摘要
新型冠状病毒(新冠病毒)在全球范围内流行,对公共卫生和人民生命健康造成了巨大威胁,新冠病毒疫苗的研发和使用对预防疾病和控制疫情起到了关键作用.基于包括重组蛋白亚单位、病毒载体、mRNA脂纳米颗粒在内的多种技术平台开发的疫苗都获得了使用.然而,由于抗原设计的差异、免疫剂量和注射间隔的差别,不同疫苗平台之间的免疫效果无法直接比较.因此,本研究以Delta-Omicron嵌合RBD二聚体为免疫原,对广泛使用的3个疫苗平台(重组蛋白亚单位疫苗、腺病毒载体疫苗和mRNA疫苗)进行了免疫原性头对头比较,通过小鼠模型比较了它们同源接种和序贯接种所诱导的体液免疫和细胞免疫反应的差异.结果显示,小鼠在免疫同源的两剂疫苗后,mRNA疫苗诱导的结合抗体和中和抗体滴度都最高,其次分别是重组蛋白亚单位疫苗和腺病毒载体疫苗;异源加强免疫的结果显示,不管是以重组蛋白亚单位疫苗、腺病毒载体疫苗或者mRNA疫苗初免,以mRNA疫苗作为第2针加强免疫均能诱导更强的体液免疫反应.此外,在疫苗激发的细胞免疫方面,mRNA疫苗诱导了较强的CD4+T细胞反应,腺病毒载体疫苗诱导了较强的CD8+T细胞反应,而亚单位疫苗刺激的细胞免疫反应以CD4+T细胞为主,但在强度上较弱.本研究具有重要的应用价值,为未来新一代的新冠病毒疫苗研发和接种策略提供了指导.
Abstract
The novel coronavirus(SARS-CoV-2)caused a global pandemic,with significant distress to human health,society stability,and development.COVID-19 vaccination has played a pivotal role to control the pandemic,with multiple vaccine approaches approved globally,including inactivated recombinant protein subunits,virus-like particles,viral vectors,mRNA,and DNA vaccines.Notably,we collaborated with Anhui Zhifei longcom Biopharmaceutical Co.,Ltd.to develop a COVID-19 vaccine(ZF2001)based on recombinant protein subunit platform,using a tandem-repeat dimeric form of receptor-binding domain(RBD)of the spike protein of SARS-CoV-2 as immunogen.Besides,the adenovirus vector vaccine,Ad5-nCoV(Convidecia,CanSino),developed jointly by the Chinese Academy of Military Medical Sciences and CanSino Biologics,employs a human adenovirus type 5 vector to express the full-length S protein of SARS-CoV-2.mRNA vaccines BNT162b2(Comirnaty),developed by BioNTech and Pfizer,and mRNA-1273(SpikeVax),developed by Moderna,have been widely administered over the world.In phase Ⅲ clinical trials,these vaccines have shown an efficacy of over 94％in preventing symptomatic infections caused by a prototype strain of the SARS-CoV-2.COVID-19 mRNA vaccines were the first globally approved mRNA vaccines.Both BNT162b2 and mRNA-1273 use gene encoding the prefusion-stabilized S-2P protein and employ lipid nanoparticles as the delivery system.Owing to the distinct characteristics of the different vaccine paltforms,there are variations in the vaccine-induced immune responses.To compare the characteristics of the immune response elicited by various COVID-19 vaccine platforms,we designed a head-to-head comparative study.We modified the RBD dimer immunogen used in the ZF2001 vaccine,to design a chimeric RBD dimer antigen composed of tandem RBDs from two different viral strains;which could induce a broader spectrum of immune responses.Using the Delta-Omicron RBD dimer as an immunogen,we selected vaccines from three platforms including recombinant protein subunit,adenovirus vector,and mRNA vaccines for a homologous and heterologous prime-boost immunization regimen in a head-to-head comparative study.We found that two doses of mRNA vaccine induced the highest antibody titers of specific IgG and neutralizing antibodies in mice,followed by the protein vaccine and AdC68 vaccine.The heterologous prime-boost studies showed that boosting with the mRNA vaccine as the second dose induced a stronger humoral immunity response,compared with protein subunit and AdC68 vaccines.In addition,the mRNA vaccine induced a strong CD4+T cell responses,and the AdC68 vaccine induced a strong CD8+T cell responses.In contrast,the protein subunit vaccine elicited a relatively weak cellular immune response.This study provides guidance for the next-generation of COVID-19 vaccine development and optimization of inoculation strategy in the real world.
基金项目
国家重点研发计划(2020YFA097100)
国家重点研发计划(2021YFC2302600)
国家自然科学基金(81991494)
国家自然科学基金(82122031)
比尔及梅琳达·盖茨基金会项目(INV-027420)
中国科学院稳定支持基础研究领域青年团队计划(YSBR-010)
中国科学院青年创新促进会项目(2018113)
维普
万方数据