Jensen Kristoffer Jarlov, Hansen Mette Sif, Skovgaard Kerstin, Svensson Erik, Larsen Lars Erik, Heegaard Peter M H, Benn Christine Stabell, Jungersen Gregers
Bandim Health Project, University of Southern Denmark, Copenhagen, Denmark.
Department of Biotechnology and Biomedicine, Technical University of Denmark, Kgs. Lyngby, Denmark.
Front Immunol. 2023 Jul 13;14:1219006. doi: 10.3389/fimmu.2023.1219006. eCollection 2023.
Clinical and immunological studies in humans show that the live attenuated (BCG) vaccine has beneficial non-specific effects, increasing resistance against diseases other than tuberculosis. The underlying mechanisms are currently being explored. The pig exhibits considerable physiological similarity to humans in anatomy and physiology, suggesting that similar responses to BCG could be expected. Studies of the non-specific effects of BCG in pigs are scarce. We investigated the feasibility of using pigs as a large animal model to investigate the non-specific immunological effects of BCG.
In a series of experiments, we randomized newborn or young piglets from conventional farms to receiving BCG or placebo and investigated the persistence of live BCG bacteria in various tissues, the immunogenicity of BCG in blood and stimulation assays, and the acute phase protein and clinical responses to heterologous infectious challenge with influenza A virus or .
The BCG vaccine was generally well tolerated. In contrast to humans, no skin reaction in the form of abscesses, ulcers, or scars was observed. Live BCG was recovered from draining lymph nodes in 2/13 animals 20 weeks after vaccination. Specific responses of IFN-γ to antigen-specific re-stimulation with mycobacterial antigen were increased but not TNF-responses to TLR2 or TLR4 agonists. A few genes were differentially expressed in blood after vaccination, including the antiviral genes and , although the effect disappeared after correction for multiple testing. Clinical symptoms after heterologous bacterial or viral respiratory infections did not differ, nor did virus copies in nasopharyngeal samples after the challenge. However, the acute phase protein response was significantly reduced in BCG-vaccinated animals after influenza challenge but not after challenge.
BCG was safe in pigs, inducing specific immunological responses, but our model did not corroborate the innate immunological responsiveness to BCG seen in humans. The dose of BCG or the bacterial and viral challenges may have been sub-optimal. Even so, the acute phase protein response to influenza infection was significantly reduced in BCG-vaccinated animals.
人体临床和免疫学研究表明，减毒活卡介苗（BCG）疫苗具有有益的非特异性效应，可增强对结核病以外其他疾病的抵抗力。目前正在探索其潜在机制。猪在解剖学和生理学上与人类具有相当大的生理相似性，这表明对卡介苗可能会有类似的反应。关于卡介苗在猪体内非特异性效应的研究很少。我们研究了使用猪作为大型动物模型来研究卡介苗非特异性免疫效应的可行性。
在一系列实验中，我们将来自传统农场的新生或幼年仔猪随机分为接受卡介苗或安慰剂组，并研究了活卡介苗细菌在各种组织中的持久性、卡介苗在血液中的免疫原性以及刺激试验，以及对甲型流感病毒或其他异源感染性挑战的急性期蛋白和临床反应。
卡介苗疫苗总体耐受性良好。与人类不同，未观察到以脓肿、溃疡或疤痕形式出现的皮肤反应。接种疫苗20周后，在13只动物中的2只引流淋巴结中发现了活卡介苗。用分枝杆菌抗原进行抗原特异性再刺激后，IFN-γ的特异性反应增加，但对TLR2或TLR4激动剂的TNF反应未增加。接种疫苗后血液中一些基因存在差异表达，包括抗病毒基因，但在多重检验校正后该效应消失。异源细菌或病毒呼吸道感染后的临床症状没有差异，挑战后鼻咽样本中的病毒拷贝数也没有差异。然而，流感病毒攻击后，接种卡介苗的动物急性期蛋白反应显著降低，但在其他攻击后未降低。
卡介苗在猪体内是安全的，可诱导特异性免疫反应，但我们的模型并未证实人类中观察到的对卡介苗的固有免疫反应性。卡介苗的剂量或细菌和病毒挑战可能不是最佳的。即便如此，接种卡介苗的动物对流感感染的急性期蛋白反应显著降低。
