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

Overview

Journal Cell Mol Immunol

Date 2022 Mar 30

PMID 35352010

Authors

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

Affiliations

Soon will be listed here.

Abstract

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.

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