Prime-boost regimens for COVID-19 vaccines elicit poor antibody responses against Omicron-based variants and employ frequent boosters to maintain antibody levels. We present a natural infection-mimicking technology that combines features of mRNA- and protein nanoparticle-based vaccines through encoding self-assembling enveloped virus-like particles (eVLPs). eVLP assembly is achieved by inserting an ESCRT- and ALIX-binding region (EABR) into the SARS-CoV-2 spike cytoplasmic tail, which recruits ESCRT proteins to induce eVLP budding from cells. Purified spike-EABR eVLPs presented densely arrayed spikes and elicited potent antibody responses in mice. Two immunizations with mRNA-LNP encoding spike-EABR elicited potent CD8⁺ T cell responses and superior neutralizing antibody responses against original and variant SARS-CoV-2 compared with conventional spike-encoding mRNA-LNP and purified spike-EABR eVLPs, improving neutralizing titers >10-fold against Omicron-based variants for 3 months post-boost. Thus, EABR technology enhances potency and breadth of vaccine-induced responses through antigen presentation on cell surfaces and eVLPs, enabling longer-lasting protection against SARS-CoV-2 and other viruses.

COVID-19 疫苗的初免加强方案对基于 Omicron 的变种产生的抗体反应较差，并采用频繁的加强方案来维持抗体水平。我们提出了一种自然感染模拟技术，通过编码自组装包膜病毒样颗粒（eVLP），结合了基于 mRNA 和蛋白质纳米颗粒的疫苗的特征。eVLP 组装是通过将 ESCRT 和 ALIX 结合区 (EABR) 插入 SARS-CoV-2 刺突胞质尾部来实现的，该尾部招募 ESCRT 蛋白以诱导 eVLP 从细胞中出芽。纯化的spike-EABR eVLP 呈现出密集排列的spike，并在小鼠中引发了有效的抗体反应。使用编码spike-EABR的mRNA-LNP进行两次免疫引发了有效的CD8 ⁺与传统的尖峰编码 mRNA-LNP 和纯化的尖峰-EABR eVLP 相比，T 细胞反应和针对原始和变体 SARS-CoV-2 的优异中和抗体反应，在治疗后 3 个月内，针对基于 Omicron 的变体的中和滴度提高了 10 倍以上促进。因此，EABR 技术通过细胞表面和 eVLP 上的抗原呈递增强了疫苗诱导反应的效力和广度，从而能够针对 SARS-CoV-2 和其他病毒提供更持久的保护。