Using Dual Toll-like Receptor Agonism to Drive Th1-Biased Response in a Squalene- and α-Tocopherol-Containing Emulsion for a More Effective SARS-CoV-2 Vaccine.
Using Dual Toll-like Receptor Agonism to Drive Th1-Biased Response in a Squalene- and α-Tocopherol-Containing Emulsion for a More Effective SARS-CoV-2 Vaccine.
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使用双重Toll样受体激动剂在含角鲨烯和α-生育酚的乳剂中驱动Th 1偏置反应以获得更有效的SARS-CoV-2疫苗。
DOI：
10.3390/pharmaceutics14071455
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发表时间：
2022-07-12
期刊：
影响因子：
5.4
通讯作者：
Burkhart, David J.
中科院分区：
文献类型：
--
作者：
Short, Kristopher K.;Lathrop, Stephanie K.;Davison, Clara J.;Partlow, Haley A.;Kaiser, Johnathan A.;Tee, Rebekah D.;Lorentz, Elizabeth B.;Evans, Jay T.;Burkhart, David J.
要降低SARS-CoV-2的死亡率和发病率，需要多种疫苗。疫苗必须有效，易于生产，并在现有冷链中稳定，以提高其在世界各地的可用性。以角鲨烯为佐剂的重组蛋白亚单位疫苗，如AS 03 ™和MF 59 ™，具有安全、有效的使用历史，生产和销售简单。在这里，亚单位疫苗是用含有新型合成的toll样受体（TLR）激动剂INI-2002（TLR 4激动剂）和INI-4001（TLR 7/8激动剂）的角鲨烯乳剂制备的，使用SARS-CoV-2 S蛋白的重组受体结合结构域（RBD）作为抗原。单独或组合添加TLR 4和TLR 7/8激动剂保持了基于角鲨烯的乳剂的制剂特征，包括无菌可过滤的液滴尺寸（<220 nm）、高均匀性和在4、25和40 °C下储存数月后的胶体稳定性。此外，TLR激动剂的加入使免疫C57 BL/6小鼠的免疫应答从Th 2向Th 1倾斜，导致IgG 2c抗体的产生增加和IL-5的抗原特异性产生降低，淋巴细胞产生的IFNγ较高。因此，将TLR 4和TLR 7/8激动剂掺入乳剂中利用了乳剂的理想制剂和稳定性特征，并且可以诱导Th 1型体液和细胞介导的免疫应答，以对抗SARS-CoV-2的持续威胁。
A diversity of vaccines is necessary to reduce the mortality and morbidity of SARS-CoV-2. Vaccines must be efficacious, easy to manufacture, and stable within the existing cold chain to improve their availability around the world. Recombinant protein subunit vaccines adjuvanted with squalene-based emulsions such as AS03™ and MF59™ have a long and robust history of safe, efficacious use with straightforward production and distribution. Here, subunit vaccines were made with squalene-based emulsions containing novel, synthetic toll-like receptor (TLR) agonists, INI-2002 (TLR4 agonist) and INI-4001 (TLR7/8 agonist), using the recombinant receptor-binding domain (RBD) of SARS-CoV-2 S protein as an antigen. The addition of the TLR4 and TLR7/8 agonists, alone or in combination, maintained the formulation characteristics of squalene-based emulsions, including a sterile filterable droplet size (<220 nm), high homogeneity, and colloidal stability after months of storage at 4, 25, and 40 °C. Furthermore, the addition of the TLR agonists skewed the immune response from Th2 towards Th1 in immunized C57BL/6 mice, resulting in an increased production of IgG2c antibodies and a lower antigen-specific production of IL-5 with a higher production of IFNγ by lymphocytes. As such, incorporating TLR4 and TLR7/8 agonists into emulsions leveraged the desirable formulation and stability characteristics of emulsions and can induce Th1-type humoral and cell-mediated immune responses to combat the continued threat of SARS-CoV-2.
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DOI：
10.1056/nejmoa2035389
发表时间：
2021-02-04
期刊：
The New England journal of medicine
影响因子：
--
作者：
Baden LR;El Sahly HM;Essink B;Kotloff K;Frey S;Novak R;Diemert D;Spector SA;Rouphael N;Creech CB;McGettigan J;Khetan S;Segall N;Solis J;Brosz A;Fierro C;Schwartz H;Neuzil K;Corey L;Gilbert P;Janes H;Follmann D;Marovich M;Mascola J;Polakowski L;Ledgerwood J;Graham BS;Bennett H;Pajon R;Knightly C;Leav B;Deng W;Zhou H;Han S;Ivarsson M;Miller J;Zaks T;COVE Study Group
通讯作者：
COVE Study Group
影响因子：
12.4
作者：
Adamo S;Chevrier S;Cervia C;Zurbuchen Y;Raeber ME;Yang L;Sivapatham S;Jacobs A;Baechli E;Rudiger A;Stüssi-Helbling M;Huber LC;Schaer DJ;Bodenmiller B;Boyman O;Nilsson J
通讯作者：
Nilsson J
影响因子：
9.2
作者：
Abhyankar MM;Mann BJ;Sturek JM;Brovero S;Moreau GB;Sengar A;Richardson CM;Agah S;Pomés A;Kasson PM;Tomai MA;Fox CB;Petri WA Jr
通讯作者：
Petri WA Jr
影响因子：
5.5
作者：
Baldwin, Susan L.;Shaverdian, Narek;Reed, Steven G.
通讯作者：
Reed, Steven G.
影响因子：
2.7
作者：
Bazin, Helene G.;Bess, Laura S.;Evans, Jay T.
通讯作者：
Evans, Jay T.