Bong Yong-Sik, Brown David, Chung Ezra, Ananthaswamy Neeti, Chen Renxiang, Lewoczko Evan, Sabbers William, Patterson-Orazem Athéna C, Dorsey Zachary, Zou Yiqing, Yu Xue, Liang Jiening, He Jiaxi, Long Steven, Shen Dong
RNAimmune, Inc., Germantown, MD, United States.
Guangzhou RNAimmune, Ltd., Guangzhou, China.
Front Immunol. 2025 Jan 3;15:1495561. doi: 10.3389/fimmu.2024.1495561. eCollection 2024.
The unrelenting emergence of SARS-CoV-2 variants has significantly challenged the efficacy of existing COVID-19 vaccines. Enhancing the stability and immunogenicity of the spike protein is critical for improving vaccine performance and addressing variant-driven immune evasion.
We developed an mRNA-based vaccine, RV-1730, encoding the Delta variant spike protein with the S6P mutation to enhance stability and immunogenicity. The vaccine's immunogenicity and protective efficacy were evaluated in preclinical models, including monovalent (RV-1730) and bivalent (RV-1731) formulations targeting the Delta and BA.1 variants. Additionally, the effectiveness of RV-1730 as a heterologous booster following primary vaccination with BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna-NIAID) was assessed.
RV-1730 elicited significantly stronger B and T cell responses and more durable neutralizing antibodies compared to S2P-based vaccines. The bivalent RV-1731 vaccine demonstrated broad neutralizing activity against emerging variants, including XBB1.5 and JN.1. Importantly, RV-1730, when used as a heterologous booster following initial immunization with BNT162b2 or mRNA-1273, significantly enhanced neutralizing antibody titers against multiple variants, including Delta and Omicron. Both RV-1730 and RV-1731 provided superior protection in preclinical models, indicating enhanced efficacy due to the S6P mutation.
The incorporation of the S6P mutation into the Delta variant spike protein significantly enhances the immunogenicity and efficacy of mRNA-based COVID-19 vaccines. The strong performance of RV-1730 as a heterologous booster and the broad-spectrum activity of the bivalent RV-1731 vaccine underscore their potential as versatile and effective vaccination strategies against SARS-CoV-2 and its evolving variants.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）变体的不断出现对现有新冠疫苗的效力构成了重大挑战。提高刺突蛋白的稳定性和免疫原性对于改善疫苗性能和应对变体驱动的免疫逃逸至关重要。
我们开发了一种基于信使核糖核酸（mRNA）的疫苗RV-1730，其编码带有S6P突变的德尔塔变体刺突蛋白，以增强稳定性和免疫原性。在临床前模型中评估了该疫苗的免疫原性和保护效力，包括针对德尔塔和BA.1变体的单价（RV-1730）和二价（RV-1731）制剂。此外，还评估了RV-1730作为用BNT162b2（辉瑞-生物科技公司）和mRNA-1273（莫德纳-美国国立过敏和传染病研究所）进行初次疫苗接种后的异源加强针的有效性。
与基于S2P的疫苗相比，RV-1730引发了显著更强的B细胞和T细胞反应以及更持久的中和抗体。二价RV-1731疫苗对包括XBB1.5和JN.1在内的新兴变体表现出广泛的中和活性。重要的是，RV-1730在用BNT162b2或mRNA-1273进行初次免疫后用作异源加强针时，显著提高了针对包括德尔塔和奥密克戎在内的多种变体的中和抗体滴度。RV-1730和RV-1731在临床前模型中均提供了卓越的保护，表明由于S6P突变而增强了效力。
将S6P突变引入德尔塔变体刺突蛋白可显著增强基于mRNA的新冠疫苗的免疫原性和效力。RV-1730作为异源加强针的强大性能以及二价RV-1731疫苗的广谱活性突出了它们作为针对SARS-CoV-2及其不断演变的变体的通用且有效疫苗接种策略的潜力。
