猪繁殖与呼吸综合征（Porcine reproductive and respiratory syndrome, PRRS）是由猪繁殖与呼吸综合征病毒（Porcine reproductive and respiratory syndrome virus, PRRSV）感染引起的一种严重危害养猪业的传染性疾病，自其首次被报道以来持续给全球养猪业造成大量经济损失。疫苗接种是控制该病重要手段，但存在明显缺点。PRRSV灭活疫苗免疫效力有限，改良活疫苗（Modified live vaccine, MLV）存在毒力返强风险。PRRSV存在基因变异，并已形成以谱系1、5、8为代表的多种PRRSV-2谱系。疫苗的广泛使用客观上加速了病毒的适应性进化。目前，PRRSV类NADC30毒株已成为优势流行毒株，其抗原性发生改变，传统疫苗对其免疫保护效力显著降低。本研究揭示了PRRSV类NADC30 FJ1402毒株中和抗体识别抗原为GP3、GP4和GP5，鉴定出7个T细胞抗原表位。通过设计疫苗抗原分子，成功构建铁蛋白纳米颗粒亚单位疫苗，证明其可诱导猪体产生细胞免疫和免疫保护作用，为PRRSV新型疫苗的研发奠定基础。本研究主要内容如下：

PRRSV中和抗体识别抗原及其关键氨基酸位点的解析

病原免疫保护性抗原通常被认为能够诱导产生中和抗体，PRRSV中和抗体识别抗原尚不十分清楚。本研究分别使用高致病性PRRSV（High pathogenic PRRSV, HP-PRRSV）毒株BB0907（美洲型谱系8）和类NADC30毒株FJ1402（美洲型谱系1）感染仔猪制备中和抗体血清，证明其交叉中和反应性比较低。随后，以BB0907毒株感染性克隆cDNA作为骨架，将其ORF2-6基因部分或全部替换为类NADC30毒株基因序列，拯救获得6株嵌合重组病毒。病毒交叉中和试验结果显示，类NADC30毒株感染猪体后诱导产生的中和抗体主要靶向病毒的结构蛋白GP3、GP4和GP5。进一步通过构建6株GP3点突变重组PRRSV，证实GP3蛋白第66位和第85位氨基酸在中和抗体识别过程中发挥的重要作用。

PRRSV类NADC30毒株FJ1402结构蛋白T细胞表位的解析

PRRSV不同谱系毒株抗原交叉保护作用比较低。PRRSV经典毒株（美洲型谱系5）T细胞表位已有研究报道，类NADC30毒株（美洲型谱系1）T细胞抗原表位尚不清晰。本研究根据PRRSV类NADC30毒株FJ1402基因序列，通过生物信息学方法预测T细胞表位再对预测表位综合评分，从4536条覆盖FJ1402毒株结构蛋白全长的8-10aa的连续短肽中优选出58条短肽进行体外合成。将FJ1402毒株接种仔猪，在感染后42 d采集抗凝血分离猪外周血淋巴细胞作为效应细胞，借助IFN-γ ELISpot检测方法，检测上述合成短肽刺激IFN-γ特异性分泌的能力。结果筛选出7条短肽可显著诱导感染猪外周血淋巴细胞产生IFN-γ，提示其为FJ1402毒株的T细胞表位，为PRRSV新型疫苗研究开发和T细胞免疫干预策略提供了重要靶点。

PRRSV结构蛋白纳米颗粒疫苗的构建与免疫保护效力研究

基于上述解析的FJ1402毒株中和抗体识别抗原及T细胞免疫抗原表位，设计构建了3种抗原分子，采用重组杆状病毒系统表达3种可溶性重组抗原（GP3m、GP4m和GP5m）。同时，采用大肠杆菌表达系统，构建表达源自炽热火球菌的铁蛋白纳米颗粒蛋白。借助SpyTag-SpyCatcher系统，将这些抗原定向展示在铁蛋白纳米颗粒（Ferritin，Fe）表面，组装形成三种单一重组抗原纳米颗粒疫苗（GP3m-Fe、GP4m-Fe和GP5m-Fe）。进一步将三种纳米颗粒与铝胶佐剂混合，制备出FeCocktail纳米颗粒鸡尾酒疫苗。小鼠免疫试验结果显示，FeCocktail疫苗能够诱导强烈的体液免疫应答并显著激活CD4⁺和CD8⁺ T细胞应答，诱导产生CD8⁺中央记忆T细胞以及CD4⁺和CD8⁺效应记忆T细胞。仔猪免疫试验结果显示，FeCocktail疫苗免疫能有效激活特异性细胞免疫应答，且诱导分泌的PRRSV特异性IFN-γ水平显著高于单一抗原组。免疫仔猪使用FJ1402毒株攻击，观察结果显示，FeCocktail免疫组仔猪临床症状评分（包括发热、呼吸频率、日增重等指标）显著优于对照组，病毒血症持续时间缩短，肺组织病毒载量显著降低且肺脏病变程度减轻。本研究表明，FeCocktail疫苗免疫后能够有效诱导产生PRRSV特异性IFN-γ，对同源毒株攻毒可提供有效的免疫保护，为PRRSV新型疫苗研究提供了重要研究思路和技术平台。

IFN-⍺增强PRRSV纳米颗粒疫苗的免疫效应

为进一步增强FeCocktail纳米颗粒鸡尾酒疫苗的免疫效果，本研究构建了融合猪源或鼠源IFN-α的PRRSV重组纳米颗粒，配伍铝胶佐剂制备出两种IFN-FeCocktail纳米颗粒鸡尾酒疫苗。在小鼠和仔猪模型中，对FeCocktail、IFN-FeCocktail及PRRSV灭活疫苗的免疫效果进行系统评估。结果显示，PRRSV灭活疫苗组在两种动物模型中均表现出Th2型免疫偏移，而FeCocktail和IFN-FeCocktail疫苗则诱导更为平衡的Th1/Th2免疫应答。在小鼠模型中，IFN-FeCocktail疫苗诱导的特异性抗体水平和IFN-γ分泌量显著高于FeCocktail组；在仔猪模型中，IFN-FeCocktail组的抗体应答出现更早，个体间差异更小，但细胞免疫强度与FeCocktail组无显著差异。免疫保护试验证实，FeCocktail和IFN-FeCocktail不仅能够诱导针对同源毒株的免疫保护，其保护效力也显著优于灭活疫苗。本研究明确了IFN-α在增强PRRSV纳米颗粒疫苗免疫效力的作用，为提升PRRSV亚单位疫苗的免疫原性提供了新的策略。

综上所述，本研究解析出PRRSV类NADC30毒株中和抗体识别抗原及结构蛋白T细胞表位。通过抗原分子设计，构建了基于铁蛋白纳米颗粒的PRRSV亚单位疫苗。动物试验发现，该类颗粒疫苗能够提高抗原免疫原性，协同激活体液免疫与细胞免疫应答，克服传统灭活疫苗免疫原性不足的局限性，具有重要应用前景。

Porcine reproductive and respiratory syndrome (PRRS) is an infectious disease caused by the porcine reproductive and respiratory syndrome virus (PRRSV), which has posed a severe threat to the swine industry and caused substantial economic losses worldwide since its initial identification. Vaccination remains a critical strategy for controlling PRRS; however, current vaccines exhibit notable limitations. Inactivated PRRSV vaccines induce weak immunogenic responses, whereas modified live virus (MLV) vaccines pose a risk of virulence reversion. PRRSV exhibits genetic variation, leading to the emergence of multiple PRRSV-2 lineages, primarily represented by lineages 1, 5, and 8. The widespread use of vaccines has objectively accelerated the virus's adaptive evolution. Currently, the NADC30 strain has emerged as the predominant variant, with antigenic changes that have reduced the protective efficacy of conventional vaccines. In this study, we identified GP3, GP4, and GP5 as the principal targets of neutralizing antibodies in the NADC30-like PRRSV FJ1402 strain and mapped seven T-cell epitopes. We designed antigenic molecules and engineered a ferritin-based nanoparticle subunit vaccine, demonstrating its capacity to elicit cellular immunity and confer protection in pigs. These findings lay a strong foundation for the development of next-generation PRRSV vaccines. The mian aspects of this study are as follows:

Characterization of PRRSV neutralizing antibody recognition antigens and key amino acid residues

Protective antigens of pathogens are typically considered capable of eliciting neutralizing antibodies; however, the precise neutralizing antibody targets of PRRSV remain unclear. In this study, sera containing neutralizing antibodies were obtained from piglets infected with the highly pathogenic PRRSV (HP-PRRSV) strain BB0907 (lineage 8, North American type) and the NADC30-like strain FJ1402 (lineage 1, North American type), revealing limited cross-neutralization between these two strains. To further investigate neutralizing antibody recognition, infectious cDNA clones of BB0907 were used as a backbone, with ORF2-6 genes partially or entirely replaced by those of the NADC30-like strain, resulting in the rescue of six chimeric recombinant viruses. Cross-neutralization assays demonstrated that neutralizing antibodies elicited by NADC30-like PRRSV primarily targeted the structural proteins GP3, GP4, and GP5. Further analysis using six recombinant PRRSV variants with point mutations in GP3 identified amino acid residues 66 and 85 as critical for neutralizing antibody recognition.

Identification of T cell epitopes in structural proteins of the PRRSV NADC30-like strain FJ1402

PRRSV strains from different lineages exhibit limited cross-protective immunity. Although T cell epitopes of classical PRRSV strains (lineage 5, North American type) have been characterized, those of NADC30-like strains (lineage 1, North American type) remain poorly defined. In this study, T cell epitopes of the NADC30-like PRRSV strain FJ1402 were identified based on its genomic sequence. Using bioinformatics prediction tools, 58 peptides were selected from an initial set of 4,536 continuous 8–10 amino acid peptides spanning the full length of the structural proteins. These peptides were synthesized in vitro and evaluated for their immunogenic potential. Piglets were infected with the FJ1402 strain, and peripheral blood mononuclear cells were isolated at 42 days post-infection for use as effector cells. An IFN-γ ELISpot assay was employed to assess peptide-induced IFN-γ secretion. Seven peptides were found to significantly stimulate IFN-γ production in PBMCs from infected pigs, identifying them as T cell epitopes of the FJ1402 strain. These findings provide critical targets for the development of novel PRRSV vaccines and T cell-based immunotherapeutic strategies.

Construction and immune protective efficacy of the PRRSV nanoparticle vaccine

Based on the neutralizing antibody recognition antigens and T cell epitopes identified form the PRRSV FJ1402 strain, three recombinant antigens (GP3m, GP4m, and GP5m) were designed and expressed as soluble proteins using the recombinant baculovirus expression system. Ferritin nanoparticle proteins were expressed using the Escherichia coli expression system. These antigens were then displayed on the surface of ferritin nanoparticles through the SpyTag-SpyCatcher system, resulting in the formation of three single recombinant antigen nanoparticle vaccines (GP3m-Fe, GP4m-Fe, and GP5m-Fe). Further, these nanoparticles were mixed with aluminum adjuvant to produce the FeCocktail vaccine. Immunization of mice with the FeCocktail vaccine induced a robust humoral immune response and significantly activated CD4⁺ and CD8⁺ T cell responses, leading to the generation of central memory CD8⁺ T cells and effector memory CD4⁺ and CD8⁺ T cells. Immunization of piglets with the FeCocktail vaccine effectively triggered specific cellular immune responses, with a significant increase in PRRSV-specific IFN-γ secretion compared to the single antigen groups. Following challenge with the FJ1402 strain, the FeCocktail-vaccinated piglets displayed significantly milder clinical symptoms (including reduced fever, respiratory rate, and weight loss) compared to the control group. Additionally, the duration of viremia was shortened, viral load in lung tissues was significantly reduced, and the degree of lung pathology was alleviated. This study demonstrates that the FeCocktail vaccine can effectively induce PRRSV-specific IFN-γ production and provide protective immunity against homologous virus challenge, offering an important research approach and technical platform for the development of novel PRRSV vaccines.

Enhancement of immune effects of PRRSV nanoparticle vaccine by IFN-α

To further enhance the immune efficacy of the FeCocktail vaccine, recombinant PRRSV nanoparticles fused with either porcine or murine IFN-α were constructed, and two IFN-FeCocktail vaccines were prepared in combination with aluminum adjuvant. The immune effects of the FeCocktail, IFN-FeCocktail, and PRRSV inactivated vaccines were systematically evaluated in both mouse and piglet models. The results showed that the inactivated PRRSV vaccine induced a Th2-type immune bias in both animal models, while the FeCocktail and IFN-FeCocktail vaccines promoted a more balanced Th1/Th2 immune response. In the mouse model, the IFN-FeCocktail vaccine significantly induced higher levels of specific antibodies and IFN-γ secretion compared to the FeCocktail group. In the piglet model, the IFN-FeCocktail group exhibited earlier antibody responses with less individual variation, but the strength of cellular immunity did not differ significantly from the FeCocktail group. Immune protection tests confirmed that both FeCocktail and IFN-FeCocktail vaccines not only induced protection against homologous strain but also exhibited significantly better protective efficacy than the inactivated vaccine. This study elucidates the role of IFN-α in enhancing the immune efficacy of PRRSV nanoparticle vaccines and provides a new strategy for improving the immunogenicity of PRRSV subunit vaccines.

In summary, this study identified the neutralizing antibody targets and structural protein T cell epitopes of NADC30-like PRRSV strains. Based on rational antigen design, we developed a ferritin-based nanoparticle subunit vaccine for PRRSV. Animal experiments demonstrated that this nanoparticle vaccine significantly enhanced antigen immunogenicity and elicited coordinated humoral and cellular immune responses, thereby addressing the limited immunogenicity associated with traditional inactivated vaccines. These findings highlight the promising application potential of this vaccine strategy in PRRSV prevention and control.

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