DataSheet1_Choice of adjuvant and antigen composition alters the immunogenic profile of a SARS-CoV-2 subunit vaccine.PDF

Introduction: Since their introduction, adjuvanted recombinant subunit vaccines against COVID-19 have played a pivotal role in protecting global populations. Optimizing the immune response’s quality, amplitude, and durability to these vaccines depends on the appropriate adjuvant choice and dose in combination with the selected antigen.
Methods: Here, we employed a preclinical mouse model to study the adaptive humoral and cellular immune responses to a SARS-CoV-2 receptor binding domain (RBD) antigen formulated with one of four different immune agonists [GLA, 3M-052, CpG-1826 (CpG), and dmLT], in combination with one of two different immune-stimulating formulations, a stabilized squalene emulsion (SE) or aluminum hydroxide (Alum). Using a weighted desirability index, we established an immunogenicity ranking for each adjuvant in combination with the RBD antigen.
Results: We found that formulations of the RBD with Alum in combination with either 3M-052 or CpG led to at least a 2-log increase in serum IgG production and a 1.3- to 2.2-log increase in the number of bone marrow-derived antibody-secreting cells compared to the RBD formulated with Alum without an additional agonist. In contrast, the RBD formulated with SE in combination with 3M-052 or CpG did not elicit an IgG response greater than the unadjuvanted control. Additionally, RBD formulated with 3M-052 or CpG on Alum generated a 0.8- or 1.6-log lower splenocyte IL-5 response (a pro-Th2 marker), respectively, than Alum without an additional agonist. When formulated with 3M-052-Alum, a bivalent vaccine containing the original lineage (Wuhan-Hu-1) and the Delta variant (B.1.617.2) RBD antigens led to a more than 2-log increase in neutralizing antibodies against an Omicron variant (B.1.1.529) pseudovirus in vaccinated animals compared to animals that received the monovalent RBD antigen.
Discussion: Our results suggest that optimal immune responses to subunit antigens may be achieved through an orthogonal approach that applies adjuvant formulation, antigen combination, and advances in rational vaccine development techniques.

引言：自问世以来，佐剂重组亚单位新型冠状病毒肺炎（COVID-19）疫苗在全球人群防护中发挥了关键性作用。优化此类疫苗诱导的免疫应答的质量、强度与持久性，取决于选择合适的佐剂、给药剂量，并结合选定的抗原。
方法：本研究采用临床前小鼠模型，探究分别配伍四种免疫激动剂[GLA、3M-052、CpG-1826（CpG）和dmLT]，并联合两种免疫刺激制剂（稳定化角鲨烯乳剂（SE）或氢氧化铝（Alum））的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）受体结合域（RBD）抗原所诱导的适应性体液免疫与细胞免疫应答。本研究通过加权期望指数法，为每种与RBD抗原配伍的佐剂建立了免疫原性排序。
结果：相较于仅配伍氢氧化铝（Alum）而未添加额外免疫激动剂的RBD抗原制剂，同时配伍Alum与3M-052或CpG的RBD制剂可使血清IgG生成量至少提升2个对数级，骨髓源性抗体分泌细胞数量提升1.3至2.2个对数级。与之相反，配伍稳定化角鲨烯乳剂（SE）与3M-052或CpG的RBD制剂所诱导的IgG应答水平，未高于无佐剂对照组。此外，配伍Alum与3M-052或CpG的RBD制剂，其诱导的脾细胞白细胞介素5（IL-5，促Th2型应答标志物）应答水平分别较仅配伍Alum的制剂降低0.8或1.6个对数级。当采用3M-052-Alum配伍时，包含原始毒株（Wuhan-Hu-1）与德尔塔（Delta）变异株（B.1.617.2）RBD抗原的二价疫苗，相较于接种单价RBD抗原的动物，可使免疫动物体内针对奥密克戎（Omicron）变异株（B.1.1.529）假病毒的中和抗体水平提升2个对数级以上。
讨论：本研究结果表明，通过佐剂配制、抗原组合以及理性疫苗开发技术的进步所构成的多维度策略，可实现亚单位抗原的最优免疫应答。