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The Bacille Calmette-Gu\u00e9rin vaccine has long been used to protect against TB, but it produces variable effects across different populations and fails to protect against adult pulmonary TB. Therefore, there is an urgent need for alternative vaccines that can offer better protection. We have developed a strategy for the rational deletion of virulence-related genes in\n                      <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                      (Mtb) to create hyperattenuation that also enhances immunogenicity. Previously, we generated both single (\n                      <jats:italic toggle=\"yes\">\u2206fbpA<\/jats:italic>\n                      ) and double knockout (DKO) (\n                      <jats:italic toggle=\"yes\">\u2206fbpA-\u2206sapM<\/jats:italic>\n                      ) mutants of Mtb and assessed their immunogenicity and efficacy using mice. Herein, we have created triple knockout (TKO) and quadruple knockout (QKO) strains to enhance the immunogenicity and safety of the DKO strain by deleting the\n                      <jats:italic toggle=\"yes\">zmp1<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">dosR<\/jats:italic>\n                      genes. The resulting TKO strains, TKO-Z (\n                      <jats:italic toggle=\"yes\">\u2206fbpA-\u2206sapM-\u2206zmp1<\/jats:italic>\n                      ) and TKO-D (\n                      <jats:italic toggle=\"yes\">\u2206fbpA-\u2206sapM-\u2206dosR<\/jats:italic>\n                      ), and the QKO strain (\n                      <jats:italic toggle=\"yes\">\u2206fbpA-\u2206sapM-\u2206zmp1-\u2206dosR<\/jats:italic>\n                      ), were evaluated for their immunogenicity and safety in mice. Whereas TKO-Z and QKO strains exhibited superior immunogenicity compared to the DKO strain, their protective efficacy in mice was comparable. However, survival studies involving SCID mice indicated that the QKO strain was highly attenuated. Therefore, rational deletion of genes in Mtb seems to be an innovative approach for developing safer and more efficacious vaccines against TB.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/iai.00500-25","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T13:32:17Z","timestamp":1776778337000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Construction and characterization of novel\n                    <i>Mycobacterium tuberculosis<\/i>\n                    -derived triple and quadruple knockout vaccines against tuberculosis"],"prefix":"10.1128","volume":"94","author":[{"given":"Omar","family":"Garnica","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/033ztpr93","id-type":"ROR","asserted-by":"publisher"}],"name":"Center of Emphasis in Infectious Diseases, Paul L. 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