De Pascalis Roberto, Frey Blake, Rice Helen M, Bhargava Varunika, Wu Terry H, Peterson Ross L, Conlan J Wayne, Sjöstedt Anders, Elkins Karen L
Laboratory of Mucosal Pathogens and Cellular Immunology, Division of Bacterial, Parasitic and Allergenic Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA.
University of Alabama-Birmingham, Birmingham, AL, USA.
NPJ Vaccines. 2022 Aug 17;7(1):95. doi: 10.1038/s41541-022-00506-9.
Francisella tularensis, the causative agent of tularemia, is classified as Tier 1 Select Agent with bioterrorism potential. The efficacy of the only available vaccine, LVS, is uncertain and it is not licensed in the U.S. Previously, by using an approach generally applicable to intracellular pathogens, we identified working correlates that predict successful vaccination in rodents. Here, we applied these correlates to evaluate a panel of SchuS4-derived live attenuated vaccines, namely SchuS4-ΔclpB, ΔclpB-ΔfupA, ΔclpB-ΔcapB, and ΔclpB-ΔwbtC. We combined in vitro co-cultures to quantify rodent T-cell functions and multivariate regression analyses to predict relative vaccine strength. The predictions were tested by rat vaccination and challenge studies, which demonstrated a clear relationship between the hierarchy of in vitro measurements and in vivo vaccine protection. Thus, these studies demonstrated the potential power a panel of correlates to screen and predict the efficacy of Francisella vaccine candidates, and in vivo studies in Fischer 344 rats confirmed that SchuS4-ΔclpB and ΔclpB-ΔcapB may be better vaccine candidates than LVS.
土拉弗朗西斯菌是兔热病的病原体，被列为具有生物恐怖主义潜力的1级选择病原体。唯一可用的疫苗LVS的有效性尚不确定，且未在美国获得许可。此前，我们采用一种普遍适用于细胞内病原体的方法，确定了预测啮齿动物成功接种疫苗的有效关联指标。在此，我们应用这些关联指标来评估一组源自SchuS4的减毒活疫苗，即SchuS4-ΔclpB、ΔclpB-ΔfupA、ΔclpB-ΔcapB和ΔclpB-ΔwbtC。我们结合体外共培养来量化啮齿动物T细胞功能，并通过多元回归分析来预测相对疫苗效力。这些预测通过大鼠接种和攻毒研究进行了验证，结果表明体外测量的等级与体内疫苗保护之间存在明确的关系。因此，这些研究证明了一组关联指标在筛选和预测弗朗西斯菌候选疫苗效力方面的潜在作用，并且在Fischer 344大鼠中进行的体内研究证实，SchuS4-ΔclpB和ΔclpB-ΔcapB可能是比LVS更好的候选疫苗。
