ArticleEBioMedicine2025
A live attenuated SARS-CoV-2 vaccine constructed by dual inactivation of NSP16 and ORF3a.
Article in EBioMedicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Article
- Live attenuated vaccination protects aged chimeric ACE2 mice from severe SARS-CoV-2 pathogenicity in vivo.PLoS pathogens · 2026Article
- A bireporter recombinant SARS-CoV-2 Omicron BA.5 forbioRxiv : the preprint server for biology · 2026Article
- Adenoviral vector oropharyngeal spray immunization elicits mucosal immunity and protects against heterologous SARS-CoV-2 infection.NPJ vaccines · 2025Article
- Perspective Overview of Changing Population Immunity to COVID-19 in the Context of Infection, Vaccination, and Emerging SARS-CoV-2 Variants.Pathogens (Basel, Switzerland) · 2025Review
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Authors and funding
17 authors.
Funding
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Abstract
backgroundLive attenuated vaccines against SARS-CoV-2 activate all phases of host immunity resembling a natural infection and they block viral transmission more efficiently than existing vaccines in human use. In our prior work, we characterised an attenuated SARS-CoV-2 variant, designated d16, which harbours a D130A mutation in the NSP16 protein, inactivating its 2'-O-methyltransferase function. The d16 variant has demonstrated an ability to induce both mucosal and sterilising immunity in animal models. However, further investigation is required to identify any additional modifications to d16 that could mitigate concerns regarding potential virulence reversion and the suboptimal regulation of the proinflammatory response.
methodsMutations were introduced into molecular clone of SARS-CoV-2 and live attenuated virus was recovered from cultured cells. Virological, biochemical and immunological assays were performed in vitro and in two animal models to access the protective efficacies of the candidate vaccine strain.
findingsHere we describe evaluation of a derivative of d16. We further modified the d16 variant by inverting the open reading frame of the ORF3a accessory protein, resulting in the d16i3a strain. This modification is anticipated to enhance safety and reduce pathogenicity. d16i3a appeared to be further attenuated in hamsters and transgenic mice compared to d16. Intranasal vaccination with d16i3a stimulated humoural, cell-mediated and mucosal immune responses, conferring sterilising protection against SARS-CoV-2 Delta and Omicron variants in animals. A version of d16i3a expressing the XBB.1.16 spike protein further expanded the vaccine's protection spectrum against circulating variants. Notably, this version has demonstrated efficacy as a booster in hamsters, providing protection against Omicron subvariants and achieving inhibition of viral transmission.
interpretationOur work established a platform for generating safe and effective live attenuated vaccines by dual inactivation of NSP16 and ORF3a of SARS-CoV-2.
fundingThis work was supported by National Key Research and Development Program of China (2021YFC0866100, 2023YFC3041600, and 2023YFE0203400), Hong Kong Health and Medical Research Fund (COVID190114, CID-HKU1-9, and 23220712), Hong Kong Research Grants Council (C7142-20GF and T11-709/21-N), Hong Kong Innovation and Technology Commission grant (MHP/128/22), Guangzhou Laboratory (EKPG22-01) and Health@InnoHK (CVVT). Funding sources had no role in the writing of the manuscript or the decision to submit it for publication.
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