around the world.Avian Dis. 2012; 56(4), 634–641..
The IBV S protein mediates host cell binding and is cleaved into the S1 and S2 subunits. S1 is responsible for cell tropism and binding to a sialic acid receptor on host cell membranes, as well as inducing virus neutralizing antibodies [95]Casais R, Dove B, Cavanagh D, et al. Recombinant avian infectious bronchitis virus expressing a heterologous spike gene demonstrates that the spike protein is a determinant of cell tropism.J. Virol. 2003; 77(16), 9084–9089. [96]Promkuntod N, van Eijndhoven REW, de Vrieze G, et al. Mapping of the receptor-binding domain and amino acids critical for attachment in the spike protein of avian coronavirus infectious bronchitis virus.Virol. 2014; 448, 26–32. [97]Cavanagh D, Davis PJ, Mockett AP. Amino acids within hypervariable region 1 of avian coronavirus IBV (Massachusetts serotype) spike glycoprotein are associated with neutralization epitopes.Virus Res. 1988; 11(2), 141–150.. There are many different serotypes of IBV and neutralizing antibodies for each type have poor cross-protection for other serotypes [93]Jackwood MW. Review of Infectious bronchitis virus around the world.Avian Dis. 2012; 56(4), 634–641.. As such, there are many different licensed IBV vaccines in the United States that are composed of a variety of serotypes, in live-attenuated virus, and killed vaccine platforms, and often in combination with other avian pathogens, including Newcastle disease virus and infectious bursal disease virus (USDA, Current Veterinary Biologics Product Catalog, Feb 2, 2023).
IBV was first described in the 1930’s; the first vaccine became available in the 1950’s, and vaccination has been practiced worldwide ever since [93]Jackwood MW. Review of Infectious bronchitis virus around the world.Avian Dis. 2012; 56(4), 634–641.. As with other animal coronaviruses, mucosal and local immunity is important for anti-IBV immunity [98]Okino CH, Alessi AC, Montassier Mde F, et al. Humoral and cell-mediated immune responses to different doses of attenuated vaccine against avian infectious bronchitis virus.Viral Immunol. 2013; 26(4), 259–267. [99]Toro H, Fernandez I. Avian infectious bronchitis: specific lachrymal IgA level and resistance against challenge.Zentralbl Veterinarmed B. 1994; 41(7–8), 467–472. [100]Chhabra R, Forrester A, Lemiere S, et al. Mucosal, Cellular, and Humoral Immune Responses Induced by Different Live Infectious Bronchitis Virus Vaccination Regimes and Protection Conferred against Infectious Bronchitis Virus Q1 Strain.Clin. Vaccine Immunol. 2015; 22(9), 1050–1059. [101]Santos RMD, Fernando FS, Montassier MFS, et al. Memory immune responses and protection of chickens against a nephropathogenic infectious bronchitis virus strain by combining live heterologous and inactivated homologous vaccines.J. Vet. Med. Sci. 2019; 81(4), 612–619. [102]Davelaar FG, Noordzij A, Vanderdonk JA. A study on the synthesis and secretion of immunoglobulins by the Jarderian gland of the fowl after eyedrop vaccination against infectious bronchitis at 1-day-old.Avian Pathol. 1982; 11(1), 63–79. [103]Orr-Burks N, Gulley SL, Toro H, et al. Immunoglobulin A as an early humoral responder after mucosal avian coronavirus vaccination.Avian Dis. 2014; 58(2), 279–286. [104]Seo SH, Collisson EW. Specific cytotoxic T lymphocytes are involved in in vivo clearance of infectious bronchitis virus.J. Virol. 1997; 71(7), 5173–5177. [105]Timms LM, Bracewell CD. Cell mediated and humoral immune response of chickens to live infectious bronchitis vaccines.Res. Vet. Sci. 1981; 31(2), 182–189.. Many commercial IBV vaccines are administered either in drinking water or in coarse spray, both methods of delivery are efficient for producers and target local mucosal immune responses. Many of the first vaccines used were live-attenuated virus vaccines administered within a few weeks of hatch. Several studies reported protection against homologous challenge, with less severe clinical disease, maintained ciliary activity in the trachea, and decreased viral shedding [106]Lohr JE, McCausland IP, Owen DJ. Studies on avian infectious bronchitis virus in New Zealand. III. Efficacy of an attenuated live infectious bronchitis vaccine of New Zealand origin in broiler birds.NZ Vet. J. 1977; 25(3), 53–55. [107]Martins NR, Mockett AP, Barrett AD, et al. IgM responses in chicken serum to live and inactivated infectious bronchitis virus vaccines.Avian Dis. 1991; 35(3), 470–475.. Protection afforded by live-attenuated IBV vaccines was short-lived and declined about 9 weeks post-vaccination but could be prolonged with a booster dose [108]Darbyshire JH, Peters RW. Sequential development of humoral immunity and assessment of protection in chickens following vaccination and challenge with avian infectious bronchitis virus.Res. Vet. Sci. 1984; 37(1), 77–86. [109]Gough RE, Alexander DJ. Comparison of duration of immunity in chickens infected with a live infectious bronchitis vaccine by three different routes.Res. Vet. Sci. 1979; 26(3), 329–332.. The live-attenuated IBV vaccines have been shown to be capable of infecting susceptible contact chickens, undergoing recombination with circulating virulent strains, and/or mutating into virulent strains themselves [110]Zhang Y, Wang HN, Wang T, et al. Complete genome sequence and recombination analysis of infectious bronchitis virus attenuated vaccine strain H120.Virus Genes. 2010; 41(3), 377–388. [111]Matthijs MG, Bouma A, Velkers FC, et al. Transmissibility of infectious bronchitis virus H120 vaccine strain among broilers under experimental conditions.Avian Dis. 2008; 52(3), 461–466.. While inactivated IBV vaccines have had mixed results on their own, they can be used in combination to extend immune protection. When administered as multiple doses by aerosol or subcutaneous routes, or as an aerosol-subcutaneous prime-boost schedule, inactivated vaccines could produce a virus neutralizing antibody response and decrease virus isolation from the trachea [112]Coria MF, Hofstad MS. Immune response in chickens to infectious bronchitis virus, strain 33 i. response to beta-propiolactone-inactivated virus.Avian Dis. 1971; 15(4), 688–695. [113]Coria MF. Protective effect of an inactivated avian coronavirus vaccine administered by aerosol.Arch Gesamte Virusforsch. 1973; 41(1), 66–70..
The main obstacle for successful IBV control is that vaccines offer limited to no protection against challenge with heterologous serotypes. IBV has a high mutation rate and only a few point mutations in the spike protein are thought to be necessary before commercial vaccines lose their protective efficacy [92]Cavanagh D. Coronavirus avian infectious bronchitis virus.Vet. Res. 2007; 38(2), 281–297.. For this reason, IBV continues to have a huge economic impact on poultry industries worldwide as newly emerging IBV strains are not protected by commercially available vaccines. Efforts at addressing waning protective efficacy and increasing cross-protection have focused on utilizing prime-boost vaccine strategies utilizing different IBV strains in combination to broaden protective coverage. When inactivated IBV vaccines were used as a booster following natural exposure or live-attenuated IBV vaccination, vaccinated chicks experienced increased antibody titers in serum, protection against drop in egg production, and/or experienced a decrease in viral load in tissues (i.e., trachea, kidney) [101]Santos RMD, Fernando FS, Montassier MFS, et al. Memory immune responses and protection of chickens against a nephropathogenic infectious bronchitis virus strain by combining live heterologous and inactivated homologous vaccines.J. Vet. Med. Sci. 2019; 81(4), 612–619. [114]Finney PM, Box PG, Holmes HC. Studies with a bivalent infectious bronchitis killed virus vaccine.Avian Pathol. 1990; 19(3), 435–450. [115]Ladman BS, Pope CR, Ziegler AF, et al. Protection of chickens after live and inactivated virus vaccination against challenge with nephropathogenic infectious bronchitis virus PA/Wolgemuth/98.Avian Dis. 2002; 46(4), 938–944. [116]Box PG, Ellis KR. Infectious bronchitis in laying hens: interference with response to emulsion vaccine by attenuated live vaccine.Avian Pathol. 1985; 14(1), 9–22. [117]Box PG, Holmes HC, Finney PM, et al. Infectious bronchitis in laying hens: the relationship between haemagglutination inhibition antibody levels and resistance to experimental challenge.Avian Pathol. 1988; 17(2), 349–361.. Currently many IBV vaccines are commercially available, the majority of which are live-attenuated virus vaccines, along with a few inactivated virus vaccines. Vaccine protocols for these IBV vaccines recommend booster doses after natural infection or primary vaccination.
Translation insights
This concise review touches on a few of the important highlights of vaccine development for each of the selected clinically important veterinary coronaviruses, with a focus on licensed commercial animal vaccines. Individual and more detailed reviews could certainly be written on each of the selected viruses, as a variety of vaccine platforms, expression systems, administration routes, and many different adjuvants and co-stimulatory molecules, have been studied in vitro and in experimental models for each virus. Thus, the knowledge in searching for effective veterinary vaccines for these selected coronaviruses has the potential to inform future coronavirus vaccine development in any species, including humans. Across the animal coronaviruses discussed in this brief review, three common themes stand out: the battle to control disease in the face of constantly mutating coronaviruses, the importance of establishing mucosal immunity in mitigating the viral life cycle, and the challenge faced with the short-term and incomplete protection provided by these veterinary coronavirus vaccines.
Coronaviruses have one of the largest RNA genomes, thereby providing ample opportunity for mutations and recombination to occur [118]McLean G, Kamil J, Lee B, et al. The Impact of evolving SARS-CoV-2 mutations and variants on COVID-19 vaccines.mBio 2022; 13(2), e0297921., and enabling the emergence of new variants. This challenging scenario is illustrated in many of the animal coronaviruses discussed here, including IBV and PEDV. Despite decades of vaccination programs, disease associated with IBV infection is still a major concern for the global poultry industry due to newly emerging variants, often with poor or no cross-protection by existing licensed vaccines. Establishing the predominant circulating virus strains on a geographical basis is necessary for planning the vaccination program for a specific region and consideration must be given to ‘regionalization’ of available vaccine products based on these data. Surveillance and tracking of the emerging mutations across the globe may help identify areas of improvement for biosecurity measures or potential trends that contribute to important vaccine updates and modifications. Similarly, molecular epidemiologic methods have been widely used for SARS-CoV-2 surveillance, with many open access systems available to track number of cases, as well as genomic and phylogenetic trends of variants worldwide [119]Lamichhane A, Azegami T, Kiyono H. The mucosal immune system for vaccine development.Vaccine 2014; 32(49), 6711–6723..
Emergence of variants also necessitates either periodic production of updated vaccines, as seen with development of the bivalent SARS-CoV-2 mRNA vaccines, or ideally, development of a broadly-protective or pan-coronavirus vaccines. The decrease noted in TGEV infection rates following emergence of PRCV provides some hope for pan-coronavirus vaccine development. Studies evaluating cross-protection between SARS-CoV-2 and other coronaviruses in either human (i.e., OC43, HUK1, NL63, 229E) or animal populations (i.e., bats) generally indicate that antibodies do not have significant cross-neutralizing effects and there is variable evidence for protection against severe disease [120]Lavelle EC, Ward RW. Mucosal vaccines—fortifying the frontiers.Nat. Rev. Immunol. 2022; 22(4), 236–250.. However, there is evidence of pre-existing, cross-reactive CD4 and CD8 T cells to non-S1 structural and non-structural proteins [120]Lavelle EC, Ward RW. Mucosal vaccines—fortifying the frontiers.Nat. Rev. Immunol. 2022; 22(4), 236–250. [121]Russell MW, Moldoveanu Z, Ogra PL, et al. Mucosal immunity in COVID-19: A neglected but critical aspect of SARS-CoV-2 infection.Front Immunol. 2020; 11, 611337. [122]Park Y-J, Pinto D, Walls AC, et al. Imprinted antibody responses against SARS-CoV-2 Omicron sublineages.Science 2022; 378(6620), 619–627.. Studies on cross-protection among coronaviruses have the potential to identify important humoral and cell-mediated immune mechanisms of protective immunity for developing broadly-protective vaccines in both veterinary and human medicine.
The potential impact and importance of a mucosal immune response for efficient protection is a strong and common theme throughout all of the animal coronaviruses discussed in this review. Many in vitro, in vivo experimental, and field studies consistently establish the beneficial effects that neutralizing mucosal IgA antibodies, as well as CMI responses, have on controlling coronavirus infection at the initial site of infection. Mucosal immunization routes across different animal species have a multitude of options, including vaccines administered via oral or intranasal routes, in eye drops or drinking water, or even applied as a coarse spray. In most instances, these routes of administration produce a better local mucosal immune response when compared to parenteral vaccines. TGEV and PEDV vaccines helped characterize the mucosal, lactogenic, passive immunity from dam to their neonates. Studies in livestock and poultry pushed the vaccine field to look at immunity in a new light, as serum antibodies, the outcome of focus for many coronavirus vaccines, were less predictive of protection against disease compared to IgA antibodies at mucosal sites and/or in mucosal secretions or fecal matter. The benefit of lactogenic immunity is driven home by the struggles with establishing protection against coronavirus in bovine species, where continuous exposure to milk containing adequate neutralizing antibodies is not practically possible. There have been many published reports across different veterinary coronaviruses on the inclusion of various mucosal adjuvants and co-stimulatory molecules to target mucosal cells and induce homing of immune cells to mucosal sites in order to induce or boost a mucosal immune response, and these strategies could be applied to future SARS-CoV-2 vaccine as well.
This review focuses mainly on experimental vaccines that were either integral to vaccine development in the respective species, and/or licensed and commercially available vaccines that have been used in a vaccination program. Many other vaccine platforms, from DNA to viral- or bacterial-vectored to virus-like-particles, have been studied for each of the veterinary coronavirus species reviewed here but are not detailed in this brief review. To date, the majority of vaccines on the market for veterinary species are modified-live or inactivated virus vaccines. With the honing of mRNA technology for successful vaccine development during the SARS-CoV-2 pandemic, it will be interesting to see how the field of veterinary vaccines evolves and whether this new mRNA platform can be applied cost-effectively to veterinary species to benefit patients of any species.
The potential benefits of vaccine-induced mucosal immunity in combating SARS-CoV-2 have been reviewed elegantly elsewhere [123]Tang J, Zeng C, Cox TM, et al. Respiratory mucosal immunity against SARS-CoV-2 after mRNA vaccination.Sci. Immunol. 2022; 7(76), eadd4853. [124]He J, Huang JR, Zhang YL, et al. SARS-CoV-2 nucleocapsid protein intranasal inoculation induces local and systemic T cell responses in mice.J. Med. Virol. 2021; 93(4), 1923–1925. [125]Bricker TL, Darling TL, Hassan AO, et al. A single intranasal or intramuscular immunization with chimpanzee adenovirus-vectored SARS-CoV-2 vaccine protects against pneumonia in hamsters.Cell Rep. 2021; 36(3), 109400.. As with other parenterally delivered vaccine platforms, the currently available mRNA vaccines induce strong protective neutralizing antibodies in serum but low levels of the same in respiratory mucosal secretions (nasal swab or bronchoalveolar lavage) [126]Authorship & Conflict of Interest [127]Contributions:All named authors take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.. Recent studies have begun to investigate the potential of mucosal vaccines for SARS-CoV-2 [127]Contributions:All named authors take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. [128]Acknowledgements: None. [129]Disclosure and potential conflicts of interest: Meng XJ did not receive specific funding for writing this manuscript. All data in this review article are from publically available published literature. From 6/1/2014 to 4/15/2018, his research work on porcine epidemic diarrhea virus (PEDV) vaccine development was funded by Elanco Animal Health Inc/Eli Lilly and Company. Meng XJ has a US patent (62/275,313. Filed on Jan 06, 2016) and US patent application (17/924,963). The other author has no conflicts of interest., and combined with the benefits consistently described in coronavirus vaccines for veterinary species, this approach provides hope for vaccine improvements in prevention of infection and further transmission in humans as well.
The final common theme from these animal coronavirus vaccines is that licensed vaccines for coronaviruses across veterinary species can decrease disease severity and lower mortality rates, but rarely confer complete protection. Observed benefits are usually short-lived, thereby requiring repeated booster immunizations. In most veterinary species, even natural infection induces only short-lived protective immunity. The closest mimic of this immune response is induced by live-attenuated coronavirus vaccines administered at the mucosal site where natural infection initially occurs. The same challenges are also known with SARS-CoV-2, as re-infection does occur following either natural infection or vaccination, further underscoring the importance of boosters and vaccine updates.
These decades of experience from animal coronavirus vaccines in veterinary species illustrate the shared challenges faced when developing long-lasting protective vaccines for coronaviruses in any species. One approach in animal coronavirus vaccination programs that seems to improve upon the incomplete protective efficacy, prolong duration of protection, improve mucosal immune responses, and provide better cross-protection, is the use of a prime-boost vaccination schedules. There is some evidence that this approach may also be beneficial in SARS-CoV-2 disease control. Neutralizing antibodies in the nasal mucosa have been isolated after natural breakthrough infection with SARS-CoV-2 in already vaccinated individuals [126]Authorship & Conflict of Interest. This has been replicated experimentally, in which immunization of mice first with a SARS-CoV-2 IM mRNA vaccine followed by an IN vaccine induced strong neutralizing antibodies in the respiratory mucosa [127]Contributions:All named authors take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.. Collectively, the available data from veterinary coronavirus vaccines and available SARS-CoV-2 data support the recommendation for periodic SARS-CoV-2 vaccine update and booster doses, and for vaccination after recovery from SARS-CoV-2 infection.
Biographies
Anna M Hassebroek is a Veterinary Anatomic Pathology Resident and PhD candidate in Virology at the Virginia-Maryland College of Veterinary Medicine at Virginia Polytechnic Institute and State University (Virginia Tech), Blacksburg, VA. She received her BA from Creighton University, MPH from University of Iowa, and DVM from Purdue University. Her research interests include pathogenesis and vaccine development against emerging zoonotic viruses, and diagnostic pathology.
Xiang-Jin Meng is a University Distinguished Professor at the Virginia-Maryland College of Veterinary Medicine at Virginia Polytechnic Institute and State University, Blacksburg, VA. He received his medical degree from Binzhou Medical College, MS in Microbiology and Immunology from Hubei Medical College, and PhD in Immunobiology from Iowa State University, Ames, Iowa. Prior to joining the faculty at Virginia Tech, he was a senior staff scientist in the Laboratory of Infectious Diseases at NIAID, NIH. His area of research interest focuses on delineating the mechanisms of virus replication, pathogenesis, and cross-species infection, and developing vaccines against emerging and zoonotic viruses of veterinary and human public health significance.
Affiliation
Anna M Hassebroek DVM-MPH
Department of Biomedical Sciences and Pathobiology,
Center for Emerging, Zoonotic, and Arthropod-borne Pathogens,
Virginia Polytechnic Institute and State University,
Blacksburg, Virginia, USA
Xiang-Jin Meng MD PhD
Department of Biomedical Sciences and Pathobiology,
Center for Emerging, Zoonotic, and Arthropod-borne Pathogens,
Virginia Polytechnic Institute and State University,
Blacksburg, Virginia, USA
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Authorship & conflict of interest
Contributions: All named authors take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Acknowledgements: None.
Disclosure and potential conflicts of interest: Meng XJ did not receive specific funding for writing this manuscript. All data in this review article are from publically available published literature. From 6/1/2014 to 4/15/2018, his research work on porcine epidemic diarrhea virus (PEDV) vaccine development was funded by Elanco Animal Health Inc/Eli Lilly and Company. Meng XJ has a US patent (62/275,313. Filed on Jan 6, 2016) and US patent application (17/924,963). The other author has no conflicts of interest.
Funding declaration: The authors received no financial support for the research, authorship and/or publication of this article.
Article & copyright information
Copyright: Published by Vaccine Insights under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.
Attribution: Copyright © 2023 Meng XJ, Hassebroek A. Published by Vaccine Insights under Creative Commons License Deed CC BY NC ND 4.0.
Article source: Invited; externally peer reviewed.
Submitted for peer review: May 23, 2023; Revised manuscript received: Jul 20, 2023; Publication date: Jul 27, 2023.