Analyze Diet
PloS one2017; 12(1); e0169072; doi: 10.1371/journal.pone.0169072

Neonatal Immunization with a Single IL-4/Antigen Dose Induces Increased Antibody Responses after Challenge Infection with Equine Herpesvirus Type 1 (EHV-1) at Weanling Age.

Abstract: Neonatal foals respond poorly to conventional vaccines. These vaccines typically target T-helper (Th) cell dependent B-cell activation. However, Th2-cell immunity is impaired in foals during the first three months of life. In contrast, neonatal basophils are potent interleukin-4 (IL-4) producers. The purpose of this study was to develop a novel vaccine triggering the natural capacity of neonatal basophils to secrete IL-4 and to evaluate if vaccination resulted in B-cell activation and antibody production against EHV-1 glycoprotein C (gC). Neonatal vaccination was performed by oral biotinylated IgE (IgE-bio) treatment at birth followed by intramuscular injection of a single dose of streptavidin-conjugated gC/IL-4 fusion protein (Sav-gC/IL-4) for crosslinking of receptor-bound IgE-bio (group 1). Neonates in group 2 received the intramuscular Sav-gC/IL-4 vaccine only. Group 3 remained non-vaccinated at birth. After vaccination, gC antibody production was not detectable. The ability of the vaccine to induce protection was evaluated by an EHV-1 challenge infection after weaning at 7 months of age. Groups 1 and 2 responded to EHV-1 infection with an earlier onset and overall significantly increased anti-gC serum antibody responses compared to control group 3. In addition, group 1 weanlings had a decreased initial fever peak after infection indicating partial protection from EHV-1 infection. This suggested that the neonatal vaccination induced a memory B-cell response at birth that was recalled at weanling age after EHV-1 challenge. In conclusion, early stimulation of neonatal immunity via the innate arm of the immune system can induce partial protection and increased antibody responses against EHV-1.
Publication Date: 2017-01-03 PubMed ID: 28045974PubMed Central: PMC5207648DOI: 10.1371/journal.pone.0169072Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research seeks to fully understand a new vaccine’s ability to stimulate an immune response in neonatal horses (foals) by leveraging the body’s natural interleukin-4 (IL-4) secretion, offering partial protection against Equine Herpesvirus Type 1 (EHV-1).

Study Background

  • This study came about due to the observation that conventional vaccines do not effectively stimulate an immune response in neonatal foals, particularly during the first three months of life.
  • Typical vaccines target the Th-cell dependent B-cell activation, but in neonatal foals, Th2-cell immunity is notably diminished.
  • However, it was identified that neonatal basophils, a type of white blood cell, were efficient producers of interleukin-4 (IL-4).

Study Objective

  • The research aimed to create a novel vaccine that would stimulate the neonatal foals’ basophils’ natural IL-4 production ability.
  • The research hypothesis was that this stimulation would lead to B-cell activation and the subsequent production of antibodies against EHV-1 glycoprotein C (gC).

Vaccine Design and Testing

  • The proposed vaccine was administered to the neonates in two groups. The first group was given an oral biotinylated IgE (IgE-bio) treatment at birth, which was followed by an intramuscular injection of a single dose of streptavidin-conjugated gC/IL-4 fusion protein (Sav-gC/IL-4) designed to crosslink the receptor-bound IgE-bio.
  • For the second group, only the intramuscular Sav-gC/IL-4 vaccine was administered.
  • Your third group, the control, did not receive any vaccine at birth.
  • Initial results did not detect any gC antibody production post-vaccination.

Protection Evaluation

  • The ability of the vaccine to induce protection was evaluated by subjecting the groups to an EHV-1 challenge infection at 7 months post-weaning.
  • The first two vaccinated groups illustrated an earlier onset and significantly increased anti-gC serum antibody responses compared to the unvaccinated control group.
  • In particular, the first group, which received the oral IgE-bio treatment as well as the intramuscular Sav-gC/IL-4 vaccine, showed a decreased initial fever peak post-infection, indicating some degree of partial protection against EHV-1.

Conclusion

  • This study demonstrates that early stimulation of neonatal immunity via the innate arm of the immune system (the basophils and their IL-4 production) can induce a memory B-cell response and partial protection alongside increased antibody responses against EHV-1.
  • The researchers conclude that utilizing the immune mechanisms of neonates could lead to more effective vaccine designs for young animals.

Cite This Article

APA
Wagner B, Perkins G, Babasyan S, Freer H, Keggan A, Goodman LB, Glaser A, Torsteinsdóttir S, Svansson V, Björnsdóttir S. (2017). Neonatal Immunization with a Single IL-4/Antigen Dose Induces Increased Antibody Responses after Challenge Infection with Equine Herpesvirus Type 1 (EHV-1) at Weanling Age. PLoS One, 12(1), e0169072. https://doi.org/10.1371/journal.pone.0169072

Publication

ISSN: 1932-6203
NlmUniqueID: 101285081
Country: United States
Language: English
Volume: 12
Issue: 1
Pages: e0169072
PII: e0169072

Researcher Affiliations

Wagner, Bettina
  • Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States of America.
Perkins, Gillian
  • Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States of America.
Babasyan, Susanna
  • Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States of America.
Freer, Heather
  • Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States of America.
Keggan, Alison
  • Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States of America.
Goodman, Laura B
  • Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States of America.
Glaser, Amy
  • Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States of America.
Torsteinsdóttir, Sigurbjorg
  • Institute for Experimental Pathology, Keldur, University of Iceland, Reykjavik, Iceland.
Svansson, Vilhjálmur
  • Institute for Experimental Pathology, Keldur, University of Iceland, Reykjavik, Iceland.
Björnsdóttir, Sigríður
  • Icelandic Food and Veterinary Authority, MAST, Office of Animal Health and Welfare, Selfoss, Iceland.

MeSH Terms

  • Animals
  • Animals, Newborn
  • Antibodies, Viral / blood
  • Antibody Formation
  • B-Lymphocytes / immunology
  • B-Lymphocytes / virology
  • Cytokines / immunology
  • Herpesviridae Infections / prevention & control
  • Herpesviridae Infections / veterinary
  • Herpesvirus 1, Equid
  • Herpesvirus Vaccines / therapeutic use
  • Horse Diseases / prevention & control
  • Horse Diseases / virology
  • Horses / immunology
  • Interleukin-4 / administration & dosage
  • Interleukin-4 / immunology
  • Lymphocyte Activation
  • Neutralization Tests / veterinary
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / immunology
  • Temperature
  • Viral Envelope Proteins / administration & dosage
  • Viral Envelope Proteins / immunology

Conflict of Interest Statement

BW and GP submitted a patent application entitled ‘Stimulation of Neonatal Immunity’. The other authors declare that they have no conflicts of interest. The competing interest statement does not alter our adherence to PLOS ONE policies on sharing data and materials.

References

This article includes 47 references
  1. Gilkerson JR, Whalley JM, Drummer HE, Studdert MJ, Love DN. Epidemiological studies of equine herpesvirus 1 (EHV-1) in Thoroughbred foals: a review of studies conducted in the Hunter Valley of New South Wales between 1995 and 1997.. Vet Microbiol 1999 Aug 16;68(1-2):15-25.
    pubmed: 10501158doi: 10.1016/s0378-1135(99)00057-7google scholar: lookup
  2. Patel JR, Heldens J. Equine herpesviruses 1 (EHV-1) and 4 (EHV-4)--epidemiology, disease and immunoprophylaxis: a brief review.. Vet J 2005 Jul;170(1):14-23.
    doi: 10.1016/j.tvjl.2004.04.018pubmed: 15993786google scholar: lookup
  3. Lunn DP, Davis-Poynter N, Flaminio MJ, Horohov DW, Osterrieder K, Pusterla N, Townsend HG. Equine herpesvirus-1 consensus statement.. J Vet Intern Med 2009 May-Jun;23(3):450-61.
  4. Goehring LS, van Winden SC, van Maanen C, Sloet van Oldruitenborgh-Oosterbaan MM. Equine herpesvirus type 1-associated myeloencephalopathy in The Netherlands: a four-year retrospective study (1999-2003).. J Vet Intern Med 2006 May-Jun;20(3):601-7.
  5. Foote CE, Love DN, Gilkerson JR, Whalley JM. Detection of EHV-1 and EHV-4 DNA in unweaned Thoroughbred foals from vaccinated mares on a large stud farm.. Equine Vet J 2004 May;36(4):341-5.
    pubmed: 15163042doi: 10.2746/0425164044890634google scholar: lookup
  6. Kydd JH, Smith KC, Hannant D, Livesay GJ, Mumford JA. Distribution of equid herpesvirus-1 (EHV-1) in respiratory tract associated lymphoid tissue: implications for cellular immunity.. Equine Vet J 1994 Nov;26(6):470-3.
  7. Slater JD, Borchers K, Thackray AM, Field HJ. The trigeminal ganglion is a location for equine herpesvirus 1 latency and reactivation in the horse.. J Gen Virol 1994 Aug;75 ( Pt 8):2007-16.
    doi: 10.1099/0022-1317-75-8-2007pubmed: 8046404google scholar: lookup
  8. Perkins GA, Goodman LB, Tsujimura K, Van de Walle GR, Kim SG, Dubovi EJ, Osterrieder N. Investigation of the prevalence of neurologic equine herpes virus type 1 (EHV-1) in a 23-year retrospective analysis (1984-2007).. Vet Microbiol 2009 Nov 18;139(3-4):375-8.
    doi: 10.1016/j.vetmic.2009.06.033pubmed: 19615831google scholar: lookup
  9. Equine Herpesvirus (Rhinopneumonitis); Vaccination guidelines; AAEP; http://www.aaep.org/-i-173.html; last accessed 9/30/16
  10. Paul WE. Interleukin 4/B cell stimulatory factor 1: one lymphokine, many functions.. FASEB J 1987 Dec;1(6):456-61.
    pubmed: 3315808doi: 10.1096/fasebj.1.6.3315808google scholar: lookup
  11. Breathnach CC, Sturgill-Wright T, Stiltner JL, Adams AA, Lunn DP, Horohov DW. Foals are interferon gamma-deficient at birth.. Vet Immunol Immunopathol 2006 Aug 15;112(3-4):199-209.
    doi: 10.1016/j.vetimm.2006.02.010pubmed: 16621024google scholar: lookup
  12. Paillot R, Daly JM, Luce R, Montesso F, Davis-Poynter N, Hannant D, Kydd JH. Frequency and phenotype of EHV-1 specific, IFN-gamma synthesising lymphocytes in ponies: the effects of age, pregnancy and infection.. Dev Comp Immunol 2007;31(2):202-14.
    doi: 10.1016/j.dci.2006.05.010pubmed: 16824599google scholar: lookup
  13. Wagner B, Burton A, Ainsworth D. Interferon-gamma, interleukin-4 and interleukin-10 production by T helper cells reveals intact Th1 and regulatory TR1 cell activation and a delay of the Th2 cell response in equine neonates and foals.. Vet Res 2010 Jul-Aug;41(4):47.
    doi: 10.1051/vetres/2010019pmc: PMC2865874pubmed: 20374696google scholar: lookup
  14. Perkins GA, Wagner B. The development of equine immunity: Current knowledge on immunology in the young horse.. Equine Vet J 2015 May;47(3):267-74.
    doi: 10.1111/evj.12387pubmed: 25405920google scholar: lookup
  15. Sheoran AS, Timoney JF, Holmes MA, Karzenski SS, Crisman MV. Immunoglobulin isotypes in sera and nasal mucosal secretions and their neonatal transfer and distribution in horses.. Am J Vet Res 2000 Sep;61(9):1099-105.
    pubmed: 10976743doi: 10.2460/ajvr.2000.61.1099google scholar: lookup
  16. Holznagel DL, Hussey S, Mihalyi JE, Wilson WD, Lunn DP. Onset of immunoglobulin production in foals.. Equine Vet J 2003 Sep;35(6):620-2.
    pubmed: 14515965doi: 10.2746/042516403775467153google scholar: lookup
  17. Wagner B, Stokol T, Ainsworth DM. Induction of interleukin-4 production in neonatal IgE+ cells after crosslinking of maternal IgE.. Dev Comp Immunol 2010 Apr;34(4):436-44.
    doi: 10.1016/j.dci.2009.12.002pubmed: 19995577google scholar: lookup
  18. Wagner B, Flaminio JB, Hillegas J, Leibold W, Erb HN, Antczak DF. Occurrence of IgE in foals: evidence for transfer of maternal IgE by the colostrum and late onset of endogenous IgE production in the horse.. Vet Immunol Immunopathol 2006 Apr 15;110(3-4):269-78.
    doi: 10.1016/j.vetimm.2005.10.007pubmed: 16343646google scholar: lookup
  19. Gessner A, Mohrs K, Mohrs M. Mast cells, basophils, and eosinophils acquire constitutive IL-4 and IL-13 transcripts during lineage differentiation that are sufficient for rapid cytokine production.. J Immunol 2005 Jan 15;174(2):1063-72.
    pubmed: 15634931doi: 10.4049/jimmunol.174.2.1063google scholar: lookup
  20. Min B, Prout M, Hu-Li J, Zhu J, Jankovic D, Morgan ES, Urban JF Jr, Dvorak AM, Finkelman FD, LeGros G, Paul WE. Basophils produce IL-4 and accumulate in tissues after infection with a Th2-inducing parasite.. J Exp Med 2004 Aug 16;200(4):507-17.
    doi: 10.1084/jem.20040590pmc: PMC2211939pubmed: 15314076google scholar: lookup
  21. Mack M, Schneider MA, Moll C, Cihak J, Brühl H, Ellwart JW, Hogarth MP, Stangassinger M, Schlöndorff D. Identification of antigen-capturing cells as basophils.. J Immunol 2005 Jan 15;174(2):735-41.
    pubmed: 15634893doi: 10.4049/jimmunol.174.2.735google scholar: lookup
  22. Oh K, Shen T, Le Gros G, Min B. Induction of Th2 type immunity in a mouse system reveals a novel immunoregulatory role of basophils.. Blood 2007 Apr 1;109(7):2921-7.
    doi: 10.1182/blood-2006-07-037739pubmed: 17132717google scholar: lookup
  23. Sokol CL, Barton GM, Farr AG, Medzhitov R. A mechanism for the initiation of allergen-induced T helper type 2 responses.. Nat Immunol 2008 Mar;9(3):310-8.
    doi: 10.1038/ni1558pmc: PMC3888112pubmed: 18300366google scholar: lookup
  24. Crabb BS, Allen GP, Studdert MJ. Characterization of the major glycoproteins of equine herpesviruses 4 and 1 and asinine herpesvirus 3 using monoclonal antibodies.. J Gen Virol 1991 Sep;72 ( Pt 9):2075-82.
    doi: 10.1099/0022-1317-72-9-2075pubmed: 1716650google scholar: lookup
  25. Packiarajah P, Walker C, Gilkerson J, Whalley JM, Love DN. Immune responses and protective efficacy of recombinant baculovirus-expressed glycoproteins of equine herpesvirus 1 (EHV-1) gB, gC and gD alone or in combinations in BALB/c mice.. Vet Microbiol 1998 Apr 15;61(4):261-78.
    pubmed: 9646476doi: 10.1016/s0378-1135(98)00189-8google scholar: lookup
  26. Wagner B, Goodman LB, Babasyan S, Freer H, Torsteinsdóttir S, Svansson V, Björnsdóttir S, Perkins GA. Antibody and cellular immune responses of naïve mares to repeated vaccination with an inactivated equine herpesvirus vaccine.. Vaccine 2015 Oct 13;33(42):5588-5597.
    doi: 10.1016/j.vaccine.2015.09.009pubmed: 26384446google scholar: lookup
  27. Hook LM, Huang J, Jiang M, Hodinka R, Friedman HM. Blocking antibody access to neutralizing domains on glycoproteins involved in entry as a novel mechanism of immune evasion by herpes simplex virus type 1 glycoproteins C and E.. J Virol 2008 Jul;82(14):6935-41.
    doi: 10.1128/JVI.02599-07pmc: PMC2446985pubmed: 18480440google scholar: lookup
  28. Chowdhury S, Naderi M, Chouljenko VN, Walker JD, Kousoulas KG. Amino acid differences in glycoproteins B (gB), C (gC), H (gH) and L (gL) are associated with enhanced herpes simplex virus type-1 (McKrae) entry via the paired immunoglobulin-like type-2 receptor α.. Virol J 2012 Jun 13;9:112.
    pmc: PMC3402990pubmed: 22695228doi: 10.1186/1743-422x-9-112google scholar: lookup
  29. Awasthi S, Lubinski JM, Friedman HM. Immunization with HSV-1 glycoprotein C prevents immune evasion from complement and enhances the efficacy of an HSV-1 glycoprotein D subunit vaccine.. Vaccine 2009 Nov 16;27(49):6845-53.
  30. Ma G, Azab W, Osterrieder N. Equine herpesviruses type 1 (EHV-1) and 4 (EHV-4)--masters of co-evolution and a constant threat to equids and beyond.. Vet Microbiol 2013 Nov 29;167(1-2):123-34.
    doi: 10.1016/j.vetmic.2013.06.018pubmed: 23890672google scholar: lookup
  31. WAHID Interface; Animal Health Information; Iceland; Diseases never reported; http://www.oie.int/wahis_2/public/wahid.php/Countryinformation/Animalsituation; last accessed 9/30/16
  32. Keggan A, Freer H, Rollins A, Wagner B. Production of seven monoclonal equine immunoglobulins isotyped by multiplex analysis.. Vet Immunol Immunopathol 2013 Jun 15;153(3-4):187-93.
    doi: 10.1016/j.vetimm.2013.02.010pubmed: 23541920google scholar: lookup
  33. Wagner B, Radbruch A, Rohwer J, Leibold W. Monoclonal anti-equine IgE antibodies with specificity for different epitopes on the immunoglobulin heavy chain of native IgE.. Vet Immunol Immunopathol 2003 Mar 20;92(1-2):45-60.
    pubmed: 12628763doi: 10.1016/s0165-2427(03)00007-2google scholar: lookup
  34. Wagner B, Hillegas JM, Babasyan S. Monoclonal antibodies to equine CD23 identify the low-affinity receptor for IgE on subpopulations of IgM+ and IgG1+ B-cells in horses.. Vet Immunol Immunopathol 2012 Apr 15;146(2):125-34.
    doi: 10.1016/j.vetimm.2012.02.007pubmed: 22405681google scholar: lookup
  35. Nugent J, Birch-Machin I, Smith KC, Mumford JA, Swann Z, Newton JR, Bowden RJ, Allen GP, Davis-Poynter N. Analysis of equid herpesvirus 1 strain variation reveals a point mutation of the DNA polymerase strongly associated with neuropathogenic versus nonneuropathogenic disease outbreaks.. J Virol 2006 Apr;80(8):4047-60.
  36. Furr M, Reed S. Neurologic Examination. Equine Neurology Ames, IA: Blackwell Publishing, 2008; 65–76.
  37. Elia G, Decaro N, Martella V, Campolo M, Desario C, Lorusso E, Cirone F, Buonavoglia C. Detection of equine herpesvirus type 1 by real time PCR.. J Virol Methods 2006 Apr;133(1):70-5.
  38. Wagner B, Freer H. Development of a bead-based multiplex assay for simultaneous quantification of cytokines in horses.. Vet Immunol Immunopathol 2009 Feb 15;127(3-4):242-8.
    doi: 10.1016/j.vetimm.2008.10.313pubmed: 19027964google scholar: lookup
  39. Wagner B, Wimer C, Freer H, Osterrieder N, Erb HN. Infection of peripheral blood mononuclear cells with neuropathogenic equine herpesvirus type-1 strain Ab4 reveals intact interferon-α induction and induces suppression of anti-inflammatory interleukin-10 responses in comparison to other viral strains.. Vet Immunol Immunopathol 2011 Sep 15;143(1-2):116-24.
    doi: 10.1016/j.vetimm.2011.06.032pubmed: 21764140google scholar: lookup
  40. Goodman LB, Wimer C, Dubovi EJ, Gold C, Wagner B. Immunological correlates of vaccination and infection for equine herpesvirus 1.. Clin Vaccine Immunol 2012 Feb;19(2):235-41.
    pmc: PMC3272919pubmed: 22205656doi: 10.1128/cvi.05522-11google scholar: lookup
  41. Perkins GA, Goodman LB, Wimer C, Freer H, Babasyan S, Wagner B. Maternal T-lymphocytes in equine colostrum express a primarily inflammatory phenotype.. Vet Immunol Immunopathol 2014 Oct 15;161(3-4):141-50.
    doi: 10.1016/j.vetimm.2014.07.009pubmed: 25174977google scholar: lookup
  42. Basha S, Surendran N, Pichichero M. Immune responses in neonates.. Expert Rev Clin Immunol 2014 Sep;10(9):1171-84.
  43. Mohr E, Siegrist CA. Vaccination in early life: standing up to the challenges.. Curr Opin Immunol 2016 Aug;41:1-8.
    pubmed: 27104290doi: 10.1016/j.coi.2016.04.004google scholar: lookup
  44. Siegrist CA, Aspinall R. B-cell responses to vaccination at the extremes of age.. Nat Rev Immunol 2009 Mar;9(3):185-94.
    doi: 10.1038/nri2508pubmed: 19240757google scholar: lookup
  45. Goodman LB, Wagner B, Flaminio MJ, Sussman KH, Metzger SM, Holland R, Osterrieder N. Comparison of the efficacy of inactivated combination and modified-live virus vaccines against challenge infection with neuropathogenic equine herpesvirus type 1 (EHV-1).. Vaccine 2006 Apr 24;24(17):3636-45.
    doi: 10.1016/j.vaccine.2006.01.062pubmed: 16513225google scholar: lookup
  46. Goehring LS, Wagner B, Bigbie R, Hussey SB, Rao S, Morley PS, Lunn DP. Control of EHV-1 viremia and nasal shedding by commercial vaccines.. Vaccine 2010 Jul 19;28(32):5203-11.
    doi: 10.1016/j.vaccine.2010.05.065pubmed: 20538091google scholar: lookup
  47. Soboll Hussey G, Hussey SB, Wagner B, Horohov DW, Van de Walle GR, Osterrieder N, Goehring LS, Rao S, Lunn DP. Evaluation of immune responses following infection of ponies with an EHV-1 ORF1/2 deletion mutant.. Vet Res 2011 Feb 7;42(1):23.
    doi: 10.1186/1297-9716-42-23pmc: PMC3045331pubmed: 21314906google scholar: lookup

Citations

This article has been cited 16 times.
  1. Blanco FC, Vazquez CL, García JSY, Rocha RV, Gravisaco MJ, Forrellad MA, Magistrelli G, Bigi F. Semi-stable Production of Bovine IL-4 and GM-CSF in The Mammalian Episomal Expression System. J Vet Res 2021 Sep;65(3):315-321.
    doi: 10.2478/jvetres-2021-0043pubmed: 34917844google scholar: lookup
  2. Warda FF, Ahmed HES, Shafik NG, Mikhael CA, Abd-ElAziz HMG, Mohammed WA, Shosha EA. Application of equine herpesvirus-1 vaccine inactivated by both formaldehyde and binary ethylenimine in equine. Vet World 2021 Jul;14(7):1815-1821.
  3. Schnabel CL, Babasyan S, Rollins A, Freer H, Wimer CL, Perkins GA, Raza F, Osterrieder N, Wagner B. An Equine Herpesvirus Type 1 (EHV-1) Ab4 Open Reading Frame 2 Deletion Mutant Provides Immunity and Protection from EHV-1 Infection and Disease. J Virol 2019 Nov 15;93(22).
    doi: 10.1128/JVI.01011-19pubmed: 31462575google scholar: lookup
  4. Saini S, Singha H, Siwach P, Tripathi BN. Recombinant horse interleukin-4 and interleukin-10 induced a mixed inflammatory cytokine response in horse peripheral blood mononuclear cells. Vet World 2019;12(4):496-503.
  5. Sharba S, Navabi N, Padra M, Persson JA, Quintana-Hayashi MP, Gustafsson JK, Szeponik L, Venkatakrishnan V, Sjöling Å, Nilsson S, Quiding-Järbrink M, Johansson MEV, Linden SK. Interleukin 4 induces rapid mucin transport, increases mucus thickness and quality and decreases colitis and Citrobacter rodentium in contact with epithelial cells. Virulence 2019 Dec;10(1):97-117.
    doi: 10.1080/21505594.2019.1573050pubmed: 30665337google scholar: lookup
  6. Wimer CL, Schnabel CL, Perkins G, Babasyan S, Freer H, Stout AE, Rollins A, Osterrieder N, Goodman LB, Glaser A, Wagner B. The deletion of the ORF1 and ORF71 genes reduces virulence of the neuropathogenic EHV-1 strain Ab4 without compromising host immunity in horses. PLoS One 2018;13(11):e0206679.
    doi: 10.1371/journal.pone.0206679pubmed: 30440016google scholar: lookup
  7. Schnabel CL, Wimer CL, Perkins G, Babasyan S, Freer H, Watts C, Rollins A, Osterrieder N, Wagner B. Deletion of the ORF2 gene of the neuropathogenic equine herpesvirus type 1 strain Ab4 reduces virulence while maintaining strong immunogenicity. BMC Vet Res 2018 Aug 22;14(1):245.
    doi: 10.1186/s12917-018-1563-4pubmed: 30134896google scholar: lookup
  8. Cooper CJ, Arroyo LG, Hammermueller JD, Botts MM, Pearl DL, Wootton SK, Lillie BN. Molecular prevalence of equine alphaherpesvirus-1 shedding in healthy broodmares in Ontario. Can J Vet Res 2026 Jan;90(1):16-24.
    pubmed: 41585008
  9. Simonin EM, Torsteinsdóttir S, Svansson V, Björnsdóttir S, Freer H, Tarsillo J, Wagner B. Early allergen introduction overrides allergy predisposition in offspring of horses with Culicoides hypersensitivity. Front Immunol 2025;16:1654693.
    doi: 10.3389/fimmu.2025.1654693pubmed: 41194920google scholar: lookup
  10. Santos L, Sharba S, Benktander J, Ojaimi Loibman S, Quintana-Hayashi MP, Erhardsson M, Lindén SK. Treatment with (R)-α-methylhistamine or IL4 stimulates mucin production and decreases Helicobacter pylori density in the murine stomach. Virulence 2025 Dec;16(1):2530173.
    doi: 10.1080/21505594.2025.2530173pubmed: 40667878google scholar: lookup
  11. Pradhan SS, Balena V, Bera BC, Anand T, Khetmalis R, Madhwal A, Kandasamy S, Pavulraj S, Bernela M, Mor P, Tripathi BN, Virmani N. Multiple Gene Deletion Mutants of Equine Herpesvirus 1 Exhibit Strong Protective Efficacy Against Wild Virus Challenge in a Murine Model. Vaccines (Basel) 2025 Jan 8;13(1).
    doi: 10.3390/vaccines13010045pubmed: 39852824google scholar: lookup
  12. Holmes CM, Wagner B. Characterization of Nasal Mucosal T Cells in Horses and Their Response to Equine Herpesvirus Type 1. Viruses 2024 Sep 25;16(10).
    doi: 10.3390/v16101514pubmed: 39459849google scholar: lookup
  13. Eady NA, Holmes C, Schnabel C, Babasyan S, Wagner B. Equine herpesvirus type 1 (EHV-1) replication at the upper respiratory entry site is inhibited by neutralizing EHV-1-specific IgG1 and IgG4/7 mucosal antibodies. J Virol 2024 Jun 13;98(6):e0025024.
    doi: 10.1128/jvi.00250-24pubmed: 38742875google scholar: lookup
  14. Ali AAH, Abdallah F, Shemies OA, Kotb G, Nafea MR. Molecular characterization of equine herpes viruses type 1 and 4 among Arabian horse populations in Egypt during the period between 2021 and 2022. Open Vet J 2024 Jan;14(1):534-544.
    doi: 10.5455/OVJ.2024.v14.i1.48pubmed: 38633187google scholar: lookup
  15. Pusterla N, Dorman DC, Burgess BA, Goehring L, Gross M, Osterrieder K, Soboll Hussey G, Lunn DP. Viremia and nasal shedding for the diagnosis of equine herpesvirus-1 infection in domesticated horses. J Vet Intern Med 2024 May-Jun;38(3):1765-1791.
    doi: 10.1111/jvim.16958pubmed: 38069548google scholar: lookup
  16. Osterrieder K, Dorman DC, Burgess BA, Goehring LS, Gross P, Neinast C, Pusterla N, Hussey GS, Lunn DP. Vaccination for the prevention of equine herpesvirus-1 disease in domesticated horses: A systematic review and meta-analysis. J Vet Intern Med 2024 May-Jun;38(3):1858-1871.
    doi: 10.1111/jvim.16895pubmed: 37930113google scholar: lookup