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However, some limitations remain to be resolved, such as the short-lived induced immune response and certain adverse effects. Therefore, there is an urgent need to develop new vaccines that address these issues. While live-attenuated vaccines are a highly effective modality, they pose a risk of adverse effects, including virulence reversion. In the current study, we constructed a live-attenuated vaccine candidate, BK2102, combining naturally occurring virulence-attenuating mutations in the\n                    <jats:italic>NSP14<\/jats:italic>\n                    ,\n                    <jats:italic>NSP1<\/jats:italic>\n                    , spike, and\n                    <jats:italic>ORF7-8<\/jats:italic>\n                    coding regions. Intranasal inoculation with BK2102 induced humoral and cellular immune responses in Syrian hamsters without apparent tissue damage in the lungs, leading to protection against a SARS-CoV-2 D614G and an Omicron BA.5 strains. The neutralizing antibodies induced by BK2102 persisted for up to 364 days, which indicated that they confer long-term protection against infection. Furthermore, we confirmed the safety of BK2102 using transgenic (Tg) mice expressing human ACE2 (hACE2) that are highly susceptible to SARS-CoV-2. BK2102 did not kill the Tg mice, even when virus was administered at a dose of 10\n                    <jats:sup>6<\/jats:sup>\n                    plaque-forming units (PFUs), while 10\n                    <jats:sup>2<\/jats:sup>\n                    PFU of the D614G strain or an attenuated strain lacking the furin cleavage site of the spike was sufficient to kill mice. These results suggest that BK2102 is a promising live-vaccine candidate strain that confers long-term protection without significant virulence.\n                  <\/jats:p>","DOI":"10.7554\/elife.97532","type":"journal-article","created":{"date-parts":[[2024,4,26]],"date-time":"2024-04-26T07:27:45Z","timestamp":1714116465000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.97532","source":"Crossref","is-referenced-by-count":0,"title":["Immunogenicity and safety of a live-attenuated SARS-CoV-2 vaccine candidate based on multiple attenuation mechanisms"],"prefix":"10.7554","volume":"13","author":[{"given":"Mie","family":"Suzuki Okutani","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/035t8zc32","id-type":"ROR","asserted-by":"publisher"}],"name":"The Research Foundation for Microbial Diseases of Osaka University","place":["Suita, Japan"]},{"id":[{"id":"https:\/\/ror.org\/035t8zc32","id-type":"ROR","asserted-by":"publisher"}],"name":"Virus Vaccine Group, BIKEN 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