Thoryk Elizabeth A, Swaminathan Gokul, Meschino Steven, Cox Kara S, Gindy Marian, Casimiro Danilo R, Bett Andrew J
Infectious Diseases and Vaccines, Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ 07033, USA.
Medical Affairs, Global Human Health, Merck & Co., Inc., Kenilworth, NJ 07033, USA.
Vaccines (Basel). 2016 Dec 6;4(4):47. doi: 10.3390/vaccines4040047.
A vast body of evidence suggests that nanoparticles function as potent immune-modulatory agents. We have previously shown that Merck proprietary Lipid NanoParticles (LNPs) markedly boost B-cell and T-cell responses to sub-unit vaccine antigens in mice. To further evaluate the specifics of vaccine delivery and dosing regimens in vivo, we performed immunogenicity studies in BALB/c and C57BL/6 mice using two model antigens, Hepatitis B Surface Antigen (HBsAg) and Ovalbumin (OVA), respectively. To assess the requirement for co-administration of antigen and LNP for the elicitation of immune responses, we evaluated immune responses after administering antigen and LNP to separate limbs, or administering antigen and LNP to the same limb but separated by 24 h. We also evaluated formulations combining antigen, LNP, and aluminum-based adjuvant amorphous aluminum hydroxylphosphate sulfate (MAA) to look for synergistic adjuvant effects. Analyses of antigen-specific B-cell and T-cell responses from immunized mice revealed that the LNPs and antigens must be co-administered-both at the same time and in the same location-in order to boost antigen-specific immune responses. Mixing of antigen with MAA prior to formulation with LNP did not impact the generation of antigen-specific B-cell responses, but drastically reduced the ability of LNPs to boost antigen-specific T-cell responses. Overall, our data demonstrate that the administration of LNPs and vaccine antigen together enables their immune-stimulatory properties.
大量证据表明，纳米颗粒可作为强效免疫调节剂发挥作用。我们之前已经表明，默克公司专有的脂质纳米颗粒（LNPs）可显著增强小鼠对亚单位疫苗抗原的B细胞和T细胞反应。为了进一步评估体内疫苗递送和给药方案的具体情况，我们分别使用两种模型抗原，即乙肝表面抗原（HBsAg）和卵清蛋白（OVA），在BALB/c和C57BL/6小鼠中进行了免疫原性研究。为了评估引发免疫反应时抗原与LNP联合给药的必要性，我们评估了将抗原和LNP分别注射到不同肢体，或者将抗原和LNP注射到同一肢体但间隔24小时后的免疫反应。我们还评估了将抗原、LNP与铝基佐剂无定形羟基磷酸硫酸铝（MAA）组合的制剂，以寻找协同佐剂效应。对免疫小鼠的抗原特异性B细胞和T细胞反应分析表明，LNP和抗原必须同时且在同一位置联合给药，才能增强抗原特异性免疫反应。在与LNP配制之前将抗原与MAA混合，不会影响抗原特异性B细胞反应的产生，但会大幅降低LNP增强抗原特异性T细胞反应的能力。总体而言，我们的数据表明，LNP与疫苗抗原一起给药可发挥其免疫刺激特性。
