Intranasal administration of a single dose of a candidate live attenuated vaccine derived from an NSP16-deficient SARS-CoV-2 strain confers sterilizing immunity in animals  

作　　者：Zi-Wei Ye Chon Phin Ong Kaiming Tang Yilan Fan Cuiting Luo Runhong Zhou Peng Luo Yun Cheng Victor Sebastien Gray Pui Wang Hin Chu Jasper Fuk-Woo Chan Kelvin Kai-Wang To Honglin Chen Zhiwei Chen Kwok-Yung Yuen Guang Sheng Ling Shuofeng Yuan Dong-Yan Jin 

机构地区：[1]Department of Microbiology,Li Ka Shing Faculty of Medicine,The University of Hong Kong,102 Pokfulam Road,Pokfulam,Hong Kong,China [2]State Key Laboratory of Emerging Infectious Diseases,The University of Hong Kong,102 Pokfulam Road,Pokfulam,Hong Kong,China [3]School of Biomedical Sciences,Li Ka Shing Faculty of Medicine,The University of Hong Kong,21 Sassoon Road,Pokfulam,Hong Kong,China

出　　处：《Cellular & Molecular Immunology》2022年第5期588-601,共14页中国免疫学杂志（英文版）

基　　金：supported by the Hong Kong Health and Medical Research Fund grants COVID190121 to JF-WC and COVID190114 to D-YJ;the Hong Kong Research Grants Council grants C7142-20GF and T11-709/21-N to D-YJ.

摘　　要：Live attenuated vaccines might elicit mucosal and sterilizing immunity against SARS-CoV-2 that the existing mRNA,adenoviral vector and inactivated vaccines fail to induce.Here,we describe a candidate live attenuated vaccine strain of SARS-CoV-2 in which the NSP16 gene,which encodes 2′-O-methyltransferase,is catalytically disrupted by a point mutation.This virus,designated d16,was severely attenuated in hamsters and transgenic mice,causing only asymptomatic and nonpathogenic infection.A single dose of d16 administered intranasally resulted in sterilizing immunity in both the upper and lower respiratory tracts of hamsters,thus preventing viral spread in a contact-based transmission model.It also robustly stimulated humoral and cell-mediated immune responses,thus conferring full protection against lethal challenge with SARS-CoV-2 in a transgenic mouse model.The neutralizing antibodies elicited by d16 effectively cross-reacted with several SARS-CoV-2 variants.Secretory immunoglobulin A was detected in the blood and nasal wash of vaccinated mice.Our work provides proof-of-principle evidence for harnessing NSP16-deficient SARS-CoV-2 for the development of live attenuated vaccines and paves the way for further preclinical studies of d16 as a prototypic vaccine strain,to which new features might be introduced to improve safety,transmissibility,immunogenicity and efficacy.

关 键 词：Live attenuated vaccine NSP16 2'-O-methyltransferase T-cell response Mucosal immunity Sterilizing immunity 

分 类 号：R563.1[医药卫生—呼吸系统]