1887

Abstract

Porcine reproductive and respiratory syndrome virus (PRRSV) causes an economically important global swine disease. Here we report the development of subunit PRRSV-2 vaccines by expressing swine leucocyte antigen (SLA) class I and class II allele-specific epitope antigens in a robust adenovirus vector. SLA I-specific CD8 and SLA II-specific CD4 T cell epitopes of PRRSV-2 NADC20 were predicted . Stable murine leukaemia cell lines (RMA-S), which are TAP-deficient and lacking endogenous class I epitope loading, were established to express different SLA I alleles. The binding stability of PRRSV T cell epitope peptides with SLA I alleles expressed on RMA-S cells was characterized. Two PRRSV poly-T cell epitope peptides were designed. NADC20-PP1 included 39 class I epitopes, consisting of 8 top-ranked epitopes specific to each of 5 SLA I alleles, and fused to 5 class II epitopes specific to SLA II alleles. NADC20-PP2, a subset of PP1, included two top-ranked class I epitopes specific to each of the five SLA I alleles. Two vaccine candidates, Ad-NADC20-PP1 and Ad-NADC20-PP2, were constructed by expressing the polytope peptides in a replication-incompetent human adenovirus 5 vector. A vaccination and challenge study in 30 piglets showed that animals vaccinated with the vaccines had numerically lower gross and histopathology lung lesions, and numerically lower PRRSV RNA loads in lung and serum after challenge compared to the controls, although there was no statistical significance. The results suggested that the Ad-NADC20-PP1 and Ad-NADC20-PP2 vaccines provided little or no protection, further highlighting the tremendous challenges faced in developing an effective subunit PRRSV-2 vaccine.

Funding
This study was supported by the:
  • Xiang-Jin Meng , Zoetis , (Award na)
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/content/journal/jgv/10.1099/jgv.0.001492
2020-09-07
2020-12-01
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References

  1. Lunney JK, Benfield DA, Rowland RRR. Porcine reproductive and respiratory syndrome virus: an update on an emerging and re-emerging viral disease of swine. Virus Res 2010; 154:1–6 [CrossRef][PubMed]
    [Google Scholar]
  2. Holtkamp DJ, Lin H, Wang C, O'Connor AM. Identifying questions in the American association of swine veterinarian's PRRS risk assessment survey that are important for retrospectively classifying swine herds according to whether they reported clinical PRRS outbreaks in the previous 3 years. Prev Vet Med 2012; 106:42–52 [CrossRef][PubMed]
    [Google Scholar]
  3. Hopper SA, White ME, Twiddy N. An outbreak of blue-eared pig disease (porcine reproductive and respiratory syndrome) in four pig herds in Great Britain. Vet Rec 1992; 131:140–144 [CrossRef][PubMed]
    [Google Scholar]
  4. Kuhn JH, Lauck M, Bailey AL, Shchetinin AM, Vishnevskaya TV et al. Reorganization and expansion of the nidoviral family arteriviridae. Arch Virol 2016; 161:755–768 [CrossRef][PubMed]
    [Google Scholar]
  5. Snijder EJ, Kikkert M, Fang Y. Arterivirus molecular biology and pathogenesis. J Gen Virol 2013; 94:2141–2163 [CrossRef][PubMed]
    [Google Scholar]
  6. Costers S, Vanhee M, Van Breedam W, Van Doorsselaere J, Geldhof M et al. GP4-specific neutralizing antibodies might be a driving force in PRRSV evolution. Virus Res 2010; 154:104–113 [CrossRef][PubMed]
    [Google Scholar]
  7. Lee C, Yoo D. The small envelope protein of porcine reproductive and respiratory syndrome virus possesses ion channel protein-like properties. Virology 2006; 355:30–43 [CrossRef][PubMed]
    [Google Scholar]
  8. Tian D, Wei Z, Zevenhoven-Dobbe JC, Liu R, Tong G et al. Arterivirus minor envelope proteins are a major determinant of viral tropism in cell culture. J Virol 2012; 86:3701–3712 [CrossRef][PubMed]
    [Google Scholar]
  9. Ostrowski M, Galeota JA, Jar AM, Platt KB, Osorio FA et al. Identification of neutralizing and nonneutralizing epitopes in the porcine reproductive and respiratory syndrome virus GP5 ectodomain. J Virol 2002; 76:4241–4250 [CrossRef][PubMed]
    [Google Scholar]
  10. Loving CL, Osorio FA, Murtaugh MP, Zuckermann FA. Innate and adaptive immunity against porcine reproductive and respiratory syndrome virus. Vet Immunol Immunopathol 2015; 167:1–14 [CrossRef][PubMed]
    [Google Scholar]
  11. Murtaugh MP, Stadejek T, Abrahante JE, Lam TTY, Leung FC-C. The ever-expanding diversity of porcine reproductive and respiratory syndrome virus. Virus Res 2010; 154:18–30 [CrossRef][PubMed]
    [Google Scholar]
  12. Hanada K, Suzuki Y, Nakane T, Hirose O, Gojobori T. The origin and evolution of porcine reproductive and respiratory syndrome viruses. Mol Biol Evol 2005; 22:1024–1031 [CrossRef][PubMed]
    [Google Scholar]
  13. Shi M, Lam TT-Y, Hon C-C, Hui RK-H, Faaberg KS et al. Molecular epidemiology of PRRSV: a phylogenetic perspective. Virus Res 2010; 154:7–17 [CrossRef][PubMed]
    [Google Scholar]
  14. Shi M, Lam TT-Y, Hon C-C, Murtaugh MP, Davies PR et al. Phylogeny-based evolutionary, demographical, and geographical dissection of North American type 2 porcine reproductive and respiratory syndrome viruses. J Virol 2010; 84:8700–8711 [CrossRef][PubMed]
    [Google Scholar]
  15. Zhou Y-J, Hao X-F, Tian Z-J, Tong G-Z, Yoo D et al. Highly virulent porcine reproductive and respiratory syndrome virus emerged in China. Transbound Emerg Dis 2008; 55:152–164 [CrossRef][PubMed]
    [Google Scholar]
  16. Yoo D, Song C, Sun Y, Du Y, Kim O et al. Modulation of host cell responses and evasion strategies for porcine reproductive and respiratory syndrome virus. Virus Res 2010; 154:48–60 [CrossRef][PubMed]
    [Google Scholar]
  17. Renukaradhya GJ, Meng X-J, Calvert JG, Roof M, Lager KM. Live porcine reproductive and respiratory syndrome virus vaccines: current status and future direction. Vaccine 2015; 33:4069–4080 [CrossRef][PubMed]
    [Google Scholar]
  18. Kimman TG, Cornelissen LA, Moormann RJ, Rebel JMJ, Stockhofe-Zurwieden N. Challenges for porcine reproductive and respiratory syndrome virus (PRRSV) vaccinology. Vaccine 2009; 27:3704–3718 [CrossRef][PubMed]
    [Google Scholar]
  19. Li X, Galliher-Beckley A, Pappan L, Trible B, Kerrigan M et al. Comparison of host immune responses to homologous and heterologous type II porcine reproductive and respiratory syndrome virus (PRRSV) challenge in vaccinated and unvaccinated pigs. Biomed Res Int 2014; 2014:1–10 [CrossRef][PubMed]
    [Google Scholar]
  20. Murtaugh MP, Genzow M. Immunological solutions for treatment and prevention of porcine reproductive and respiratory syndrome (PRRS). Vaccine 2011; 29:8192–8204 [CrossRef][PubMed]
    [Google Scholar]
  21. Lu WH, Tun HM, Sun BL, Mo J, Zhou QF et al. Re-emerging of porcine respiratory and reproductive syndrome virus (lineage 3) and increased pathogenicity after genomic recombination with vaccine variant. Vet Microbiol 2015; 175:332–340 [CrossRef][PubMed]
    [Google Scholar]
  22. Kotturi MF, Botten J, Sidney J, Bui H-H, Giancola L et al. A multivalent and cross-protective vaccine strategy against arenaviruses associated with human disease. PLoS Pathog 2009; 5:e1000695 [CrossRef][PubMed]
    [Google Scholar]
  23. Chiang C-Y, Liu S-J, Tsai J-P, Li Y-S, Chen M-Y et al. A novel single-dose dengue subunit vaccine induces memory immune responses. PLoS One 2011; 6:e23319 [CrossRef][PubMed]
    [Google Scholar]
  24. Levine MM, Sztein MB. Vaccine development strategies for improving immunization: the role of modern immunology. Nat Immunol 2004; 5:460–464 [CrossRef][PubMed]
    [Google Scholar]
  25. Cao QM, Tian D, Heffron CL, Subramaniam S, Opriessnig T et al. Cytotoxic T lymphocyte epitopes identified from a contemporary strain of porcine reproductive and respiratory syndrome virus enhance CD4+CD8+ T, CD8+ T, and gammadelta T cell responses. Virology 2019; 538:35–44 [CrossRef][PubMed]
    [Google Scholar]
  26. Catanzaro N, Meng X-J. Induction of the unfolded protein response (UPR) suppresses porcine reproductive and respiratory syndrome virus (PRRSV) replication. Virus Res 2020; 276:197820 [CrossRef][PubMed]
    [Google Scholar]
  27. Halbur PG, Paul PS, Frey ML, Landgraf J, Eernisse K et al. Comparison of the pathogenicity of two US porcine reproductive and respiratory syndrome virus isolates with that of the Lelystad virus. Vet Pathol 1995; 32:648–660 [CrossRef][PubMed]
    [Google Scholar]
  28. Tian D, Sooryanarain H, Matzinger SR, Gauger PC, Karuppannan AK et al. Protective efficacy of a virus-vectored multi-component vaccine against porcine reproductive and respiratory syndrome virus, porcine circovirus type 2 and swine influenza virus. J Gen Virol 2017; 98:3026–3036 [CrossRef][PubMed]
    [Google Scholar]
  29. Ljunggren HG, Stam NJ, Ohlén C, Neefjes JJ, Höglund P et al. Empty MHC class I molecules come out in the cold. Nature 1990; 346:476–480 [CrossRef][PubMed]
    [Google Scholar]
  30. Ross P, Holmes JC, Gojanovich GS, Hess PR. A cell-based MHC stabilization assay for the detection of peptide binding to the canine classical class I molecule, DLA-88. Vet Immunol Immunopathol 2012; 150:206–212 [CrossRef][PubMed]
    [Google Scholar]
  31. Vu HLX, Ma F, Laegreid WW, Pattnaik AK, Steffen D et al. A synthetic porcine reproductive and respiratory syndrome virus strain confers unprecedented levels of heterologous protection. J Virol 2015; 89:12070–12083 [CrossRef][PubMed]
    [Google Scholar]
  32. Martelli P, Gozio S, Ferrari L, Rosina S, De Angelis E et al. Efficacy of a modified live porcine reproductive and respiratory syndrome virus (PRRSV) vaccine in pigs naturally exposed to a heterologous European (Italian cluster) field strain: clinical protection and cell-mediated immunity. Vaccine 2009; 27:3788–3799 [CrossRef][PubMed]
    [Google Scholar]
  33. Jiang Y-feng, Xia T-qi, Zhou Y-jun, Yu L-xue, Yang S et al. Characterization of three porcine reproductive and respiratory syndrome virus isolates from a single swine farm bearing strong homology to a vaccine strain. Vet Microbiol 2015; 179:242–249 [CrossRef][PubMed]
    [Google Scholar]
  34. Tian D, Cao D, Lynn Heffron C, Yugo DM, Rogers AJ et al. Enhancing heterologous protection in pigs vaccinated with chimeric porcine reproductive and respiratory syndrome virus containing the full-length sequences of shuffled structural genes of multiple heterologous strains. Vaccine 2017; 35:2427–2434 [CrossRef][PubMed]
    [Google Scholar]
  35. Barry M. Single-Cycle adenovirus vectors in the current vaccine landscape. Expert Rev Vaccines 2018; 17:1–11 [CrossRef][PubMed]
    [Google Scholar]
  36. Sharma PK, Dmitriev IP, Kashentseva EA, Raes G, Li L et al. Development of an adenovirus vector vaccine platform for targeting dendritic cells. Cancer Gene Ther 2018; 25:27–38 [CrossRef][PubMed]
    [Google Scholar]
  37. Fernandez-Sainz I, Medina GN, Ramirez-Medina E, Koster MJ, Grubman MJ et al. Adenovirus-vectored foot-and-mouth disease vaccine confers early and full protection against FMDV O1 Manisa in swine. Virology 2017; 502:123–132 [CrossRef][PubMed]
    [Google Scholar]
  38. Lokhandwala S, Waghela SD, Bray J, Sangewar N, Charendoff C et al. Adenovirus-vectored novel African swine fever virus antigens elicit robust immune responses in swine. PLoS One 2017; 12:e0177007 [CrossRef][PubMed]
    [Google Scholar]
  39. Renukaradhya GJ, Meng X-J, Calvert JG, Roof M, Lager KM. Inactivated and subunit vaccines against porcine reproductive and respiratory syndrome: current status and future direction. Vaccine 2015; 33:3065–3072 [CrossRef][PubMed]
    [Google Scholar]
  40. Trible BR, Popescu LN, Monday N, Calvert JG, Rowland RRR. A single amino acid deletion in the matrix protein of porcine reproductive and respiratory syndrome virus confers resistance to a polyclonal swine antibody with broadly neutralizing activity. J Virol 2015; 89:6515–6520 [CrossRef][PubMed]
    [Google Scholar]
  41. Li Y, Shyu D-L, Shang P, Bai J, Ouyang K et al. Mutations in a highly conserved motif of nsp1β protein attenuate the innate immune suppression function of porcine reproductive and respiratory syndrome virus. J Virol 2016; 90:3584–3599 [CrossRef][PubMed]
    [Google Scholar]
  42. Lunney JK, Fang Y, Ladinig A, Chen N, Li Y et al. Porcine reproductive and respiratory syndrome virus (PRRSV): pathogenesis and interaction with the immune system. Annu Rev Anim Biosci 2016; 4:129–154 [CrossRef][PubMed]
    [Google Scholar]
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