ImmunityBio, Inc., Culver City, CA, United States.
Access to Advanced Health Institute (AAHI), Seattle, WA, United States.
Front Immunol. 2022 Jul 15;13:910136. doi: 10.3389/fimmu.2022.910136. eCollection 2022.
We assessed if immune responses are enhanced in CD-1 mice by heterologous vaccination with two different nucleic acid-based COVID-19 vaccines: a next-generation human adenovirus serotype 5 (hAd5)-vectored dual-antigen spike (S) and nucleocapsid (N) vaccine (AdS+N) and a self-amplifying and -adjuvanted S RNA vaccine (AAHI-SC2) delivered by a nanostructured lipid carrier. The AdS+N vaccine encodes S modified with a fusion motif to increase cell-surface expression and an N antigen modified with an Enhanced T-cell Stimulation Domain (N-ETSD) to direct N to the endosomal/lysosomal compartment and increase MHC class I and II stimulation potential. The S sequence in the AAHI-SC2 vaccine comprises the D614G mutation, two prolines to stabilize S in the prefusion conformation, and 3 glutamines in the furin cleavage region to confer protease resistance. CD-1 mice received vaccination by homologous and heterologous prime > boost combinations. Humoral responses to S were the highest with any regimen that included the AAHI-SC2 vaccine, and IgG bound to wild type and Delta (B.1.617.2) variant S1 at similar levels. An AAHI-SC2 prime followed by an AdS+N boost particularly enhanced CD4+ and CD8+ T-cell responses to both wild type and Delta S peptides relative to all other vaccine regimens. Sera from mice receiving AAHI-SC2 homologous or heterologous vaccination were found to be highly neutralizing for all pseudovirus strains tested: Wuhan, Beta, Delta, and Omicron strains. The findings here, taken in consideration with the availability of both vaccines in thermostable formulations, support the testing of heterologous vaccination by an AAHI-SC2 > AdS+N regimen in animal models of SARS-CoV-2 infection to assess its potential to provide increased protection against emerging SARS-CoV-2 variants particularly in regions of the world where the need for cold-chain storage has limited the distribution of other vaccines.
我们评估了 CD-1 小鼠通过两种不同的基于核酸的 COVID-19 疫苗进行异源接种时，免疫反应是否增强：一种是下一代人腺病毒血清型 5（hAd5）载体双抗原刺突（S）和核衣壳（N）疫苗（AdS+N），另一种是自我扩增和佐剂增强的 S RNA 疫苗（AAHI-SC2），由纳米结构脂质载体递呈。AdS+N 疫苗编码的 S 融合了一个增强细胞表面表达的融合基序，以及一个增强 T 细胞刺激结构域（N-ETSD）修饰的 N 抗原，以将 N 引导到内体/溶酶体区室，并增加 MHC Ⅰ类和Ⅱ类刺激潜力。AAHI-SC2 疫苗中的 S 序列包含 D614G 突变、两个脯氨酸稳定 S 在预融合构象中的构象以及 3 个在弗林切割区域的谷氨酰胺以赋予蛋白酶抗性。CD-1 小鼠通过同源和异源初免>加强组合进行接种。任何包含 AAHI-SC2 疫苗的方案均可诱导最高的 S 体液反应，并且 IgG 与野生型和 Delta（B.1.617.2）变异 S1 的结合水平相似。AAHI-SC2 初免后再用 AdS+N 加强，与所有其他疫苗方案相比，特别增强了对野生型和 Delta S 肽的 CD4+和 CD8+T 细胞反应。接受 AAHI-SC2 同源或异源接种的小鼠血清对所有测试的假病毒株均具有高度中和作用：武汉株、Beta 株、Delta 株和奥密克戎株。考虑到这两种疫苗均有热稳定制剂，这些发现支持在 SARS-CoV-2 感染的动物模型中进行 AAHI-SC2 > AdS+N 方案的异源接种试验，以评估其提供针对新兴 SARS-CoV-2 变异体的增加保护的潜力，特别是在世界上冷链储存需求限制了其他疫苗分发的地区。
