Xu Jinghan, Wang Busen, Zhao Zhenghao, Wu Shipo, Zhang Zhe, Liu Shuling, Huo Nan, Zheng Wanru, Chen Yi, Gao Zhiqiang, Jia Zuyuan, Liu Tianyu, Zhu Li, Hou Lihua
Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, Beijing, China.
Front Immunol. 2025 Apr 10;16:1572081. doi: 10.3389/fimmu.2025.1572081. eCollection 2025.
Adenovirus (Ad) vectors are widely used for gene delivery, and some of them have been approved for vaccine development. In particular, the recombinant COVID-19 vaccine for inhalation, which was developed using adenovirus type 5 (Ad5), represents a milestone in respiratory immunization. Owing to the high pre-existing immunity (PEI) to Ad5, the development of an adenoviral vector with lower PEI and higher immunogenicity has been explored. However, the majority of the developed novel Ad vectors showed suboptimal immunogenicity compared to Ad5 in animal models.
In this study, we constructed a novel replication-deficient viral vector based on human adenovirus type 4 (Ad4), which has long been used as a live virus vaccine with a favorable safety profile in the U.S. military. The mice were immunized intramuscularly or intranasally with an Ad4-vectored vaccine to verify immune responses and protective efficacy.
Compared with Ad5, the novel Ad4 vector showed comparable viral growth kinetics and transgene expression in cells and similar exogenous protein expression and distribution in mice. Furthermore, the Ad4-vectored vaccine elicited superior humoral and cellular responses and protective effects when vaccinated intranasally than those triggered by the Ad5-vectored vaccine. Finally, the heterologous Ad5 prime and Ad4 boost immunization showed better immunogenicity and protective efficacy.
This study broadens the research trajectory of adenovirus-vectored vaccines and offers a new option for the development of recombinant viral-vectored vaccines.
腺病毒（Ad）载体被广泛用于基因递送，其中一些已被批准用于疫苗研发。特别是，利用5型腺病毒（Ad5）研发的吸入式重组新冠疫苗代表了呼吸道免疫领域的一个里程碑。由于对Ad5存在较高的预存免疫（PEI），人们一直在探索开发一种具有较低PEI和较高免疫原性的腺病毒载体。然而，在动物模型中，与Ad5相比，大多数已开发的新型Ad载体显示出次优的免疫原性。
在本研究中，我们构建了一种基于4型人腺病毒（Ad4）的新型复制缺陷型病毒载体，Ad4长期以来在美国军方被用作一种安全性良好的活病毒疫苗。用Ad4载体疫苗对小鼠进行肌肉注射或鼻内免疫，以验证免疫反应和保护效果。
与Ad5相比，新型Ad4载体在细胞中显示出相当的病毒生长动力学和转基因表达，在小鼠中显示出相似的外源蛋白表达和分布。此外，Ad4载体疫苗经鼻内接种时引发的体液和细胞反应以及保护作用优于Ad5载体疫苗。最后，异源的Ad5初免和Ad4加强免疫显示出更好的免疫原性和保护效果。
本研究拓宽了腺病毒载体疫苗的研究路径，并为重组病毒载体疫苗的开发提供了新的选择。
