Adeno-associated virus delivery of anti-alpha toxin monoclonal antibodies confers protection against Staphylococcus aureus infections.

Staphylococcus aureus is a major cause of infections, ranging from mild skin conditions to severe life-threatening systemic diseases. Despite decades of effort, vaccine development has been unsuccessful, highlighting the need for alternative approaches. One promising candidate is MEDI4893 (Suvratoxumab), a monoclonal antibody that neutralizes α-toxin (AT), a key virulence factor with diverse functions including cellular lysis and induction of platelet aggregation during sepsis. MEDI4893 has demonstrated efficacy in various preclinical models of infection and showed encouraging results in a phase IIb clinical trial for ventilator-associated pneumonia. However, as an exogenous antibody, MEDI4893 is limited by its short half-life, high production costs, and restricted availability. To overcome these challenges, we investigated vectored immunoprophylaxis as a novel strategy for long-term protection. This approach uses an adeno-associated viral vector (AAV) to deliver the MEDI4893 gene, enabling sustained in vivo antibody expression. Following AAV-MEDI4893 administration, mice developed high and stable antibody levels in plasma and detectable titers at mucosal surfaces. Using intravital microscopy, we observed that vector-mediated MEDI4893 effectively prevented AT-induced platelet aggregation and microvascular thrombosis, thereby protecting animals from the lethal effects of intravenous toxin challenge. Infection studies confirmed that this protective effect extended to clinically relevant models. In murine pneumonia models, treated mice showed improved survival and reduced sickness behavior despite similar bacterial burdens, while in skin infection models, they were protected from dermal necrosis and exhibited lower bacterial loads. These findings highlight that AT is a major driver of pathology across multiple tissues and that its neutralization can mitigate disease severity. Together, our results demonstrate that AAV-mediated delivery of MEDI4893 provides durable, protective antibody levels and effectively neutralizes AT in vivo. This strategy represents a cost-effective, long-lasting alternative to traditional monoclonal antibody therapy and offers a promising prophylactic approach to mitigate S. aureus infections in the absence of a vaccine.