Vaccination With Detoxified Leukocidin AB Reduces Bacterial Load in a Staphylococcus aureus Minipig Deep Surgical Wound Infection Model

Abstract

Vaccines against Staphylococcus aureus have eluded researchers for over three decades while the burden of staphylococcal diseases has increased. Early vaccine attempts mainly used rodents to characterize preclinical efficacy, and all subsequently failed in human clinical efficacy trials. More recently, the leukocidin LukAB has gained interest as a vaccine antigen. We developed a minipig deep surgical wound infection model offering three independent efficacy readouts: bacterial load at the superficial and at the deep-seated surgical site, and dissemination of bacteria. Due to similarities with humans, minipigs are an attractive option to study novel vaccine candidates. With this model, we characterized the efficacy of a LukAB toxoid as vaccine candidate. Compared to control animals, a 3-log reduction of bacteria at the deep-seated surgical site was observed in LukAB-treated minipigs and dissemination of bacteria was dramatically reduced. Therefore, LukAB toxoids may be a useful addition to S. aureus vaccines and warrant further study.

Non-protective immune imprint underlies failure of Staphylococcus aureus IsdB vaccine

“…These findings support the recall of non-protective Ab response and Ab competition as two critical mechanisms that could explain the failure of active and passive staphylococcal immunizations. Consistent with these proposed mechanisms, a study of SA-colonized minipigs demonstrated inefficacy of a SA capsular polysaccharide (CPS) vaccine (Fernandez et al, 2022) that has been shown to be protective in mice (Lee et al, 1988;Yoshida et al, 1987).…”

The influenza-injured lung microenvironment promotes MRSA virulence, contributing to severe secondary bacterial pneumonia

“…[9][10][11][12][13] a-Hemolysin (also known as a-toxin or Hla) and Panton-Valentine leukocidin (PVL) have been identified as important factors in necrotizing pneumonia in the healthy and injured lung. [14][15][16][17] Leukocidin AB (known as LukAB or LukHG), a similar bicomponent PFT to PVL, is implicated in severe infections and immune evasion [18][19][20][21][22][23][24][25][26] but its role in severe staphylococcal pneumonia to our knowledge has not been studied.…”

Staphylococcus aureus infections in children

“…Recent findings suggest that the pore-forming toxins warrant continued investigation as potential targets of intervention, particularly for the amelioration or prevention of invasive disease and bloodstream infections [55]. This intervention could occur via active immunization against toxoid constructs, as recently demonstrated in animal models for LukAB [63 ▪ ,64], PVL and Hla [65], or via passive immunization with neutralizing antibodies (i.e. monoclonal or oligoclonal preparations) in high-risk hosts [62,66,67].…”