Anti-PBP2a Vaccines and Immunotherapies Against Methicillin-Resistant Staphylococcus Aureus: Current Evidence, Challenges, and Perspectives

Methicillin-resistant Staphylococcus aureus (MRSA) is a major antimicrobial-resistant pathogen worldwide and a high-priority target for new therapeutic strategies. Methicillin resistance is primarily mediated by the mecA gene, which encodes penicillin-binding protein 2a (PBP2a), a transpeptidase with reduced affinity for β-lactam antibiotics. Because PBP2a plays a key role in bacterial survival under β-lactam pressure, highly specific to Methicillin-resistant Staphylococci, and immunologically recognizable, it represents an attractive target for immunotherapeutic approaches. This review summarizes current knowledge of PBP2a structure, biological function, and immunological relevance, focusing on vaccine and antibody-based strategies. Studies employing DNA vaccines, recombinant proteins, multi-epitope constructs, and passive immunization have demonstrated protective immune responses and reduced bacterial burden in animal models of MRSA infection. Monoclonal antibodies targeting PBP2a have also shown prophylactic and therapeutic efficacy, including activity independent of Fc-mediated effector functions, suggesting direct interference with PBP2a function. Their potential use in rapid immunodiagnostic assays for methicillin resistance is also discussed. Emerging strategies, including antibody engineering, glycoengineering, antibody-drug conjugates, mucosal vaccination, and combination therapies with antibiotics, may further enhance clinical applicability. Although evidence remains preclinical, PBP2a represents a promising target for active and passive immunization against Methicillin-resistant staphylococci.