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Antibiotic-resistant bacteria, with this review focusing on\n                    <jats:italic toggle=\"yes\">Staphylococcus aureus<\/jats:italic>\n                    , cause significant morbidity and mortality and put considerable strain on the global healthcare system. In a vaccinated individual, bacteria are less likely to develop resistance mechanisms compared to an individual treated with antibiotics, highlighting a potential method for conserving antibiotic use. However, despite over a century of research, a\n                    <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                    vaccine candidate is yet to progress past phase III clinical trials, and to develop a successful\n                    <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                    vaccine, the shortcomings of previous attempts require critical analysis. After consideration of the five most successful\n                    <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                    vaccine programs, it is identified in this review that future attempts should (i) be polyvalent to circumvent immune evasion, (ii) include carefully chosen antigens to avoid maladaptive memory, (iii) include T cell targeting to provide a comprehensive immune response, (iv) utilize multiple measures of preclinical efficacy in pre-exposed models, and (v) implement considered clinical study design, including appropriate vaccine formulation for the target population. By combining these attributes, such as in the form of epitope-based or nanoparticle vaccines, there is a promising future for the development of\n                    <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                    vaccines that circumvent the issues that caused the downfall of previous vaccine programs, thereby protecting the global population from development toward a future where bacteria are resistant to all antibiotic treatments.\n                  <\/jats:p>","DOI":"10.1128\/cmr.00112-26","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T13:03:57Z","timestamp":1792587837000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Solving the\n                    <i>Staphylococcus aureus<\/i>\n                    puzzle: lessons to guide future MRSA vaccine development"],"prefix":"10.1128","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-2199-7378","authenticated-orcid":true,"given":"Eleanor","family":"Mills","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02bfwt286","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacology, Biomedicine Discovery Institute, Monash University","place":["Clayton, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3724-9814","authenticated-orcid":false,"given":"Mark P.","family":"Del Borgo","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02bfwt286","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pharmacology, Biomedicine Discovery Institute, Monash University","place":["Clayton, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0779-4654","authenticated-orcid":true,"given":"Meredith","family":"O\u2019Keeffe","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02bfwt286","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry & Molecular Biology, Biomedicine Discovery Institute, Monash University","place":["Clayton, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","published-online":{"date-parts":[[2026,10,21]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/sji.12336"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2013.00047"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1810840115"},{"key":"e_1_3_4_5_2","unstructured":"Centers for Disease Control and Prevention (U. 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