Porcine reproductive and respiratory syndrome (PRRS) remains a formidable challenge for the global pig industry. Caused by PRRS virus (PRRSV), this disease primarily affects porcine reproductive and respiratory systems, undermining effective host interferon and other immune responses, resulting in vaccine ineffectiveness. In the absence of specific antiviral treatments for PRRSV, vaccines play a crucial role in managing the disease. The current market features a range of vaccine technologies, including live, inactivated, subunit, DNA, and vector vaccines, but only modified live virus (MLV) and killed virus (KV) vaccines are commercially available for PRRS control. Live vaccines are promoted for their enhanced protective effectiveness, although their ability to provide cross-protection is modest. On the other hand, inactivated vaccines are emphasized for their safety profile but are limited in their protective efficacy. This review updates the current knowledge on PRRS vaccines’ interactions with the host interferon system, and other immunological aspects, to assess their current status and evaluate advents in PRRSV vaccine development. It presents the strengths and weaknesses of both live attenuated and inactivated vaccines in the prevention and management of PRRS, aiming to inspire the development of innovative strategies and technologies for the next generation of PRRS vaccines.

Ranaviruses (Iridoviridae), including Frog Virus 3 (FV3), are large dsDNA viruses that cause devastating infections globally in amphibians, fish, and reptiles, and contribute to catastrophic amphibian declines. FV3’s large genome (~105 kb) contains at least 98 putative open reading frames (ORFs) as annotated in its reference genome. Previous studies have classified these coding genes into temporal classes as immediate early, delayed early, and late viral transcripts based on their sequential expression during FV3 infection. To establish a high-throughput characterization of ranaviral gene expression at the genome scale, we performed a whole transcriptomic analysis (RNA-Seq) using total RNA samples containing both viral and cellular transcripts from FV3-infected Xenopus laevis adult tissues using two FV3 strains, a wild type (FV3-WT) and an ORF64R-deleted recombinant (FV3-∆64R). In samples from the infected intestine, liver, spleen, lung, and especially kidney, an FV3-targeted transcriptomic analysis mapped reads spanning the full-genome coverage at ~10× depth on both positive and negative strands. By contrast, reads were only mapped to partial genomic regions in samples from the infected thymus, skin, and muscle. Extensive analyses validated the expression of almost all of the 98 annotated ORFs and profiled their differential expression in a tissue-, virus-, and temporal class-dependent manner. Further studies identified several putative ORFs that encode hypothetical proteins containing viral mimicking conserved domains found in host interferon (IFN) regulatory factors (IRFs) and IFN receptors. This study provides the first comprehensive genome-wide viral transcriptome profiling during infection and across multiple amphibian host tissues that will serve as an instrumental reference. Our findings imply that Ranaviruses like FV3 have acquired previously unknown molecular mimics, interfering with host IFN signaling during evolution.

Background/Objectives: Porcine reproductive and respiratory syndrome virus (PRRSV) significantly impedes swine production due to rapid genetic variation and suppression of antiviral interferon (IFN) responses, leading to ineffective immunity. To address this, we developed IFNmix, a replication-competent PRRSV modified live vaccine (MLV) candidate co-expressing three Type I IFN subclasses (IFNα, IFNβ, IFNδ) to enhance antiviral immunity. Methods: In two independent in vivo experiments, we compared the protection of IFNmix and a commercial PRRSV MLV vaccine during challenge with a virulent PRRSV strain. Clinical signs, antibody and cytokine production, viral replication, and lung pathology in IFNmix-vaccinated pigs were compared to those of commercial PRRSV vaccines and controls. Results: Pigs vaccinated with IFNmix exhibited similar anti-PRRSV antibody development, serum viral loads, lung lesions, and cytokine responses post-challenge with the virulent NADC34 strain, with comparable or lower body temperatures and weight gain, to pigs vaccinated with the commercial vaccines. While IFNmix showed early viral load reduction compared to the commercial vaccine (Days 7–14 post-challenge), it demonstrated similar efficacy in controlling PRRSV replication and lung pathology. Conclusions: These findings suggest that IFNmix, by expressing multiple IFNs, can potentially enhance innate and adaptive immune responses, offering a promising approach to improving PRRSV vaccine efficacy. Further studies are needed to evaluate IFNmix against a broader range of PRRSV strains and to optimize its attenuation and immunogenicity.

Porcine Reproductive and Respiratory Syndrome (PRRS) causes significant economic losses in the swine industry. Circular RNAs (circRNAs), a class of stable non-coding RNAs, are increasingly recognized as regulators in immune responses and host–virus interactions. This study investigated the genome-wide circRNA responses in porcine alveolar macrophages (PAMs), key cell targets of PRRSV, following treatment with a modified live virus (MLV) vaccine or two interferon (IFN) subtypes (IFN-α1, IFN-ω5). Using RNA sequencing, we identified over 1000 differentially expressed circRNAs across treatment groups, revealing both conserved and distinct expression profiles. Gene Ontology and KEGG pathway analyses indicated that circRNA-associated genes are significantly enriched in immune-related processes and pathways, including cytokine signaling and antiviral defense. Notably, IFN-ω5 treatment induced a pronounced circRNA response, aligning with its potent antiviral activity. We further explored the regulatory potential of these circRNAs by predicting miRNA binding sites, revealing complex circRNA-miRNA interaction networks. Additionally, we assessed the coding potential of differentially expressed circRNAs by identifying open reading frames (ORFs), internal ribosome entry sites (IRESs), and N6-methyladenosine (m⁶A) modification sites, suggesting a subset may undergo non-canonical translation. These findings provide a comprehensive landscape of circRNA expression in PAMs under different antiviral conditions, highlighting their potential roles as immune regulators and novel players in interferon-mediated antiviral responses, particularly downstream of IFN-ω5. This work contributes to understanding the non-coding RNA landscape in the PRRSV-swine model and suggests circRNAs as potential targets for future antiviral strategies.

Porcine reproductive and respiratory syndrome virus (PRRSV) poses significant challenges to swine production due to its rapid generation of genetic variants and its ability to suppress antiviral interferon (IFN) responses, leading to ineffective immunity. To address this, we developed a replication-competent PRRSV modified live vaccine (MLV) candidate, IFNmix, engineered to co-express three type I IFN subclasses (IFNα, IFNβ, IFNδ) to enhance antiviral immunity. In two independent experiments, we compared IFNmix to two commercial PRRSV MLV vaccines. Pigs vaccinated with IFNmix exhibited similar anti-PRRSV antibody development, serum viral loads, lung lesions, and cytokine responses post-challenge with the virulent NADC34 strain. IFNmix induced comparable or lower body temperatures and weight gain patterns relative to commercial vaccines. While IFNmix showed viral load reduction compared to a commercial vaccine especially during the early phase (Day 7-14 post challenges), it demonstrated similar efficacy in controlling PRRSV replication and lung pathology. These findings suggest that IFNmix, by expressing multiple IFNs, can potentially enhance innate and adaptive immune responses, offering a promising approach to improving PRRSV vaccine efficacy. Further studies are needed to evaluate IFNmix against a broader range of PRRSV strains and to optimize its attenuation and immunogenicity.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a major threat to the global swine industry. Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of antiviral immunity, but their roles in porcine alveolar macrophages (PAMs)—the primary target of PRRSV—remain poorly characterized. This study presents a genome-wide analysis of lncRNA expression in PAMs stimulated with a PRRS modified live virus (MLV) vaccine and two type I interferons, IFN-α1 and IFN-ω5. Whole-transcriptome sequencing identified over 2000 differentially expressed lncRNAs, with IFN-ω5 inducing the most extensive transcriptional reprogramming. Weighted gene co-expression network analysis (WGCNA) revealed interferon-specific lncRNA-mRNA modules, and functional enrichment showed these lncRNAs are involved in key immune and metabolic pathways, including chemokine signaling, MAPK, and mTOR. Our findings establish a comprehensive landscape of lncRNA regulation in PAMs, highlighting their role in fine-tuning the antiviral responses and suggesting novel targets for interferon-based antiviral interventions against PRRSV.