Advances in PRRS Vaccine Development: Subunit, Vector, Plant-Based, and mRNA Vaccines

The rapid evolution of porcine reproductive and respiratory syndrome virus (PRRSV) continues to challenge conventional vaccination strategies. Frequent genetic recombination and the emergence of new variants have reduced the effectiveness of traditional vaccines against diverse field strains, highlighting the need for next-generation vaccine platforms¹. In response, vaccine development has shifted toward technologies designed to improve immune protection while addressing the safety concerns associated with conventional vaccines. 

Emerging approaches, including subunit vaccines, recombinant viral vectors, plant-based expression systems, and mRNA technologies, represent promising directions for future PRRS control. While many of these platforms are still under development, they provide valuable insights into how more targeted and adaptable vaccines may enhance disease management. 

Subunit Vaccines: Targeted Immunity with Improved Safety 

Subunit vaccines contain only selected viral antigens rather than the whole virus, eliminating the risk of reversion to virulence and making them a safer alternative for immunization². Because these vaccines include only pathogen-specific components, they are suitable for stimulating immune responses without exposing animals to live virus. 

Among PRRSV structural proteins, GP3, GP5, and M proteins have received considerable attention due to their ability to induce protective immune responses¹. Vaccine constructs expressing combinations of these proteins have demonstrated stronger neutralizing antibody production and enhanced cytotoxic T-lymphocyte (CTL) responses compared with single-antigen formulations¹. 

Several recombinant platforms are also being explored, including baculovirus, replication-deficient adenovirus, nanoparticle-based systems, and recombinant viral vectors. One recombinant vaccine expressing the E2 protein of classical swine fever virus generated long-lasting antibody responses against both PRRSV and classical swine fever virus while providing complete protection against challenge with highly pathogenic PRRSV and CSFV under experimental conditions¹. 

Despite these advances, subunit vaccines generally produce weaker immune responses because they lack pathogen-associated molecular patterns (PAMPs). Consequently, effective adjuvants remain essential for maximizing their immunogenicity³. 

Nanoparticle and Plant-Based Platforms 

Nanoparticle technology has emerged as an innovative strategy for improving antigen delivery and strengthening immune responses. Ferritin-based nanoparticles carrying modified GP5 proteins have enhanced Th1-type cellular immunity while reducing fever, viremia, and lung lesion scores following vaccination^4,5. Multiepitope vaccine designs delivered through layered double hydroxides (LDH) have also generated sustained humoral responses while promoting favorable cytokine responses⁶. 

Plant-based expression systems offer another promising direction by combining vaccine production with reduced manufacturing costs. PRRSV antigens expressed in Arabidopsis thaliana, banana, and tobacco have successfully induced PRRSV-specific antibody responses following oral administration^1,7. 

These platforms provide several practical advantages: 

• Lower production costs 

• Rapid recombinant protein production 

• Elimination of extensive protein purification 

• Oral administration through edible plant tissues 

• Enhanced mucosal IgA responses, particularly within the intestinal and respiratory tracts¹ 

Such characteristics make plant-derived vaccines an attractive option for future veterinary vaccine development. 

mRNA Vaccines: A New Direction for PRRS Control 

The success of mRNA technology has accelerated interest in its veterinary applications. Unlike live or inactivated vaccines, mRNA vaccines encode only selected viral antigens, allowing precise antigen expression while stimulating both humoral and cellular immune responses¹. 

Compared with DNA vaccines, mRNA platforms offer improved safety because they carry virtually no risk of genomic integration, and antigen expression is naturally transient, typically lasting only a few days^8,9. 

Experimental PRRSV mRNA vaccines encoding GP5 or GP2-GP5-M proteins have generated strong GP5-specific antibody responses, higher neutralizing antibody titers, and increased CD8+ T-cell activity, accompanied by elevated IFN-γ, TNF-α, and IL-4 production¹⁰. 

Self-amplifying RNA (SaRNA) technology represents a further advancement by enabling prolonged antigen production using substantially lower vaccine doses^11,12. SaRNA constructs expressing modified GP5 proteins have demonstrated stronger neutralizing antibody responses and improved protection against both homologous and heterologous PRRSV strains¹. 

Although highly promising, RNA vaccines still face practical challenges related to molecular instability and efficient delivery into target cells. Lipid nanoparticle formulations remain essential for protecting RNA molecules and facilitating cellular uptake¹. 

Moving Toward Smarter Vaccine Design 

Emerging vaccine platforms are expanding the possibilities for PRRS control by combining improved safety with more targeted immune stimulation. While many of these technologies require further development before widespread field application, they represent important steps toward vaccines capable of addressing the genetic diversity and continuous evolution of PRRSV. 

Key Takeaway 

Next-generation vaccine platforms are designed to overcome many limitations of conventional PRRS vaccines by improving safety, targeting protective immune responses more precisely, and adapting to the evolving nature of PRRSV. 

References 

1. He Z, Li F, Liu M, Liao J, Guo C. Porcine reproductive and respiratory syndrome virus: challenges and advances in vaccine development. Vaccines. 2025 Feb 28;13(3):260. https://www.mdpi.com/2076-393X/13/3/260 

2. Bayani F, Hashkavaei NS, Arjmand S, Rezaei S, Uskoković V, Alijanianzadeh M, Uversky VN, Siadat SO, Mozaffari-Jovin S, Sefidbakht Y. An overview of the vaccine platforms to combat COVID-19 with a focus on the subunit vaccines. Progress in biophysics and molecular biology. 2023 Mar 1;178:32-49. https://pmc.ncbi.nlm.nih.gov/articles/PMC9938630/pdf/main.pdf 

3. Bashiri S, Koirala P, Toth I, Skwarczynski M. Carbohydrate immune adjuvants in subunit vaccines. Pharmaceutics. 2020 Oct 14;12(10):965. https://www.mdpi.com/1999-4923/12/10/965 

4. Ma H, Li X, Li J, Zhao Z, Zhang H, Hao G, Chen H, Qian P. Immunization with a recombinant fusion of porcine reproductive and respiratory syndrome virus modified GP5 and ferritin elicits enhanced protective immunity in pigs. Virology. 2021 Jan 2;552:112-20. https://www.sciencedirect.com/science/article/pii/S0042682220302099 

5. Chang X, Ma J, Zhou Y, Xiao S, Xiao X, Fang L. Development of a ferritin protein nanoparticle vaccine with PRRSV GP5 protein. Viruses. 2024 Jun 20;16(6):991. https://www.mdpi.com/1999-4915/16/6/991 

6. Alonso-Cerda MJ, García-Soto MJ, Miranda-López A, Segura-Velázquez R, Sánchez-Betancourt JI, González-Ortega O, Rosales-Mendoza S. Layered double hydroxides (LDH) as delivery vehicles of a chimeric protein carrying epitopes from the Porcine Reproductive and Respiratory Syndrome Virus. Pharmaceutics. 2024 Jun 21;16(7):841. https://www.mdpi.com/1999-4923/16/7/841 

7. An CH, Nazki S, Park SC, Jeong YJ, Lee JH, Park SJ, Khatun A, Kim WI, Park YI, Jeong JC, Kim CY. Plant synthetic GP4 and GP5 proteins from porcine reproductive and respiratory syndrome virus elicit immune responses in pigs. Planta. 2018 Apr;247(4):973-85. https://www.researchgate.net/profile/Amina-Khatun-6/publication/322314210 

8. Maruggi G, Zhang C, Li J, Ulmer JB, Yu D. mRNA as a transformative technology for vaccine development to control infectious diseases. Molecular therapy. 2019 Apr 10;27(4):757-72. https://www.cell.com/molecular-therapy-family/molecular-therapy/pdf/S1525-0016%2819%2930041-3.pdf 

9. Steinle H, Behring A, Schlensak C, Wendel HP, Avci-Adali M. Concise review: application of in vitro transcribed messenger RNA for cellular engineering and reprogramming: progress and challenges. Stem Cells. 2017 Jan 1;35(1):68-79. https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdfdirect/10.1002/stem.2402 

10. Zhou L, Wubshet AK, Zhang J, Hou S, Yao K, Zhao Q, Dai J, Liu Y, Ding Y, Zhang J, Sun Y. The mRNA vaccine expressing single and fused structural proteins of porcine reproductive and respiratory syndrome induces strong cellular and humoral immune responses in BalB/C mice. Viruses. 2024 Mar 30;16(4):544. https://www.mdpi.com/1999-4915/16/4/544 

11. Lundstrom K. Self-amplifying RNA viruses as RNA vaccines. International journal of molecular sciences. 2020 Jul 20;21(14):5130. https://www.mdpi.com/1422-0067/21/14/5130 

12. Vogel AB, Lambert L, Kinnear E, Busse D, Erbar S, Reuter KC, Wicke L, Perkovic M, Beissert T, Haas H, Reece ST. Self-amplifying RNA vaccines give equivalent protection against influenza to mRNA vaccines but at much lower doses. Molecular Therapy. 2018 Feb 7;26(2):446-55. https://www.cell.com/molecular-therapy-family/molecular-therapy/pdf/S1525-0016(17)30594-4.pdf