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A Next Generation Bivalent Human Ad5 COVID-19 Vaccine Delivering Both Spike and Nucleocapsid Antigens Elicits Th1 Dominant CD4+, CD8+ T-cell and Neutralizing Antibody Responses
bioRxiv - Immunology Pub Date : 2020-07-30 , DOI: 10.1101/2020.07.29.227595
Adrian Rice , Mohit Verma , Annie Shin , Lise Zakin , Peter Sieling , Shiho Tanaka , Helty Adisetiyo , Justin Taft , Rosheel Patel , Sofija Buta , Marta Martin-Fernandez , Brett Morimoto , Elizabeth Gabitzsch , Jeffrey T. Safrit , Joseph Balint , Kyle Dinkins , Patricia Spilman , Dusan Bogunovic , Shahrooz Rabizadeh , Kayvan Niazi , Patrick Soon-Shiong

In response to the health crisis presented by the COVID-19 pandemic, rapid development of safe and effective vaccines that elicit durable immune responses is imperative. Recent reports have raised the concern that antibodies in COVID-19 convalescent patients may not be long lasting and thus even these individuals may require vaccination. Vaccine candidates currently in clinical testing have focused on the SARS-CoV-2 wildtype spike (S) protein (S-WT) as the major antigen of choice and while pre-clinical and early clinical testing have shown that S elicits an antibody response, we believe the optimal vaccine candidate should be capable of inducing robust, durable T-cell responses as well as humoral responses. We report here on a next generation bivalent human adenovirus serotype 5 (hAd5) vaccine capable of inducing immunity in patients with pre-existing adenovirus immunity, comprising both an S sequence optimized for cell surface expression (S-Fusion) and a conserved nucleocapsid (N) antigen designed to be transported to the endosomal subcellular compartment, with the potential to generate durable immune protection. Our studies suggest that this next generation bivalent vaccine is optimized for immunogenicity as evidenced by the following findings: (i) The optimized S-Fusion displayed improved S receptor binding domain (RBD) cell surface expression compared to S-WT where little surface expression was detected; (ii) the expressed RBD from S-Fusion retained conformational integrity and recognition by ACE2-Fc; (iii) the viral N protein modified with an enhanced T-cell stimulation domain (ETSD) localized to endosomal/lysosomal subcellular compartments for MHC I/II presentation; and (iv) these optimizations to S and N (S-Fusion and N-ETSD) generated enhanced de novo antigen-specific B cell and CD4+ and CD8+ T-cell responses in antigen-naive pre-clinical models. Both the T-cell and antibody immune responses to S and N demonstrated a T-helper 1 (Th1) bias. The antibody responses were neutralizing as demonstrated by two independent SARS-CoV-2 neutralization assays. Based on these findings, we are advancing this next generation bivalent hAd5 S-Fusion + N-ETSD vaccine as our lead clinical candidate to test for its ability to provide robust, durable cell-mediated and humoral immunity against SARS-CoV-2 infection. Further studies are ongoing to explore utilizing this vaccine construct in oral, intranasal, and sublingual formulations to induce mucosal immunity in addition to cell-mediated and humoral immunity. The ultimate goal of an ideal COVID-19 vaccine is to generate long-term T and B cell memory.

中文翻译:

提供穗状和核仁抗原的下一代二价人类Ad5 COVID-19疫苗可激发Th1优势CD4 +,CD8 + T细胞并中和抗体反应。

为了应对COVID-19大流行带来的健康危机,必须快速开发引发持久免疫反应的安全有效的疫苗。最近的报道引起了人们的关注,即COVID-19康复患者中的抗体可能不会持续很长时间,因此,即使这些人也可能需要接种疫苗。目前正在临床测试中的候选疫苗已将SARS-CoV-2野生型加标(S)蛋白(S-WT)选作主要抗原,而临床前和早期临床测试表明S会引发抗体反应,我们认为最佳的候选疫苗应该能够诱导强大,持久的T细胞反应以及体液反应。我们在这里报告了一种下一代二价人类腺病毒血清型5(hAd5)疫苗,该疫苗能够在已有腺病毒免疫力的患者中诱导免疫力,包括针对细胞表面表达(S-Fusion)优化的S序列和保守的核衣壳(N )抗原,被设​​计为转运至内体亚细胞区室,具有产生持久免疫保护的潜力。我们的研究表明,这种下一代二价疫苗已针对免疫原性进行了优化,具体体现在以下发现:(i)与表面活性极低的S-WT相比,优化的S-Fusion具有改善的S受体结合域(RBD)细胞表面表达。检测到 (ii)从S-Fusion表达的RBD保留了构象完整性和被ACE2-Fc识别; (iii)用增强的T细胞刺激结构域(ETSD)修饰的病毒N蛋白,定位于用于MHC I / II呈递的内体/溶酶体亚细胞区室;(iv)对S和N的这些优化(S-融合和N-ETSD)在未进行过抗原的临床前模型中产生了增强的从头抗原特异性B细胞以及CD4 +和CD8 + T细胞反应。T细胞和抗体对S和N的免疫反应均显示出T辅助1(Th1)偏倚。如两个独立的SARS-CoV-2中和测定所证明的,抗体反应已被中和。基于这些发现,我们正在推进这种下一代二价hAd5 S-融合+ N-ETSD疫苗,作为我们的主要临床候选药物,以测试其针对SARS-CoV-2感染提供强大,持久的细胞介导和体液免疫的能力。正在进行进一步的研究以探索在口服,鼻内和舌下制剂中使用这种疫苗构建体以诱导粘膜免疫以及细胞介导和体液免疫。理想的COVID-19疫苗的最终目标是产生长期的T和B细胞记忆。
更新日期:2020-07-31
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